Current Research in Physiology 8 (2025) 100138

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Current Research in Physiology

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Review Article

From molecular to physical function: The aging trajectory

Tom A.H. Janssen a,1, Caroline V. Lowisz a,1, Stuart Phillips a,b,*
a
Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada
b
Department of Sport and Exercise Science, Manchester Metropolitan University Institute of Sport, Manchester, UK

A R T I C L E I N F O A B S T R A C T

Keywords: Aging is accompanied by a decline in muscle mass, strength, and physical function, a condition known as sar­
Protein copenia. Muscle disuse attributed to decreased physical activity, hospitalization, or illness (e.g. sarcopenia) re­
Sarcopenia sults in a rapid decline in muscle mass in aging individuals and effectively accelerates sarcopenia. Consuming
Exercise
protein at levels above (at least 50–100% higher) the current recommended intakes of ~0.8 g protein/kg
Skeletal muscle physiology
bodyweight/d, along with participating in both resistance and aerobic exercise, will aid in the preservation of
Inflammaging
Nutrition muscle mass. Physiological muscle adaptations often accompany the observable changes in physical indepen­
Atrophy dence an older adult undergoes. Muscle fibre adaptations include a reduction in type 2 fibre size and number, a
loss of motor units, reduced sensitivity to calcium, reduced elasticity, and weak cross-bridges. Mitochondrial
function and structure are impaired in relation to aging and are worsened with inactivity and disease states but
could be overcome by engaging in exercise. Intramuscular connective tissue adaptations with age are evident in
animal models; however, the adaptations in collagenous tissue within human aging are less clear. We know that
the satellite muscle cell pool decreases with age, and there is a reduced capacity for muscle repair/regeneration.
Finally, a pro-inflammatory state associated with age has detrimental impacts on the muscle. The purpose of this
review is to highlight the physiological adaptations driving muscle aging and their potential mitigation with
exercise/physical activity and nutrition.

nor gain in muscle mass. However, throughout the day, there are times
1. Introduction when MPS is greater than MPB and vice versa (McKendry et al., 2021).
Exercise, particularly that employing higher loads, and the ingestion of
The confluence of an aging population and a growing incidence of dietary protein can cause rates of MPS to increase resulting in a net
chronic disease as individuals age places an increasing demand on positive protein balance (McKendry et al., 2021). In the long term, this
healthcare systems. By the year 2050, a quarter of the Canadian popu­ constant elevation in MPS may translate to an increase in muscle mass if
lation will be above the age of 65 (Nauenberg et al., 2023) and similar the stimulus is frequent and triggering enough. However, there are also
demographic trends are seen in the US (Zoe Caplan, 2023) and EU conditions where MPB is chronically greater than MPS, such as during
(Affairs D-GfEaF, 2024 Ageing Report, 2024). Several factors influence inactivity, especially when in combination with being in a fasted state.
health with age; however, an inactive lifestyle, along with excess energy With reduced daily physical activity levels, complete muscle disuse, and
intake and poor nutrition, can accelerate the natural aging process. inadequate protein and energy intake, muscle protein balance would be
Sedentary behaviour and poor nutrition can contribute to a reduction in in a net negative state, contributing to a loss of muscle. As we age, MPS
muscle mass and a gain in fat mass, contributing to numerous metabolic does not increase as robustly in response to the ingestion of protein and
diseases. the ensuing hyperaminoacidemia (Moore et al., 2015). The changes
Skeletal muscle is a highly plastic tissue in which proteins turnover at affecting the natural sway of protein balance make gaining/maintaining
a rate of ~1.5% per day, and overall skeletal muscle makes up ~40 ± muscle mass when aging more difficult. Besides alterations in the fluc­
10% of our body mass (Koopman and van Loon, 2009). Muscle mass is tuations in MPS and MPB, many physiological adaptations occur with
dictated by the balance between muscle protein synthesis (MPS) and age that underlie the decline in muscle mass observed. This review fo­
muscle protein breakdown (MPB). When MPS and MPB are in equilib­ cuses on the molecular and physiological changes of the muscle with age
rium (i.e., net protein balance), an individual experiences neither loss and highlights the main reasons why maintaining a healthy amount of

* Corresponding author. Department of Kinesiology, McMaster University 1280 Main Street West, Hamilton, Ontario, Canada.
E-mail address: [email protected] (S. Phillips).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.crphys.2024.100138
Received 16 July 2024; Received in revised form 18 October 2024; Accepted 15 December 2024
Available online 16 December 2024
2665-9441/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
T.A.H. Janssen et al. Current Research in Physiology 8 (2025) 100138

Silva et al., 2010) and is dictated by the balance between MPS and MPB,
Abbreviations as previously mentioned. Muscle strength and power decline at a faster
rate of ~3% per year, indicating that processes other than muscle mass
MPS muscle protein synthesis contribute to declines in muscle function (von Haehling et al., 2010). A
MPB muscle protein breakdown period of disuse, such as a hospital stay, illness, or a reduction in ac­
RDA recommended dietary allowance tivity, may result in aging individuals crossing the threshold of physical
1RM one repetition maximum dependence a lot sooner due to mobility loss (Phillips et al., 2020; Visser
CSA cross-sectional area et al., 2005). On the contrary, exercise training and increased physical
COPD chronic obstructive pulmonary disease activity in older adults are related to improved mobility and function
EAA essential amino acids (Paterson and Warburton, 2010). Activities of daily living become more
RET resistance exercise training difficult for aging individuals, and so these individuals will often avoid
ROS reactive oxygen species engaging in these tasks. The result is an increasing cycle of sedentarism
AGEs advanced glycation end-products that can eventually lead to dependency. This vicious cycle of inactivity
ECM extracellular matrix and increased risk for physical dependence is shown schematically in
Fig. 1 (Oikawa et al., 2019).
The progression of sarcopenia can affect an individual’s life due to its

Fig. 1. The vicious cycle of reduced physical independence. Figure created using BioRender.

muscle when aging is so challenging. We do, however, offer some influence on health span, quality of life, and the interplay between these
practical strategies to combat age-related sarcopenia. factors. Firstly, a reduction in muscle mass puts individuals at risk of
developing metabolic disorders such as type 2 diabetes mellitus. Muscle
2. Implications of declining muscle on health and strategies to mass is inversely related to insulin resistance as muscle is a metaboli­
mitigate muscle loss with age cally active ‘sink’ for the storage and metabolism (oxidation and con­
version to other substrates) of glucose (Srikanthan and Karlamangla,
Muscle loss is a hallmark of aging; in fact, it has been said that no loss 2011). Secondly, a decline in strength, most frequently assessed as grip
of tissue with aging is more remarkable than that of skeletal muscle. As a strength, is correlated with a reduced health-related quality of life and
tissue, its decline is seen by many as inevitable, but there is the ability to an increased risk of declines in physical mobility (Sayer et al., 2006).
change the downward trajectory of muscle mass (and function/strength) Finally, functional decline and declines in strength and aerobic capacity
with aging. play roles in the development of cardiovascular disease (Corsi et al.,
2018). Interventions that positively affect aging and specifically negate
the development of sarcopenia continue to be explored to improve both
2.1. Sarcopenia and muscle aging-related diseases quality of life and health span.
The loss of muscle mass is common with advancing age; however,
Sarcopenia is characterized by a progressive loss of skeletal muscle several disorders and conditions may be worsened or add to the devel­
mass, strength, and function with age, which is measurable (compared opment of sarcopenia, such as metabolic syndrome, obesity, type 2
to peak muscle mass at age 20–30) in the fourth-fifth decade of life (i.e. diabetes mellitus, cardiovascular disease, and other chronic diseases like
40-50 years old) (von Haehling et al., 2010). The decline in muscle mass dementia (Santilli et al., 2014). It is difficult to determine a
beyond age 30 occurs at a rate of ~0.8% per year (Mitchell et al., 2012;

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Fig. 2. Myofibrillar changes in skeletal muscle aging. Figure created using BioRender.

cause-and-effect relationship between these conditions as human sys­ The step-reduction model has shown the profound impact of even
tems are linked with one another and often display similar underlying short-term periods of reduced activity (Breen et al., 2013; Oikawa et al.,
molecular changes. Sarcopenic obesity, for example, is characterized by 2018; McGlory et al., 2018; Devries et al., 2015; Arentson-Lantz et al.,
a reduction in muscle mass and accumulation of fat mass that is 2019). While a period of reduced steps may seem somewhat benign, our
commonly related to age (Cauley, 2015). Mitochondrial dysfunction, data and those of others have shown that older individuals would be
increased inflammation, and unmitigated oxidative stress are all con­ adversely affected after as little as weeks in which they stayed inside of
tributors to the worsening of health and are presented as a result of their homes due to inclement weather, were bedridden or convalescing
sarcopenic obesity (Polyzos and Margioris, 2018). The natural aging due to illness, or seated for the majority of the day due to an injury
process encompasses a reduction in muscle mass, though chronological (Oikawa et al., 2019). Individuals who are generally healthy may
age is not the only contributor to muscle atrophy. Molecular adaptations believe that they are at reduced risk of muscle loss during a period of
such as mitochondrial dysfunction, increased inflammation, and un­ disuse; however, compared to younger individuals, older adults expe­
mitigated oxidative stress are not only a result of chronic disease states rience greater muscle mass loss in response to bed rest and appear to
(e.g. sarcopenic obesity) but are also related to the natural aging process, have a more difficult time returning to pre-inactivity conditions (Pišot
making it difficult to isolate the effect of the illness or aging on the in­ et al., 2016).
fluence of physiological adaptations. Healthy older adults experience exacerbated rates of loss of muscle
mass in response to muscle disuse and bed rest (Oikawa et al., 2018;
Pišot et al., 2016). In real-world settings, individuals are often placed in
2.2. Muscle disuse contributes to accelerated aging these conditions due to illness and injury (Quinn et al., 2019).
Controlled models of disuse, inactivity, and bed rest tend to utilize
Decreased physical activity (relative sedentarism) or muscle disuse healthy older adults, and so the outcome data from these studies likely
in healthy adults induces muscle atrophy. Full recovery from disuse does represents the best-case scenario for health outcomes. We propose that
not commonly occur in older adults (Suetta et al., 2009, 2013), and the presence of an underlying chronic condition – type 2 diabetes, pe­
those with chronic disease states face a more challenging time with re­ ripheral arterial disease, metabolic syndrome – would make older adults
covery (Della Peruta et al., 2023). Not only do older adults experience much more vulnerable to muscle atrophy and the development of sar­
increased atrophy in response to muscle disuse (Kortebein et al., 2007, copenia. Older individuals experiencing elective hip surgery experi­
2008; Coker et al., 2015), but they also have an impaired ability enced substantial leg muscle atrophy after only 6 days of hospitalization
(compared to younger persons) to regain lost muscle and strength (Kouw et al., 2019). The increased muscle loss experienced following
(Suetta et al., 2013). hip arthroplasty in the non-operated limb puts an individual at increased
A period of disuse (i.e. bedrest or single-leg immobilization) can have risk of delayed recovery from surgery, leading to a cycle of further
profound implications for an older individual’s physical health and decreased physical activity. If an individual is in a health-compromised
function. A two-week-long reduction in daily total steps (a model of (pre-diabetes, type 2 diabetes, peripheral arterial disease) state prior to
abrupt sedentarism but not full disuse) not only reduced postprandial hospitalization, this could play an additive role in the drastic reduction
rates of MPS and impaired insulin sensitivity but also significantly in muscle mass (Barreiro and Sieck, 2013; Bruggeman et al., 2016).
reduced leg fat-free mass (Breen et al., 2013). To make matters even Current research focuses on strategies to mitigate the reduction in
worse, older individuals who were immobilized for two weeks not only muscle mass seen with disuse through methods of prevention and
experienced a reduction in muscle mass but also a decline in muscle respective recovery in both disease and non-disease states (Nunes et al.,
strength that was the equivalent of ~2–3 years of normal aging 2022).
(Rommersbach et al., 2020). Highlighting that disuse in older in­
dividuals can lead to muscle atrophy that resembles accelerated aging.

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Fig. 3. Phosphorylation/activation of multiple protein signalling pathways changes with aging resulting in decreases in MPS and mitochondrial biogenesis post-
exercise when compared to healthy young individuals. The green circles with a white cross in the middle of it indicate an increase in phosphorylation/activa­
tion, and the amount of bubbles indicates the amount of proteins that are phosphorylated/activated. The red circles with a white line in the middle of it indicate a
decrease in phosphorylation/activation, and the amount of bubbles indicates the amount of proteins that are phosphorylated/activated. Figure created
using BioRender.

3. Physiological adaptations that drive muscle aging most of these changes are fiber type specific, the focus is on the type 2
fibers that show the most change with aging (Verdijk et al., 2007).
We are beginning to uncover several salient changes that occur with With age, there is a decline in number of motor units and decreased
aging in skeletal muscle. Most of these age-related changes result in stability of neuromuscular junctions (Piasecki et al., 2016). The reduc­
reduced muscle function, and they range from intra to extracellular in tion in motor units may be substantial, and a loss of 40% of motor units
location. Here, we outline some of the more prevalent adaptations that can be seen by the age of ~70 (Piasecki et al., 2016). The loss of motor
occur with age and that are linked to declines in muscle mass and units with age is accompanied by a reduced ability of remaining motor
function. nerves to reinnervate muscle fibres and compensate for this loss
(Hepple, 2018). An impaired capacity for reinnervation of denervated
muscle fibres, along with the aforementioned anabolic resistance,
3.1. Muscle fibre changes with age correlated to increased muscle loss with age (Hepple, 2018). A study by
Rowan and colleagues discovered that age-associated muscle fibre at­
Muscle fibre adaptations with age encompass not only a decrease in rophy can be largely attributed to muscle denervation (Rowan et al.,
muscle fibre size but a loss of muscle fibres, a reduction in motor units, 2012). Long-term physical activity, at least based on cross-sectional
and a disruption of the mechanical properties of myofibrils (Fig. 2). data, has been shown to improve capacity for reinnervation and was
These myofibrillar changes with age can have drastic implications for related to better relative preservation of muscle strength (Mosole et al.,
the physical function, strength, and muscle mass of older adults. 2014).
It is well known that type 1 and 2 muscle fibres play distinctive roles Impairments in myofibril mechanical properties can have drastic
in muscle force production and have characteristics that make their role implications for optimal muscle contraction. Single skeletal muscle fi­
in specific activities predominant (Linssen et al., 1991). With age, there bres from older men experience increased instantaneous stiffness or
is a reduction in fibre number and size, yet the reduction is most evident reduced elasticity in comparison to younger men (Ochala et al., 2007).
in type 2 fibres (Nilwik et al., 2013). Type 2 fibres have a greater ca­ This reduction in elasticity is also observed in the fascia, which can
pacity for force production, whereas type 1 or slow oxidative fibres are contribute to reduced flexibility and mobility in older adults (Marcucci
less fatigable (Linssen et al., 1991). Not only are muscle fibres reduced in and Reggiani, 2020). A reduction in myosin protein content and
number and size, but they also have a reduced ability for force pro­ post-translational modifications may disrupt the mechanism of
duction (lower force/fibre CSA) and a lower capacity to trigger contraction at the cross-bridge level (Miljkovic et al., 2015).
contraction, as indicated by a decreased sensitivity to calcium Post-translational modifications of myosin in aging affect its ability to
(Lamboley et al., 2015), especially in type 2 fibers. Resistance exercise bind to actin, thus reducing the number of strong cross-bridges formed
has been shown to increase type 2 muscle fibre size in older adults and is during muscle contraction (Li et al., 2015). Both the reduced elasticity
responsible for most of the increases observed in the quadriceps and poorly formed cross-bridges affect force production during muscle
cross-sectional area in response to exercise (Nilwik et al., 2013). Since

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contraction and are deleterious with aging (Fig. 2). showed that with aging, the type 2 muscle fibres are mainly affected,
and they suggested that a reduction in oxidative capacity of the mito­
3.2. Mitochondrial changes with age chondria, specifically in type 2 fibres, is causing the decline in the
cross-sectional area (CSA) of type 2 fibres with aging. However, it can
On top of the myofibrillar changes in our skeletal muscle with aging, also be speculated that the decline in CSA of type 2 muscle fibres is
changes in the mitochondria of the muscle are also observed (Zhu et al., caused by the reduction in engagement in higher-intensity physical ac­
2022; Burtscher et al., 2023; Distefano and Goodpaster, 2018). Mito­ tivity that would mainly require recruitment of the type 2 muscle fibres.
chondrial dysfunction can be associated with age; however, a detailed It seems logical that a combination of aging and inactivity would be the
causal relationship can be difficult to find since there are many variables cause of the decrease in CSA in type 2 fibres; however, this remains
affecting the muscle’s mitochondria other than aging, with relative speculative, and more research needs to be done in order to come to a
inactivity being a significant factor(Webb and Sideris, 2020). In addi­ clear consensus.
tion, in 1996 it was already shown that mitochondrial MPS, oxidative Some of the age-related changes in the mitochondria of skeletal
capacity of the skeletal muscle, and mitochondrial function decline with muscle are partially reversible with different types of exercise, and
age (Rooyackers et al., 1996). Whether the changes in the mitochondria practically all age-related changes are exacerbated with inactivity
are caused by or causes of sarcopenia remains unclear. Regardless of the (Gram et al., 2014; Hackney and Ploutz-Snyder, 2012; Pillon, 2023),
order of events, the function of mitochondria with aging is a target for type 2 diabetes mellitus (Jornayvaz and Shulman, 2010), and other
intervention, as mitochondrial dysfunction has been identified as a key diseases such as cancer or Alzheimer’s (Jornayvaz and Shulman, 2010;
theory in aging (Bratic and Larsson, 2013; Guo et al., 2023). Palmer et al., 2021). Previous research shows that endurance exercise
That age affects the structure of the mitochondria, and the cristae is seems to be an effective mode of exercise to stimulate muscle mito­
not new. Miquel et al. (1980) described that changes in mitochondrial chondrial biogenesis and function. Endurance exercise increases the
structure and cristae in skeletal muscle but also liver, kidney, and the phosphorylation of PGC-1a, which is a marker for mitochondrial
cerebral cortex have been found in mammals (e.g., mice, rats, and biogenesis (Coggan et al., 1990, 1992; Spina et al., 1996). Resistance
human subjects). It has been discovered that with age, there is an exercise is found to be very effective in preventing the decline in the CSA
increased reactive oxygen species (ROS) production that can have of type 2 fibres, mainly by stimulating the mTOR pathway (Moro et al.,
deleterious effects on a number of metabolic pathways, including the 2020; Kosek et al., 2006; Verdijk et al., 2009). It is also suggested that a
phosphorylation of the Akt/mTOR pathway, see Fig. 3. There is an in­ combined exercise protocol could be beneficial for older adults when
crease in damaged mitochondrial DNA, reduced DNA repair systems, specifically looking at the decreased oxidative capacity found in an older
and reduced PGC-1a protein expression thought to be consequences of population. Irving et al. (2015), showed that an 8-week combined
increased ROS with age (Boengler et al., 2017). PGC-1a plays an training protocol was superior in increasing muscle oxidative capacity
important role in the regulation of mitochondrial biogenesis, meaning when directly compared to an 8-week resistance exercise protocol, an
that when there is a reduced PGC-1a protein expression, mitochondrial 8-week endurance exercise protocol, and a control group.
biogenesis is also reduced (Liang and Ward, 2006). Additionally, ROS To summarize, with aging, there is a decline in mitochondrial vol­
production can hinder the phosphorylation of proteins in anabolic ume and a breakdown in structure and function, with differences be­
pathways such as the Akt/mTOR pathway and its downstream targets tween muscle fibre types (i.e. greater loss in type 2 fibres). The observed
4E-BP1 and p70S6K can inhibit MPS (Gomez-Cabrera et al., 2020). In decline in mitochondrial function can, at least partly, be prevented/
addition, the increased amount of damaged mitochondrial DNA, in reversed by different types of exercise and can be exacerbated by inac­
combination with a reduced DNA repair system, can reduce mitochon­ tivity and disease states.
drial biogenesis and repair. Damaged mitochondria ultimately nega­
tively affect the mitochondrial structure and function (Joseph et al., 3.3. Connective tissue and extracellular matrix changes
2012). It is also known that the mitochondrial gene (Melov et al., 2007;
Phillips et al., 2013) and protein (Murgia et al., 2017; Robinson et al., Intramuscular connective tissue is a crucial part of skeletal muscle
2017; Ubaida-Mohien et al., 2019) content are lower in older adults. function and is critical for force translation. The intramuscular con­
Some of these downregulated proteins are part of respiratory chain nective tissue consists of 3 different extracellular matrix structures (the
complexes and are consistent with lowering the mitochondrial respira­ epimysium, perimysium, and endomysium), serves as protection, and
tory function in muscle fibres from older adults (Ubaida-Mohien et al., plays an important role as a supportive force-transferring lattice to the
2019). The reductions in mitochondrial protein abundance are likely contractile portion of the muscle to the tendon to the bone resulting in
driven by the dysregulation of mitochondrial fusion and fission pro­ contraction (Purslow, 2020). It has been suggested that the turnover rate
cesses (Murgia et al., 2017). of intramuscular connective tissue protein was lower compared to
Short et al. (2005) analyzed muscle from 146 healthy men and skeletal muscle turnover (Holm et al., 2010; Trommelen et al., 2020).
women aged 18–89 years old and looked at the functional changes in However, a recent study showed that intramuscular connective tissue
mitochondria with aging and some of the mechanisms behind the aging showed a relatively greater fractional synthetic rate when compared to
process. They found that mtDNA and mtRNA declined with age, which the myofibrillar fractional synthetic rate after an acute bout of resistance
resulted in a reduced mitochondrial protein. In addition, they concluded exercise (Aussieker et al., 2023). Meaning, that even though intramus­
that the abundance of mtDNA was positively correlated with mito­ cular connective tissue turnover might be lower than myofibrillar
chondrial ATP production which in turn is closely correlated with turnover, intramuscular connective tissue shows characteristics of a
oxidative capacity and glucose tolerance. Therefore, with aging, the highly plastic portion of the skeletal muscle.
reduced capacity of ATP production by the mitochondria is, at least Research in murine models has shown that older mice show an in­
partly, caused by the reduction in mtDNA and mtRNA. Collectively, the crease in collagen crosslinks when compared to younger mice
processes mentioned above are suggested to contribute to the lower (Wohlgemuth et al., 2023). While enzymatic collagen crosslinks can
muscular function and the higher insulin resistance commonly seen in rapidly change due to external stimuli like exercise, injury, or disease,
an older population. during aging, there is an increase in non-enzymatic crosslinks, also
It is clear that with aging, the main loss of muscle is found in type 2 known as advanced glycation end products (AGEs), as we get older. As a
muscle fibres (Lexell, 1995), and the distribution of fibre type between result of the increase in AGEs, the extracellular matrix (ECM) can
different muscles within the same person can be vastly different become stiffer, impair the range of biomechanical properties, and the
(Johnson et al., 1973). It is suggested that with aging, differences in ECM becomes more resistant to turnover (Wohlgemuth et al., 2023). The
function within different muscles can be observed. Conley et al. (2007) increase in difficulty in turning over ECM collagen, most likely due to a

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reduced degradation (Nowotny and Grune, 2014), helps to explain the responsible for this increase in fibrosis with age (Brack et al., 2007;
accumulation of collagen, or fibrosis, in older individuals. Interestingly, Brack and Rando, 2007; Lukjanenko et al., 2019). However, a very small
periods of immobilization worsen ECM stiffness (Järvinen et al., 2002). amount of research has been done on human muscle tissue, and there­
The intramuscular connective tissue (in this case, the endomysium and fore, a lot remains to be confirmed and discovered.
perimysium specifically) undergoes both quantitative (i.e. collagen The muscle satellite cell pool decreases with age (Shefer et al., 2006).
accumulation) and qualitative AGE-induced alteration (Wohlgemuth Interestingly, the impaired regeneration of muscle with aging may be
et al., 2023; Järvinen et al., 2002), further impairing the biomechanical reversible with exercise (Joanisse et al., 2016a). It has been shown that
properties of the intramuscular connective tissue with aging. with exercise, mice can increase satellite cell content and improve the
In mice, it is clear that with aging, the collagen content of the muscle systemic environment. The importance of the systemic environment is
increases (Kragstrup et al., 2011). However, in aging humans, it remains stressed due to the development of the capillary impact zone theory
debatable whether the collagen content of the muscle actually increases. (Joanisse et al., 2016b). This theory suggests that each capillary within
Even though some evidence suggests that with human aging, the the muscle has a specific area in which it can send blood-borne signals to
collagen content of the muscle tends to increase, a clear consensus has the muscle satellite cells in order to activate the satellite cell for muscle
not yet been formed (Pavan et al., 2020; Fede et al., 2022). Similarly, regeneration, repair, and remodelling. It is good to know that with ex­
collagen synthesis rates, as mice data show, are reduced with aging ercise, the capillary impact zone can be increased. A study in older men
(Mays et al., 1991; Goldspink et al., 1994), whereas human data shows has shown that with age, the satellite cells are located further away from
an increase in collagen synthesis with aging (Babraj et al., 2005). This capillaries, which would suggest that more satellite cells are outside or
raises the question if collagen degradation is the main factor at play here on the far end of these capillary impact zones, which could impair/delay
and it seems that heavily crosslinked collagen is more difficult to break regeneration, repair, and remodelling of the muscle (Nederveen et al.,
down (Nowotny and Grune, 2014). However, more research is needed to 2016). We refer the interested reader to a review by Sousa et al.
settle this issue. (Sousa-Victor et al., 2022) and a book by Hwang and Brack (2018) for
It is clear that with resistance exercise, the turnover of muscle con­ deeper reading in this area.
nective tissue protein can be increased (Holm et al., 2010; Miller et al.,
2005); in addition, whether exercise has a positive effect on the detri­ 3.5. Changes in systemic factors – inflammaging
mental effects in older persons on intramuscular connective tissue re­
mains to be determined. In addition, it seems to be clear that additional Inflammaging can be defined as ‘sterile’ immune dysregulation (i.e.,
supplementation of protein does not increase intramuscular connective inflammation in the absence of a pathogenic vector: bacteria or virus)
tissue protein synthesis (Holm et al., 2010; Holwerda and van Loon, and, specifically, an increase in systemic concentrations of pro-
2022; Dideriksen et al., 2011; Mikkelsen et al., 2015; Moore et al., 2009; inflammatory markers with age (Franceschi et al., 2000). The
Wilkinson et al., 2008). pro-inflammatory state is characterized by an increase in
More human research is needed to draw firm conclusions about the pro-inflammatory markers, including IL-1, IL-1 receptor antagonist
relationship between age-associated changes in the muscle ECM/intra­ protein (IL-1RN), IL-6, IL-8, IL-13, IL-18, C-reactive protein (CRP), IFNα
muscular connective tissue and the decline in force production in older and IFNβ, transforming growth factor-β (TGFβ), tumour necrosis factor
adults. Since the older population is generally less active, it remains (TNF) and its soluble receptors (TNF receptor superfamily members 1A
difficult to associate changes in the ECM/intramuscular connective tis­ and 1B), and serum amyloid A (Ferrucci and Fabbri, 2018).
sue with aging specifically and not with other external factors like A large-scale longitudinal aging study showed that high levels of
increased inactivity. cytokines, specifically IL-6 and CRP, are associated with an increased
risk of muscle loss and reductions in strength (Schaap et al., 2006). The
3.4. Changes in the muscle stem cell niche exact mechanism of how the pro-inflammatory state seen in older adults
results in the loss of muscle and strength is unknown; however, it is
The muscle stem cell niche in skeletal muscle can be described as the speculated that there could be an increase in the ubiquitin-protease
microenvironment that surrounds the muscle stem cells (i.e., satellite pathway induced via inflammation (Mitch and Goldberg, 1996; Fer­
cells). The stem cell niche provides structural and biochemical support rucci et al., 1999). This ubiquitin-proteasome pathway system is mainly
to regulate satellite cell behaviour, including maintenance, activation, responsible for muscle proteolysis but not the myofibrillar lattice. In
proliferation, differentiation, and self-renewal, which is crucial for addition, it is known that the main intramuscular signalling pathways
muscle growth, repair, and regeneration (Mashinchian et al., 2018). that are influenced by this inflammatory state are the NF-κB, JAK/STAT,
It has been demonstrated that when a younger mouse is connected to and p38MAPK pathways that contribute to the loss of muscle and
an older mouse through the use of parabiosis the decline of satellite cell strength (Huang et al., 2020; Fang et al., 2021; Zanders et al., 2022;
activity of the old mice (common with age) can be restored (Conboy Ueno et al., 2021). Finally, inactivity and the development of type 2
et al., 2005). Whereas when combining the vascular systems of two old diabetes mellitus can lead to an accelerated loss of muscle with age due
mice (again through parabiosis) the progenitor cell activity is not to increased blood glucose levels and a pro-inflammatory state than in
restored. To clarify, parabiosis is a surgical procedure in which the skin healthy, active older persons (Prattichizzo et al., 2018; Ji et al., 2022).
and blood vessels of two mice are surgically connected, with the goal of With the continued developments of (in vivo/vitro in human) mea­
creating a shared circulatory system allowing for the blood of both mice surement techniques, the intricate relationship between inflammaging
to mix. This study (Conboy et al., 2005) suggests that the local vascular and the muscle niche with aging will become clearer. Unfortunately, due
environment of these progenitor cells negatively influences the pro­ to the complex nature of these studies, there is a lack of human mech­
genitor cell activity with aging. anistic data, and therefore, more studies are required.
It is suggested that the ECM of the muscle fibres becomes thicker (i.
e., fibrosis) with age and impairs the crosstalk of the muscle stem cell 4. Mitigating muscle loss in aging
niche. Nederveen et al. showed that the thickness of laminin in type 2
muscle fibres was higher in older participants than in younger partici­ Two main strategies proposed to mitigate sarcopenia include the
pants (Nederveen et al., 2020). In addition, they also showed a greater incorporation of exercise and sufficient dietary protein intake
amount of satellite cells that were surrounded by laminin in the older (McKendry et al., 2021). The common issue is that in addition to poor
population (they labelled such cells as incarcerated), which may inhibit nutrition, or possible malnutrition, and decreased physical activity
the satellite cell activation in older persons following exercise levels, aging individuals experience anabolic resistance (Burd et al.,
(Nederveen et al., 2020). Based on mouse models, multiple pathways are 2013). Anabolic resistance describes the observation that skeletal

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muscle is less sensitive to either (or both) post-absorptive hyper­ aging individuals (Izquierdo et al., 2021). Guidance for the development
aminoacidemia (Wall et al., 2015) or resistance exercise (Kumar et al., of muscle (or at least to prevent its loss), enhancement of strength, and
2009), leading to the reduced response of MPS. Due to this anabolic increased function has been comprehensively summarized (Izquierdo
resistance, aging individuals require additional anabolic stimuli to et al., 2021). It is important to note, however, that various resistance
optimally simulate MPS compared to younger individuals (Burd et al., exercise training (RET) protocols show benefits for hypertrophy and
2013). Most nutritional and exercise recommendations are based on strength outcomes (Currier et al., 2023; McLeod et al., 2024). Impor­
studies performed using younger individuals, and it has been recognized tantly for older persons, the benefits of improving function, as assessed
that the results observed in a younger population do not always translate by tests like the short physical performance battery, time-up-and-go, and
to older individuals (Volpi et al., 2013). various walk tests, is that many RET protocols achieve positive outcomes
with very little distinction between the different protocols as longs as the
4.1. Older individuals require specific recommendations for protein intensity is high (i.e. low repetitions with higher weights or higher
consumption repetitions with lower weights) (Currier et al., 2023; McLeod et al.,
2024). Thus, lower-load (30–50% 1RM, higher volume) RET may be a
Based on data from previous studies, adults are recommended to viable option for RET and may target more of the physiological deficits
consume (with some variability between estimates) ~0.8g protein/kg/ observed in older adults (e.g., increasing mitochondria content and
day (Traylor et al., 2018) from mixed protein sources. A study by improving glycemic control) than traditional higher-load RET (80%
McKendry and colleagues has recently highlighted that the current 1RM) (Burd et al., 2010; Beaudry et al., 2024; Lim et al., 2019). Lower
recommended dietary allowance (RDA) or Recommended Nutrient load RET provides an alternate training mode to higher loads and may
Intake (RNI) for protein consumption does not optimally simulate MPS be a means to combat age- and obesity-related health decrements
rates in older adults (McKendry et al., 2024a). There are several other simultaneously.
observations around the requirement of specific essential amino acid
needs for optimizing MPS (Szwiega et al., 2021; Rafii et al., 2024), and 4.3. Combined lifestyle strategies are the key to muscle maintenance and
protein needs to optimize glutathione synthesis (Paoletti et al., 2024; preservation
Jackson et al., 2004) that indicate the insufficiency of the RDA or RNI to
optimize protein synthesis. In addition, McKendry et al. (2024a) utilized A combination of both resistance and aerobic exercise, along with
specific strategies to combat anabolic resistance by increasing total adequate protein consumption, appears to be a potent strategy to miti­
protein intake (Traylor et al., 2018), increasing per meal protein dose gate muscle aging detriments (Churchward-Venne et al., 2012; Burich
(Moore et al., 2015), evenly distributing protein throughout the day et al., 2015; Deutz et al., 2014). Performing aerobic exercise combined
(Norton et al., 2016; Farsijani et al., 2016), and utilizing high-quality with a resistance exercise training regimen demonstrated improvements
proteins (Pinckaers et al., 2021), which may be important for older in glycemic control, body composition, strength, and function in older
persons, based on previous research. By manipulating the previously adults with type 2 diabetes mellitus (Tan et al., 2012). Exercise is im­
mentioned strategies of protein intake, rates of MPS were elevated in pactful for the muscles of older adults, but when combined with
older adults compared to consuming the current RDA for protein, with adequate protein intake may be utilized as a sarcopenia-preventive or at
more protein being consumed at dinner and less during breakfast and least mitigative strategy. As previously mentioned, a reduction in daily
lunch, which are typical of older adult eating patterns. physical activity can exacerbate the muscle aging process, this process is
A study by Moore and colleagues recommended that aging in­ potentially mitigated through the combined use of nutrition and exer­
dividuals should consume 0.4 g/kg of protein per meal, leading to a total cise. Consuming a whey supplement (20g) and performing lower-load
dose (assuming three daily meals) of at least 1.2 g/kg/day in order to RET thrice weekly attenuated the decline in rates of MPS and pre­
maintain muscle mass (Moore et al., 2015). Furthermore, consuming an served muscle mass during a two-week step reduction protocol (<1500
even distribution of protein in all meals throughout the day ensures that steps/day) (Devries et al., 2015). Hence, it is evident that the combi­
MPS is optimally stimulated during the day and that protein re­ nation of both nutrition and exercise could be an effective target to slow
quirements are met (Mamerow et al., 2014). Regarding protein sources, down muscle aging.
dairy proteins are a high-quality source as they contain a higher relative
proportion of leucine (an essential amino acid that is critical for the 4.4. Pre-habilitation: the importance of getting active now
stimulation of MPS) and is rapidly digested (Szwiega et al., 2021; Tang
et al., 2009). Older individuals should consider, in priority order, total Often in life, there are instances that we cannot prevent that place us
protein intake, per meal dose, protein distribution throughout the day, at risk for muscle atrophy. For example, some older adults undergo hip
and quality of a protein source when making food selections to take surgery, which requires them to be bedridden for a short time. While
advantage of all available tools to preserve or increase muscle mass others may, unfortunately, experience a fall that sends them to the
(Murphy et al., 2016). Older adults are at risk of inadequate energy hospital, requiring the immobilization of a limb for recovery. Pre-
intake, which may make it difficult to achieve the aforementioned habilitation is a strategy that has come to light to prevent the risk of
protein recommendations. By focusing on achieving adequate energy poor postoperative outcomes, such as increased length of stay and loss of
and protein intake older adults can mitigate potential losses of muscle function, which puts an individual at risk of greater muscle atrophy due
due to poor nutrition (Miller and Wolfe, 2008; Yannakoulia et al., 2018). to sedentary behaviour (Halloway et al., 2015). Pre-habilitation is a
strategy utilized prior to surgery to improve outcomes postoperatively
4.2. Exercise provides benefits for aging muscle (Baimas-George et al., 2020). A study done by Smeuninx et al. (2023)
had older adults perform a unilateral bout of RET prior to 5 days of bed
Increased physical activity and exercise provide a multitude of rest (Smeuninx et al., 2023). Although it was not possible to mitigate all
benefits for not only healthy young adults but also for older individuals reductions in quadriceps CSA due to bed rest, the exercising leg expe­
(Rebelo-Marques et al., 2018). However, specific recommendations and rienced less muscle loss and a less drastic reduction in integrated
evidence-based training protocols for older adults are less myofibrillar protein synthesis. Various other strategies have been pro­
well-researched. posed pre-, during-, and post-disuse to aid in mitigating skeletal muscle
Resistance exercise is a potent stimulator of MPS leading to muscle atrophy and are discussed in a review by McKendry and colleagues
hypertrophy and strength. Older individuals should aim to increase, or (2024) (McKendry et al., 2024b). Further research is warranted to
at least preserve, muscle mass and strength over time. There are various discover the optimal strategy to preserve muscle mass during disuse.
modes of resistance exercise, and there are various training strategies for However, it is evident that resistance exercise increases MPS and muscle

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T.A.H. Janssen et al. Current Research in Physiology 8 (2025) 100138

Fig. 4. Several factors influence/change muscle physiology with aging, such as fibrosis, anabolic resistance, mitochondrial structure, decreased muscle mass, lower
phosphorylation of several signalling pathways, mitochondrial ROS production increases, higher systemic inflammation, stiffer connective tissue, a greater chance of
developing T2D, increased use of medication, and fibrosis of the ECM. The changes/consequences in muscle physiology with aging are divided in 3 subsections. ROS;
Reactive oxygen species, T2DM; Type 2 diabetes mellitus, ECM; extracellular matrix. Figure created using BioRender.

mass, so getting active now may put you in a better position later in life. adult populations, such as those with overweight/obesity (Watanabe
et al., 2024; Mahase, 2024). However, currently, studies are done on
5. Research issues in aging muscle physiology in humans older adults who are not taking these certain medications. Numerous
studies have specifically recruited older adults who are not taking any
Working with older persons in muscle physiology research presents medications. However, this methodology substantially increases the
several challenges. Researchers face many difficulties when investi­ time and resources required to achieve adequate participant enrollment.
gating age-related muscular adaptations in older adults. As much as This raises concerns about the generalizability of such findings to the
researchers in this field acknowledge the issues with completing clinical broader older population, given that it is uncommon to find individuals
trials and studying in this area, here we outline some of the barriers to over the age of 60 who are not on any pharmacological treatment. In
work in this field. summary, it is difficult to isolate conditions within aging when in­
dividuals are on medication that affects the muscle; however, finding
5.1. Medication use older adults not on medications is difficult and often limits the gener­
alizability of the results.
The exclusion criteria of any given study would ideally include a
variety of medications that may affect muscle metabolism or the 5.2. Causal relationships
response to an exercise and/or nutritional intervention; for example,
chemotherapy, use of anabolic steroids, use of hormones, etc. Older When looking at the causal relationships of sarcopenia, the effects of
individuals are, however, prescribed a combination of medications the natural aging process, inactivity, and medication use are almost
either prophylactically or to control the symptoms of a current condi­ impossible to separate. As mentioned before, older inactive persons
tion, such as hypertension, hypercholesterolemia, and various others. In usually take one or more medications that can influence the muscle
2015–2016, according to the National Center for Health Statistics, environment or the muscle directly, and therefore, it becomes difficult to
53.3% of the older population aged 60–79 years old took 1 or more discern the effect of the natural aging process in an individual. In
medications, of which 10.4% took 5 or more medications (Hales et al., addition, since older adults typically have lower muscle mass and
2019). It can be assumed that this percentage is even higher in older reduced ability to build muscle or recover from disuse than healthy
adults with a BMI higher than 25. The increasing popularity of GLP-1 adults, bed rest studies to investigate the effect of inactivity are difficult
agonists as a medication for type 2 diabetes mellitus or as a weight to justify ethically.
loss strategy highlights the difficulties in recruitment in specific older

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6. Future directions Acknowledgements

Conducting research in an older population and specifically focusing It is with great gratitude that the authors thank the researchers
on the effect of aging can be challenging. However, the outcomes of involved in the studies included in our review.
these studies will provide valuable information to help mitigate declines
in muscle with aging, and thus, participation in aging studies should be Data availability
promoted. Focusing on isolating the causal relationships between
normal aging, (in)activity, medication use, and medical complications is No data was used for the research described in the article.
crucial, and creating new models in which we can effectively isolate
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