![Primary aging refers to intrinsic changes occurring with
age, unrelated to disease or environmental influences.
Secondary aging refers to changes caused by the
interaction of primary aging with environmental influences
or disease processes.
the phenotype is the end result of the interaction between genotype and
external factors:
• [phenotype]=[genotype]+[(diet,lifestyleandenvironment)].](https://image.slidesharecdn.com/physiologyofaging-250118055313-af7f6624/85/Physiology-of-aging-and-recent-advances-pptx-4-320.jpg)
![Thank you!
References
- da Silva PFL, Schumacher B. Principles of the molecular and cellular
mechanisms of aging. [journal name, volume number, page range].
-Gavrilov LA, Gavrilova NS. Evolutionary theories of aging and longevity.
[journal name, volume number, page range]. Published February 7, 2002.
-Flint B, Tadi P. Physiology, Aging. [journal name, volume number, page
range]. Last updated January 4, 2023.
-A synopsis on aging—Theories, mechanisms and future prospects" by
João Pinto da Costa, Rui Vitorino, Gustavo M. Silva, Christine Vogel, Armando
C. Duarte, and Teresa Rocha-
-Li Y, Tian X, Luo J, Bao T, Wang S, Wu X. Molecular mechanisms of aging and
anti-aging strategies](https://image.slidesharecdn.com/physiologyofaging-250118055313-af7f6624/85/Physiology-of-aging-and-recent-advances-pptx-35-320.jpg)
Physiology of aging and recent advances.pptx
- 1. Physiology of Aging Dr Ankita Mishra JR2 Department of Physiology
- 2. Overview of presentation • Introduction • Why to study physiology of aging • Theories of Aging • Mechanism • What happens at organ level • Clinical Point of view Slowing aging (role of exercise / diet) Accelerated Aging recent advances
- 3. What is Age & Aging? AGE- Length of time an individual has existed. Chronological AGING / Senescence- Progressive deteriorative changes, during the adult period of life, which underlie an increasing vulnerability to challenges and thereby decrease the ability of the organism to survive. Biological Age
- 4. Primary aging refers to intrinsic changes occurring with age, unrelated to disease or environmental influences. Secondary aging refers to changes caused by the interaction of primary aging with environmental influences or disease processes. the phenotype is the end result of the interaction between genotype and external factors: • [phenotype]=[genotype]+[(diet,lifestyleandenvironment)].
- 5. Life expectancy and trends: • Global: Life expectancy increased from 66.8 years in 2000 to 73.4 years in 2019 • Life expectancy increased from 37.1 years for males and 36.1 years for females in 1951 to 68.2 years for males and 70.7 years for females in 2014-2018. • In 2000, India's life expectancy was 63.2 years • In 2021, India's life expectancy was 67.3 years. • In 2022, India's life expectancy was 67.7 years.
- 6. Why to study physiology of aging : • With increase in life expectancy due to development of medicine and medical sciences need to understand aging and related processes stared to came into light as to : understand the physiology for development and promotion of lifestyles to avoid age related chronic illness to develop geriatric medicine, which focused on providing care for the unique health needs of the elderly.
- 7. Theories of aging Evolutionary theory/Geneti c theory Mutation accumulation theory antagonistic pleiotropy Disposable Soma Theory Error-Damage Theory Free radical theory Hayflick theory of limited division At present most acceptable theories (based on experimental findings) can be studied as :
- 8. Mutation accumulation theory • 1952- Peter Madawar • most deleterious mutations in gametes will result in progeny that are defective during most of life, and natural selection removes such genes from the population. However, a very few mutated genes will not have deleterious effects until advanced ages, and natural selection would fail to eliminate such genes antagonistic pleiotropy theory • 1957- George William • the genes with deleterious actions in late life actually increase evolutionary fitness in early adulthood. Disposable Soma Theory • 1977- Tom Kirkwood • the fundamental life role of organisms is to generate progeny. Natural selection would apportion the use of available energy between reproduction and body (i.e., somatic) maintenance, to maximize the individual’s lifetime yield of progeny
- 9. Free radical theory: • first introduced by Dr. Gerschman in 1954 • Developed by Dr. Denham Harman, 1981 • proposed that “superoxide and other free radicals cause damage to the macromolecular components of the cell, giving rise to accumulated damage causing cells, and eventually organs, to stop functioning” • Incomplete reduction of oxygen can generate a variety of biologically relevant ROS such as, hydrogen peroxide, the anion radical superoxide and the hydroxyl radical.
- 10. Free radical theory: • Free radicals have an unpaired electron in the outer orbital. These free radicals are extremely unstable because they react with a target molecule to capture an electron and thus become a stable molecule with only paired electrons in the outer shell. • However, the target molecule left behind becomes a free radical, initiating a chain reaction that continues until two free radicals meet to create a product with a covalent bond. • The body does possess some natural antioxidants in the form of enzymes, which help to curb the dangerous build-up of these free radicals, without which cellular death rates would be greatly increased, and subsequent life expectancies would decrease
- 11. Glycation Hypothesis of Aging. • Glycation and Glycoxidation Glycation refers to nonenzymatic reactions between the carbonyl groups of reducing sugars (e.g., glucose) and the amino groups of macromolecules (e.g., proteins, DNA) to form advanced glycation end products (AGEs). • the level of glycemia is a major factor in glycation, and periods of hyperglycemia are probably the reason glycation
- 12. Hayflick theory of limited division • 1961, Leonard Hayflick and Paul Moorhead • reported that human fibroblasts in culture could divide only a limited number of times, a phenomenon known as the Hayflick limit. This concept also applies to many other somatic cell types in culture. • Although recent findings indicate unsuccessful as a valid model of organismic aging, this led to consideration of the role of telomeres in aging.
- 13. Potential triggers molecular and celluar mechanisms of aging
- 14. a) DNA Damage
- 16. c) mitochondrial dysfunction • healthy mitochondrial network generates adenosine triphosphate (ATP) through the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation, which maintain the basic energy conversion and information exchange within the cell and are essential for life • Mitochondrial dysregulation by pleiotropic stress pathways
- 17. d) cellular senescence • Cell senescence is a kind of cell state caused by stress injury and some physiological processes, which is characterized by irreversible cell cycle arrest, accompanied by secretory features, macromolecular damage and metabolic changes, these functions can depend on each other to jointly drive the aging process.
- 18. e) stem cell exhaustion • Stem cells are progenitor cells with the potential for self-replication and multidirectional differentiation. • they promote a steady state of continuous organisation throughout the life course • As aging progresses, stem cells tend to accumulate DNA damage, which reduces their ability to regenerate cell lineages, exhibiting age-related loss of organ function and homeostasis, and increasing the incidence of age-related diseases
- 19. What happens at different organ system level • Virtually all organ systems are involved in physiologic changes associated with aging. • Because of the great reserve capacity or redundancy of some physiological systems, the effect of aging on a physiological process is often not apparent until either the individual faces an unusual challenge or function has fallen to less than some critical level
- 21. Musculoskeletal • The peaks of height starts to decline, starting adulthood and by the age of 70 years, height has fallen 2.5% to 5% lower than peak level. • Skeletal Muscle A steady loss in skeletal muscle mass —sarcopenia—occurs with aging, particularly beyond 50 years, and it primarily reflects a loss of number and, to a lesser extent, size of muscle fibers. • Until middle age, bone resorption and formation are in balance. However, starting in middle age, resorption exceeds formation, thus leading to a progressive loss in bone mass.
- 22. Neurological Unlike common misconception that advancing age causes marked deterioration in the nervous system in the absence of neurodegenerative disorders such as Alzheimer disease, impairment of the nervous system with age is much less severe. Although changes like – • Decreased catecholamine secretion • Decreased brain dopaminergic synthesis • Decreased righting reflexes • Decreased stage 4 sleep • Impaired thermal regulation
- 23. Cardiovascular - Respiratory • aging decreases the distensibility of arteries. • the resistance to ejection of blood from the left ventricle, increases with advancing age, primarily because of reduced arterial compliance. • The strength and endurance of the respiratory muscles decrease with age, primarily because of atrophy of type IIa muscle fibers. Lung volumes—both static volume and forced expiratory volume gradually decrease with age.
- 24. GIT-Renal-Endocrine functions • Changes in taste and smell, altered gut motility, and intestinal microbiota abnormalities can lead to age-related anorexia and subsequent caloric and/or nutritional deficiency. • a normal decrease in glomerular filtration rate is observed in advanced age, with reduced number of functional glomeruli and an increased prevalence of sclerotic changes within the glomeruli. • Thyroxin and triiodothyronine secretion decrease, resulting in overall decreased metabolic activity. • Alterations in glucose metabolism and insulin secretion develop with age, promoting the development of diabetes mellitus.
- 26. The changes with age when combined with environmental factors raises future issues of concern as predispose individuals to- • Organ System: Common medical and surgical issues associated with aging • Neurological: Cerebrovascular accident, Alzheimer disease, and other dementias, Parkinson disease • Cardiovascular: Coronary artery disease and atherosclerosis, heart failure, hypertension, hematologic malignancy • Pulmonary: Chronic obstructive pulmonary disease, lung cancer, pneumonia • Musculoskeletal: Osteoporosis, osteoarthritis, fractures, skeletal malignancies • Endocrine: Diabetes mellitus • Urological/Gynecologic: Urinary tract infections, urogenital cancer, cervical cancers, breast cancers, prostate cancer • Special Senses: Presbycusis, presbyopia, cataract, macular degeneration, glaucoma • Gastrointestinal: Malabsorption, gastrointestinal malignancies, bowel obstruction, diverticular disease • Other special considerations: Independence, falls, elder abuse and neglect, psychiatric concerns, skin breakdown, skin tears
- 28. Aging slowly • Slowing the aging process and thereby extending life have been human goals throughout recorded history and probably in preliterate times as well. •
- 29. Slowing down Aging : Diet • Diet is strongly correlated with longevity and disease development Mechanisms of Calorie Restriction in Aging Deceleration 1. Reduction in Oxidative Stress 1. CR reduces the production of reactive oxygen species (ROS), thereby minimizing oxidative damage to cellular components like DNA, proteins, and lipids. 2. Improved Mitochondrial Function 1. Calorie restriction enhances mitochondrial biogenesis and efficiency, which supports energy production and reduces the accumulation of damaged mitochondria. 3. Upregulation of Longevity-Associated Genes 1. CR activates genes like sirtuins (SIRT1) and FOXO transcription factors, which are involved in DNA repair, stress resistance, and cellular homeostasis. 4. Enhanced Autophagy 1. CR promotes autophagy, the process of clearing damaged cellular components, which helps maintain cellular integrity and function over time. 5. Improved Insulin Sensitivity 1. Reduced caloric intake enhances insulin sensitivity, thereby lowering the risk of age-related metabolic disorders such as diabetes. 6. Hormesis Effect 1. CR acts as a mild stressor, activating adaptive responses that increase cellular resilience
- 30. Slowing down Aging • Exercise approach
- 31. Recent advances and out-look- • Removal of senescent cells Senolytics for targeting senescent cel • Targeting inflammaging Chronic inflammation and inflammaging • Using endogenous metabolites and precursors to optimize metabolism • Stem cells to reverse aging
- 32. A new class of drugs, “Senolytics,” eliminate senescent cells by inhibiting a targeted pathway that ultimately damages cell apoptosis . The senolytic approach aims to selectively eliminate senescent cells, with a pioneering study showing that about 30% of senescent cells are cleared and that heart, kidney and adipose tissue function is improved • Senolytics: Compounds such as dasatinib and quercetin have been shown to selectively eliminate senescent cells. In animal models, this removal has led to improved tissue function and extended healthspan. • Clinical Trials: Preliminary human studies indicate that a combination of dasatinib and quercetin can reduce senescent cell burden. For instance, a clinical trial involving individuals with diabetic kidney disease demonstrated a decrease in senescent cells following treatment. Ongoing research continues to assess the safety and efficacy of senolytic therapies in humans, aiming to translate these findings into viable treatments for age-related conditions.
- 33. Stem cell Research - • Stem Cell Replacement Therapy: • Procedure: Transplanting healthy stem cells into damaged tissues to restore function. • Examples: • Mesenchymal stem cells (MSCs) for cartilage repair and anti-inflammatory effects. • Hematopoietic stem cells (HSCs) for rejuvenating blood and immune cells. • Rejuvenation of Aged Stem Cells: • Approaches: • Modulating signaling pathways like Wnt, Notch, and mTOR to restore stem cell function. • Epigenetic reprogramming to reverse age-related changes. • Stem Cell Niche Optimization: Strategies to restore the supportive environment, such as using growth factors, extracellular matrix components, and cytokines.
- 35. Thank you! References - da Silva PFL, Schumacher B. Principles of the molecular and cellular mechanisms of aging. [journal name, volume number, page range]. -Gavrilov LA, Gavrilova NS. Evolutionary theories of aging and longevity. [journal name, volume number, page range]. Published February 7, 2002. -Flint B, Tadi P. Physiology, Aging. [journal name, volume number, page range]. Last updated January 4, 2023. -A synopsis on aging—Theories, mechanisms and future prospects" by João Pinto da Costa, Rui Vitorino, Gustavo M. Silva, Christine Vogel, Armando C. Duarte, and Teresa Rocha- -Li Y, Tian X, Luo J, Bao T, Wang S, Wu X. Molecular mechanisms of aging and anti-aging strategies
Editor's Notes
- #3: Age can also be view as biological age- i.e sum of how old the tissue are or how well the organs are functioning Imparied ability to maintaine homeostasis so when these changes
- #4: All these definitions were surprisingly not very well defined although there existied a philosophical need to understand aging . It was not until start of 20th century when marked increase of life expectancy started to be observed better understing of physiology of aging being to appear , at start of early 20th century NIA was establisted
- #5: Number of adults of older age will reach upto 88.5 million by 2050
- #7: Other notable theories ; -Wear and tear theory -Dr. August Weismann, a German biologist, in 1882 Rate of Living Theory of Aging. nurtent sensening theory
- #9: oxidative stress theory
- #10: Glycation and Glycoxidation Glycation refers to nonenzymatic reactions between the carbonyl groups of reducing sugars (e.g., glucose) and the amino groups of macromolecules (e.g., proteins, DNA) to form advanced glycation end products (AGEs). In humans, the Amadori product can undergo a series of intramolecular and intermolecular rearrangements that include oxidation (glycoxidation) to form AGE molecules.
- #11: AGE formation in lens proteins of the eye probably contribute to age-associated opacification. Moreover, with advancing age, the increased stiffness of collagen in connective tissues (e.g., blood vessels
- #13: Those theories paves way to understanding the mechanisms that can be associated with aging, ----Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis.
- #14: Damage to genomic DNA and mtDNA can occur as the result of radiation and other environmental agents, such as toxic chemicals. In recent years, oxidative stress has been recognized as a major source of DNA damage. Cells can repair much of the damage to DNA, and the level of damage is in a steady state between damaging and repair processes DNA Repair Theory of Aging proposes that DNA repair declines with advancing age and eventually falls, the steady-state level of DNA damage consequently rises, and the integrity of the genome is thereby compromised.
- #15: mutations in these protein components of telomerese can disrupt the shelterin-telomere complex, resulting in terminal fusion and premature senescence. ---Rap1 is a key telomere-capping protein that prevents non-homologous end joining and telomere fusion, and its overexpression causes histone loss and accelerates cellular senescence *** if telomeres become so short that they are perceived as double-stranded DNA breaks, then these telomeres will recruit the DDR and induce the cells into a normal apoptotic or senescence program.
- #16: The functional integrity of mitochondria is affected by intramitochondrial protein folding, mitochondrial membrane dynamics, mitosis, and intracellular environmental stress Products - PCG1NRF1 induces the expression of mitochondrial-encoding genes
- #17: increase in the cytoplasm-to-nucleus ratio. Another obvious marker for senescent cells is the lack of DNA replication. Increased levels of p21 and p16 are two cyclin-dependent kinase inhibitors
- #20: The graph shwing how as functional reserve decreses
- #21: primarily because of compression of the cartilaginous disks between the vertebrae and loss of vertebral bone.
- #23: - along with widen pluse pressue, elevate systolic pressure, increased afterload causes thickening of the left ventricular wall, -
- #27: Aging can also be accelerated in absence of genetic changes and cause of environmental influences- by stress high caloric diet , sedentary life style But these brings us to role of environmental factors that could help decarcerate aging
- #29: in laboratory animals ,have postulated that with high caloric diet there is increased formation of free radicals within the mitochondria, which causes a secondary induction of increased antioxidant defense capacity while others suggest that the limited availability of nutrients forces the metabolism to undergo optimization Role of antioxidants – works on AG
- #30: Role of sleep
- #32: Definition: Senescent cells are damaged or stressed cells that cease division but remain metabolically active, secreting inflammatory molecules known as the senescence-associated secretory phenotype (SASP). Impact: With aging, these cells accumulate, leading to tissue dysfunction, chronic inflammation, and various age-related diseases.
- #33: Stem Cell-Based Anti-Aging Strategies