Stop the Clock

The Optimal Anti-Aging Strategy

P. D. Mangan

Phalanx Press

2
Copyright 2015 by P. D. Mangan
This book may not be reproduced in whole or in part, except for
brief excerpts in reviews, without written permission from the
author.

Disclaimer: The author is not a medical professional and the

contents of this book do not constitute medical advice. The
information presented herein is believed to be accurate at the time
of publication, but the author makes no warranties regarding its
accuracy. The author shall not be liable for any omissions or
inaccuracies or for any actions taken as a result of the contents of
this book, and he disclaims all responsibility for decisions made as a
consequence of this book. The reader should consult a qualified
medical professional before implementing any of the suggestions in
this book and before beginning any diet, exercise, or fasting
program or taking any vitamin or other nutritional supplement.

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4
 Contents
Introduction
1: Couch Potatoes vs. Hormesis
2: Exercise: Why It's Crucial in Fighting Aging
3: Diet, or what you eat affects how fast you age
4: Fasting: When You Eat Is As Important As What
You Eat
5: Demolition and Renewal: The Optimal Anti-Aging
Strategy
6: Conclusion
Bibliography

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6
 Introduction

A strategy to slow or reverse aging already exists

In this book, we'll discuss the best strategy that is currently available
for slowing and even reversing the aging process. This strategy
requires nothing expensive – in fact, if so inclined, you could
implement it at no cost whatsoever.

The strategy, while in theory and in practice is simple enough, is

backed solidly by science. No wild claims will be made here, and no
sales pitches made for some kind of magic potion or hormone that
will cure all your ills and make you live to 120, because no such
potion exists.

Humans have been concerned with preventing or slowing down

aging ever since they understood what it means to get old. From the
quest for the Fountain of Youth to modern-day quack treatments,
men stumbled their way trying to find something, anything, that
would restore to them a measure of youth. In the first years of the
16th century, one man, Luigi Cornaro, made a major discovery in
anti-aging medicine, and although he applied his discovery
successfully to his own life, lengthening it to over 100 years, he
lacked the means to understand its mechanism of action. More
major discoveries had to wait until the 20th century, when the
science of biology had advanced enough that scientists could make
sense of their results and to expand on them.

The science of aging in the 21st century is now in full bloom, with
literally dozens of scientific journals devoted exclusively to that
topic, and thousands of scientists working on the problem of aging.
Those scientists are making real progress, and we can now say that
we possess fundamental knowledge of the causes of aging as well as
the knowledge of various techniques and substances that have the
ability to retard aging. Scientific journals publish new advances in
the science of aging daily.

7
This is not to say that the problems of aging have been solved, not by
a long shot. But we can now quite accurately describe many of the
processes that occur during aging, and with this ability comes the
opportunity and maybe the ability to counteract them. What is
more, many of the substances and processes that can counteract
aging can be easily obtained or practiced by almost everyone. No
expensive anti-aging clinics and no expensive drugs are required.
Anyone who has the interest and a bit of discipline can make
available to themselves nearly everything science currently knows
about retarding the aging process.

Aging as it is properly understood begins when a person is in his or

her twenties. Already by the decade of the late twenties, brainpower
begins to decline. By the decade of the thirties, muscle mass and
strength are noticeably lower in both men and women. This fact
explains why many professional athletes retire when in their late
twenties or early thirties: their bodies are aged in terms of elite
athletics, even though they're chronologically young, and they can't
keep up with the younger athletes, who are in their prime, which is
their teens and twenties. The process of aging at what we consider a
relatively youthful age is merely more noticeable in athletes, since
they must be on top of their game, but it happens to everyone. The
point is that it's never too early to do something about aging. It
shouldn't be a concern of only the elderly, who would like to prolong
their lives and prevent and cure disease, but of virtually all adults, in
order to live full of strength and vitality and to extend the time that
they are able to live healthy, active lives.

Fighting aging and living a longer life does not mean extending the
time in which we are old and frail and living in a nursing home,
which is a common objection to the idea of life extension. The
purpose of fighting aging is to remain in a youthful, vital state,
free of disease and illness, as long as possible. Ideally, life extension
means that “old age” should be a period in our lives when we can
remain in a youthful state as much as possible, and any decline in
function or susceptibility to disease will be confined to a period very
shortly before death.

Personally, I am not looking for an extension of decades in which I

need to use a cane, or a walker, or an oxygen tank, or powerful drugs
with huge unwanted side effects, and the reader undoubtedly is not
either. What I am looking for is many decades in which I do not
need these things.

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For the elderly, aging can take on a tragic aspect, with the specter of
diseases like Alzheimer's and Parkinson's, sarcopenia (muscle
wasting), diabetes, heart disease, and cancer. Many of the elderly
become so frail that they become unable to take care of themselves,
and end up in nursing homes. Many of these problems can be
entirely avoided if the right steps are taken, and some of them can
be fixed even in the very old.
While it's never too early to start taking steps to fight aging, in
many cases it's never too late either.

Even people that are considered young are not immune to the
ravages of age. How many middle-aged men and women have we
seen that suffer from obesity, diabetes and metabolic syndrome,
who do not sleep well, suffer from anxiety and depression, and in
general have little vitality and do not enjoy the energy and vitality
that is theirs by birthright? A rhetorical question. All of these
ailments increase dramatically with age, that is, they are symptoms
of aging.

A lifestyle that incorporates the anti-aging practices discussed in

this book need not be either expensive or time-consuming, but it
will, as I say, take a bit of discipline. The world tempts us with
obesogenic food, a passive and inactive way of life, a desire for a
quick fix for everything that ails us, and conspires to lure us into its
pro-aging ways. Make no mistake, if you do what almost everyone
around you is doing, you will age just as fast as they do, buoyed
only by the hope that some new drug will save you from a
debilitating disease of old age.

To fight aging, you must resist the siren songs of the pro-aging
environment which is everywhere around us.

Actuarial Escape Velocity

The concept of actuarial escape velocity has been championed by the

theorist of aging Aubrey de Grey, and by the futurist Ray Kurzweil.
The idea is that science and medicine have been able to increase the
human lifespan year after year, and that the rate at which they do
this is itself increasing. As a hypothetical example, ten years from

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now, scientific advances may have been able to increase the average
human lifespan by five years; but in the next ten year span, it may
have increased average lifespan by eight years. Eventually a point
comes such that for each year of scientific research, average lifespan
will go up by more than one year, and at that point actuarial escape
velocity will have been reached. At that point, and assuming that the
rate of scientific advance at least remains the same, the average
person could expect to live indefinitely, if of course they have access
to the advances that have been made, and other events don't
intercede, such as wars, accidents, or homicides.

From a logical point of view, it looks like actuarial escape velocity is

all but inevitable, unless there is something about aging and
absolute limits that exists but that we do not currently understand,
or if the current rate of technological and scientific advance slows
for some reason.

However, to see the day that actuarial escape velocity becomes a

reality, we must do what is in our power to avoid and retard aging
now. Most people would likely be surprised to learn just how much
is possible in this area. Many of the techniques and compounds that
slow or reverse aging are the same as those that keep us in good
general health. Exercise is an example of this. It's been said that if
exercise were a pill, it would be the most widely prescribed medicine
there is. Exercise can prevent and even cure diabetes, heart disease,
cancer, dementia, and a host of other diseases and symptoms of
aging.

Median versus maximum lifespan

Exercise is, however, an example of something that increases

median lifespan, but not maximum lifespan.

What's the difference between median and maximum lifespan?

When scientists study a substance or process that may extend
lifespan, they distinguish between the two. Take the example of
exercise. If one group of animals is exercised, or allowed to exercise,
while another group of animals (the “controls”) remain or are kept
sedentary, more of the exercising animals will live into old age than

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the sedentary; but the absolute, or maximum, lifespan of the two
groups will remain the same. Exercise increases median lifespan.

If a substance or process causes a large fraction of the test group to

live longer lives than the controls, then that substance or process
extends maximum lifespan.

Greater median lifespan means that some form of illness or disease

that reduces lifespan has been overcome. But other aging processes
then come to the fore, and the absolute lifespan remains the same.

An increase in maximum lifespan means that aging itself has been

slowed. So, while incorporating practices that lead to good health
generally will conduce to an increase in median lifespan, they will
not increase maximum lifespan.

Good health practices such as a decent diet or a good exercise

regimen will help increase or median lifespan, that is, they will help
us reach our full life expectancy. These are absolutely necessary in
the fight against aging. There are other processes and compounds
that do more than keep us in good health, however; they can go
beyond this and slow or reverse aging. An example of a process that
can do this is fasting in any of its many variations. Intermittent or
alternate day fasting mimics the process of calorie restriction, which
has been shown to be the most robust anti-aging treatment known
to date. This is where some discipline comes into play, since if you
feel the need to eat every three hours, you can't fast and you will not
have available the option of fasting in order to intervene in the aging
process. Certain well-known, safe, and cheap chemical compounds
can mimic the effects of calorie restriction and fasting, compounds
such as resveratrol and curcumin.

In this book, we'll discuss these processes and compounds, as well

as the optimal anti-aging strategy, so that those who put these into
practice will have the best chance possible of reaching the time of
actuarial escape velocity. But they must be put into practice; merely
reading about them will do nothing.

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 Chapter 1: Couch Potatoes vs.
Hormesis

We've all heard the term “couch potato”, referring to someone who
takes things easy at all times. The term conjures up the image of an
overweight person, lying on the couch with a TV remote in his
hands, eating from a bag of potato chips, never bothering to get up if
he (usually it's a he) can possibly help it. The couch potato puts
himself (or of course, herself) at serious risk for the diseases of
modern life, which include heart disease, cancer, diabetes,
depression, arthritis, and if he's old enough, osteoporosis and
dementia, to name a few. Intuitively we know that the couch potato
does virtually everything wrong from the standpoint of health,
without knowing exactly why that is. So let me explain.

Humans evolved in an environment of physiological

stress

Humans evolved in an environment in which various physiological

stresses were a fact of everyday life. In fact, if we go back further, to
a time before humans, we see that all of life evolved that way.
Competition from the members of the same species, as well as
predation from members of other species, has always been endemic
for all living things. Humans have always been subject to periods of
time in which they've had little to eat. This doesn't mean that they
endured constant famines or the threat of them, and in fact, recent
research has uncovered the fact that hunter-gatherer peoples have
faced famine less often than agricultural peoples.[1] However,
humans were hunter-gatherers for about 99% of the time that
they've existed as humans, only 1% of the time have they lived as

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farmers and herders, and even less time still have they lived in an
industrial age with cheap and plentiful food, so we can profit from
the point of view of health by paying attention to how the hunter-
gatherers lived.

Hunter-gatherers did not endure famine as much as did

agriculturalists, but they did face having to hunt and gather their
food on a daily basis, and thus they could not eat until these tasks
had been completed. Given the near total absence of any means of
preserving food such as refrigeration or canning, most humans
throughout history just could not eat whenever they felt hungry,
unlike today. Those humans would likely have experienced near
daily periods of many hours in which they didn't eat. Among many
hunter-gatherer groups that have been studied, it appears that the
usual practice was to spend the day in food collecting activities, and
then to have a huge meal toward the end of the day when all the
food was ready to be cooked and eaten. To compare ourselves with
them, it might be good to ask yourself when was the last time you
went without food for twenty-four hours, or even sixteen hours.
For the vast majority of people in the modern world, the answer is
“never”. Compared to our ancestors of long ago, we are practically
all couch potatoes. We eat whenever we feel like it, which is a
privilege that few humans in history could have even dreamed of.
Yet it affects our health in ways that few understand.

We evolved in a rugged environment, and that is what we're adapted

to. Our environment now is luxurious by comparison, and we are
not adapted to that. Hence, the “diseases of civilization”.

The evolution of human beings in this rugged environment means

that our genes have been selected to be optimal for going relatively
long periods, say from twelve to twenty four hours or even longer,
without food. When we then switch environments to one in which
food is plentifully and readily available at any time of day or night,
our genes go awry and lead us into ill health, such as diabetes, and
worse.[2] We are not cut out to be couch potatoes; good health and
long life requires that our bodies be subject to stresses of various
kinds, one such stress being regular periods of refraining from
eating. These stresses were a regular part of human life for 99% of
our history, and we are adapted to them.

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 The concept of hormesis

Going without food for a dozen or more hours at a stretch indeed

places a stress on the body, a good kind that has been called
eustress, but which modern science refers to as hormesis. Hormesis
means simply to the placing of a stress on a living organism that the
organism is able to respond to and recover from by becoming
stronger. Think of it in Nietzschean terms: what doesn't kill you
makes you stronger (though of course that's an exaggeration not
meant to be taken literally).

Paracelsus (1493-1541), the Renaissance physician and alchemist

and founder of the discipline of toxicology, first enunciated the
principle that “the dose makes the poison”. This expression refers to
the fact that any substance at all, even water, can be poisonous in
the right dose. But it also follows from this that some substances
that we normally think of as poisons are not toxic in low doses, and
in fact some of these putative poisons can be healthful for the
human body if taken in the right amount. They do this by placing a
stress on the body, and on each of the cells in it, and by doing so
strengthen the body.

The process of going without food, that is, fasting, is an example of

hormesis, although in this case it is not a chemical substance that
places the stress, but the absence of nutrients from food. With
fasting, as with other forms of hormesis, the dose makes the poison.
Fasting for long periods of time can lead to weakness, a declining
immune system, and ultimately death. But in low doses, fasting
places a hormetic stress on the body, which then strengthens itself
to deal with the stress.

The concept of hormesis has broad applicability to a wide range of

practices, processes, and substances that humans are exposed to, or
in the case of many modern humans, not exposed to. It might even
be said that hormesis is the key to health, for without regular
applications of hormetic substances and processes, the body
cannot remain healthy. We'll see shortly how hormesis is one leg of
our anti-aging regimen. The key to the effect of hormesis is that we
have evolved with genes that expect stresses, and our health suffers
when we are not exposed to them. Since health is so intimately
linked with aging, in order to retard the aging process, we must
expose ourselves regularly to healthy hormetic stresses.

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Hormesis can result from low-dose exposure to anything, or any
process, that in larger doses is toxic. When a substance or process is
toxic, this means that it causes damage to the body and to its cells,
damage which causes illness and from which recovery may be
difficult or impossible, and in the most extreme cases leads to death.
In hormesis, low-doses of the same substance or process signal the
body that it must prepare itself for defense, and it does this by
various means.

Exercise is an example of hormesis.[3] When a human or animal

exercises enough to go beyond its normal limits of adaptation, cells
generate reactive oxygen species (ROS), which are more familiarly
known as free radicals. These ROS act as signaling molecules which
tell the cells to increase their production of antioxidant defenses,
DNA repair enzymes, and muscle protein synthesis. In this way,
cells and organs thus strengthen themselves in response to a low-
dose of a toxin, in this case free radicals, and the person who
exercises ends up healthier and stronger than before. This is classic
hormesis. Yet, recall the story of the first marathon runner,
Phillipides: he ran much farther than what he was trained for, and
died. His exercise went beyond the capabilities of his body and was
therefore extremely toxic for him.

The free radical theory of aging holds that aging occurs because free
radicals cause the accumulation of damage, and therefore the body
becomes unable to function as well as it did in the youthful state,
much like an automobile runs worse as it gets older, and is more
subject to breakdown.[4] While this theory has its merits, it's lately
become less compelling as a description of what really happens in
aging. One reason for this is the phenomenon of free radical
hormesis, which causes damage, as in the case of exercise, yet leaves
the organism in a more youthful state than before. Damage is an
intrinsic part of the exercise process, yet there's universal
agreement among medical scientists that exercise is among the
most healthful things that anyone can undertake. If exercise were a
drug, it would be the most widely prescribed one in the world.

So there's a paradox here: hormesis causes damage, yet it leaves the

organism better off, more youthful, than before. Therefore, it seems,
the cause of aging cannot be the accumulation of damage, since
hormesis would then increase aging, when in fact it decreases it.

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Consider other cases of hormesis, for example, the unusual case of
arsenite, a molecule that contains an arsenic atom and that's one of
the most toxic substances known to man. (Don't worry, this book
will not be advocating the ingestion of arsenite.) Arsenite has been
linked to a number of diseases, including heart disease, diabetes,
and cancer; yet it was also used in traditional Chinese medicine, and
a 1% solution of sodium arsenite, known as Fowler's solution, was in
general medical use for the treatment of parasitic infections and
other indications until the 1950s. When mammalian (human and
mouse) cells are cultured with low doses of arsenite, their growth is
increased, and when the model organism C. elegans, a worm, is
raised with arsenite as part of its growth medium, it increases its
lifespan[5].

What's happening here? Well, it appears that arsenite causes a

transient increase in those damaging free radicals, and the cells then
upgrade their internal, biochemical stress mechanisms in order to
deal with them. One of the more potent mechanisms, which is
known as Nrf-2, is a gene transcription factor, which causes the
activation of many different genes, most of them related to stress
defense. (Later in this book, we'll see how other factors that are
more commonly encountered than arsenite also increase Nrf-2, and
how this leads to better health and retards aging.) Basically, this
means that causing damage through an increase in free radicals
ultimately results in less damage and less aging.

Evolutionarily conserved mechanisms

These results are also important because they show an

evolutionarily conserved mechanism. This means that natural
selection chose the means of dealing with abundant free radicals by
upgrading cellular stress defenses a long time ago, in primitive
organisms, and that through the course of evolution, higher
organisms including mammals and humans have retained the ability
to do so. Eukaryotic cells, that is, the cells of all organisms further
along in evolution than bacteria, share fundamental similarities, and
this is one of them. This can be seen in the fact that the same
chemical, arsenite, both extended lifespan in a small worm and
caused mammalian cells in culture to grow better. Keep this in mind
as we extend this discussion throughout the book, as many of the

16
studies and experiments that will I will use as illustrative were done
on non-human animals and cell cultures. A common objection to
these types of studies is that they do not necessarily translate into
what is good for humans; while there's some truth in that objection,
and we must carefully consider each study in detail to determine
whether it has validity for human beings, the main point of
performing studies on non-human animals and cell cultures is
because we can find out things that we never could if only humans
were used. For example, it would be unethical to give arsenite to
humans, but it's acceptable to feed it to a worm. Similarly, scientists
can't force humans to swim until they can't hold themselves above
water, something that they do with mice. In this book, I will be
citing a number of animal and cell culture studies, and except where
noted, I consider them to have validity for human beings.

Hormesis is characterized by a so-called U-shaped curve, usually

depicted upside down. This can be seen in the following graph,
generalizable to all kinds of hormetic responses. It can be seen that a
very low or zero dose of a hormetic agent or process, in this
particular case exercise, does not create good health, but that as the
dose increases, the organism that exercises moves into the zone of
good health. At some dose of exercise, the organism reaches optimal
health, and at higher doses, movement away from the optimal dose
occurs, until a point is reached at which the dose is too high, and ill
health or even death occurs.

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To use a more concrete example, the couch potato who does no
exercise lives around point number 1 in the graph. If he starts to
exercise even a little, he will rapidly move up the hormetic curve
toward the healthy zone, at say point 3 or 4. Someone who exercises
the right amount, about which we'll speculate later, lives in the
optimal zone, between points 5 and 6. Someone who exercises too
much, and in my opinion elite marathon runners may fall into this
category, tips into the unhealthy zone, at points 8 through 10.

What evidence is there that hormesis can retard aging? Studies like
the one cited above concerning arsenite show that small doses of
toxins extend lifespan in laboratory animals and cause human
cultured cells to grow better, which is the very definition of

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hormesis. One study showed that injecting duck eggs with small
doses of methylmercury, an extremely toxic compound, or feeding
low doses of it to female ducks, led to a hatching success rate of
93%, as opposed to one for controls not fed methylmercury of 73%.
[7] In this case, low doses of a toxin led to lower mortality.

Low-dose radiation is another example of hormesis.[8] Low doses of

radiation have been shown to decrease the incidence of cancer in
mice by more than half.[9] Exposure to solar radiation is negatively
associated with the incidence of breast cancer and colon cancer [10],
which is another way of saying that the more exposure to the sun
people get, within reason, the fewer the number of them that come
down with breast or colon cancer, or indeed, other types of cancer.
While some of the effect of solar radiation may be due to its
interaction with the skin in the production of vitamin D, the effect of
the actual ionizing radiation from the sun likely has its own effect on
reducing cancer rates. Perhaps the most amazing example of
exposure to radiation leading to lower cancer rates occurred in
Taiwan, where apartment buildings were constructed with steel that
was contaminated with cobalt-60, a radioactive isotope. Up to
10,000 people were unwittingly exposed to ionizing radiation in
these apartments for periods of up to several years. A study that
looked at these people found dramatically reduced rates of both
cancer and congenital malformations.[11]

Older people including centenarians who are in good health often

have high levels of the important internal antioxidant glutathione.
This is significant for hormesis and aging because hormetic agents
frequently result in an increase in glutathione levels, thus
demonstrating that hormesis can result in good health and longer
life.[12] In aging, levels of the enzymes that increase glutathione
levels decline, but healthier elderly people have higher levels than
the non-healthy. The increase in glutathione levels through
substances and processes that cause hormesis is one of the most
important of their health-producing and anti-aging effects, one that
we'll look at in more detail later.

In contrast, lack of hormesis results in accelerated aging. Diabetes is

perhaps the archetype of aging, with increased insulin resistance,
increased inflammation and oxidative stress, fat gain, muscle loss,
and increased susceptibilities to all of the diseases of aging,
including cancer, heart disease, and infections. Diabetes (type 2) is
also basically a lifestyle disease, caused by lack of exercise, weight

19
gain, and eating too much dietary carbohydrate, along with genetic
susceptibility. Hormetic factors such as exercise, fasting, and dietary
phytochemicals such as those in fruits and vegetables and certain
supplements defend against the development of diabetes, and at
least in some cases can lead to a complete cure.[13,14] Low-
carbohydrate diets should be considered the first line of treatment
in diabetes [15], and since diabetes is the archetype of aging, this has
implications for life extension as well, which we'll discuss later. In
practicing an anti-aging lifestyle, we should avoid as much as
possible all those things that lead to diabetes, and to remain in a
state opposed to that: lean, with good insulin sensitivity and with
low levels of inflammation and oxidative stress, as this state is the
anti-aging phenotype.

Hormetic stresses lead to better health and longer life, whether in

laboratory animals or in humans. The couch potato life leads to
accelerated aging, greater mortality, more illness, and much less
vitality.

Most health-conscious people are likely to encounter three main

forms of hormesis in their everyday life: exercise, dietary
phytochemicals, and fasting. Health experts have of course
recommended exercise since the days of Hippocrates, and most
people know that eating your fruits and vegetables, the source of
most dietary phytochemicals, is also a healthy thing to do. Fasting
hasn't received much notice until relatively recently, that is, outside
of fairly fringe health movements, but its potential is quite real, and
easy-to-do methods of fasting can be incorporated into the routine
of anyone interested in slowing the aging process. The next three
chapters in the book will discuss each of these three anti-aging
modalities in some detail.

The old expression “use it or lose it” finds new meaning in the
process of hormesis, or good stress. Muscles atrophy if we don't
place regular stress on them, as do our brains, our bones, and
virtually every other part of our bodies. Exercise can be thought of
as the prototype of good stress or hormesis, since each type of
hormesis, whether a chemical compound or a physical activity,
essentially causes the cellular systems of our bodies to experience a
workout, the physiological equivalent of a hard session at the gym.
From these, the cellular systems emerge stronger, ready to defend
themselves from outside toxins and foreign invaders such as

20
pathogenic bacteria and viruses, and from internal stresses,
resulting in lower levels of inflammation and oxidative stress.

One of the keys to aging lies in the old wisdom to never let yourself
go and to stay in good shape. It might almost be said that much of
the advice to live a long, healthy life can be boiled down to two
words: avoid comfort, at least most of the time. Aging must be
combated pro-actively, since it is an all-but-inexorable force that
will succeed if we don't fight back. This requires some discipline,
though not necessarily an iron will, since the benefits of anti-aging
compounds and processes become apparent relatively soon in the
form of good health and abundant energy, not merely in retarding
aging. Most people will find the program I outline in this book to be
enjoyable, or at least, not too difficult; in any case, I enjoy them, and
the results in terms of increased physical energy, mental clarity, and
good mood make me very much inclined to continue doing them.

Fighting the aging process is much like keeping a building in good

repair: the old must be swept out to make way for the new, and
maintenance must be made a priority. When we fail to maintain the
roof of our house, or let it go without new paint, sooner or later the
house will become a decrepit mess, falling apart at the seams and at
some point no longer fit to live in. So with our bodies, except that
our bodies have the advantage over a house in that if we give them
what they need, they will do the repair and maintenance themselves.

Indiscipline, as manifested in eating too much, or too much of the

wrong kind of food, or as we'll see, too often, as well as failure to
exercise, results in accelerated aging and the diseases of age, such as
heart disease, cancer, and diabetes. The couch potato lifestyle in
which one indulges oneself with modern, industrial foods and the
complacencies of the peignoir (to quote Wallace Stevens) or, as we
might say, the comforts of the sofa, allows the aging process full
reign. Fighting aging doesn't at all mean that the pleasures of life
must be avoided, although depending on your definition of pleasure,
some of them certainly will. (I like a good glass of wine as much as
the next person, and fortunately wine in moderation turns out to be
one of the healthy pleasures.) But it does mean that attention must
be paid, that some part of every day must be devoted to ensuring
that you have all of your anti-aging ducks in a row.

21
 The Three Processes Involved in Aging

Aging correlates most notably with an increase in the susceptibility

to illness and disease, which is practically the definition of aging.
Getting older almost always equates with being in a state of worse
health: minor illnesses like colds are easier to get and harder to
overcome, while infections such as the flu that cause transient
illness in younger people have the potential to kill the elderly.
Diseases resulting from a breakdown of the body's structure range
from arthritis to dementia and increase greatly with aging. Strokes,
heart disease, cancer: they all come from a fundamental inability of
the aging body to properly maintain and repair itself. Therefore, to
fight aging, we must do those things that allow the body to keep its
maintenance and repair capabilities.

Why does aging cause the loss of these capabilities? Younger people
have a far greater ability to defend their bodies against infection and
to maintain the body's normal, youthful structure. Aging means a
breaking down of capacity for renewal. Something occurs as we
age that hinders that capacity.

Three main processes are responsible for the deterioration of aging:

1) an increase in oxidative stress; 2) an increase in inflammation;
and 3) a decline in autophagy, or the process of ridding cells of junk
in order to replace it with new, more functional structures. They are
all closely linked, and in most cases improvement in one of these
processes entails improvement in the others.

Oxidative stress refers to the inability of cells to maintain a proper

balance of free radicals. As we've mentioned, free radicals (or
reactive oxygen species, ROS) function as signaling molecules, but
too many of them cause damage that cannot be repaired. The body
must balance the amount of free radicals present: not too few, not
too many. As we age, that balance becomes more difficult to attain,
and free radicals overwhelm the body's internal antioxidant system;
when that happens, a state of oxidative stress exists. In oxidative
stress, free radicals have free reign inside cells, and cause damage to
cellular structures, meaning that these structures will no longer
function as well as in a youthful state. If we consider the case of
infections, which afflict the elderly harder and more often than they
do the young, the reason is that the immune system doesn't function
as well in the elderly, so it can't fight infections effectively. The

22
immune cells have been damaged by oxidative stress among other
things.

In the inflammation of aging, the immune system is activated

consistently but at a low level. This is such a strong characteristic of
aging that it has been dubbed “inflammaging”.[6] The cause of
inflammaging appears to be lifelong exposure to various infectious
agents, against which the immune system mounts a response. This
results in a chronic, low level of inflammation that contributes to
illness and death from old age. Healthy centenarians appear to have
a higher level of anti-inflammatory compounds, called cytokines,
that balance and counteract inflammatory cytokines. As we get
older, inflammaging causes increasing susceptibility to heart
disease, cancer, and neurological diseases like Alzheimer's and
Parkinson's.

The third main dysfunction seen with aging is a decline in the level
of autophagy, a process that is regularly and strongly activated in
young, healthy people but which declines in amplitude in older
people. Autophagy comes from the Greek for “self-eating”, which
nicely describes the process. In conditions in which food is
unavailable, for example overnight while asleep, and in healthy
organisms, cells produce structures that degrade and “eat” parts of
themselves. The structures that are targeted for destruction
preferentially include old and damaged cellular organelles and
proteins, and even infectious agents inside the cell such as viruses
and some forms of bacteria. Autophagy is essential for maintaining
our cells in a healthy and youthful state.

Autophagy normally proceeds at a low, basal level, but as mentioned

a lack of food, as well as exercise and certain dietary
phytochemicals, activate the process and kick it into high gear. As
we age, however, our cells become less able to respond to stimuli
that result in autophagy, and the process does not proceed as
normal. Instead of a strong response, there is a weak one, or none at
all. In this way, our cells become literally cluttered with junk, and
our skin sags, organs and immune system don't do what they
should, and we become increasingly susceptible to cancer and heart
disease.

Oxidative stress, inflammation, and the decline in autophagy are all

intimately linked in a vast network of physiological processes and
enzyme and signaling systems; they all feed back and reinforce each

23
other. How all that works is beyond the scope of this book, as it
would require a vast detour into the realms of biochemistry and
physiology. But suffice it to say that attacking one of these problems
means attacking all of them. In this book, we will look at a number
of ways to do so.

Of all of these aging processes, the decline in autophagy is perhaps

the most fundamental, the most salient cause and consequence of
aging. The reason for this statement is that laboratory animals that
have been subject to various genetic and chemical interventions
that increase the level of autophagy live much longer than normal
animals. While they do eventually die of some other cause of aging,
this shows that the decline in autophagy is probably the most
important cause of aging and death. With increased levels of
autophagy, decreased levels of oxidative stress and inflammation
follow.

Fortunately, a number of ways exist to increase autophagy and

decrease oxidative stress and inflammation, and it is possible for
just about anyone to access them. The methods of attacking the
problems of aging can be readily understood and are relatively easy
to do. They are neither stem cell injections nor hormones. The
methods that we can use to retard the aging process, and in many
cases to actually turn the clock back to a more youthful state of body
and mind, consist mainly of the application of various kinds of
hormetic stresses. A few of them, such as the dietary phytochemicals
in supplement form that we will discuss, cost something, but not
much. But mostly they cost nothing other than the will and
discipline needed to put them into practice.

24
Chapter 2: Exercise: Why It's Crucial
in Fighting Aging

Regular exercise is perhaps the most powerful health-enhancing tool

in the kit. If exercise were prescribed as medicine, which it hardly
ever is, mortality from the top diseases would fall dramatically and
billions of dollars in healthcare costs would be saved.[1] Exercise
prevents older people from becoming frail and from consignment to
the nursing home; it decreases rates of heart disease, diabetes, and
cancer; it prevents dementia. Anyone planning to live a long time
must add exercise to his or her regimen in order to have a healthy
old age.

Exercise extends lifespan, but here we must invoke the distinction

between median and maximal lifespan; exercise increases median
lifespan, that is, it will help you live a full, healthy life free of illness,
and as such it increases the number of people who reach the
median, or average, lifespan. To attain a longer lifespan than the
median, that is, to attain your maximum lifespan, you must first
reach the median. It goes without saying that someone who dies of a
heart attack at age 65 has attained neither his median nor maximum
lifespan. Animal studies have found that exercise increases
“healthspan”, that is, the length of time that they live free of illness
and disease, but not their maximum lifespan.[2] In humans,
exercise is associated with an increase in life expectancy of up to
seven years.[3] The problem here is with the word “association”,
since this type of study was not an experimental but an
epidemiological one. Other factors, such as genes, IQ, social status,
or general health can play a role in determining how much a person
wants to exercise, and these factors appear to have an independent
effect on lifespan. A review of studies on the effect of exercise on
lifespan concluded that it does extend lifespan, but none of the

25
studies reviewed included confounding factors (genes, etc.). The
review found that endurance athletes lived longer than non-athletes,
but of course excellent health may be one reason that people become
athletes in the first place.[4] We'll leave all of that to one side,
however, since you cannot change your genes, nor your IQ or social
status (much). Most people who exercise recognize that it improves
health and quality of life generally, and doctors and scientists agree.

One of the functions of exercise is to improve muscle function and

strength, and muscular strength has been found to be associated
with a much lower rate of cancer, with those in the top third of
muscular strength having about a 40% lower risk.[5] Muscular
strength is so important to cancer risk that, according to the study,
the “associations of BMI, percent body fat, or waist circumference
with cancer mortality did not persist after further adjusting for
muscular strength.” Increasing and maintaining muscle strength
and muscle mass profoundly increases the odds of living in a
youthful state and disease-free for a long time.

Exercise also prevents coronary heart disease, with those who

vigorously exercise in their leisure time having, other things being
equal, less than half the risk of heart disease compared to those who
did not exercise. Those who are in the highest level of fitness, in the
top fifth, have only about 20% of the risk of heart disease as the least
fit.[6]

How does exercise work its magic?

Exercise is a form of hormesis which places a stress on the body and

its cells; the cells then activate stress defense mechanisms so that it
can withstand future stress. What happens is this: exercise increases
the levels of reactive oxygen species (ROS) which act as signals to
the cells. Levels of the internal antioxidant glutathione and of the
enzymes catalase and superoxide dismutase increase as a
consequence of the increase in ROS, as these molecules are largely
responsible for protecting the body against oxidative stress, which,
as we noted previously, rises dramatically with age.

In untrained people, exercise produces damage via free radicals; this

accounts for the soreness and fatigue that beginners experience
when they start an exercise program. But as the person continues
the exercise program, the biochemical machinery that protects
against oxidative stress becomes activated, and this is largely

26
responsible for the training effect, through which the exercising
person becomes adapted to his or her exercise. Regular exercise has
been shown to reduce the levels of oxidized proteins and other
compounds, and to increase the numbers of cellular mitochondria,
both of which are very good things. (More on mitochondria below.)
The paradox of hormesis explains this: causing damage (through
exercise) ultimately reduces damage as the body strives to defend
itself.

Antioxidants do not extend lifespan, and may even

shorten it

Antioxidants, which have been touted for several decades as

promoting health, actually diminish or abolish altogether the effects
of exercise. In a widely cited recent scientific paper [7], scientists
under the direction of Dr. Michael Ristow discovered that humans
who took vitamins C and E during a program of exercise did not
develop many of the beneficial adaptations to exercise, and this
result has been replicated in other studies. The importance of this
study lies in the fact that antioxidants such as vitamins C and E
function as extinguishers of free radicals; hence, if free radicals from
exercise are blunted or abolished, then no beneficial adaptations
take place. In other words, the slight damage that exercise causes is
intrinsic to its anti-aging effect; abolish the damage (through
antioxidants) and you abolish the effect. You can't have hormesis
without damage.

While vitamin C remains an important nutrient that's vital for

health, taking it or other antioxidant vitamins or supplements does
not prolong life, and it may abrogate the healthful effects of exercise,
and by doing so potentially even shorten lifespan. Keep in mind that
one sees references in popular articles and even the scientific press
to “antioxidants”, such as those in fruits and vegetables, when in
reality they are not antioxidants, but toxic agents.

Fruits and vegetables promote health not because they contain

antioxidants, but because the various phytochemicals in them
produce a hormetic response, with our cells increasing stress
defense mechanisms. Plants do not want to be eaten, and since they
are literally rooted to the ground, they defend themselves in the only

27
way possible, through chemical warfare. They produce chemical
toxins to defend themselves from pests, including humans, and
when we eat plants we ingest these toxins, which promote our health
when eaten in small amounts.

Another very healthful aspect of exercise, one that retards aging, is

that it increases the numbers and quality of mitochondria, the
cellular organelles which are often called the powerhouses of the
cell. Every cell in the body contains hundreds or thousands of
mitochondria, which are the source of most of the cell's energy
generation, the location in which chemicals derived from food are
“burned” metabolically and used for the cell's energy needs. From
this standpoint, it can be easily seen why exercise has the effect that
it does on mitochondria: free radicals, increased by exercise, signal
the cells to make more and better mitochondria, since more energy
is required. The feeling of greater energy that a fit person or a young
person has when compared to an unfit or an elderly person may
largely be due to increased numbers, density, and quality of
mitochondria.

Fewer and poorer quality mitochondria characterize aging cells.

So characteristic is this of aging that an entire theory, the
mitochondrial theory of aging, has been developed to explain the
infirmities of age. In essence, as humans age, we become less able to
recycle and renew our mitochondria, something that younger
humans can readily do. Older mitochondria swell in size and
become dysfunctional, unable to produce as much energy due to
their inefficiency. In turn, inefficient mitochondria produce higher
levels of free radicals and, with the internal antioxidant system also
compromised by age, the cell becomes damaged. The mitochondria
also damage themselves, and so, in a vicious cycle, old and
inefficient mitochondria cause oxidative stress, which leads to more
damaged mitochondria, more oxidative stress, and so on.

Having appropriate numbers of high-quality mitochondria is

essential to attaining and maintaining a youthful physiological state.

Exercise has the capability, through the production and renewal of

mitochondria, to make our bodies literally more youthful. We'll have
more to say later about other tactics that can be used to keep our
mitochondria in their youthful state.

28
Recall that autophagy is the process of self-, or cell-cleaning.
Autophagy turns out to be a critically important effect of exercise,
and seems to be important to its metabolic benefits such as better
blood sugar control and lower insulin levels.[8] Since autophagy
declines with age and is a critical factor in aging, inducing it through
exercise turns out to be a brilliant anti-aging tactic. The increase in
autophagy that exercise causes also connects to the renewal of
mitochondria, since when autophagy increases, some of the first
things the cells rid themselves of is old, degenerated mitochondria.

One of the more important sites of increased exercise-induced

autophagy is the brain.[9] This has implications for brain health, as
aging is characterized by declining cognitive function and dementia,
including Alzheimer's disease, so increased activation of autophagy
will help prevent these. We already know that physically active
people are much less likely to experience cognitive decline or
dementia, and a normal (high) level of autophagy is one of the main
reasons for that. In essence, maintaining a high level of autophagy
keeps the brain's mitochondria in a fresh and youthful state, the old
mitochondria being broken down and recycled and new ones made
to put in their place.

Slowing or reversing brain aging is in all respects similar to slowing

or reversing aging in the rest of the body: one must maintain normal
levels of autophagy, keep inflammation and oxidative stress low, and
properly renew mitochondria.

Exercise also increases brain volume and the genesis of new

neurons. Even an exercise as low intensity as walking can do this,
increasing the volume of brain regions with both white and gray
matter.[9] The brain's cognitive capacity is also increased by
exercise, and increased cognitive ability means lower risk of
dementia. Exercising lab animals have greater memory and learning
ability, and so do exercising humans. Keeping one's mental faculties,
or rather, losing them, is one of the chief worries of all of us as we
get older; exercise provides a robust defense against shrinking
brain volume and cognitive decline.

Neurons, of which the brain and nervous system is composed,

secrete a protein called brain-derived neurotrophic factor (BDNF),
higher levels of which are associated with both neurogenesis, or the
growth of new nervous tissue, and protection against depression.
Exercise increases levels of BDNF robustly, and more exercise

29
training causes the BDNF response to increase even more than in
untrained people.[10] Activating autophagy and increasing levels of
BDNF appear to be the chief way in which exercise protects and
improves the brain.

Sarcopenia

Another very important aspect through which exercise counteracts

the aging process is through the building of muscle. Sarcopenia,
which simply means muscle wasting, or loss of muscle mass and
other lean tissue, is an all too common condition in the elderly, and
even the not so elderly. It is a serious problem both for the
individuals who have it, as well as for public health, since sarcopenia
often leads to frailty, which in turn leads to falls, breaking bones,
and a one-way trip to a nursing home. Healthy aging and extending
lifespan entails avoiding sarcopenia at all costs.

But what causes sarcopenia? The body normally breaks down and
builds up muscle continually, and the strong diurnal rhythm of
autophagy is intimately involved here. When people and other
animals get old, two things happen: autophagy levels decline,
interfering with the proper breakdown of older cellular structures,
and anabolic resistance occurs. Normally, in healthy young people, a
given dose of either exercise or dietary protein has a stimulatory
effect on muscle. For example, when a healthy person eats protein as
part of his or her breakfast, that protein stimulates the muscle to
rebuild itself from the breakdown it experienced through the
previous night. Anabolic resistance refers to the phenomenon in
which older people do not exhibit as intense a response in terms of
muscle building to either exercise or dietary protein as do younger
people. When that occurs for an extended period of time, muscles
atrophy, ultimately resulting in sarcopenia.

Sarcopenia appears in aging because of increased inflammation and

oxidative stress, which cause anabolic resistance. It can be quite
effectively combated by two means: exercise, and proper nutrition,
including enough protein. (We'll discuss protein as it relates to
muscle and aging more in a later chapter.) The exercise that best
ameliorates sarcopenia is the one known to academics as resistance
training, and to the rest of us as weightlifting. By placing a stress on

30
muscles, weightlifting causes them to grow, and is a sovereign cure
for anabolic resistance.

Don't think that because you're not elderly, sarcopenia or muscle

wasting of any kind is of no concern to you. The loss of muscle starts
early in life, by some accounts before age 50, such that by age 80
most people will have lost a full 50% of their muscle mass.[11] The
time to start doing something about muscle loss is when you are
young.

But then again it's never too late either. Elderly people respond
robustly to weightlifting, often showing dramatic increases in
strength with just a few months of training. Even small increases in
strength can be enough to erase frailty and keep an elderly person
out of the nursing home, so this is very important.

Exercise decreases inflammation, one of the trio of major age-

related physiological defects. It also increases immune response.[12]
By increasing the immune response, older people can turn back
their immunological clocks to that of a younger person and resist
infections much more effectively. This may also have major
implications for resisting cancer as well, since the immune system
monitors the body's other cells for cancer and fights it when
detected. One reason for higher cancer rates in the aged is due to a
decreased immune response, so increasing the response can help
prevent cancer.

Older men who exercise regularly do not demonstrate age-related

vascular oxidative stress.[13] This type of oxidative stress is
implicated in coronary artery disease, and increases with age.
Regular exercise abolishes it, causing increased levels of anti-stress
enzymes, and making the physiological processes in the older men's
arteries like those of younger men. In this respect, that of the
arteries, regular exercise stops aging in its tracks.

In summary, exercise is one of the most powerful anti-aging and

longevity-promoting processes known, and anyone who wants to
combat the aging of his or her body must exercise regularly,
preferably daily.

31
 The type and dose of exercise

Next comes the question, what dose and type of exercise are
required to fight aging? First of all, any exercise is better than none.
Being sedentary brings with it a train of illnesses and much higher
risks of diseases and higher rates of all-cause mortality, or death, to
us lay people. Even mere standing improves health over being
completely sedentary. It's been said that sitting is the new smoking.

After standing instead of sitting, walking would be the next step up.
What we want to know, however, is whether certain forms of
exercise might be better at promoting longevity and retarding aging
than others. The exercise that is most efficient at doing so should
have certain characteristics: it should be intense enough that it
causes the production of new mitochondria; it should promote
maintenance or growth of muscle and combat sarcopenia; it should
up-regulate levels of antioxidant enzymes. The benefits of a low-
intensity exercise like walking include things like improving insulin
resistance and glucose control, lowering blood pressure, and
improving sleep, and those who are normally sedentary and
somewhat out of shape can certainly benefit from a walking program
of 30 minutes or more daily. Indeed, for the elderly or people with
illnesses, this may amount to a substantial amount of exercise and
be completely appropriate.

However, to get more of the benefits of exercise, it must exceed a

certain threshold, which will differ depending on the person.

To use a simple example, someone who has been training for

marathons by running ten miles a day will get zero exercise benefit
from a leisurely 30-minute walk. The walk that he or she undertakes
simply does not rise above the threshold of intensity and energy
expenditure needed to activate mitochondrial production and all of
the other physiological effects of exercise, above the level that this
highly trained person already has. In fact, as far as strictly aerobic
exercise goes, there's likely little our marathon runner can do to
make himself in better shape, since he's reached the point of

32
diminishing returns with regard to exercise: the more exercise he
does, the less effect it has.

But it's also possible to exercise too much.

Most of us do not train for marathons, and in fact, decent evidence

supports the notion that a level of exercise that high is not just
superfluous, but definitely unhealthy.[13] In a study of long-term
runners, “strenuous joggers” had nearly double the risk of death as
did light or moderate joggers. Other studies have shown that long-
distance running causes heart damage[14]; fully 50% of veteran
endurance athletes in one study had myocardial fibrosis, as
compared to no fibrosis at all in age-matched controls[15]. The
prevalence of fibrosis in these runners was not associated with their
age or weight, but “was significantly associated with the number of
years spent training, number of competitive marathons, and
ultraendurance (>50 miles) marathons completed.” Many other
studies showing heart and other damage in long-term runners could
be cited, but I think that the point is clear enough: it's possible to
overdo exercise and take it into the realm in which it harms health.
We saw in the chapter on hormesis that the health benefits of
hormetic processes or substances depend on the dose, and too much
of anything that causes hormesis moves the needle into the frankly
toxic end of the gauge. Too much exercise damages health and will
not promote healthy aging or extend lifespan. On the contrary, you
may end up with a serious illness because of it.

Exercise that is too frequent can result in a syndrome known as

overtraining. This is perhaps less serious than the myocardial
damage that marathon running can cause, for the reason that it is
usually possible to overcome it with rest and proper nutrition. Elite
athletes, for instance those at the national or Olympic levels, often
train so hard and so often that they become increasingly susceptible
to infections, especially of the upper respiratory tract, and feel so
run down and fatigued that they cannot train at the level that they
and their coaches feel is optimal.[16] The cure for overtraining is
backing off the level of exercise and ensuring proper nutrition,
especially with regard to protein, as well as more rest. Some people
report having been in a state of overtraining for years, since the idea
that more and more exercise conduces to health is a popular one
that mainstream health sources encourage. While, as noted, the
overtraining syndrome is not as serious as the outright damage that
distance running can do, if you have this syndrome you will not feel

33
well and have more colds and flu than others; overtraining signifies
too much stress and does not lead to healthy aging.

So we have an idea of the amount of exercise that goes beyond

health-promoting and into the toxic range: long bouts of distance
running may do this. It's unfortunate that among fitness-minded
people and in the health media generally, ever longer and more
strenuous running is promoted as being the way to health. It is not.

Based on the above considerations, it's clear that exercise must be

intense enough to cause beneficial physiological adaptations, but
not so intense, too long in duration, or too frequent to cause damage
or overtraining.

Two forms of exercise seem to fit the bill when it comes to getting
into that sweet spot where beneficial anti-aging actions take place,
yet no damage or overtraining is done, and they are resistance
training (weightlifting) and high-intensity training, often known by
its acronym HIT.

Weightlifting

Weightlifting's great advantage comes from the fact that it works the
entire body, and as such, it counteracts and even abolishes muscle-
wasting and frank sarcopenia. Exercises like running do not involve
the entire musculature, so while they do improve cardiovascular
fitness, they do nothing to stop the diminishing of muscle as we age.
If done properly, weightlifting also has a profound beneficial effect
on cardiovascular health.

Weightlifting is not just for the bros in the gym; it can and should be
done by almost everyone. To give an example of how and why this is
true, consider one study in which elderly patients who had
experienced a hip fracture were enrolled in a program of “high-
intensity progressive resistance training”, the “progressive” referring
to the fact that weights lifted are increased as training proceeds. The
patients also received nutritional support. Now, if elderly hip
fracture patients don't meet the definition of frail, I don't know who
does; a hip fracture is often a one-way ticket to the nursing home,
and death within a year or so is often the tragic, ultimate result. In

34
these patients who lifted weights, mortality was reduced by a
whopping 81%[17] and nursing home admissions were reduced by
84%. Besides the tremendous magnitude of these results in terms of
reducing the death rate of hip fracture patients, they emphasize the
power of exercise and particularly weightlifting. Most hip fracture or
nursing home residents are likely completely sedentary, which
accounts for high rates of frailty and death in those conditions.
Exercise turns back the clock, rejuvenating the body.

Many other studies of a similar nature have shown that virtually all
elderly people can benefit from weightlifting, even into their 90s. As
for younger people, a weightlifting program can prevent many of the
infirmities of age from ever occurring.

Lifting weights also results in lower levels of myostatin, a protein

which decreases the growth of muscle and which, in mice, is
negatively correlated with lifespan. That is, less myostatin, longer
life. It follows from this that the myostatin-lowering effect of lifting
weights prolongs life. Other forms of exercise don't lower myostatin
as much as lifting weights. How do we know this? Because less
myostatin means bigger muscles, and weightlifting, along with some
forms of high-intensity training, are the only forms of exercise that
result in larger muscles.

While this book is not meant to serve as a weight-training or

exercise manual, a few pointers about a proper weightlifting
program are in order here. For the best health effects, as opposed to
bodybuilding effects, weight training should focus on so-called
compound exercises, which are those that involve the use of two or
more joints. For example, a bench or chest press involves the use of
the shoulder and elbow joints. An example of a non-compound
exercise is biceps curls, in which the weight moves only around the
elbows.

“The Big Five” refers to the main set of compound exercises, and
these are all that are necessary for a health-promoting weightlifting
program. The exercises consist of the following: 1) pull down, which
works the muscles of the arms, shoulders, and back; 2) overhead
press, which works the shoulders; 3) bench or chest press, which
works the chest muscles; 4) rows, that is pulling weight towards
oneself, which works the arm and back muscles; and 5) squats or leg
press, which work the leg muscles. There's no need to get fancy with

35
other, more elaborate exercises – although you certainly can if you
want to – as these will provide all the exercise necessary for good
muscle strength, better metabolism, and body weight control. If you
are a beginner, some instruction is advised, as it is possible to hurt
oneself if not properly trained. Older people especially should have
some supervision when attempting these.

All of these exercises can be done on machines, which lessen the

chance of injury, an important consideration for everyone but
especially for beginners and older people. More advanced
practitioners of weightlifting usually use free weights such as
barbells and dumbbells to perform many of these (as I do), but that
isn't necessary to obtain beneficial effects on health.

It is worth emphasizing that performing the main five compound

weightlifting exercises also results in a tremendous cardiovascular
and metabolic workout. Unfortunately, popular notions of exercise
(which are also encouraged by health journalism) hold that
weightlifting is for building muscles, but good cardiovascular and
metabolic health necessitates aerobic exercise. This is just not the
case. A properly structured weight workout, performed with
sufficient intensity, increases cardiovascular fitness as well as does
aerobic exercise, and increases metabolic fitness, as indicated by
insulin sensitivity and weight loss, even better than aerobics. A
recent study found that long-term weightlifters kept off belly fat
much better than did long-term aerobics exercisers, so weightlifting
is better for fat loss too.

How often should one lift weights? If done properly, weightlifting

places a large stress on the skeletal muscles, which causes them to
grow; but this large stress also means that the practitioner of
weightlifting needs plenty of rest between exercise sessions. Some
experts actually recommend only one session per week of
weightlifting, and for older people this can be appropriate, if the
exercise is done with sufficient intensity. (Walking or other less
intense exercise can be used to fill in on the days in which
weightlifting is not performed.) Younger people will probably find
that they can lift weights several times a week without overtraining.

High-Intensity Training

36
High-intensity training (HIT) refers to a program of exercise that
has received increasing attention from exercise scientists over the
past decade. HIT takes varied forms, but in essence it involves just a
few minutes of exercise a few times a week. One of the advantages of
HIT is that it completely negates the excuse that most people use for
why they don't exercise: lack of time. HIT has been shown to
produce the same or better beneficial effects on health as other,
longer forms such as aerobics or “cardio”. And while most forms of
steady-state exercise do little for weight loss, HIT appears to be
much more effective in shedding fat.[18]

The original forms of HIT were so intense that only young

volunteers could be induced to do it. But it was later discovered that
the exercise need not be quite so intense to produce highly beneficial
effects.[19] In six training sessions over a two-week period, markers
of mitochondrial activation increased more than 50%, and markers
of improved glucose control also increased. All this came about in
only two weeks with a total of less than two hours of actual exercise.
Other studies have shown improved glucose control in diabetics,
and better insulin sensitivity in healthy young people.

HIT much more closely resembles forms of exercise that would have
been done by our distant ancestors, and this being the case, we are
likely to be more adapted in evolutionary terms to it. That is, our
genes were meant to function in an environment in which high
intensity forms of exercise were regularly done. While our
forerunners undoubtedly did plenty of walking, long-distance
running was probably not a regular occurrence. Instead, the
demands of hunting or avoiding predators, human or otherwise,
likely meant that sprinting, jumping, and lifting and carrying heavy
things formed the major part of their exercise. They didn't call it
exercise of course; to them it was “living”.

Recall that fighting aging requires maintaining a high level of insulin

sensitivity. High-intensity exercise performs way better in this
category than continuous, that is, aerobic, exercise. This occurs after
a single session of HIT exercise that consisted of four 30-second, all-
out sprints.[20] This alone is reason enough to ditch the aerobics
and do HIT.

How does one implement a HIT program anyway? In reality, the

variations of HIT are limited only by your imagination. Calisthenics,
for example – pushups, air squats or what we used to call knee

37
bends, jumping jacks, burpees – can be readily combined into a HIT
routine. For example, pushups for 30 seconds at as high a speed as
one can do, followed by up to one minute of rest, then squats for 30
seconds, and so on. Jumping rope for 30 second intervals
interspersed with short rest periods is another way. Sprinting makes
for an excellent HIT routine: sprint as fast as you can for 20 to 30
seconds, walk slowly for one minute (you may need more rest time,
especially at first), then sprint again, and repeat half a dozen times.
These exercises are truly intense, yet take only minutes.

In the Tabata form of HIT training, the exerciser performs an

exercise as fast as possible for 20 seconds, then rests only 10
seconds, and starts in again, for a total of 20 repetitions. For
example, as above, pushups for 20 seconds, 10 seconds rest, then
jumping jacks, and so on.

But the exact intervals and exercises do not matter as much as doing
them with intensity for up to 10 minutes or so including rest
intervals, and a few times a week.

A day or two of weightlifting a week with a day of two of HIT makes

the ultimate exercise program: these will activate all the
physiological responses necessary for peak health and long life,
while avoiding the excesses of overtraining and possible damage.
Naturally, those who love exercise (as I do) or who want to
maximize their anti-aging will probably want to do a bit more, while
also avoiding the dangers of long-distance running.

38
Chapter 3: Diet, or what you eat
affects how fast you age

Aside from exercise, there are few more powerful agents affecting
the aging process than what we eat, how much of it, and when we do
so. In fact, these factors are probably more powerful than exercise,
which is shown by the fact that exercise, or at least the type of
exercise most people perform, has little effect on weight loss. (For
much more on this, see my book, Top Ten Reasons We're Fat,
2015.) Close attention must be paid to diet in all of its
permutations, that is, amount, quality, and timing, to effectively
fight the aging process.

Low-fat eating is a big mistake

Let's get one thing out of the way first: the low-fat craze that the
government and mainstream health authorities foisted on the
American public, and which unfortunately is still followed with great
enthusiasm by most health-conscious people, was a huge mistake.
The rise of the obesity epidemic coincided with the adoption of low-
fat guidelines, a fact that many people, and even the government,
are now beginning to appreciate. The main reason for this is that
eating a low-fat diet necessarily means the ingestion of higher
amounts of carbohydrates, which can cause many people to become
overweight or obese. Since it is becoming clearer by the day that
saturated fat is not only not harmful but necessary for good health,
and that the ingestion of a high-carbohydrate diet leads to
overweight and diabetes, we have good reasons to believe that the
low-fat diet is not optimal for human health and will do nothing to
retard aging.

39
On the contrary, optimal anti-aging requires staying lean and along
with this, sensitive to the effects of the hormone insulin. Recall that
diabetes and obesity are archetypes of aging. The more body fat a
person has, the higher the risk of death.[1] In general, the risks of
obesity to health have been greatly underestimated, as shown by
looking at mortality compared to highest ever body mass index
(BMI). Popular understanding, evidenced by many mainstream
articles, is that obesity isn't really all that unhealthy, but this is
based on research that used BMI at time of death. However, when
people die of an illness, they have often lost a great deal of weight by
the time they die. When the all-time high BMI of a person is used,
the mortality risk of obesity is shown to be much higher, and
estimates of BMI at the time of death have substantially
underestimated risks.[2]

Excess body weight accelerates aging

A recent review article by the noted anti-aging scientist Luigi

Fontana and obesity expert Frank Hu took a look at all the factors
relating to body mass index (BMI), and concluded that the optimal
BMI was 20 to 21.[2] It's worthwhile to quote from their report:
“Excess body weight and adiposity cause insulin resistance,
inflammation, and numerous other alterations in metabolic and
hormonal factors that promote atherosclerosis, tumorigenesis,
neurodegeneration, and aging.” As we've noted previously, insulin
resistance and inflammation – and “numerous other...metabolic and
hormonal factors” - are characteristics of aging and must be kept in
check to retard the aging process. Excess body weight accelerates
aging. Staying lean is crucial for life extension. This point cannot be
emphasized enough.

Fontana and Hu go on to say, “Studies in both animals and humans

have demonstrated a beneficial role of dietary restriction and
leanness in promoting health and longevity. Epidemiological studies
have found strong direct associations between increasing body mass
index (BMI) and risks of developing type 2 diabetes, cardiovascular
disease, and several types of cancer, beginning from BMI of 20–21.”

40
In layman's terms, any BMI above 20 or 21 associates with an
increased risk of the major diseases of aging. Any indications that
higher levels of BMI and even obesity are healthy, as you might read
in the mainstream press, are false and have come about because of
faulty interpretations of the data, especially data confounded by
smoking, which results in a lower BMI. As the authors state,
“...maintaining a healthy weight through diet and physical activity
should remain the cornerstone in the prevention of chronic diseases
and the promotion of healthy aging.”

Therefore, the first objective in staving off aging is to attain and

maintain a normal body weight. All other anti-aging interventions
won't make much of a difference if you are overweight or obese.
Leaner is almost always better, other things being equal, than
heavier. An important caveat here is that the reason that BMI means
faster aging is because of excess fat, “adiposity”, and not more
muscle. Adding more muscle and hence attaining a higher BMI
through a weightlifting program causes an increase in health, not a
decrease; only more fat tissue causes a decrease in health. Health
researchers can usually ignore the effect of extra muscle when doing
population-based studies, since so few people have any.

A calorie is not a calorie, especially when it comes to

aging

The composition of the diet matters a great deal for both lean body
weight and the metabolic aspects of health. Despite what the media
tells us, a calorie from one type of macronutrient (carbohydrate, fat,
and protein) is not the same as a calorie from another; the body
handles them differently, and levels of hormones such as insulin and
glucagon, blood sugar, and muscle and fat mass are all affected by
the macronutrient composition of our food. Dietary composition is
of course the subject of libraries of books, so we'll narrow our focus
here to aging.

To understand why the composition of our diet matters for aging,

let's take a quick detour into the arena of longevity experiments in
lower animals. One of the primary animals that scientists use in
such experiments is the tiny worm called C. elegans, which has a
short natural lifespan of about two weeks, allowing for faster and

41
cheaper testing of possible anti-aging processes and substances.
Many of the discoveries of the aging process in C. elegans were
made by using genetic mutants in which specific physiological
pathways were abolished.

C. elegans genetic mutants with disrupted insulin signaling can live

twice as long as normal.[3] This is significant for aging in humans
and for the composition of our diets because insulin is maximally
stimulated by dietary carbohydrates. When we eat carbohydrates,
they are broken down into glucose and enter the blood stream, and
this glucose needs somewhere to go, since high blood sugar is toxic.
To remove glucose from the bloodstream, the pancreas secretes
insulin, which promotes the uptake of glucose into cells. Therefore
every time we eat carbohydrates, insulin signaling increases, and
insulin promotes aging.

Reduced insulin signaling also works in mice to extend lifespan; this

is the means by which certain hormones, such as klotho, extend
lifespan. Many proven anti-aging substances, such as rapamycin,
both increase insulin sensitivity, meaning less insulin is produced,
and increase lifespan, also in mice.

Keeping insulin signaling low is a very important component of

retarding aging.

The reader may be asking whether a result like this found in worms
and mice could really apply to humans. Cynthia Kenyon, the
scientist who found the link between insulin and lifespan in worms,
certainly thinks so; she switched to a low-carbohydrate diet shortly
after she made the discovery.[4] She avoids all sugar and bread and
other highly refined carbohydrates, saying that increased insulin
signaling is the reason she does so. According to her, “Sugar is the
new tobacco.”

Other studies in C. elegans have found that giving them sugar

shortens their lifespan[5] and that restricting glucose increases their
lifespan,[6] so not only genetic disruption but diet directly affects
aging. All of this confirms that activating insulin signaling via the
ingestion of glucose has a profound effect on aging in this model
organism. The physiological pathways, such as insulin signaling, are
evolutionarily conserved, meaning that they are similar in the cells
of all organisms. This is because these mechanisms arose early in
the course of evolution, and were conserved by all subsequent

42
evolution. For example, in mice, which are mammals like humans
are, disruption of insulin signaling also increases lifespan.[7] The
hormone klotho has been associated with longevity not just in mice
but in humans, and this hormone disrupts insulin signaling.[8]
Americans eat loads of carbohydrates, by some accounts greater
than 50% of their calories as carbohydrate. In fact, the Institute of
Medicine, one of the arms of establishment medical consensus in
the U.S., actually recommends that people eat from 45 to 65% of
their calories as carbohydrate. Carbohydrates, which are composed
of glucose (sugar) molecules linked in long chains, becomes sugar in
the bloodstream when digested, and all that sugar has to go
somewhere. To allow it to be taken up by cells, the pancreas secretes
insulin which, as we've seen, is implicated in aging. When the cells
receive their glucose load, they turn it into fat.

If you follow mainstream advice on carbohydrates, such as that of

the Institute of Medicine, you will likely have difficulty staying lean,
keeping insulin levels low, and fighting the aging process.

A common objection to the idea that carbohydrates accelerate aging

is that many traditional societies eat large fractions of their diet as
carbohydrates. For instance, the Kitavans, residents of a remote
South Pacific island, eat up to 70% carbohydrate, and are known for
excellent health; the older generations of the Okinawans are famous
for long lives, and they appear to eat lots of carbs. The most likely
explanation for certain anomalies like these is that these peoples
ingest their carbohydrates in the form of relatively unrefined plants,
which do not raise insulin levels as high. In contrast, in Western
societies and other societies that have adopted Western diets, most
carbohydrates take the form of flour, sugar, and processed food,
much of it junk, made from these. Indeed, Kitavans, despite
ingesting a high proportion of their diets as carbohydrate, have
lower insulin levels than Westerners, and this may be due to the
specific type of food they eat.[9] (A higher level of physical activity
may also be important here.)

The lesson from the Kitavans is that any carbohydrates in your diet
should come from whole, unrefined plant sources, and not highly
processed forms such as flour and sugar.

43
 Low-carbohydrate diets can lower biomarkers of
aging

Low-carbohydrate diets work to lower the biomarkers of aging in

humans as well as lab animals. Two of the leading physician
advocates of low-carbohydrate diets, Ron Rosedale and Eric
Westman, put their patients on strict carbohydrate restriction and
measured some of the important biomarkers of aging, before and
after. After only two to three months, insulin levels dropped by
nearly half, and glucose and leptin levels dropped substantially.
Their blood pressure decreased too.[10]

What does a low-carbohydrate diet look like? In the Rosedale and

Westman study, the dieters were instructed that only “non-starchy,
fibrous vegetables were acceptable: lettuce, greens, broccoli,
cauliflower, cucumbers, mushrooms, onions, peppers, sprouts,
asparagus, and seaweed.” So in terms of carbohydrate, that means
no bread, pasta, tortillas, rice, cereal, potatoes, or anything else that
contains large amounts of starch. And of course, no added sugar.
Although the dieters were not instructed to cut calories or even
watch them, since this study was designed only to look at aging
biomarkers and not for weight loss, they did indeed all lose weight,
and average of 7 kilograms (over 15 pounds) or about 8% of their
body weight. Often, low-carbohydrate diets result in a spontaneous
decrease in calorie consumption, that is, these diets usually induce
lower calorie intake without the dieters even trying. Usually this is
attributed to better satiety: the dieters are less hungry on fewer
calories when those calories come from fat and protein than when
they come from carbohydrates. Sometimes, however, reports
indicate that people on low-carbohydrate diets lose weight even
when they do not decrease calorie intake, and if so, this is likely due
to the effects of lower amounts of insulin, which decrease the
storage of calories as fat and allow fat already in storage to be
released from fat cells and burned for energy.

Low-carbohydrate diets can also decrease the incidence of cancer

and benefit those who already have cancer.[11] Metabolic syndrome
and diabetes, both disorders of carbohydrate metabolism, are
associated with a higher incidence of cancer. The higher insulin
levels in these conditions conduces to cancer formation; and when
cancer already exists, the tumor cells feed nearly exclusively on
glucose, so the higher blood glucose levels of metabolic syndrome
and diabetes encourage their survival and growth. Ketone bodies

44
that result from very low carbohydrate diets can negatively affect the
proliferation of tumor cells. Since cancer rates increase dramatically
with age, cancer being essentially a disease of older people, the fact
that low-carbohydrate diets can decrease cancer rates is yet another
indication of their pro-longevity and anti-aging effect.

How low is a low-carbohydrate diet? Definitions are disputed, and

the issue is important because of studies that have reported no
difference in weight loss or aging biomarkers such as insulin on low-
carbohydrate as compared to low-fat diets. It appears that some
researchers are happy to deem a diet with 40% or greater calories as
carbohydrate as a low-carbohydrate diet, merely because that's
lower than the average consumption, or because of researcher bias,
or even because they mistakenly believe that going lower than that is
unsafe. So a categorization here is important.

A group of prominent medical scientists in the area of obesity and

diabetes have suggested the following definitions for low-
carbohydrate diets[12]:

 Ketogenic low-carb: This is the lowest of the low-carb, and

results after a few days in the production of ketones, which
many parts of the body use for energy in place of glucose. On
a ketogenic diet, carbohydrate consumption is less than 30
to 50 grams per day.
 Low-carbohydrate diet (full stop): Anything up to 130 grams
of carbohydrate per day.
 Moderate carbohydrate diet: more than 130 grams but less
than 45% carbohydrate as calories, which on a 2,000 calorie
a day diet equates to about 225 grams.

Any decrease at all in carbohydrate consumption will have beneficial

effects on aging biomarkers, but greater restriction is usually better,
and many people do very well on a ketogenic diet. Anything above
130 grams of carbohydrate a day, a “moderate carbohydrate” diet, is
not really restricting carbs in the way we mean here.

Later in this book, we'll be discussing the benefits of fasting, but it's
worth noting here that many of those benefits are due to the
restriction of dietary carbohydrate.[13] A group of volunteers
underwent a fast of 84 hours – that's three and a half days, a very
long one. Half of them received intravenous infusions of a lipid
emulsion that met their daily energy requirements. Yet ultimately,

45
changes in glucose, insulin, free fatty acids, and other biomarkers
were the same in both groups, the study's authors concluding that
“restriction of dietary carbohydrate, not the general absence of
energy intake itself, is responsible for initiating the metabolic
response to short-term fasting.” Not all relevant biomarkers were
measured, but this makes the case that the mere lowering of
carbohydrate intake has many health benefits.
The science behind insulin signaling and lifespan is complex, and by
no means have the discoveries come to an end or all the difficulties
been ironed out. But what I have hoped that this brief tour through
insulin signaling and lifespan shows is how an anti-aging diet must
be a low-carbohydrate diet. In humans, low-carbohydrate diets
result in lower insulin levels and better insulin sensitivity. All
carbohydrates eventually become glucose in the bloodstream, and
this causes the release of insulin. While it is absolutely required for
life, too much insulin shortens life. Other manipulations such as
exercise and fasting that fight aging also increase insulin sensitivity.

Dietary Phytochemicals

While dietary carbohydrates are a net negative for decreasing

disease and increasing lifespan, a number of dietary constituents
play a positive role in lifespan extension, many of these constituents
being polyphenols and other compounds derived from plants, which
are generally known as phytochemicals. A fairly large number of
compounds extend life in C. elegans, and others also in mammals
such as mice, and since so many exist, we'll focus here on those that
show the biggest benefit or the most promise. Note also that most
foods contain relatively low amounts of many of phytochemicals,
and so if you want to use them for life extension purposes,
supplements are often the best way to get them.

Many or most of these plant phytochemicals work by increasing the

activation of AMPK, which is a highly evolutionarily conserved
cellular energy sensor. AMPK senses the energy status of cells,
becoming more activated when energy levels are low, and when
activated it in turn regulates gene expression, increasing stress
defense mechanisms and making for efficient metabolic control.
Ultimately, it controls the aging process through its integrated cell-

46
signaling network.[14] Therefore, activation of AMPK slows, stops,
or even reverses aging, and if we can activate it using
phytochemicals (or other agents, of which we'll discuss more later),
then we can slow or stop our own aging.

In the past few decades, a huge amount of research has been

devoted to a great number of plant compounds that have beneficial
health effects, such as the prevention of the diseases of civilization
like heart disease and cancer. Over 10,000 potentially beneficial
phytochemicals exist, many of them having not been characterized
well. Many fruits and vegetables are loaded with them, but as noted
they may be difficult to obtain in sufficient concentration in the diet,
and most studies have been done using relatively large doses of
these compounds, large enough that humans would need
supplements of them to obtain a sufficient amount.

Probably more research has been done on resveratrol than any other
phytochemical that promises to halt aging. Resveratrol is found in
red wine, although the amounts there are small, about 5 milligrams
in a bottle. It extends lifespan in a number of model organisms,
including the nematode (worm) C. elegans, and promotes survival
in mice fed a high-fat diet.[15] Resveratrol promotes the production
of mitochondria, improves insulin sensitivity, prevents cancer, and
enhances the beneficial effects of exercise, and one of the main
reasons, if not the only reason, for its beneficial health effects is
through the activation of AMPK.

Most of the work on resveratrol has been done on lab animals, but
some human trials exist, and have had good results[11], with this
compound functioning as a calorie restriction mimetic. As we'll see
later, calorie restriction is one of the most powerful anti-aging
strategies, and ways exist, such as the use of resveratrol, to mimic its
actions. These mimetics dispense with all that pesky hunger that
characterizes calorie restriction.

While resveratrol isn't quite the cure-all for aging that many had
hoped in the beginning, it's well worth supplementing with. In the
cited human study, the scientists used a dose of 150 mg a day, and
they stated that, “although the dosage of 150 mg of resveratrol per
day is around 133- to 266-fold lower compared to the high doses of
200–400 mg/kg/day used to supplement mice, plasma resveratrol
levels in our human intervention...were even higher than those
obtained in mice”. This is important to note because of reports that

47
the human body metabolizes resveratrol too quickly for this
compound to be effective. This human study showed that it is not.
Resveratrol lowered systolic blood pressure by about 5 mm, a
substantial amount, it increased mitochondrial activity, and of
course increased activity of AMPK. While the results were not
miraculous, they show that resveratrol has essentially the same
action in humans as in animals.

Resveratrol causes increases in memory and cognitive function in

humans.[17] As a decline in brain volume occurs during aging,
maximizing brain power and preventing brain shrinkage becomes
an important part of fighting aging. One doesn't want to live to an
old age if it means substantial brain shrinkage – at least, I don't.
Resveratrol activates the anti-aging gene klotho[18] and has
substantial anticancer effects.[19] The doses used in most human
studies have approximated 150 milligrams daily; this dose appears
safe for humans and is the amount this writer takes daily.

Other chemical compounds can also activate AMPK and thus mimic
calorie restriction, for example, curcumin, which is derived from the
Indian spice turmeric. Curcumin extends lifespan in C. elegans, fruit
flies, and in mice, and it appears to do so in part by promoting
autophagy, the cellular process of self-cleaning. It inhibits
inflammation, and prevents cancer by activating stress defense
mechanisms, i.e. through hormesis. Sulforaphane is another such
compound with similar activities; broccoli and other cruciferous
vegetables contain relatively large amounts of it.

One problem in aging that scientists would like to solve is that of

cellular senescence. As cells age, they enter a stage known as
senescence, in which they cease to grow and divide like normal cells.
Their senescent phenotype does, however, produce large numbers of
inflammatory cytokines which can cause many of the hallmarks of
aging. The problem of senescence differs from some of the other
biological problems of aging discussed in this book in that it is not
readily overcome through the easily available anti-aging agents of
diet and exercise. Now, though, it looks like a dietary phytochemical
has come to the rescue, in the form of quercetin, which is found in
sources like apples and onions.[20] In a recent study, quercetin
showed remarkable effects on cellular senescence, and improved the
health of old mice after a single dose.[21] While quercetin was
effective, the best results were obtained in combination with an anti-
cancer drug, dasatinib. While the researchers cautioned that this is

48
all very preliminary, and that much more research is needed, the
results show the promise of using dietary phytochemicals like
quercetin to fight aging.

Eating a diet high in fruits and vegetables allows for the

consumption of a wide range of beneficial dietary phytochemicals,
and with them the possibility of preventing cancer, heart disease,
dementia, and other diseases of aging. Other dietary components
also contain high levels of beneficial phytochemicals, notably coffee,
tea, chocolate, and red wine, all of which have been shown to
improve health. Caffeine has in fact been shown to extend lifespan
in C. elegans. Supplementation can increase the level of selected
phytochemicals, and from the above list, this writer supplements
both resveratrol and curcumin, which provide for hormesis.

Coffee is the single largest source of phytochemicals for the average

American, who doesn't appear to be eating many of his or her fruits
and vegetables. The upside of that is that coffee does provide high
levels of polyphenols, and recently it was found that coffee induces
autophagy[22]; therefore coffee promotes longevity. Coffee drinking
is also associated with greatly decreased risks of diabetes.

Consumption of tea, especially but not exclusively green tea, has

also been associated with longer life, and much of its life-extension
and health-promoting power likely comes from its phytochemicals,
mainly catechins, such as the nearly unpronounceable
epigallocatechin gallate, which fortunately we can refer to by its
initials, ECGC. This phytochemical promotes autophagy, and has
increased lifespan in mice.[23] In rats, EGCG caused a 13% increase
in lifespan, and the longer-lived animals had decreased levels of
oxidative stress and inflammation.[24] The dose of EGCG used in
these rats was 25 mg per kilogram of body weight, which translates
into a human dose of about 220 mg a day, assuming a 70 kg (154
lbs.) person, and taking the rats' higher metabolism and surface to
volume ratio into account. This dose is easily achievable with a
green tea supplement of 400 mg, which contains ECGC of about 200
mg.

Other chemical compounds exist which extend lifespan in lab

animals, but which are almost impossible to obtain with food,
lithium, for example. Lithium not only increases lifespan in C.
elegans, but humans who drink high-lithium water have lower death
rates.[25] Lithium is also a somewhat mysterious required nutrient,

49
and it appears that the recommended daily allowance is about 1 mg.
(Which is, by the way, far lower than the dose used in bipolar
disorder, which is hundreds or even thousands of milligrams daily.)
If you don't have lithium in your water, and most people don't, a
supplement is needed here; lithium orotate, a common formulation,
is available in 5 mg tablets, and could be taken, say, every other day
or every third day.

The daily use of low-dose aspirin, that is, the size of a baby aspirin
or about 80 mg, is associated with a reduction in risk of certain
cancers, notably colon cancer, in humans of about 40%. Reductions
in risk of esophageal cancer were a whopping 75%. (Higher doses of
aspirin show no additional benefit, but may have higher risk.)
Aspirin also extends lifespan in C. elegans[26] via activation of
AMPK. Aspirin has of course been used for years in the prevention
of heart attacks, but it carries with it the risk of major bleeding, so
doctors have been generally reluctant to recommend it to anyone
who is not at high risk for heart disease. However, that may be
changing, since adding the lowering of cancer risk to the equation
means that the risk to benefit ratio of aspirin has changed. Peter
Rothwell, the medical scientist and physician who has done many of
the studies on aspirin and cancer risk, now takes aspirin himself,
despite having no known cardiovascular risk factors, and has said,
“In terms of prevention, anyone with a family history would be
sensible to take aspirin”. (From the New York Times.) Some anti-
aging experts believe that aspirin could be the easiest and cheapest
life extension drug now available, since it has a demonstrable effect
in lowering mortality.

Aspirin has two different effects.

The first is that it lowers the risk of cardiovascular events like heart
attack and stroke by reducing the chance of blood clots, which are
the precipitating factors for these cardiovascular diseases. It does
this by reducing the ability of blood platelets to stick together and to
other surfaces. This effect is also the same one that may cause
bleeding.

Aspirin's second effect is that it lowers inflammation by inhibiting

certain enzymes and activating the energy sensor AMPK; this is the
source of its anti-cancer and anti-aging effects. Recall that one of the
hallmarks of aging is greater levels of inflammation, so a drug like
aspirin that reduces inflammation can be of benefit for life

50
extension. The tendency of aspirin to promote internal bleeding is
certainly a downside, and some people will be more likely than
others to manifest this risk. But the reduction in cancer risk may be
even more important than the reduction in cardiovascular risk. The
medical consensus currently recommends aspirin only for those who
have had a previous heart attack or are otherwise at high risk for
one, but as noted that consensus may be changing. For those of us
who are trying to fight aging, aspirin poses a conundrum: any doctor
that you might consult about taking low-dose aspirin will likely
recommend against it, assuming that you have low cardiovascular
risk. I'm not here to tell you otherwise, but you should be aware of
aspirin and what it can do.

Omega-3 fatty acids, which are abundant in fish oil, are another
dietary component important to aging. Modern, industrial diets are
loaded with omega-6 fats, mostly from vegetable oils, and this has
skewed the ratio of omega-6 to omega-3 fats far in excess of what
our distant ancestors experienced. Excess omega-6 fats are
associated with cancer and heart disease. Aside from limiting the
intake of vegetable oils, preferably to zero, supplementing with fish
oil can help bring the balance of omega-6 to omega-3 back to
normal. A teaspoon of cod liver oil is about 5 grams and contains
about one gram of omega-3 fatty acids. Taking this amount a few
times a week should be sufficient for anti-aging purposes.

Omega-3 fatty acids lower levels of inflammatory cytokines, thus

lowering one of the three main biomarkers of aging. They also have
salutary effects on the brain, and may also aid in exercise recovery.

Dietary Protein

We mentioned dietary carbohydrate above, and noted that, for anti-

aging purposes, generally speaking the lower the amount of
carbohydrate in the diet the better. Lowering the level of
carbohydrates in the diet improves insulin sensitivity, which notably
declines with age, and improves weight control. There is no dietary
requirement for carbohydrates, so they may be decreased or omitted
from the diet with no ill effects and in fact for most people, great
benefit.

51
Protein is another matter: it is a required nutrient and we cannot
live without it. Low protein levels may lead to all kinds of functional
difficulties and illness, from frailty and sarcopenia to chronic fatigue
and depression. Vegetarianism is, for example, associated with a
number of health problems due to its low protein content, and many
vegetarians report a distinct lack of energy, and is one reason some
of them give up on their vegetarian diet.

The Growth-Longevity Trade-Off

However, in the context of life extension and fighting aging, it is

possible to eat too much protein. The reason is that a fundamental
trade-off between growth, on the one hand, and longevity, on the
other, exists. More growth equals more aging, other things being
equal. Protein raises the levels of insulin-like growth factor, or IGF-
1, which is, as the name suggests, a type of growth hormone. IGF-1
acts in a number of ways and is connected to many other cellular
and biochemical sensors, but in essence it promotes growth. In
doing this, the body's natural anti-aging programs, such as the
AMPK sensor, which affects autophagy, inflammation, and oxidative
stress, are shut off. Higher levels of IGF-1 are associated with cancer
and earlier death, and centenarians appear to have lower levels of
growth hormones.

People who have genetic mutations that cause growth hormone

receptor deficiency essentially have very low levels of growth
hormone, insulin, and IGF-1 effects on their cells, and they appear
to be nearly free of diabetes and cancer.[27] They have “a major
reduction in pro-aging signaling”, and serum from these people even
reduced DNA breaks and increased apoptosis (killing of cancerous
and pre-cancerous cells) in cell culture. Growth hormone receptor
deficiency also leads to much higher levels of insulin sensitivity,
which decreases with aging and leads to diabetes and other diseases
of aging.

Unfortunately, growth hormone deficiency also causes very short

stature. Unless you are one of the few who is indeed very short, we
don't need to worry about this though, as we're already fully grown.
The key is to maintain growth hormone signaling at a lower level
once adulthood has been reached.

52
Growth signaling fundamentally links to pro-aging biochemical
pathways. Block or diminish the growth pathways, and pro-aging
signaling decreases, and with it the risks of the diseases of aging:
heart disease, cancer, diabetes, and the rest.

Why does the trade-off between growth and longevity exist? Lots of
speculation has gone into this question; one answer is that genes
which are necessary for growth, such as IGF-1, are not turned off
sufficiently in later life, and thus cause cellular senescence and other
pro-aging phenomena. IGF-1 is absolutely necessary for normal
growth and development: mice lacking it die after birth, and as
noted those people with growth hormone receptor deficiency are
very short in stature.

The existence of hormones and other substances and processes that

promote growth while an organism is maturing, and which promote
aging when an organism is older, has led some scientists to propose
the idea that aging is quasi-programmed. The organism has a
necessary physiological program that causes growth and is unable to
completely shut it off later. Whether this theory is true or not, it
does seem to fit the facts of the growth-longevity tradeoff.

Many anti-aging clinics and doctors advocate the supplementation

of human growth hormone (HGH) as an anti-aging intervention.
(As well they might, since it's expensive and they can make lots of
money from it.) Provision of HGH superficially decreases markers of
aging by lowering levels of body fat and increasing muscle mass, and
many of those who take HGH report higher levels of energy and
well-being. However, this comes with a price, as higher HGH
actually accelerates aging by, for example, increasing insulin
resistance; by causing growth, HGH can also increase the rate of
cancer and probably heart disease as well.

The effects of HGH seem paradoxical, for how can a hormone both
increase markers of aging, such as insulin resistance, and decrease
other markers, such as those involving body fat and muscle, at the
same time? Science doesn't have all the answers to this yet, but the
tradeoff between growth and longevity appears inescapable.

As we'll discuss in much more detail later, calorie restriction is one

of the most robust anti-aging interventions in existence; it's been
known since the 1930s or even earlier that feeding animals

53
drastically less food, say 30% less, increases their lifespans
dramatically, sometimes by up to 50%. Much research and
speculation has gone into understanding why this occurs, but one
way calorie restriction works is through lowering levels of growth
hormone and IGF-1. The way that calorie restriction appears to
lower the levels of these hormones is through lower protein intake.
Many of the benefits on lifespan of calorie restriction disappear if
protein intake is not lowered, and even the deficiency of a single
amino acid (of which proteins are composed), methionine, increases
lifespan in rodents, even without calorie restriction.[28]

The effects of calorie restriction and protein intake in humans on

IGF-1 was nicely illustrated in a recent study. Researchers measured
levels of IGF-1 in a group of people who belong to the Calorie
Restriction Society and who had been restricting their food intake
for a number of years. Since calorie restriction must be accompanied
by good nutrition in order to be effective for anti-aging purposes,
these people had been very conscientious about their protein intake,
and consumed a diet that was around 24% protein, or 1.67 grams of
protein per kilogram of body weight. This level of protein intake is
high, similar to that consumed by bodybuilders. (By contrast, most
people consume around 15% of calories as protein.) Their IGF-1
levels averaged 194 nanograms per milliliter (ng/ml), a level similar
to that in people eating a standard, non-calorie restricted diet. Then,
they cut back on their protein consumption to around 1 gram per
kilogram for three weeks, and their IGF-1 levels dropped to 152
ng/ml, a drop of about 25%.[29]

The precise levels at which IGF-1 either lowers or promotes aging in

humans is not known, so we can't say with certainty that either the
higher level that came with higher protein promotes aging, nor that
the lower level fights it. However, all things considered lower levels
are probably better. The important point about this study is that at
least in humans, calorie restriction by itself does not lower IGF-1
levels, and protein is a key determinant of those levels. The authors
of this study remark that “reduced protein intake may become an
important component of anticancer and anti-aging dietary
interventions.”

To be fully aboard the anti-aging program, attention must be paid to

how dietary protein and other habits and interventions affect the
levels of growth hormone and IGF-1.

54
 Protein and muscle

We need to consider another aspect of protein intake and how it

relates to aging, and that is the issue of muscle-wasting and
sarcopenia. We saw earlier that muscle wasting begins early in life,
and that the continuation of this wasting into old age can result in
sarcopenia, or the loss of enough muscle mass to make people frail
and their lives difficult. Protein, along with exercise, also determines
the level of muscle mass, so people need to eat enough protein to
maintain muscle and avoid frailty in older age.

Optimal protein intake involves balancing the two desirable factors

of 1) avoidance of muscle wasting (and even increasing muscle
mass); and 2) keeping IGF-1 levels from being too high. This is
especially important if you do resistance training, since that won't
increase muscle mass without sufficient protein.

Fortunately for the goal of increasing lifespan, the amount of protein

needed to build muscle appears to have been exaggerated. Most
weightlifters use an approximation of 2 g protein per kilogram of
body weight – compare to the admittedly low U.S. recommended
daily allowance of 0.8 g/kg – but this appears to be much more than
necessary. A number of studies have found that experienced
weightlifters need only about 1 g/kg.[30. This study is representative
of others that found similar results.] Trained athletes need less
protein than beginners, as the body adapts to use protein more
efficiently with training. Also, keep in mind that these were
experienced bodybuilders who were maintaining a large muscle
mass; for those of us not quite so zealous in muscle building and
maintenance, less protein than that may suffice. In this particular
study, the authors concluded that “bodybuilders during habitual
training require a daily protein intake only slightly greater than that
for sedentary individuals in the maintenance of lean body mass”.

Interestingly, endurance athletes such as runners require much

more protein than strength athletes, probably because this type of
exercise tends to break down muscle through higher levels of
cortisol, among other things. All the more reason to make resistance
training the core of your exercise regimen.

55
Muscle growth appears to be much more linked to lower levels of
myostatin, a protein produced during exercise, than it does to
increased systemic levels of IGF-1. A quote from a study called
“Resistance training alters plasma myostatin but not IGF-1 in
healthy men” gets to the heart of this matter: “… growth factor
responses local to the muscle may be more important than
circulating factors in contributing to muscle hypertrophy with
resistance training.”[31] Large systemic increases in IGF-1 are
unnecessary to promote hypertrophy of our muscles; decreasing
myostatin levels does the job. Therefore, at least as far as IGF-1
goes, we don’t need as much protein.

The lesson in all this is to keep protein intake under control, neither
too much nor too little. Insufficient protein conduces to sarcopenia,
and with it to frailty and dependence; too much protein leads to
higher levels of IGF-1 and faster aging. Based on what has been set
out above, we can tentatively state that a daily protein intake of a bit
above 1 gram protein per kilogram of body weight may be about
right. This amounts to around 0.5 grams per pound of body weight.
Anything more than that, other than for beginning weightlifters, is
likely superfluous and leads to faster aging. Lower than that, it may
lead to muscle wasting. This level is still above the recommended
daily allowance for protein, which is 0.8 grams of protein per
kilogram of body weight, and which has been criticized as being too
low.[32]

How can we optimize the amount of protein we eat? Aside from

counting the number of grams, an easier way may be to eat enough
protein on exercise days, and to lower protein consumption on non-
exercise days. (By non-exercise days, I don't mean days that
incorporate low-intensity exercise like walking, which requires no
extra protein, but weightlifting or HIT days, which do.) Fasting,
wholly or partially, on non-exercise days can accomplish this, and
we'll explore this in more detail in the next chapter.

56
Chapter 4: Fasting: When you eat is as
important as what you eat

Diet, in the sense of the composition and quality of the food we eat,
is rightly emphasized as important for health and lifespan. Low-
carbohydrate diets impede aging by curtailing insulin resistance and
obesity, and added sugar can degrade health and accelerate aging.
The amount of protein, as we have seen, can make the difference
between muscle-wasting and frailty, on the one hand, and faster
aging on the other. And of course optimal health and lifespan
extension require adequate supplies of vitamins and minerals.
Health experts routinely blame the obesity epidemic on changes to
our diets, especially the consumption of more refined carbohydrates
including sugar, and in this they are surely correct, at least in part.

Most people used to fast regularly, because they had

to

Besides the quality and composition of our diet, another aspect of

food may be equally or even more important for our health, levels of
body fat, and aging, and that is the matter of when and how often we
eat.
Looking at the obesity epidemic, is it the case that most people
followed impeccable eating habits before the epidemic began? And
is it also the case that scientific knowledge of what humans should
eat and how that affects health was greater than today? Certainly,

57
the answer to both of these questions is “no”. Before the 1970s,
when the obesity epidemic began, most people not only didn't have a
clue as to how food affected their health, but they didn't care all that
much either. Before the 1970s, cakes, pies, and cookies featured
regularly in Americans diets; sugary cereal was (and still is) eaten
regularly for breakfast, and soda pop from a vending machine was
never far away. So how did most of the population avoid being
overweight or obese, unlike today?

The answers to that question are complex, and most of them lie
outside the scope of this book, but one aspect of eating that has
changed is the timing and frequency of meals. Think back to the
real old days, long before the 1970s, when refrigeration didn't exist.
In those days, food was difficult to store, and leftovers didn't last
long. No convenience foods either. The wife and mother of the
household prepared meals for her family from scratch, and this was
a time-consuming job. Restaurants were fewer and most people
couldn't afford them anyway.

What changed? We now not only have refrigeration, but frozen and
packaged convenience foods aplenty. Fast food restaurants are
everywhere, and many more people can afford them and have access
to them. Eating a meal or snack now is as close as the refrigerator or
cupboard – no wives or mothers necessary – or a drive a few blocks
to the nearest McDonalds or other fast food joint, where the food is
cheap. We are now able to eat around the clock, and we do so.

Surely the increased availability of food bears some responsibility

for the obesity epidemic.
Before the current day, people regularly fasted, going without food
for perhaps 12 hours between dinner and breakfast. Snacks were not
as readily available, so most people ate only at meals.
Fasting, or going without food for some arbitrary amount of time,
not only helps keep us lean, but as we're about to see, also has a
powerful influence on health and lifespan, and is possibly the most
potent instrument currently available for this purpose. It's free and
has no toxic side effects, and can be done by almost anyone.

58
To understand how fasting can extend healthy lifespan, we'll start
with the science behind calorie restriction, the most robust
intervention for fighting aging known to date. These effects have
been known, if not understood, for hundreds of years and possibly
longer.

Calorie restriction extends lifespan

In the introduction to this book, I mentioned a man who discovered

calorie restriction in the 16th century and successfully applied it to
his own life, managing to live past the age of 100 in an era when
hardly anyone at all did this. That man was Alvise, or Luigi, Cornaro
(1467-1566 – sources vary on his age at death, with some sources
reporting 102. In any case, whether 99 or 102, he was very old.)

Cornaro was an Italian nobleman who became wealthy enough to

have Tintoretto paint his portrait. At the age of 35, he found himself
with “a heavy train of infirmities”[1] that he believed were caused by
“too freely eating and drinking, to which I had been addicted”, and
which included a “disordered” stomach, “and I suffered much pain
from colic and gout, attended by that which was still worse, an
almost continual slow fever, a stomach generally out of order, and a
perpetual thirst. From these disorders, the best delivery I had to
hope was death.” It sounds very much like he had a case of diabetes,
which in the case of type 2 diabetes can indeed be caused by
excessive eating and drinking. Excessive fructose intake causes gout,
from which Cornaro suffered, and this is a feature of the
consumption of sugar, which is half fructose.

If Cornaro was not near death, he certainly felt like it and almost
wished for it, so much was he suffering from ill health. His
physicians had little to help him, until one suggested that he eat and
drink sparingly. Cornaro, “feeling it was my duty as a man to do so”,
immediately undertook to eat only 12 ounces of food daily, “neither

59
more nor less”, and to drink 14 ounces of wine, or a little over half a
modern bottle. His meals, other than wine, consisted of meat,
poultry, eggs, fish, bread, and vegetables. His infirmities quickly
disappeared, and he resolved to live that way the rest of his life,
which he did. Worthy of note also is Cornaro's declaration about
how his “sober life” improved his disposition, that he was “freed by
God’s grace from the perturbations of the mind”, and that he no
longer experienced any “contrary emotions”.

The physician who suggested to Cornaro that he eat sparingly may

have been the recipient of a long line of knowledge that went back
an undetermined number of years or centuries; but we can never
know that for sure. (Fasting as a cure for illnesses dates back to
Hippocrates.) But Cornaro may be the first case of a man cured of
his illness and allowed to live a long life through restriction of food,
or at least he's the first one we know about.

The modern study of calorie restriction began with a project of the

scientist McKay in 1930, who discovered that rats fed less food lived
substantially longer than rats fed “ad lib”, that is, who ate all they
wanted and at any time.

Calorie restriction, or CR as we'll refer to it, works on many fronts to

prolong healthy lifespan, and scientists are still unraveling the
biochemical and physiological mechanisms by which it does so. In
essence, CR acts as a stress on the organism, that is, it's a form of
hormesis, and the body reacts by up-regulating stress defense
mechanisms.

CR involves the feeding of 30 to 50% fewer calories to lab animals

than they would normally eat, or want to eat. When started early,
CR can extend lifespan up to 50% in rodents, and decreases levels of
oxidative stress, inflammation, and mitochondrial dysfunction, and
helps maintain youthful levels of autophagy. It also lowers levels of
insulin and the growth hormone IGF-1, which is important to its
mechanism of action.

60
In what physiologists refer to as the “fed state”, which is just what it
sounds like, the period of time when food is being digested and its
components being shuttled to the various places that need it, insulin
and IGF-1 levels are increased, and this abolishes the cellular self-
cleaning process of autophagy. In the fasted state, with no food
being taken, autophagy is strongly up-regulated, allowing cells to rid
themselves of accumulated junk. CR is actually a form of partial
starvation, and this has the effect of increasing autophagy. Since one
of the functions of autophagy is to provide nutrients for the
organism when none other are available, it's not difficult to see why
CR increases it.

Calorie restriction means cleaner, younger cells

As mentioned, decreased stimulation of insulin and IGF-1 is

believed partly responsible for the mechanism of action of CR. It
turns out that animals with selective mutations, or knockouts, in
genes for insulin and IGF-1 signaling live much longer than normal
animals. The physiological mechanism here is that lower levels of
insulin and IGF-1 cause decreased stimulation of the mammalian
target of rapamycin (mTOR), which in turn means increased levels
of autophagy.

Higher levels of autophagy mean that animals, and the cells of which
they are composed, continually rid themselves of accumulated junk,
such as malfunctioning mitochondria, glycated proteins, and other
cellular components that have passed their expiration date. They
then replace these structures with newly manufactured ones, and in
this way, autophagy results in younger cells, and a younger
organism. Maintaining autophagy levels in their youthful state is
critical for lifespan extension, and based on the state of scientific
knowledge at present, the most important physiological process in
retarding aging and stopping the clock.

Many scientists have expressed great enthusiasm for CR with regard

to lifespan extension, and with good reason.

61
However, CR is not without its drawbacks.

For one thing, many people will find the prospect of reducing their
calorie intake by 30% or more to be daunting, if not repugnant.
Those reading a book on anti-aging are in a minority, and while they
may be willing to consider CR, most people will not. (This writer is
one of those uninterested in practicing CR.)

The other drawback of CR is that if it isn't done with precision,

ensuring complete nutrition with minimal calories, and sometimes
apparently even if it is, then malnutrition, frailty, and immune
deficiency can be the result. For example, it's recently been found
that CR in mice has “distinct but deleterious consequences to the
aging immune system”; in particular, mice subject to CR were much
more prone to infection than normally fed mice.[2] Since a declining
immune system is already a feature (or a bug) of older age, and since
infectious diseases take quite a toll on older humans, if these results
translate to humans (and there's no reason why they would not), CR
may not be a very good strategy for lifespan extension. This comes
with the caveat that particular forms or modalities of CR may be
discovered that do not have a deleterious effect on the immune
system. That remains to be seen.

There's also concern that CR could lead to brittle bones, a low

muscle mass, and other consequences to physiological systems that
are already at risk in older people.

Intermittent fasting, the CR alternative

An alternative to CR exists, one that has virtually all of its benefits

and perhaps even more, and that has practically no downside, and
that is intermittent fasting. The practitioner of intermittent fasting
merely goes without food for some prescribed amount of time,

62
which can vary greatly. Fasting has the great advantage over CR that
lower calorie intake doesn't necessarily feature in it. Animals and
humans typically eat the same amount of food, or perhaps just
slightly less, as do ad lib fed animals and non-fasting people. They
do this because during the so-called feeding window, that is, the
time during which food may be taken, they make up for lost calories
during fasting by eating more. Almost the only difference is in the
timing of eating. Therefore, intermittent fasting does not have the
downsides of reduced immune function or malnutrition and frailty.

In fact, one can even build muscle on a regime of regular

intermittent fasting, and many bodybuilders have taken to fasting,
as evidenced by the popular bodybuilding website Leangains. It's
even better for fat loss, another aspect of body composition to which
bodybuilders pay close attention.

Fasting may effective for both improved health and longer lifespan
because our evolutionary history has caused humans to be adapted
to it. Many animals that are high on the food chain might eat only
once every few days, after a kill. Human hunter-gatherers certainly
do not eat breakfast, lunch, and dinner, interspersed with snacks;
rather, the typical pattern seems to be the hunting and gathering of
food during the day followed by a large meal at night when the food
has been prepared. If our genes are indeed adapted to bouts of
fasting, then our usual pattern of three meals a day plus snacks
could interfere with our physiological makeup and lead to the
diseases of civilization.

The practice of “grazing”, that is, eating every two or three hours,
long said to be healthful and useful for keeping off excess body fat, is
in reality a harmful practice that you should stop, whether or not
you plan to fast. The impetus behind grazing seems to be the idea
that it will maintain blood sugar and metabolism at a higher level;
in reality, grazing just makes people fat. Along with the low-fat
dieting craze, grazing must be one of the more harmful of recently
invented dieting practices. Grazing promotes aging.

63
Mark Mattson, a leading scientist in the study of aging, along with
colleagues, studied mice subjected to alternate-day fasting.[3] In
this form of fasting, the animals were fed no food at all on one day,
and allowed to eat as much as they wanted the next, and this
schedule was repeated continually. They found that their food intake
did not decrease and they maintained the same body weight as mice
fed ad lib. The authors stated that “intermittent fasting resulted in
beneficial effects that met or exceeded those of caloric restriction
including reduced serum glucose and insulin levels and increased
resistance of neurons in the brain to excitotoxic stress.” (My
emphasis.) These results show that intermittent fasting has
beneficial effects on metabolism and on neuronal stress resistance
that is independent of the amount of food intake. So judging by this
study, restriction of food intake isn't necessary to retard aging, so
long as the timing is right.

Intermittent fasting also causes increased heart rate variability in

rodents, as well as increased resistance to myocardial infarction
(heart attack) and stroke.[4] Heart rate variability has come to be
seen as a key sign of the integrity and youthfulness of an organism;
when the heart responds to minor stimuli with a minute variation in
rate according to the organism's needs, this is a sign that all
physiological systems are finely tuned and in optimal condition.[5]
Intermittent fasting causes increased resistance to heart attack and
stroke by up-regulating the transcription of genes that encode for
cellular antioxidant and other stress defense mechanisms. As before,
there's no reason why all of this should not apply in humans as well
as rodents.

Intermittent fasting also exerts profoundly beneficial effects on the

brain and nervous system, and it has been suggested that this
regimen may be very useful in the prevention and treatment of
Alzheimer's and Parkinson's diseases, two of the specters of old age.
[6] One of the ways in which it does is through increasing the levels
of an important protein, brain-derived neurotrophic factor, or
BDNF, which allows the brain to maintain its plasticity and ability to
grow new neurons and make new neuronal connections. In
senescence-accelerated mice, intermittent fasting allows them to
maintain normal levels of BDNF, in contrast to their well-fed
counterparts.[7]

64
In a study of experimental congestive heart failure in mice,
intermittent fasting led to vastly increased survival compared to
their ad lib fed counterparts, at 88.5% vs 23%, a 3.5 fold difference.
[8] It would be no exaggeration to say that this magnitude difference
in survival is amazing.

We see that intermittent fasting can prevent insulin resistance,

improve brain function, and even increase survival from congestive
heart failure, and is a profoundly anti-aging regimen. Increased
insulin sensitivity, which results in increased levels of autophagy, is
key to the benefits of fasting.

Short-term fasting results in profound neuronal autophagy in mice.

[9] The scientists who discovered that fasting causes autophagy in
the brain and nervous system state, “Our data lead us to speculate
that sporadic fasting might represent a simple, safe and inexpensive
means to promote this potentially-therapeutic neuronal response.”
Fasting rids the brain of junk and allows it to be healthier at an older
age, essentially rejuvenating it. For many of us, keeping our brains
in a youthful state will be reason enough to practice intermittent
fasting.

Intermittent fasting: schedules and durations

The duration of an intermittent fast can vary greatly. Unfortunately,

human data on the effects of various lengths of time of fasting
regimens is lacking, but we can make some educated guesses. For
starters, we know that in healthy young people, an overnight fast of
perhaps twelve hours is enough to strongly initiate autophagy. We
also know that a decline in levels of autophagy is prominent in aging
and perhaps the most important correlate of it. Therefore, older
people, that is, anyone beyond say the decade of his or her twenties,
should consider fasts of longer than twelve hours if they want to
maximally activate autophagy and turn back the aging process.

65
A very common method and duration of intermittent fasting as it's
currently practiced is sixteen hours in length, with the only missed
meal being breakfast. In this version, one eats a regular dinner at
the regular time, at perhaps 6:00 P.M. Then, nothing else is eaten
until about noon the next day, resulting in a sixteen to eighteen hour
fast. This fast is easily done, and this writer does it regularly. Coffee
or tea are acceptable to drink during a fast; purists might take them
black, but small amounts of cream – but not half-and-half, as it
contains milk – are acceptable, as cream, which is 100% fat in
calories, only very weakly activates insulin signaling and thus will
not interfere with the health benefits of your fast. Coffee itself
activates autophagy, so this may be a bonus, and both coffee and tea
are well-known for appetite suppression, so either or both of these
may make a fast easier. This writer considers coffee and tea essential
for fasting.

Should one wish to, this fast can be extended into the afternoon or
evening, for a 20 to 24 hour fast, and others extend their fasts even
longer, up to 36 hours. Beyond this length of time, it is no longer
really an intermittent fast, but a prolonged one, which we'll discuss
in a moment.

Intermittent fasting of sixteen to twenty hours can be done daily.

Another way of looking at it is the inverse, that is, the length of the
feeding window, that time during which you allow yourself food. A
daily feeding window of eight hours ought to allow for a strong
increase in autophagy during the fasting phase, and results should
become apparent in a few days to a few weeks. Many people of
course use fasting to lose weight, and if you have this as a goal, keep
in mind that the existence of a feeding window doesn't give
permission to eat anything you want and still lose weight. Those for
whom losing weight is not a goal need not restrict the quantity of
food they eat during the feeding window, although attention to
quality is highly recommended, as eating junk food and/or lots of
refined carbohydrates could negate many of the beneficial effects of
your fast. Many bodybuilders who use fasting for fat loss are in the
habit of taking branched-chain amino acids (BCAAs) or whey
protein during their fast in order to prevent any loss of muscle, and
this is an acceptable practice for that goal. But BCAAs or whey will

66
completely abolish autophagy, so if you're fasting for the health
benefits, namely increased autophagy, do not do this.

If losing weight is one of your goals in undertaking intermittent

fasting, many people find that it's an easier regimen than dieting.
With dieting, constant attention must be paid to the type and
quantity of food being eaten, and many dieters fail for the reason
that this attention can be difficult to adhere to over long periods of
time. With fasting, you simply don't eat, and you know what you're
going to do well ahead of time: if it's a fasting day, or if it's currently
during your fasting window, you don't eat. Simple.

Some of the initial difficulty in intermittent fasting is psychological.

In fact, probably most of it is. So many of us are used to eating every
few hours or whenever the fancy strikes us that deliberately going
without food for any stretch of time seems unnatural. Most of us
have never gone any length of time without eating, and have never
even skipped one meal. The practice of snacking is ridiculously
widespread; it's as if the body wasn't designed for going without
food for even a few hours, which of course it is.

Most people seem to think that fasting is crazy. If you're going to

practice intermittent fasting successfully, you will simply have to
ignore what anyone else says about, and do your own thing. You will
however have the satisfaction of becoming healthier and leaner than
those around you.

Prolonged fasting

Beyond intermittent fasting, more prolonged fasting has also been

advocated by several medical researchers, perhaps most
prominently by Valter Longo, a scientist who studies aging and
fasting at the University of Southern California.[10] Longo
emphasizes that he prefers the health effects of fasting to calorie

67
restriction, as he does not believe that restrictions on the amount of
food over a longer term are good for most people. Much of his work
has centered around the effect of fasting on retarding the growth of
tumors, and he has also shown that several days of fasting can
prevent the bad side effects of chemotherapy.[11] Fasting for several
days strongly lowers levels of insulin and IGF-1, and this likely
accounts for its benefits. Prolonged fasting also has been shown, in
mice, to promote regeneration of the immune system.[12]
Autophagy, as we've discussed, removes cellular waste, and in the
case of prolonged fasting whole cells of the immune system are
broken down. These cells are then replaced with new ones, and
immunosuppression is reversed. Prolonged fasting essentially has
the ability to make the entire immune system young again.

Cancer patients may be of course more highly motivated to

undertake fasts of this length than the rest of us, and probably most
people won't be willing to fast for a number of days strictly for life
extension purposes, although I've met people who have done so.
One great motivator for many people to undertake prolonged fasts is
fat loss, which these fasts do quite well. The well-known health
blogger and advocate for low-carbohydrate diets, Jimmy Moore,
undertook a 7-day fast.[13] The data on prolonged fasting as it
affects aging is sparse, but given adequate nutrition, and provided
that they are not done too often, are likely very effective in
combating aging, and in particular they lower IGF-1 and insulin
levels a substantial amount. To get effects such as the regeneration
of immune cells, longer fast such as these may be necessary.

Fasting, whether intermittent or prolonged, is generally quite a safe

thing to do. There may be some people, however, who need to be
careful and also may need a doctor's supervision; these would be
people whose health is not generally good, such as the very
overweight, or those with serious illnesses such as heart disease and
cancer. Diabetics may need to alter the doses of their medications,
so these folks should always consult a doctor before beginning any
fasting regimen.

If you already eat a relatively low-carbohydrate diet, hunger pangs

that may come with fasting are easy to overcome. It's been remarked

68
by many people that on a low-carb diet, one does not experience
hunger in the same way as when eating high-carb. That sounds
strange, but it's been my experience too, and when fasting, hunger
doesn't really bother me much. One comes to enjoy the sensation; in
fact, the increase in various hormones and neurotransmitters during
fasting may contribute to a sense of well-being and even elation.

Autophagy enhancers and inducers

The fact that fasting fights aging through boosting autophagy has led
some scientists to study autophagy enhancers or inducers, chemical
substances that activate autophagy, which these scientists refer to as
calorie restriction mimetics, although they could just well be called
fasting mimetics.[14] Among these are the over-the-counter weight
loss aid hydroxycitrate, which induces “massive” autophagy in mice.
Other compounds that induce autophagy are nicotinamide (a form
of vitamin B3), resveratrol, curcumin, and EGCG, a compound
abundant in green tea and probably responsible for most of its
health benefits. The study of autophagy inducers is in its infancy, yet
the compounds listed here all have a good safety profile. It's
probable that small doses of these taken during a fast will enhance
the already increased autophagy. This isn't a recommendation, but
I'm putting this information out there because these compounds
have promise in inducing and increasing autophagy, and thus may
have true anti-aging effects. Some of them, namely resveratrol,
curcumin, and EGCG, have been shown to extend life in lab animals,
and it wouldn't surprise me if hydroxycitrate turned out the same.
This writer has used 300 mg of hydroxycitrate during fasting, as
well as nicotinamide at 500 mg.

Hydroxycitrate, resveratrol, and curcumin (but not nicotinamide, to

my knowledge) have all been shown to have anticancer properties.
In my view, this is likely intimately linked with their ability to
promote autophagy.

Staying in tune with human evolutionary heritage through fasting

will result in better health and will retard aging. The aforementioned

69
Mark Mattson has written of “challenging oneself intermittently for
health”.[15] Humans and those from whom they are descended
evolved in environments in which there was scarcity of food, a high
level of fitness was required in order to hunt and fight, and dietary
phytochemicals which contain toxic elements were eaten and from
which physiological defense mechanisms must defend us. As a result
of not challenging ourselves, through a sedentary, couch-potato
lifestyle and the constant eating of processed food high in refined
carbohydrates and devoid of dietary phytochemicals, we are in the
midst of an epidemic of diabetes and obesity.

The burning of fat for energy, as opposed to the use of glycogen, is

one of these adaptations. Glycogen is the storage form of
carbohydrate, and our bodies typically carry only about a one-day
supply of it. By contrast, even lean people have enough fat on their
bodies to keep them supplied with energy for weeks. (The apparent
world record for fasting was made by an obese man of about 450
pounds who fasted for over a year and lost some 250 pounds in the
process. He was medically supervised, it is worthwhile to note.)

When we graze, and never allow ourselves to enter the fat-burning

mode, we're in a physiological state which our ancestors did not
experience much of the time, and as a consequence become ill and
overweight. The restoration of ancestral conditions, in part through
fasting, allows gene expression to proceed in the proper way, and
can restore health and prolong lifespan.

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Chapter 5: Demolition and Renewal:
The Optimal Anti-Aging Strategy

Our bodies are like cities

The fabric of a city is composed of buildings and other

infrastructure, which organically evolve to suit the needs of its
inhabitants over time. A city of today typically looks nothing at all
like the same city of one hundred years before. Buildings that are no
longer useful have been torn down in order to make room for new
ones in their place. The buildings themselves have been constantly
renovated with new roofs and furniture and plumbing. Even without
advances in technology or increases in population, cities must still
be renewed in this way because things simply wear out.

The city in this analogy is like the body of an organism. The body
one has today is not the same body one had last year, and even more
so the same one as decades ago. The cells of which the body is
composed, as well as the furniture and plumbing in them, the
organelles and proteins and other elements, have been replaced in a
process of controlled demolition, and new ones erected in their
place. Some parts of our bodies are rather static, such as the bones
and the brain, but even these have a degree of plasticity that allows
for renewal. Other parts, such as skeletal muscle, skin, or the cells
that line the intestines, are more responsive to environmental
conditions such as nutrition and exercise and can turn over in the
process of self-renewal much more quickly.

71
But, like a decaying civilization that can't manage to maintain its
cities, so that these cities accumulate rubbish, the buildings become
decrepit and unusable, and the roads narrowed or blocked, aging
makes bodies become less adept at tearing down older structures as
well as less able to erect new ones in their place. This inability for
self-renewal is perhaps the most important hallmark of aging.[1]
While other markers and pathologies of aging, such as insulin
resistance, oxidative stress, mitochondrial dysfunction, and systemic
inflammation, are important to the aging process, they are all
correlated to a decline in autophagy, the process of demolition that
clears the way for renewal.

Increased levels of autophagy through calorie restriction or fasting

or genetic manipulation extend the lifespan of animals more than
any other intervention known. The word “intervention” is an
important one here, since this means that we can modify at least this
particular aspect of aging. Fixing other aspects of aging, such as
increasing telomere length or renewing stem cells are more difficult
and so far have only been done in laboratories, and in any case seem
to be of less critical importance than kick-starting autophagy.

Increasing autophagic activity requires no expensive drugs nor

consultation with a doctor in an anti-aging clinic. It does require a
bit of self-discipline, and the knowledge of how it all works will help
keep you on the right track. So here's a bit of that knowledge,
hopefully not too full of science jargon, that will help guide the
reader.

As mentioned, autophagic activity declines with age. Can we get an

idea of how great the decline is? In some studies, very old rodents
had about one-sixth the autophagic activity of young ones.[1]
Human data on this is lacking, but it's clear enough that such a
decline exists and that bringing levels of autophagy up to those of
young people is necessary if not sufficient to slow aging.

Dysfunctional mitochondria have been thought to play a major role

in aging, so much so that scientists came up with a mitochondrial
theory of aging.[2] Mitochondria are the cellular organelles often

72
referred to as the cells' powerhouses, since their function is to
produce energy for the cell and the organism as a whole.
Mitochondria that have passed their sell-by date produce a higher
level of free radicals, which damage both the mitochondria
themselves as well as surrounding cellular structures. In addition,
they are unable to produce as much energy, which is manifested as,
among other things, physical fatigue. In essence, dysfunctional
mitochondria cause the cell as well as the organism to which it
belongs to become old and rundown. Ultimately, whole organ failure
can result.

Autophagy targets old, dysfunctional mitochondria

One of the principal tasks of autophagy is to break down old,

malfunctioning mitochondria. The cell can sense which
mitochondria need to be broken down, and selectively targets them.
When autophagy doesn't function at a high level, as in aging, the old
mitochondria remain in place, emitting free radicals and generally
poisoning the cellular environment. Increasing autophagic activity,
other things being equal, means that an older person will have
better renewal of mitochondria and a cleaner, more youthful cellular
environment.

Free radicals, or reactive oxygen species as they're technically

known, were also long thought to be critical to aging through the
damage they cause. The late Denham Harman developed this
theory, but newer research shows that it cannot be the fundamental
cause of aging, since cells require reactive oxygen species for
signaling purposes, and since some animals have high longevity
coinciding with high levels of oxidative damage; the naked mole rat
is one such animal. Increased levels of free radicals are also part of
the response in hormesis, and hormesis is a healthy, anti-aging
process. (This also explains why antioxidants have such a dismal
record in life extension, not only not working, but perhaps even
harmful.) In light of the previous section on mitochondria, and in
light of the fact that old mitochondria are the main sources of free
radicals, it can also be seen that free radicals are not the

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fundamental source of pathology in aging, but rather a consequence
of it.

Why antioxidants won't help

Oxidative stress and inflammation are also two very important

pathologies in aging. As we noted above, free radicals or reactive
oxygen species are required by cells for signaling, so abolishing free
radicals through supplementation of antioxidants or any other
method is not on the program, since cells don't even do this when
the organism is in its youthful state. Instead, cells and the organism
strive to maintain reactive oxygen species in balance, neither too
many nor too few.

To maintain oxidative balance, an elaborate, internal antioxidant

mechanism exists, of which the small peptide molecule glutathione
is quantitatively and qualitatively the most important. Glutathione
quenches free radicals and becomes oxidized, and is itself then
recycled back into its active, reduced form. When the glutathione
system is overwhelmed by too many free radicals, and when it
cannot be replenished quickly enough or at all, the antioxidant
system is overwhelmed, too many free radicals damage cells, and a
state of oxidative stress is said to exist.

In a normally functioning, youthful organism that has access to good

nutrition, excess free radicals cause an increase in antioxidant
enzymes, including those that deal with the production and
recycling of glutathione. Substances and processes that cause
hormesis, for example exercise and dietary phytochemicals, cause
an increase in free radicals and consequently an increase in
glutathione and other antioxidants. Abolishing the free radical
signal, for example through the provision of relatively large amounts
of vitamin C, can also abolish the healthy hormetic effect of physical
stressors, as seen in the suggestively titled study “Antioxidants
prevent health-promoting effects of physical exercise in humans”.[3]
Those free radicals are an essential part of becoming healthier.

74
In organisms that are not functioning normally, or in aging
organisms, the internal antioxidant system that produces and
recycles glutathione may not react properly to increased levels of
free radicals, and oxidative stress occurs. Why does this happen?
One reason cells cannot respond properly is if they are unable to
make enough glutathione. As this molecule is a small tripeptide, that
is, it's composed of three amino acids, and amino acids in turn are
derived from protein, an insufficient intake of dietary protein can
ultimately lead to insufficient glutathione.

Glutathione is critical

To get to the heart of the matter of increased oxidative stress as it

relates to aging, we need to dig a little deeper into glutathione, what
it is, and how it's made. The three amino acids of which glutathione
is composed are cysteine, glycine, and glutamine. Cysteine is the
rate-limiting constituent in glutathione synthesis, meaning that the
cellular machinery can only produce glutathione if sufficient
cysteine is provided; the other two amino acids are usually present
abundantly. As the organism ages, cysteine becomes less available
for glutathione synthesis, and this is so characteristic of aging that
it's been asked whether aging is a syndrome of cysteine deficiency.
[4] It may very well be.

Cysteine becomes less available in aging because it is partly the job

of autophagy to supply it, and autophagy declines in aging.

During periods when no food is available during fasting, even

overnight fasting, the body must maintain a balance of nutrients,
electrolytes, and chemical gradients that allow it to function
normally. This is the process of homeostasis. When the organism
goes without food long enough, autophagic activity increases, and
tissue, especially skeletal muscle, is partially broken down, and the
molecular components that result from the breakdown of tissue are

75
used to supply the other cells and to maintain homeostasis. In the
case of skeletal muscle, the main components supplied are amino
acids, one of which is cysteine, and that cysteine is used to make
glutathione. When autophagy doesn't proceed at a level appropriate
for the organism, which occurs in aging, then cysteine is in short
supply, and not enough glutathione is made.

Therefore a decline in autophagy can lead directly to increased

oxidative stress.

Skeletal muscle is an amino acid storage organ

Skeletal muscle, in addition to its other functions, acts a kind of

storage organ, whose function is to retain amino acids from protein
consumption for later use, when no protein is available. It builds
itself up when protein is consumed, and beaks itself down through
autophagy when it is not.

A lack or decrease in autophagy means that muscle fails to perform

one aspect of its storage function, since it cannot release amino
acids for use.

Levels of glutathione actively fluctuate inside the body, the turnover

in young healthy people being close to 100% in one day.[5] In
comparison, in elderly people the turnover is about half of that, that
is, the rate of synthesis is lower. Overnight, glutathione levels can
drop substantially because of this. To compound a shortage of
glutathione, many people, especially the elderly, do not eat enough
protein and thus have even less cysteine available for glutathione
synthesis.

The result of all this, a lower level of autophagic activity in the

elderly leading to less cysteine and lower glutathione, is increasing
oxidative stress, since not enough glutathione is available to mop up
excess free radicals. It can be seen that oxidative stress in aging,

76
which is highly characteristic of it, can ultimately be traced back to
lower levels of autophagy.

Cysteine supplementation

Cysteine supplementation can partly compensate for low autophagy

and relieve oxidative stress, and supplementation is relatively easy.
[5] The inexpensive over-the-counter supplement n-acetylcysteine
(NAC) supplies cysteine; it is rapidly absorbed from the gut, taken
up by cells, where it is de-acetylated, and the resultant cysteine used
for glutathione production or other uses for which it is needed.
Whey protein, a supplement used enthusiastically by bodybuilders,
is rich in cysteine, and provision of whey protein can increase levels
of glutathione, whereas casein, the other main milk protein, does
not.[6]

The cysteine content of whey is about five times higher than that of
casein, the other protein component of milk, and also much higher
than in meat. (In case you were wondering, whey is the protein
fraction of milk that remains when milk has been curdled in
preparation for making cheese. The casein protein curdles, the whey
stays liquid. Until recently, with the increase in use of protein
powders, cheese producers practically gave it away.) We'll discuss
whey supplementation below.

Oxidative stress, which virtually everyone older than 30 has to some

degree, and which radically increases in old age, can be relieved with
NAC supplementation.[7] Elderly people, aged between 60 and 75,
had their glutathione levels measured, along with levels of plasma
hydroperoxide, which is a measure of oxidative stress. The level of
oxidative stress in the elderly was about 40% higher than in younger
control subjects, and levels of glutathione were about 50% lower.
After supplementation with NAC for 14 days, as well as with another
component of glutathione, glycine, levels of both oxidative stress
and glutathione became nearly identical to levels in the young
controls.

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To banish oxidative stress in older age, it is critical to maintain
proper intake of the amino acid cysteine, which helps to maintain
glutathione.

The most important way to maintain high blood levels of cysteine,

and therefore ensure high (appropriate) levels of glutathione, is
through the process of autophagy. This is how nature does it, and by
keeping our recommendations in tune with nature and amplifying
nature's dictates, we stand the best chance of remaining in health
and fighting aging. As we've copiously noted, autophagy declines
with age, and is one of the chief correlates of age. The lower your
level of autophagy, the older you are physiologically, regardless of
your chronological age.

The main way to increase levels of autophagy is through fasting.

Now, younger people with a finely tuned physiological apparatus
have no trouble in this area. Overnight fasting is enough to strongly
activate autophagy. Critically important is that one of the most
important products of autophagy is cysteine. When skeletal muscle
tissue is cleansed through autophagy, and old, dysfunctional cellular
structures and proteins are targeted for recycling, amino acids
appear in the bloodstream, one of which is cysteine. The other cells
in the body, mainly those of the liver, take up cysteine and use it to
make glutathione. So the levels of glutathione increase, and
oxidative stress decreases.

As we age, we need more than just an overnight fast to activate

autophagy to levels useful for life extension purposes. The same
amount of time fasting that strongly induces autophagy in the cells
of a young person will not do the same in an older person. But if that
older person extends the amount of time fasting, then he or she can
activate autophagy to levels normally seen in younger people, and
this is key.

As we've seen in previous chapters, fasting activates autophagy quite

strongly.

78
To combat aging, autophagy should be activated and/or enhanced in
such a way that it amplifies its normal circadian rhythm. To do this,
we will extend our overnight fast into the next day. By how much is a
good question, but I suggest that we aim for a minimum of a 16-hour
fast, and do this regularly, even every day if you can handle it.

Others may want to lengthen their fasts even more. Many people do
24-hour fasts, some do 36, and others even longer. (But as noted,
this gets into the area of prolonged, not intermittent, fasting, which
is another kettle of fish.) This writer currently fasts for 16 hours two
to three times a week. I do occasional fasts of 20 to 22 hours, from
6:00 P.M. one evening, after dinner, to around 4:00 P.M. the next
day, and this hasn't been terribly difficult at all. One of the secrets to
eliminating hunger is to drink coffee and tea, which won't spoil your
fast, and I take full advantage of this effect.

Autophagy boosters, such as hydroxycitrate or nicotinamide may be

appropriate during your fast. I often take either 250 milligrams of
the over-the-counter weight loss aid hydroxycitrate or 500
milligrams of nicotinamide (vitamin B3) midway through my fast in
order to amplify fasting's effects on autophagy. (Interestingly, the
weight loss effects of hydroxycitrate has been found to depend on its
activation of autophagy, probably through activation of AMPK, the
cellular energy sensor. This likely causes an increase in fat-burning.
That's speculation at this point though.)

If you worry about losing muscle mass during a fast, you shouldn't.
Calorie restriction in middle-aged lab animals actually means that
they retain muscle and have improved muscle function.[8]
Intermittent fasting is a better intervention than calorie restriction,
since generally it entails the same number of calories ingested as for
animals and people who eat all they want. It's even possible, using
the right strategies and schedule, to increase muscle mass all the
while practicing intermittent fasting. We'll discuss how to do that
shortly.

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Fasting causes a strong increase in levels of growth hormone, and
the body does this in order to preserve muscle and bone. Meals
actually suppress production of growth hormone.[9]

Diabetics, or anyone with issues of blood sugar control such as

hypoglycemia, should consult a doctor before engaging in fasting.
Fasting longer than overnight is also inappropriate for growing
children, who need the calories and protein to ensure their proper
development. For most other people, fasting for relatively short
periods poses little risk, but when in doubt, consult your doctor.

The title of this chapter is “Demolition and Renewal”, and since

we've discussed the process of controlled demolition, which is
autophagy, we'll now discuss renewal.

The renewal of the body in aging

Renewal involves building up new structures in place of the old

ones. To do this, good nutrition is a must, and in particular, the
right kinds and quantity of protein are necessary. For example,
we've seen that cysteine is a critical component for the maintenance
of our body's internal antioxidant system, because glutathione
production requires it. The other essential amino acids, that is, those
that the body can't make for itself and must be ingested in the diet,
should also be optimized.

Protein can be characterized by biological value. Biological value

refers to the proportion of essential amino acids a protein contains,
and higher biological value means just what it sounds like,
organisms thrive and grow better on protein of higher biological
value. If a protein is of lower biological value, then the body can use
only a fraction of that protein, since the proportions of amino acids
don't match the body's needs.

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Animal proteins are always of higher biological value than vegetable
proteins. Whey protein has the highest value, at an index of 104,
with milk at 91, and beef at 80.[10] By contrast, wheat gluten comes
in at 64, and soybeans at 74. There's also a digestibility factor to be
accounted for, the details of which we need not go into here, but
when this is taken into account, vegetable sources of protein fare
even worse. For instance, whey comes in at 1.00 on this scale, gluten
at 0.25.

Does this mean that vegetarians have trouble getting enough, good
quality protein? Not necessarily, but it may be difficult for vegans,
who do not eat any animal products at all. While this is not the place
to get into the entire debate surrounding omnivorous versus
vegetarian diets, staving off the ravages of aging means eating at
least some animal protein, in my opinion. The reason for that is the
phenomenon of muscle wasting.

We've seen in previous chapters that sarcopenia, or muscle wasting,

is one of the main maladies of aging, and strongly to be avoided, as
it leads to frailty and nursing homes and in many cases, death. Most
80-year-olds will have lost 50% of their lean body mass – replaced
in most cases with fat. Muscle wasting also occurs to some degree
starting at relatively young ages unless we take measures to stop it.
Eating high quality protein is one such measure.

Sarcopenia occurs gradually. A small imbalance between breaking

down and building up muscle, a phenomenon which happens daily,
can over a long period of time result in sarcopenia. Since one leg of
our anti-aging program is to encourage the body's normal
mechanisms of breakdown and amplify it, we must carefully balance
that with properly building everything back up. And if we don't
supply the right quantity and quality of protein, that won't happen.

Scientists have long debated, and still debate, how much protein
humans need. The topic is necessarily complex, since protein
requirements depend on things like the presence and amount of
other macronutrients like carbohydrate and fat, the energy status of
the person – for example, whether he or she is currently gaining or

81
losing weight – and the health status of the person. Certain illnesses
and injuries, such as burns and trauma, greatly increase the body's
protein requirements. For the purposes of this discussion, we'll
assume that the reader has no major illnesses, wants to build and
retain muscle, remain in optimal health, and retard the aging
process.

Now, bodybuilders definitely want to build and retain muscle, and

most of them eat very high amounts of protein. They are also, other
things equal, in excellent health. (That is assuming they don't take
steroids or other performance-enhancing drugs.) But it's been found
that even trained bodybuilders require about 1.1 grams of protein
per kilogram of body weight.[11] If bodybuilders get by on that
amount of protein, then the rest of us can also. Note that this
amount of protein is still above the recommended daily allowance
(RDA) of 0.8 gram so protein per kilogram of body weight, which
has been criticized as too low. People who eat this amount of
protein, 0.8 g/kg, can lose lean muscle mass, and below that level
things become even worse, with lower immune function and
increased oxidative stress, for example.

Shooting for a protein intake of above 1.0 grams per kilogram, and
below 1.5, might be optimal. This way we're sure to be able to retain
and build muscle, but without radically increasing levels of IGF-1,
which promotes aging.

Most people will have little trouble eating this amount of protein, so
long as one follows a paleo(ish) diet, relatively low in carbohydrates,
that features some form of animal-derived protein at each meal.
Meat, fish, eggs, yogurt (without sugar), all have high levels of high-
quality protein. Wheat gluten, which some vegetarians promote as
an alternative protein source, does not make the cut.

If you are vegetarian, I strongly recommend that you include some

animal protein sources in your diet. These sources could be, for
example, whey protein powder, other dairy products like yogurt, or
eggs. As for veganism, I'm afraid that I don't recommend it for a
number of reasons. Humans did not evolve to eat that way, and

82
protein intake on a vegan diet will almost necessarily be inadequate.
There are no vegan societies and apparently there never have been,
so that should give us a strong hint about the viability and
desirability of being vegan. Sorry, just the truth as I see it.

To build ourselves up, we also need exercise. As pointed out in a

previous chapter, exercise is a sovereign cure for many, many ills,
and someone who doesn't exercise cannot expect to live a long,
healthy life. (A few people with superior genetics seem to manage;
the rest of us need to work at it.) But as I also pointed out, resistance
training (weightlifting) and high-intensity training (HIT) are
superior forms of exercise, superior because they result in much
better muscle mass and retention and better metabolic control.
Aerobic exercise can help retain muscle, but not nearly so well as
lifting weights and HIT.

Of course, some older people may not be able to engage in these

activities as much, although resistance training has been shown to
be effective in people into their 90s. Assuming that one has some
degree of infirmity or frailty, walking for exercise is completely
appropriate, and should be engaged in daily. Walk for at least a half
hour at a decent pace, and increase this with time if possible. If one
is so infirm that one can't do this, a supervised exercise program
specially designed for very old or infirm people may be an
alternative.

For the rest of us, not so old and not so infirm, we should lift
weights and do high-intensity training.

In weightlifting, concentrate on the big compound lifts, which

exercise large parts of the body and provide a good metabolic and
cardiovascular workout. The big compound lifts are comprised of
bench or chest press, military or shoulder press, rows, pull-downs or
pull-ups, squats, and dead lifts. This isn't the place to go into all the
details of a weightlifting program, but a little further detail may be
helpful.

83
These exercises may all be done on machines, and for the beginner
that's probably the best course of action, since machines minimize
any chance of injury. Using free weights (barbells and dumbbells)
requires a certain level of skill and coordination, which many older
people may not have, and which many others might not care enough
to learn. (Popular books on weightlifting seem to assume that
everyone wants to learn to squat 300 pounds.) A little instruction
from a decent book or from a personal trainer will be helpful. My
own weight workouts are done using a combination of free weights
and machines, but I'm a little more serious about my weightlifting
than the average person.

If you lift weights, added exercise in the form of HIT may not be
necessary. That is because weightlifting itself, if done with sufficient
intensity and with short rest periods in between sets, is a form of
high-intensity training itself, resulting in a great metabolic and
cardiovascular workout. While I still do some form of HIT once in a
while, my main exercise when away from the gym is walking.
Weightlifting requires plenty of rest, and in fact one book on the
topic (Body by Science) recommends lifting weights only once a
week. I like to lift more than that, but that means one needs even
more rest, so normally I don't perform exercise of high intensity on
my off-gym days.

A word to the women in the audience: all of this applies to you too.
If as a woman you are concerned with building too much muscle and
becoming masculine looking, stop worrying. Building muscle to the
degree that well-built men have requires not only tons of hard work,
but lots of testosterone too. Women have only about one-tenth the
level of testosterone that men do, so building large amounts of
muscle is very difficult for women. As for the level of work, men who
seriously try to build muscle spend many hours a week of very
difficult training doing so. Building muscle isn't easy. So get into the
gym – or get a set of weights to use at home – and lift. You may be
surprised at how welcoming the guys in the weight room are.

High-intensity training of the sort that includes working all parts of

the body also builds muscle, although not to the same degree as
weightlifting does. But HIT of this type will almost certainly be

84
enough to retain muscle and to avoid sarcopenia and frailty. So
when you do HIT, make sure to include exercise like pushups,
burpees, squats (knee bends, we use to call them), dips, and sprints.
These, while not making you look like Arnold, will keep muscles in
fine shape as well as help keep you lean with a low percentage of
body fat.

Weightlifting and other intense exercise should be followed by food,

and fasting should not follow exercise. This is essential to the
building-up phase of our anti-aging program. Eat high-quality,
unprocessed food along with high-quality protein in the 24 hours
after a bout of hard exercise. (We can exclude walking or other
relatively less intense exercise from this stricture.) The body can't
build muscle and repair itself without food.

Whey protein is ideal for building muscle after a workout. Taken

either right before or right after a workout, whey raises levels of
critical, essential amino acids in the bloodstream and strongly
promotes muscle synthesis. Some studies have shown that whey
taken at other times of the day, hours before or after the workout,
does not promote muscle building, but other studies dispute this,
and the matter is still open for debate. But it seems a good
precaution to drink your whey near the workout, either within one
hour before or one hour after.

As for other food in the 24 hours after a workout, meat, eggs, yogurt,
and the like will all help build muscle.

Ideally, one should not contemplate starting a fast until at least 24

hours after hard exercise. Resistance exercise strongly up-regulates
levels of muscle protein synthesis for about 24 hours after the bout
of exercise, so it's important to get proper nutrition in that time
window.

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 Synthesis: breakdown and renewal

Putting all of this together, our optimal anti-aging strategy cycles

between fasting and feeding, and the feeding period coincides with
the time in which we want to exercise. Fasting means controlled
demolition through autophagy, the cellular self-cleaning process,
and renewal is the building of muscle and the maintenance of
cardiovascular and metabolic health through exercise.

Our body normally cycles this way too, with controlled demolition
occurring during the night when we do not have access to food, and
rebuilding during the day, when we do. Our strategy merely
amplifies natural, physiological cycles so that they proceed like
they do in young people.

In young people, the cycles of breakdown and renewal are like sine
waves, with high peaks and low valleys, and they proceed without
much help or input from the person. In older people, that is, anyone
older than his or her twenties, the peaks begin to decrease and the
valleys begin to rise, so that the sequence of sine waves that
represent breakdown and renewal are flattened. To return these sine
waves of breakdown and renewal to their normal, youthful
configuration requires interventions, and the most important of
these will be intermittent fasting, on the one hand, and proper
exercise and nutrition, on the other.

Variations in schedules of intermittent fasting and feeding/exercise

can be nearly infinite, so one can only offer examples that may be
useful. Here is a sample schedule, one that the author follows.

Day 1, morning: Exercise consisting of weightlifting at the gym.

Either before or immediately after my workout, 25 grams of whey.

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In the following 24 to 36 hours, meals with decent quantities of
high-quality protein, such that I take in >1 gram of protein per
kilogram of body weight.
Day 2: In the evening, following dinner, fasting begins, with nothing
to eat until much later on the next day.
Day 3: Fasting. Coffee in the morning, tea at mid-morning.
Depending on my daily agenda and other things, like how I'm
feeling, I may fast until 4 P.M., making a total fasting duration of 22
hours. If I have things to get done, or if I'm feeling less than
energetic, I may fast only until noon, making my fast from 16 to 18
hours long. Then I eat several good meals.
Day 4: Back to the gym for a workout, and then the feeding phase.
Etc.

This schedule works well for me. In this way, I can properly attend
to the renewal of my body's resources ion the form of building up
muscle. I then have plenty of time to be properly fed to assure that
the renewal proceeds optimally. Then, every third day, I maximize
the activation of autophagy through fasting, assuring that the cells of
my body will rid themselves of dysfunctional mitochondria and
outdated proteins. I help to ensure that IGF-1 levels remain in a
lower range, thus helping to prevent cancer, diabetes, heart disease,
and other aging maladies.

Different schedules may work better for others. One variation

sometimes practiced is a weekly fast of 24 hours or more. This
variation will strongly promote autophagy, yet it will leave one free
to exercise and feed on all other days and perhaps even go to a party
or two, all without overthinking the schedule. A recent popular diet
book promotes alternate day fasting on two days a week, and this
might also be rather convenient.

Intermittent fasting is also great for fat loss, and those with some
pounds to lose shouldn't hesitate to try it. However, one word of
caution is to be careful during the feeding windows. If you eat as
much or then some during feeding as you omitted when you fasted,
or if diet quality is poor, fat loss may be slow to non-existent.

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Chapter 6: Conclusion

Aging represents the decline in functional capacity of the organism

and the increasing susceptibility to disease. Scientists who study
aging have greatly enlarged our understanding of aging, yet we still
do not know its fundamental cause. In theory, there seems to be no
reason why we should age at all, or why we shouldn't live forever,
barring accidents or predation. When we are young, the body
repairs itself and recovers from injury easily; the decline in our
ability to repair ourselves is at the heart of aging.

To combat aging and live long enough to see actuarial escape

velocity, we need to recover our ability to repair ourselves. Until
the day comes when technology can mend the molecular structure of
the cell, our own repair mechanisms must suffice. We must keep our
repair mechanisms in good repair.

To do this, we must understand the evolutionary pressures that

formed the current human genome. Our genes evolved in an
environment in which meals were irregular and fasting for hours to
days happened regularly; in which dietary phytochemicals promoted
the hormetic up-regulation of cellular stress defense mechanisms,
and in which vigorous physical activity, not sedentary behavior, was
the norm. To achieve health and to have a shot at retarding aging,
we can't be couch potatoes living on junk food, whose only
recreation is hours of watching television.

The guidelines for fighting aging in the best way we currently know
are:

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1. Stay active. Sedentary behavior was all but unknown to our
human ancestors. If you work long hours at a desk, consider a
standing desk, or at a minimum take regular breaks for brief
exercise. Being active is an important part of a lifestyle in which
hormesis plays a role.

2. Stay lean. Even having just a little extra fat on your body causes
an increase in levels of inflammation and oxidative stress, which can
also lead to insulin resistance, metabolic syndrome, and diabetes.
The physiology of obesity is the archetype of pro-aging. The optimal
body mass index (BMI) is around 20 to 21, somewhat higher if you
lift weights and add muscle.

3. Beyond just staying active, exercise. Exercise combats

inflammation, oxidative stress, and mitochondrial dysfunction,
three of the hallmarks of aging, and increases autophagy to youthful
levels. Consider doing the most healthful forms of exercise that have
the biggest anti-aging effects, weightlifting and high-intensity
training.

4. A low-carbohydrate diet is an anti-aging diet. Strive to eat <20%

of daily calories as carbohydrate, and eat paleo style: no sugars,
grains, legumes, or vegetable oils. Don't eat processed junk.

5. Include ample dietary phytochemicals in your diet. Main sources

of these include cruciferous vegetables (such as broccoli), berries
(such as blueberries), chocolate, tea, coffee, and red wine.

6. Consider supplementation with select phytochemical

supplements, such as resveratrol, curcumin, and green tea extract.
These promote hormesis and up-regulate cellular stress defense
mechanisms.

7. Dietary protein should be neither too high nor too low.

Bodybuilders often eat 2 grams of protein per kilogram of body
weight, which is too high, as this causes elevated levels of IGF-1, a

89
pro-aging molecule. The Recommended Daily Allowance of protein
is 0.8 gram per kilogram, which is too low, and can lead to muscle
wasting and oxidative stress.

8. Practice regular intermittent fasting. At a bare minimum, do not

eat snacks and do not eat between dinner and breakfast to ensure
regular promotion of the anti-aging process of autophagy, which
clears cellular junk and renews mitochondria. For a stronger pro-
longevity effect, fast for 16 hours or more several times a week, or 24
hours once a week.

9. Finally, combine intermittent fasting, weight training, and protein

feeding into a cyclical schedule, such that the natural diurnal
rhythms of breakdown and renewal are reinforced. Fast for a period
of time to clear cellular junk through autophagy, then train with
weights (or do other forms of intense exercise) and eat sufficient
protein to renew body tissues.

There's much more that I could have put into this book, since any
substance or process that promotes general health and prevents
illness also conduces to a longer life. But I presume that anyone
interested enough in a longer life to read a book on the topic will
already be doing almost all of these things, and besides, general
health advice (however inaccurate or misleading) is not lacking
either in books or on the internet.

The steps I've outlined in this book to slow the aging process are
somewhat, but not entirely, outside of mainstream health advice.
Exercise, for example, is well nigh universally recommended for
better health. (Although in the mainstream, it's often assumed that
more exercise is always better, and it is not.) On the other hand,
fasting is still fairly outside mainstream health advise, and in fact
many people think it is crazy. But it seems to be rapidly entering
mainstream acceptance; in a few years time, I suspect that fasting
will be as commonly touted as a healthy process as running is today.

90
The paleo movement has gained a lot of traction in the past few
years, but mostly it is considered only under the aspect of food
quality. Yet the conditions under which we evolved differ in much
more than merely food: the timing of eating, the amount and types
of exercise, social environment, sleep, all of these differ from the
modern environment. If we want to maximize health and prolong
our lives, it makes sense to pay attention to these.

However, maximizing health has only some overlap with

maximizing lifespan. Aging is an entirely natural process, so in some
sense we must go against nature to maximize lifespan. If
reproductive capacity can be seen as a subset of health, then
maximizing it also maximizes health. Yet some interventions that
may increase reproductive capacity, for instance eating large
amounts of protein that cause an increase in muscle mass or height
in youth, may dispose towards shorter lifespan through an increase
in cancer risk in later life. Calorie restriction, conversely, may
decrease reproductive capacity and strength in youth while
preventing disease in later life.

The scientific quest to fight aging involves the attempt to

understand the nature of aging so that we can interfere with it. Until
we understand how to do this, the processes outlined in this book
may give us our best shot at slowing the aging process and
prolonging our lives.

91
Bibliography

Chapter 1

1. Berbesque, J. Colette, et al. "Hunter–gatherers have less famine

than agriculturalists." Biology Letters 10.1 (2014): 20130853.
2. Kolb, Hubert, and Décio L. Eizirik. "Resistance to type 2 diabetes
mellitus: a matter of hormesis?." Nature Reviews Endocrinology
8.3 (2012): 183-192.
3. Radak, Zsolt, Hae Young Chung, and Sataro Goto. "Exercise and
hormesis: oxidative stress-related adaptation for successful aging."
Biogerontology 6.1 (2005): 71-75.
4. Harman, Denham. "Free radical theory of aging." Mutation
Research/DNAging 275.3 (1992): 257-266.
5. Schmeisser, Sebastian, et al. "Mitochondrial hormesis links low‐
dose arsenite exposure to lifespan extension." Aging Cell 12.3
(2013): 508-517.
6. Franceschi, Claudio. "Inflammaging as a major characteristic of
old people: can it be prevented or cured?." Nutrition Reviews
65.suppl 3 (2007): S173-S176.

Chapter 2: Exercise

1. Myers, Jonathan, et al. "Exercise capacity and mortality among

men referred for exercise testing." New England Journal of
Medicine 346.11 (2002): 793-801.
2. Garcia-Valles, Rebeca, et al. "Life-long spontaneous exercise does
not prolong lifespan but improves health span in mice." Longev.
Healthspan 2 (2013): 14.
3. Moore, Steven C., et al. "Leisure time physical activity of
moderate to vigorous intensity and mortality: a large pooled cohort
analysis." PLoS Medicine 9.11 (2012): e1001335.
4. Reimers, C. D., G. Knapp, and A. K. Reimers. "Does physical
activity increase life expectancy? A review of the literature." Journal
of Aging Research 2012 (2012).
5. Ruiz, Jonatan R., et al. "Muscular strength and adiposity as
predictors of adulthood cancer mortality in men." Cancer
Epidemiology Biomarkers & Prevention 18.5 (2009): 1468-1476.
6. Myers, Jonathan. "Exercise and cardiovascular health."
Circulation 107.1 (2003): e2-e5.

92
7. Ristow, Michael, et al. "Antioxidants prevent health-promoting
effects of physical exercise in humans." Proceedings of the National
Academy of Sciences 106.21 (2009): 8665-8670.
8. He, Congcong, et al. "Exercise-induced BCL2-regulated
autophagy is required for muscle glucose homeostasis." Nature
481.7382 (2012): 511-515.
8. He, Congcong, Rhea Sumpter, Jr, and Beth Levine. "Exercise
induces autophagy in peripheral tissues and in the brain."
Autophagy 8.10 (2012): 1548-1551.
9. Colcombe, Stanley J., et al. "Aerobic exercise training increases
brain volume in aging humans." The Journals of Gerontology Series
A: Biological Sciences and Medical Sciences 61.11 (2006): 1166-
1170.
10. Yarrow, Joshua F., et al. "Training augments resistance exercise
induced elevation of circulating brain derived neurotrophic factor
(BDNF)." Neuroscience Letters 479.2 (2010): 161-165.
11. Faulkner, John A., et al. "Age‐related changes in the structure
and function of skeletal muscles." Clinical and Experimental
Pharmacology and Physiology34.11 (2007): 1091-1096.
12. Simpson, Richard J., et al. "Exercise and the aging immune
system." Ageing Research Reviews 11.3 (2012): 404-420.
12. Pierce, Gary L., et al. "Habitually exercising older men do not
demonstrate age‐associated vascular endothelial oxidative stress."
Aging Cell 10.6 (2011): 1032-1037.
13. Schnohr, Peter, et al. "Dose of jogging and long-term mortality:
the Copenhagen City Heart Study." Journal of the American College
of Cardiology 65.5 (2015): 411-419.
14. Breuckmann, Frank, et al. "Myocardial Late Gadolinium
Enhancement: Prevalence, Pattern, and Prognostic Relevance in
Marathon Runners 1."Radiology 251.1 (2009): 50-57.
15. Wilson, Mathew, et al. "Diverse patterns of myocardial fibrosis in
lifelong, veteran endurance athletes." Journal of Applied
Physiology 110.6 (2011): 1622-1626.
16. Lowery, Lonnie, and Cassandra E. Forsythe. "Protein and
overtraining: potential applications for free-living athletes." J Int
Soc Sports Nutr 3.1 (2006): 42-50.
17. Singh, Nalin A., et al. "Effects of high-intensity progressive
resistance training and targeted multidisciplinary treatment of
frailty on mortality and nursing home admissions after hip fracture:
a randomized controlled trial." Journal of the American Medical
Directors Association 13.1 (2012): 24-30.
18. Boutcher, Stephen H. "High-intensity intermittent exercise and
fat loss."Journal of Obesity 2011 (2010).

93
19. Little, Jonathan P., et al. "A practical model of low‐volume high‐
intensity interval training induces mitochondrial biogenesis in
human skeletal muscle: potential mechanisms." The Journal of
Physiology 588.6 (2010): 1011-1022.
20. Ortega, J. F., et al. "Higher Insulin-sensitizing Response after
Sprint Interval Compared to Continuous Exercise." International
Journal of Sports Medicine(2014).

Chapter 3: Diet

1. Bigaard, Janne, et al. "Body fat and fat‐free mass and all‐cause
mortality."Obesity Research 12.7 (2004): 1042-1049.
2. Stokes, Andrew. "Using maximum weight to redefine body mass
index categories in studies of the mortality risks of obesity."
Population Health Metrics 12.1 (2014): 6. Fontana, Luigi, and Frank
B. Hu. "Optimal body weight for health and longevity: bridging
basic, clinical, and population research." Aging Cell 13.3 (2014):
391-400.
3. Kenyon, Cynthia, et al. "A C. elegans mutant that lives twice as
long as wild type." Nature 366.6454 (1993): 461-464.
4. The Guardian, 16 March 2013
5. Lee, Seung-Jae, Coleen T. Murphy, and Cynthia Kenyon. "Glucose
shortens the life span of C. elegans by downregulating DAF-
16/FOXO activity and aquaporin gene expression." Cell Metabolism
10.5 (2009): 379-391.
6. Schulz, Tim J., et al. "Glucose restriction extends Caenorhabditis
elegans life span by inducing mitochondrial respiration and
increasing oxidative stress."Cell Metabolism 6.4 (2007): 280-293.
7. Tatar, Marc, Andrzej Bartke, and Adam Antebi. "The endocrine
regulation of aging by insulin-like signals." Science 299.5611 (2003):
1346-1351.
8. Kurosu, Hiroshi, et al. "Suppression of aging in mice by the
hormone Klotho."Science 309.5742 (2005): 1829-1833.
9. Lindeberg, Staffan, et al. "Low serum insulin in traditional Pacific
Islanders—the Kitava Study." Metabolism 48.10 (1999): 1216-1219.
10. Rosedale, Ron, Eric C. Westman, and John P. Konhilas. "Clinical
experience of a diet designed to reduce aging." The Journal of
Applied Research 9.4 (2009): 159.
11. Klement, Rainer J., and Ulrike Kämmerer. "Is there a role for
carbohydrate restriction in the treatment and prevention of cancer."
Nutr Metab (Lond) 8.75 (2011): 75.

94
12. Accurso, Anthony, et al. "Dietary carbohydrate restriction in type
2 diabetes mellitus and metabolic syndrome: time for a critical
appraisal." Nutrition & Metabolism 5.1 (2008): 9.
13. Klein, S., and R R. Wolfe. "Carbohydrate restriction regulates the
adaptive response to fasting." American Journal of Physiology-
Endocrinology and Metabolism 262.5 (1992): E631-E636.
14. Salminen, Antero, and Kai Kaarniranta. "AMP-activated protein
kinase (AMPK) controls the aging process via an integrated
signaling network." Ageing Research Reviews 11.2 (2012): 230-241.
15. Baur, Joseph A., et al. "Resveratrol improves health and survival
of mice on a high-calorie diet." Nature 444.7117 (2006): 337-342.
16. Witte, A. Veronica, et al. "Effects of resveratrol on memory
performance, hippocampal functional connectivity, and glucose
metabolism in healthy older adults." The Journal of Neuroscience
34.23 (2014): 7862-7870.
17. Timmers, Silvie, et al. "Calorie restriction-like effects of 30 days
of resveratrol supplementation on energy metabolism and metabolic
profile in obese humans." Cell Metabolism 14.5 (2011): 612-622.
18. Hsu, Shih-Che, et al. "Resveratrol increases anti-aging Klotho
gene expression via the activating transcription factor 3/c-Jun
complex-mediated signaling pathway." The International Journal
of Biochemistry & Cell Biology 53 (2014): 361-371.
19. Jang, Meishiang, et al. "Cancer chemopreventive activity of
resveratrol, a natural product derived from grapes." Science
275.5297 (1997): 218-220.
20. Russo, Maria, et al. "The flavonoid quercetin in disease
prevention and therapy: facts and fancies." Biochemical
pharmacology 83.1 (2012): 6-15.
21. Zhu, Yi et al., The Achilles’ Heel of Senescent Cells: From
Transcriptome to Senolytic Drugs, Aging Cell, DOI:
10.1111/acel.12344
22. Pietrocola, Federico, et al. "Coffee induces autophagy in vivo."
Cell Cycle 13.12 (2014): 1987-1994.
23. Kitani, Kenichi, Toshihiko Osawa, and Takako Yokozawa. "The
effects of tetrahydrocurcumin and green tea polyphenol on the
survival of male C57BL/6 mice." Biogerontology 8.5 (2007): 567-
573.
24. Niu, Yucun, et al. "The phytochemical, EGCG, extends lifespan
by reducing liver and kidney function damage and improving age‐
associated inflammation and oxidative stress in healthy rats." Aging
Cell 12.6 (2013): 1041-1049.

95
25. Zarse, Kim, et al. "Low-dose lithium uptake promotes longevity
in humans and metazoans." European Journal of Nutrition 50.5
(2011): 387-389.
26. Wan, Qin-Li, et al. "Aspirin extends the lifespan of
Caenorhabditis elegans via AMPK and DAF-16/FOXO in dietary
restriction pathway." Experimental Gerontology 48.5 (2013): 499-
506.
27. Guevara-Aguirre, Jaime, et al. "Growth hormone receptor
deficiency is associated with a major reduction in pro-aging
signaling, cancer, and diabetes in humans." Science Translational
Medicine 3.70 (2011): 70ra13-70ra13.
28. Richie, JOHN P., et al. "Methionine restriction increases blood
glutathione and longevity in F344 rats." The FASEB Journal 8.15
(1994): 1302-1307.
29. Fontana, Luigi, et al. "Long‐term effects of calorie or protein
restriction on serum IGF‐1 and IGFBP‐3 concentration in humans."
Aging Cell 7.5 (2008): 681-687.
30. Tarnopolsky, M. A., et al. "Evaluation of protein requirements
for trained strength athletes." Journal of Applied Physiology 73.5
(1992): 1986-1995.
31. Walker, KYLIE S., et al. "Resistance training alters plasma
myostatin but not IGF-1 in healthy men." Medicine and Science in
Sports and Exercise 36.5 (2004): 787-793.
32. Wolfe, Robert R. "The underappreciated role of muscle in health
and disease."The American Journal of Clinical Nutrition 84.3
(2006): 475-482.
33. Mirzaei, Hamed, Jorge A. Suarez, and Valter D. Longo. "Protein
and amino acid restriction, aging and disease: from yeast to
humans." Trends in Endocrinology & Metabolism 25.11 (2014):
558-566.

Chapter 4: Fasting

1. Cornaro, A, Discourses on the temperate life.

http://www.soilandhealth.org/02/0201hyglibcat/020105c
ornaro.html
2. Goldberg, Emily L., et al. "Lifespan‐extending caloric restriction
or mTOR inhibition impair adaptive immunity of old mice by
distinct mechanisms." Aging Cell (2014).
3. Anson, R. Michael, et al. "Intermittent fasting dissociates
beneficial effects of dietary restriction on glucose metabolism and

96
neuronal resistance to injury from calorie intake." Proceedings of
the National Academy of Sciences 100.10 (2003): 6216-6220.
4. Mattson, Mark P., and Ruiqian Wan. "Beneficial effects of
intermittent fasting and caloric restriction on the cardiovascular and
cerebrovascular systems."The Journal of Nutritional Biochemistry
16.3 (2005): 129-137.
5. Reardon, Michael, and Marek Malik. "Changes in heart rate
variability with age." Pacing and Clinical Electrophysiology 19.11
(1996): 1863-1866.
6. Martin, Bronwen, Mark P. Mattson, and Stuart Maudsley.
"Caloric restriction and intermittent fasting: two potential diets for
successful brain aging." Ageing Research Reviews 5.3 (2006): 332-
353.
7. Tajes, M., et al. "Neuroprotective role of intermittent fasting in
senescence-accelerated mice P8 (SAMP8)." Experimental
Gerontology 45.9 (2010): 702-710.
8. Katare, Rajesh G., et al. "Chronic intermittent fasting improves
the survival following large myocardial ischemia by activation of
BDNF/VEGF/PI3K signaling pathway." Journal of Molecular and
Cellular Cardiology 46.3 (2009): 405-412.
9. Alirezaei, Mehrdad, et al. "Short-term fasting induces profound
neuronal autophagy." Autophagy 6.6 (2010): 702-710.
10. IGF-1 & Intermittent Fasting: Discussion with Valter Longo.
http://michelsonmedical.org/2014/12/26/igf-1-fasting-
discussion-valter-longo/
11. Safdie, Fernando M., et al. "Fasting and cancer treatment in
humans: A case series report." Aging (Albany NY) 1.12 (2009): 988.
12. Cheng, Chia-Wei, et al. "Prolonged fasting reduces IGF-1/PKA to
promote hematopoietic-stem-cell-based regeneration and reverse
immunosuppression."Cell Stem Cell 14.6 (2014): 810-823.
13. Moore, Jimmy. “Seyfried Cancer Textbook Cites My 7-Day Fast
Experience.” http://livinlavidalowcarb.com/blog/seyfried-
cancer-textbook-cites-my-7-day-fast-experience/14541
14. Mariño, Guillermo, et al. "Caloric restriction mimetics:
natural/physiological pharmacological autophagy inducers."
Autophagy 10.11 (2014): 1879-1882.
15. Mattson, Mark P. "Challenging Oneself Intermittently to
Improve Health." Dose-Response 12.4 (2014): 600.

Chapter 5: Demolition and Renewal

1. Cuervo, Ana Maria, et al. "Autophagy and aging: the importance

of maintaining "clean" cells." Autophagy 1.3 (2005): 131-140.

97
2. Bratic, Ana, and Nils-Göran Larsson. "The role of mitochondria in
aging." The Journal of clinical investigation 123.123 (3) (2013): 951-
957.
3. Ristow, Michael, et al. "Antioxidants prevent health-promoting
effects of physical exercise in humans." Proceedings of the National
Academy of Sciences 106.21 (2009): 8665-8670.
4. Dröge, Wulf. "Oxidative stress and ageing: is ageing a cysteine
deficiency syndrome?." Philosophical Transactions of the Royal
Society B: Biological Sciences 360.1464 (2005): 2355-2372.
5. Sekhar, Rajagopal V., et al. "Deficient synthesis of glutathione
underlies oxidative stress in aging and can be corrected by dietary
cysteine and glycine supplementation." The American Journal of
Clinical Nutrition 94.3 (2011): 847-853. \
6. Kent, K. D., W. J. Harper, and J. A. Bomser. "Effect of whey
protein isolate on intracellular glutathione and oxidant-induced cell
death in human prostate epithelial cells." Toxicology in vitro 17.1
(2003): 27-33.
7. Sekhar, Rajagopal V., et al. "Deficient synthesis of glutathione
underlies oxidative stress in aging and can be corrected by dietary
cysteine and glycine supplementation." The American Journal of
Clinical Nutrition 94.3 (2011): 847-853.
8. Chen, Chiao-nan Joyce, et al. "Late-onset Caloric Restriction
Alters Skeletal Muscle Metabolism by Modulating Pyruvate
Metabolism." American Journal of Physiology-Endocrinology and
Metabolism (2015): ajpendo-00508.
9. Ho, Klan Y., et al. "Fasting enhances growth hormone secretion
and amplifies the complex rhythms of growth hormone secretion in
man." Journal of Clinical Investigation 81.4 (1988): 968.
10. Hoffman, Jay R., and Michael J. Falvo. "Protein–which is best?."
Journal of Sports Science & Medicine 3.3 (2004): 118.
11. Tarnopolsky, Mark A., J. Duncan MacDougall, and Stephanie A.
Atkinson. "Influence of protein intake and training status on
nitrogen balance and lean body mass." Journal of Applied
Physiology 64.1 (1988): 187-193.

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About the author

P. D. Mangan has written a number of books on health and fitness,

of which this is his fourth. The others include Smash Chronic
Fatigue, Best Supplements for Men's Health, Strength, and Virility,
and Top Ten reasons We're Fat. They can all be found on his
Amazon Author page. He blogs at Rogue Health and
Fitness.com.

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