Although deteriorating function of all organs accompanies aging, this review focuses on skeletal muscle, the largest organ in the body, because of its central role in frailty. Aging across species (from worms and flies to mice and humans) is associated with slowing of movement, and sarcopenia—the loss of muscle mass and function—is a major contributor to decreased mobility in older adults. With aging, loss of muscle mass and strength (as much as 1% per year after age 30) results in a prevalence of age-related sarcopenia of at least 6%–12% in people over age 65, but prevalence estimates varying widely.1 The wide range in prevalence estimates is due to different definitions used for sarcopenia, and to the superimposition of muscle loss from other disease processes associated with aging. Loss of muscle mass with aging in men is also associated with fiber-type switching from fast fiber types to slower ones. Sarcopenia involves both the loss of muscle fibers and thinning of individual fibers, with fast fibers more susceptible to loss than slow fibers.
Anesthesiologists should be aware that sarcopenia is associated with increased perioperative mortality and hospital costs. Central sarcopenia, quantified on computerized tomography (CT) by measuring psoas muscle area (or area of dorsal muscle groups), is associated with increased mortality after liver transplantation, and higher payer costs after other major surgeries.2 Using analytic morphomics of psoas muscle, Englesbe et al3 showed that morphometric aging (ie, sarcopenia) is associated generally with increased surgical risk. Notably, sarcopenia not only increases risk after major surgery, sarcopenia (radiographic cross-sectional muscle area at L3) increases risk for complications after smaller procedures like ear, nose, and throat (ENT) surgery4 and is a predictor of difficult weaning from mechanical ventilation.5 In the intensive care unit (ICU), acute muscle wasting can be profound especially in the context of sepsis, exacerbating underlying age-related sarcopenia.6
Many disease processes can exacerbate sarcopenia including chronic obstructive pulmonary disease (COPD), diabetes, heart failure, chronic kidney disease. and chronic liver disease. Liver disease massively disrupts the balance between anabolism (protein synthesis) and catabolism (proteolysis) needed to maintain muscle mass, such that sarcopenia is very common in liver transplant patients and may not be reversible after successful transplantation.7 Unfortunately, drugs commonly used in older populations, particularly statins, can also contribute to sarcopenia. On the other hand, angiotensin-converting enzyme inhibitors may help maintain muscle mass.8 Sarcopenia here is discussed as distinct from cachexia, often associated with cancers; cachexia is more driven by inflammation than is sarcopenia.
Sarcopenia and osteoporosis often occur concurrently in older adults, leading some researchers to suggest they are 1 disease (“osteosarcopenia”).9 Whether a single disease or not, the molecular crosstalk between the muscle secretome and bone cytokines is critical for maintaining bone and muscle health, such that the 2 disorders share several pathophysiologic mechanisms. The secreted products of fat (adipokines) exacerbate muscle loss. Adipocytes in the setting of obesity produce excess lipid which they cannot store, and so lipid accumulates intramuscularly. Intramuscular lipids (with paracrine signaling) in turn contribute to loss of muscle mitochondrial function and induce local accumulation of proinflammatory cells including macrophages. Via these mechanisms, obesity exacerbates sarcopenia.10 The loss of motor neurons and motor neuron function also contribute significantly to sarcopenia with aging, with motor neuron deficits a function of the aging oxidized redox state.11
Here the focus is on “pure” age-related sarcopenia, which has complex, multifactorial causes (Figure 1). Genetics is certainly a determinant in patterns of sarcopenia, but genetics can be positively modified by lifestyle—that is, good nutrition, resistance training, physical activity. A role of the microbiome in sarcopenia has recently been raised but is not addressed here, as the data are currently speculative. Here the causes of sarcopenia are addressed at multiple levels: the cellular (stem cells, senescent myoblasts), subcellular organelle (mitochondria, lysosomes), and circulating factor (hormones, inflammatory mediators, oxidative pathways) levels (Figure 1). Though frailty and longevity are controlled by overlapping pathways, longevity mechanisms are not discussed. This review only grazes the surface of the complexity of mechanisms contributing to sarcopenia, with emphasis on interplay between them, and readers are referred to other excellent reviews throughout.12
MEDIATORS OF SARCOPENIA
Mitochondria as Drivers of Sarcopenia
Mitochondrial function generally declines with aging in all organs. Mitochondrial homeostasis of number and quality of mitochondria and mitochondrial deoxyribonucleic (mtDNA) acid is maintained by the processes of mitochondrial fission and fusion, as well as regeneration or biogenesis, balanced by mitophagy, all independent of the cell cycle (Figure 2). Of these processes, only mitophagy can turn over entire mitochondrial genomes, so it functions to clear out mtDNA mutations that accumulate with aging and contribute to muscle dysfunction.13
Regulation of mitochondrial biogenesis, fusion, and fission is complex, but illustrates the interdependence of mechanisms that lead to age-related sarcopenia, and the difficulty of pinpointing the relative contributions of these various regulators. Thyroid hormones are potent regulators of mitochondrial biogenesis. Though hypothyroidism is common in older adults, the magnitude of hypothyroidism contributing to sarcopenia is unclear. (Hyperthyroidism also causes muscle weakness.) Testosterone regulates mitochondrial biogenesis and the prevalence of testosterone deficiency increases with age. Cellular senescence (including irreversible exit from the cell cycle) is driven by mitochondria but during development of cellular senescence, mitochondrial biogenesis may increase, likely as an aberrant regenerative response to increased reactive oxygen species (ROS) and expression of senescence-related proteins, resulting in accumulation of dysfunctional mitochondria. Though mitochondrial biogenesis can be dysregulated with aging, the capacity for positively regulating mitochondrial biogenesis is not lost even at the extremes of age, and improved muscle function with exercise in older adults is associated with increased mitochondrial biogenesis.
Declining mitochondrial function with aging translates into a decreased mitochondrial respiratory capacity and increased production of harmful ROS. Dysfunctional mitochondria also enhance protein turnover and protein loss, contributing to sarcopenia. Mitochondria are generally considered drivers of sarcopenia, but the mitochondrial population of a cell is composed of both healthy and dysfunctional mitochondria, and methods to selectively target the damaging mitochondria have not yet emerged.
Mitochondrial Life Cycle Events Associated With Aging
Regulation of mitochondrial biogenesis involves expression-level changes in more than 1000 genes and crosstalk between the mitochondrial and nuclear genomes. In general, aging is associated with reduced capacity for mitochondrial biogenesis. A central nuclear regulator of mitochondrial biogenesis and oxidative phosphorylation in both skeletal and cardiac muscle is the peroxisome proliferator–activated receptor-gamma (PPAR-γ)γ transcriptional coactivator, PPAR-γ transcriptional coactivator (PGC-1α).14 PGC-1α activity is upregulated by exercise, but blunted by inactivity, obesity, and excess caloric intake. At the molecular level, PGC-1α activity is increased by resveratrol (via sirtuin-1) and diet restriction, nitric oxide (known to be reduced with aging), cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), 5′adenosine monophosphate–activated protein kinase (AMPK), and the p38 mitogen–activated protein kinase (P38MAPK) pathway in response to cellular stress. Negative regulators of PGC-1α activity include receptor-interacting protein (RIP)140 and 160 myelin basic protein (MBP; reviewed in reference 15). At the systems level, PGC-1α plays a central role in energy metabolism and glucose homeostasis.
PGC-1α promotes mitochondrial biogenesis by activating nuclear respiratory factors 1 and 2 (Nrf1, Nrf2); in turn, they activate mitochondrial transcriptional factor A (TFAM), the deoxyribonucleic acid (DNA)-binding protein that drives transcription in the mitochondrial genome and mtDNA replication (Figure 2). Biopsy studies of human muscle to quantitate these important factors are few, so there are disparate results about abundance of Nrf1, Nrf 2, and TFAM in muscle with aging. Some studies suggest reduced expression of these factors with aging while others suggest increased expression,16 with reduced levels more consistently demonstrated in insulin-resistant or frankly diabetic subjects. However, there is consensus that exercise results in upregulation of PGC-1α and Nrfs,17 and that this response is blunted in diabetics.
AMPK is a metabolic sensor at the core of energy homeostasis and stress resistance, with mitochondrial biogenesis only 1 of many major ways the molecule regulates the balance of anabolism and catabolism in skeletal muscle. Simplistically when muscle anabolism outpaces catabolism, muscle growth is enhanced; when catabolism dominates, muscle atrophies. AMPK acts as an energy sensor by inhibiting anabolic processes that consume adenosine triphosphate (ATP) and activating catabolic processes that generate ATP. The protein synthetic promoting activity of AMPK is mediated through the mammalian target of rapamycin (mTOR) pathway, which regulates the cell cycle by integrating intracellular and extracellular signals. AMPK together with the ubiquitin-proteasome complex mediates protein catabolism in muscle. AMPK also regulates fat oxidation, and satellite stem cell dynamics (see below). These and other signaling pathways engaged by AMPK place this molecule as a central regulator of muscle size.18 Like PGC-1α, AMPK is upregulated by exercise, and has been dubbed an exercise mimetic by Narkar et al,19 making it an attractive drug target.20 AMPK and silent mating type information regulation 2 homolog 1 (sirtuin-1, SIRT1) are both activated by adenosine monophosphate (AMP) and nicotinamide adenine dinucleotide (NAD+).
SIRT1 is also a regulator of mitochondrial biogenesis, in part through its modification (deacetylation) of PGC-1α to increase PGC-1α–mediated transcriptional activation. Caloric restricted humans show upregulation of SIRT1, endothelial nitric oxide synthetase (eNOS), mitochondrial TFAM, and mitochondrial number on muscle biopsies. SIRT1 is thought to decrease ROS production by increasing mitochondrial biogenesis and mitochondrial activity. Biogenesis is thought to reduce ROS production by increasing the electron transport chain components and availability of entry points for electrons to enter the electron transport chain.21
Mitochondrial quality control is promoted by dynamic reshaping of mitochondrial structure through fission versus fusion, and through deletion of malfunctioning mitochondria by mitophagy. An important principle in evaluating mitochondrial structure is that mitochondrial morphology reflects respiratory activity, so that significant insights about function can be gained using electron microscopy.22 Loss of mitochondrial fusion capacity leads to mitochondrial dysfunction and decreased respiratory capacity, and muscle atrophy. Fusion leads to mixing of mitochondrial content (including heteroplasmic mtDNA) to generate larger mitochondrial networks and is a way to protect against pathologic mtDNA genomes by complementation. Further, loss of mitochondrial fusion in muscle is also associated with increased mtDNA mutations.23 With aging, fusion is a way to compensate for accumulated mtDNA mutations, as well as to dissipate energy in muscle. The main genes regulating mitochondrial fusion are mitofusin 1 (Mfn 1) and mitofusin 2 (Mfn 2) located in the outer mitochondrial membrane and optic atrophy-1 (OPA1) located in the inner mitochondrial membrane.24
Fission is another mitochondrial quality control mechanism and a necessary prerequisite for removing damaged mitochondria by autophagy. Fission results in “daughter” mitochondria that are very distinct from each other. In particular, fission-generated daughter mitochondria with a lower mitochondrial membrane potential (a characteristic of senescent cell mitochondria) are targeted for degradation, leaving behind a “daughter” with a relatively normal membrane potential and ROS levels.25 The main genes involved in mitochondrial fission are dynamin-related protein-1 (Drp1), mitochondrial fission factor (Mff), and mitochondrial fission 1 protein (Fis1). Drp1 is a dynamin guanosine triphosphatase (GTPase; recruited from the cytosol to mitochondrial by Mff) that constricts the mitochondrial membrane, often in locations where mitochondria contact endoplasmic reticulum (ER).26 Mechanistically, Drp1 and Fis1 colocalize to mark scission sites.27
With aging, an imbalance between mitochondrial fusion and fission can lead to mitochondrial dysfunction in 2 different directions: A predominance of fission over fusion leads to fragmented mitochondria, less mtDNA integrity than would be accomplished with complementation/fusion, and increased ROS stress. A predominance of fusion over fission leads to enlarged mitochondria that cannot be easily degraded, and ROS stress.27
Mitophagy (mitochondrial autophagy) is also a highly regulated process in which damaged and/or damaging mitochondria are selectively eliminated. Loss of ability to remove damaged mitochondria and damaged cells is considered a hallmark of aging. An activator of mitophagy, urolithin A, is the focus of an interesting antiaging clinical trial (NCT04160312), with a long-term goal of improving skeletal muscle function in older adults. The major regulators of mitophagy are phosphatase and tensin homolog–induced kinase (PINK1), the cytosolic C3 ubiquitin ligase Parkin (familial early-onset Parkinson disease is associated with mutations in these genes), and nonspecific immunosuppressive protein3–like protein (NIX; in red blood cells).28 Loss of mitochondrial membrane potential is an important initiator of mitophagy, with an early event accumulation of PINK1 on the outer membrane of damaged mitochondria. PINK1 activates and recruits Parkin, which translocates to the mitochondrial surface and ubiquitinylates mitochondrial outer membrane proteins (including the voltage-dependent anion channel [VDAC]) and recruits other mitophagy machinery proteins. Other programs including NIX (beside PINK1/Parkin) can regulate mitophagy especially in the setting of hypoxia (reviewed in reference 29). The process of decorating the mitochondria with molecules that modify membrane proteins leads to nucleation of the membrane, then engulfment by the autophagosome. The autophagosome is a double-membrane vesicle formed by the sealing of a membranous phagophore. The source of membranes (a subject of some controversy) is ER, Golgi complex, and plasma membrane. In general, the size and number of autophagosomes are regulated by a family of autophagy-related genes as well as the internal cargo of the autophagosome. Accumulation of autophagosomes that do not fuse with lysosomes is cytotoxic but the role of these skeletal muscle accumulated prefusion vesicles per se in sarcopenia is not clear, whereas this accumulation is increasingly recognized in the pathophysiology of neurodegenerative disease. The final stage of autophagy is fusion of the autophagosome and its mitochondrial cargo with the lysosome.
Lysosomes and Sarcopenia
Lysosomes are the catabolic organelles of the cell, the regulators of autophagy, or degradation of unwanted cellular cargo, acting as an important quality control for the cell. Lysosomal degradation of dysfunctional organelles, pathogens, and pathogenic proteins is central to cell and tissue homeostasis. The importance of lysosomal dysfunction in a broad range of disease processes was recognized with the Nobel prize in 2016 to Yoshinori Ohsumi, who identified the first genes essential for autophagy.
Autophagy is not just a bulk process, it is highly selective, and with aging, a decline in autophagy can lead to decreased clearance of oxidatively damaged proteins and dysfunctional mitochondria, further feeding a cycle of cell damage.30 Lipid changes in the lysosomal membrane are thought to contribute to autophagy dysfunction with aging, and these changes may be regulated in part by lipids in the diet, and positively impacted by exercise. Lysosomal dysfunction as well as decreased proteasome activity and decreased autophagy lead to accumulation of damaging proteins that perpetuate muscle damage. Autophagy is also important for regulating the resident stem cells of skeletal muscle, called satellite cells. Loss of or dysfunctional autophagy with aging can lead to loss of satellite stem cell function resulting in the satellite cells entering a state of senescence, so that they cannot contribute to muscle regeneration as needed.
The molecular regulation of autophagy is intricate and complex and not reviewed here, instead, the wide range of major pathways regulated by lysosomal turnover in muscle is depicted in Figure 3. The lysosome is not just a “wastebasket,” it is a source of signals regulating cell growth, division, and differentiation, and a center for recycling. Lysosomal V-type adenosine triphosphatase (V-ATPase) is a nutrient sensor that acidifies the lysosome interior.31 A variety of amino acid and ion transporters control intralysosomal concentration of amino acids, calcium, iron, and copper. The interior of lysosomes is rich in enzymes that break down lipid, protein, sugars, and nucleotides. Lysosomes fuse or make membrane contact with mitochondrial-containing autophagosomes and autophagosomes carrying other cargo; with peroxisomes transporting cholesterol from the lysosome32; and with lipid droplet organelles. At the systems level, reduced lipophagy and mobilization of intracellular lipids contributes to age-associated obesity and metabolic syndrome.33 Lipid deposition in skeletal muscle is a well-recognized age-associated pathology, contributing to insulin resistance and loss of muscle strength.34
Satellite Stem Cell Number and Function
The adult resident stem cells of skeletal muscle (satellite cells), like other stem cells, can self-renew or differentiate depending on physiologic context. Throughout life, with muscle injury, the satellite cells mobilize to recapitulate developmental pathways and build new muscle. Satellite cells are the major cellular source of regeneration of new muscle throughout life, though other myogenic stem cell populations have been identified in skeletal muscle and marrow. Like hematopoietic stem cells in marrow, satellite cells are highly regenerative and on injury, exit from their usual quiescent state and proceed through highly regulated mobilization, proliferation, and differentiation processes.35 Also like hematopoietic stem cells in marrow, satellite cells occupy a particular niche inside skeletal muscle, between the sarcolemma and basal lamina on the muscle fiber surface.
The programs of skeletal muscle development and adult regeneration are summarized in Figure 4. The definitive marker of the satellite stem cell is the homeobox transcription factor paired box (Pax)7,36 but the cells also characteristically express the hepatocyte growth factor receptor, tyrosine protein kinase Met (c-met); heparan sulfate proteoglycans syndecan-3 and syndecan-4 involved in fibroblast growth factor signaling37; cluster of differentiation (CD)56, neural cell adhesion molecule; CD29, integrin β-1; and chemokine receptor type 4 (CXCR4), the receptor for stromal-derived factor-1. Across mammalian species, the number of Pax-7–positive satellite stem cells is likely reduced with aging, though this is somewhat controversial. Aging is associated (again analogous to hematopoietic stem cells) with loss of satellite stem cell population heterogeneity and function.
Across the top of Figure 4, the major transcriptional regulators controlling myogenic differentiation are shown at approximately the stage where they are turned on. Pax7 and Pax3 are involved in activation of the satellite cells, but activation is also regulated by a variety of cytokines and chemokines secreted from immune cells on muscle injury, various growth factors, and signaling pathways including Notch and wingless and int-1 (Wnt; summarized in reference 38). With aging, studies in mice suggest that satellite cells express inhibitors of activation, making them more difficult to mobilize when needed.39
The myogenic regulatory factors (myogenic factor 5 [Myf5], myoblast determination protein 1 [MyoD], myogenin, myogenic regulatory factor 4 [Mrf4]) take over the regeneration of muscle at the myoblast stage. These are basic helix-loop-helix transcription factors, with MyoD expression induced by other transcription factors including Pax 7 and Pax 3. Myoblast proliferation is followed by differentiation, with myoblasts fusing into multinucleated myotubes.35 Transforming growth factor-β (TGF-β) and the TGF-β family member myostatin inhibit muscle regeneration and differentiation at every stage of these processes.
A minority of myoblasts return to a quiescent satellite state to replenish the stem cell pool, but regenerated muscle cross-sections show that these cells do not return to their original stem cell niche. The loss of intrinsic myogenic potential of myoblasts (separate from satellite cell number) from aged muscle is a subject of some debate. The ability to build muscle with proper exercise and training at any age is clinical evidence that myogenic potential is at least relatively preserved with aging. However, senescent human myoblasts studied ex vivo are unable to make large myotubes to the extent mediated by young myoblasts.40
Rather than downregulation of the myogenic transcription factors with aging, loss of muscle regenerative potential is attributed to oxidative damage and altered mitochondrial function and metabolism, proteostasis, and entry into a senescence phenotype. Extrinsic factors in the local stem cell niche and in circulation (ie, hormones, growth factors, vitamins, minerals, other signaling molecules, oxidants) also play an important role in satellite cell aging. The reversibility of satellite cell aging was dramatically demonstrated in mouse heterochronic parabiosis experiments, in which the circulations of old mouse and young mouse are surgically joined. Exposure of aged satellite cells to the young circulation resulted in rejuvenation (restored regenerative potential) of the aged stem cells in situ.41 The precise combinations of circulating factors mediating rejuvenation of muscle stem cells in this context are not completely understood. However, hormones certainly contribute to this experimental rejuvenation and support a role for hormonal changes with aging contributing to sarcopenia.
The hormonal contribution to sarcopenia with aging has mostly focused on androgens, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). In men, testosterone levels decrease with age, starting at about age 40 years; about half of men over age 80 years have hypogonadal testosterone levels, associated with muscle and bone loss, decreased strength, and increased central body fat. Testosterone loss also negatively impacts glucose and lipid metabolism, contributing to age-related development of diabetes. Androgen levels also decline in women with aging and this loss similarly contributes to loss of muscle mass and function.42 Estradiol (derived from testosterone aromatization) which stimulates satellite cell function, is also lost with aging in women, and though considered important for maintenance of muscle mass in women, is poorly studied. Estrogen therapy in women is associated with maintenance of skeletal muscle mass.
Testosterone therapy recommendations have evolved considerably and though testosterone replacement can substantially improve muscle mass, strength, and body composition, these gains do not last after therapy is discontinued, and testosterone replacement is complicated and controversial. In hypogonadal men, testosterone improves skeletal muscle strength and function, but is associated with increased risk for myocardial infarction and stroke, so must be individually tailored. Women are increasingly treated with testosterone (for decreased libido) and can see improved muscle mass and function with therapy, but the role for testosterone therapy in older sarcopenic women is not defined, and the therapy is associated with significant side effects. Estrogen is thought to be muscle-protective through its anti-inflammatory effects.
Reduced somatotropic signaling (GH and IGF-1) is an important contributor to sarcopenia with aging.43 Some but not all circulating IGF-1 depends on GH-dependent secretion. GH is anabolic, and treatment with GH can increase muscle mass and reduce adiposity in older adults, but prevention and treatment of sarcopenia with GH has not attracted much attention compared to its purported antiaging and prolongevity properties. Some studies have noted that GH therapy is not effective for increasing muscle mass without exercise as part of the therapeutic regimen. In addition to its anabolic properties, GH may help maintain muscle mass through antioxidant and anti-inflammatory effects. Though GH therapy in older adults can increase lean body mass, it is associated with significant acute side effects and a theoretical risk of carcinogenesis. Similarly, IGF-1 independently maintains muscle mass through antioxidant pathways and mitochondrial protection as well as improving insulin resistance and may be the most important hormonal mediator of muscle repair. However, IGF-1 is considered a risk factor for cancers, particularly breast cancer, and so has not been developed for treatment of sarcopenia.
A summary of hormonal mediators contributing to sarcopenia is shown in the Table, and the reader is referred to several good reviews of this subject that discuss the mechanisms through which these myriad hormones contribute to sarcopenia.44–46
Hormones Involved in Age-Related Sarcopenia
| Cortisol (but blunted diurnal pattern)a
| Thyroid hormone
| Parathyroid hormone
| 11β-HSD1 (cortisone reductase)a
| Insulin (resistance)
| Vitamin D
Dysregulation of hormones from multiple systems may contribute to sarcopenia with aging. Hormones that are increased with aging are noted with a. All others are usually decreased with aging. Hormones produced in more than 1 organ are only noted in a single organ. Evidence for the hormones discussed in the text is most compelling for a role in sarcopenia (GH, IGF-1, sex hormones).
aHormones that are increased with aging.
Abbreviations: 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; GDF-11, growth and differentiation factor-11; GH, growth hormone; GI, gastrointestinal; IGF-1, insulin-like growth factor-1.
Myostatin, though not a hormone, deserves mention here because of its potential as a target for treating sarcopenia. This cytokine produced in skeletal muscle is a member of the TGF-β family and is the most potent negative regulator of muscle mass.47 The role of increased myostatin levels with aging in promotion of sarcopenia has not been established but antimyostatin therapies hold considerable promise for prevention or treatment of sarcopenia.
Inflammatory Mediators of Sarcopenia
Aging is a proinflammatory process and many inflammatory mediators are associated with sarcopenia, though the associations may not be specific for muscle. Elevated levels of C-reactive protein (CRP), interleukins 6 (IL-6), and IL-8 (downstream of nuclear factor-kappa B [NF-kB] signaling), tumor necrosis factor-α, interferon-γ, and granulocyte-monocyte colony-stimulating factor among others have all been associated with reduced muscle mass and function with age-related sarcopenia.48 The source of some of these proinflammatory cytokines is the senescent cells that accumulate with aging in muscle and other tissues.
IL-6 and CRP in particular are called “geriatric cytokines,” and chronic elevation of these cytokines is associated with loss of muscle strength, but a direct catabolic role for these cytokines has not been established.49 Loss of estrogen in older women may contribute to increased IL-6 levels. IL-6, IL-1β, tumor necrosis factor-alpha (TNF-α) and interleukin-1 receptor antagonist (IL-1ra) are all produced in muscle in older people and have been linked to the so-called inflammaging process.50 Anti-inflammatory IL-10 is also produced in muscle, and some (but not all) studies suggest that its production is reduced with aging.51
Increased numbers of senescent cells accumulate with aging, an example of antagonistic pleiotropy: senescent cells by definition lose capacity to proliferate, so cellular senescence acts as to suppress cancer development in early adulthood, but later in life cellular senescence contributes to frailty.51 In tissue culture, senescent myoblasts assume a very obvious, distinctive phenotype (Figure 5). They become splayed out, enlarged and flattened, with very irregular borders. Muscle that accumulates senescent cells becomes thinner, a feature of sarcopenia, also seen in cultured myoblasts. Senescent cells express increased levels of the tumor-suppressing cyclin-dependent kinase inhibitors p16 and p21 and accumulate senescence-associated β-galactosidase (which is useful for staining/marking senescent cells in the lab), and reduced nuclear levels of lamin B1, involved in integrity of the nuclear lamina matrix.52 Contrary to expectation, increased activation of caspase-8 and its downstream caspase-3 is characteristic of senescent cells.53 Telomere shortening also leads to activation of caspase-3. Caveolin-1 is upregulated by cell stress and mediates the senescence response through activation of p53/p21, focal adhesion kinase, and small GTPase pathways, and inhibition of epidermal growth factor receptor/extracellular signal–regulated kinase (EGFR/ERK)-1/2 pathways.54
The senescence-associated secretory phenotype (SASP) refers to the distinctly more proinflammatory secreted products of senescent cells compared to their neighboring nonsenescent cells.55 In addition to the inflammatory mediators mentioned above, other secreted factors from senescent cells contribute to sarcopenia including matrix metalloproteinases, TGF-β, oxidized lipids, and ROS. The SASP also induces the unfolded protein response in the ER, activating transcription factors that encode chaperones and ER-associated autophagy proteins. Cytoplasmic chromatin fragments (CCF) promote the SASP.56 Furthermore, the SASP can be induced locally in normal bystander myocytes by the secreted products of senescent cells via autocrine or paracrine mechanisms. The remarkable toxicity of a few senescent cells is highlighted by experimental transplantation of these cells into nonsenescent mice, resulting in recapitulation of aging disability. Further, experimental ablation of senescent cells results in functional improvement, or reversion to a more youthful phenotype, raising hope for “senolytic” drug strategies.57 Other experimental antisenescent strategies, such as inhibition of signal transducer and activator of transcription-3 (STAT3) involved in cytokine and growth factor signaling, also have the potential to restore regenerative capacity in sarcopenic muscle.58,59
Reactive oxygen species (ROS) drive cell damage and cellular senescence with aging. The mitochondrial electron transport chain is the major source of ROS in skeletal muscle, such that mitochondria are locally susceptible to ROS damage, and increased production of ROS with dysfunctional mitochondria is a well-characterized aging pathology. MtDNA is more susceptible to damage than nuclear DNA, because mtDNA sits next to ROS production machinery, lacks protective histones, and is more transcriptionally active than nuclear DNA.60 Aging is also associated with the loss of antioxidant capacity in skeletal muscle, including in the satellite cells. Further, ROS modulate signal transduction involved in calcium homeostasis in skeletal muscle by changing the redox status of important muscle contractile proteins such as calcium-activated adenosine triphosphatase (Ca2+-ATPase) and the ryanodine receptor (RyR).61
Smoking and excessive alcohol consumption contribute to sarcopenia. Diet across the lifespan is important in preventing sarcopenia, though much of the literature supporting this conclusion is observational. Adequate protein intake, vitamin D, antioxidant, and anti-inflammatory nutrients are considered important for maintaining muscle mass with aging, as well as avoidance of excess fats. Good nutrition and exercise together are critical for maintaining muscle mass with aging, and several groups have shown that exercise is not effective without good nutrition. A sedentary lifestyle with aging is a very important contributor to muscle atrophy, exacerbating the effects of natural age-related muscle loss. Exercise is the best-characterized therapy for prevention and treatment of sarcopenia with aging and has beneficial effects on many of the underlying drivers of sarcopenia,62 including mitochondria, lysosome, and stem cell function, as well as antioxidant and anti-inflammatory effects. In particular, loss of fat mass reduces inflammation from adipokines and insulin resistance.
Sarcopenia is a degenerative disease associated with aging and a major contributor to frailty. The underlying mechanisms leading to sarcopenia are complex, multifactorial, and interconnected. Despite increased understanding of the molecular underpinnings of sarcopenia, exercise remains the main well-characterized (epigenetic) therapy for sarcopenia, affecting many pathophysiologic factors that drive the loss of muscle mass at the systems, cellular, subcellular, and molecular levels. Future new therapies for sarcopenia likely to emerge from the basic sciences include specific targeting of mitochondrial biogenesis, drugs that enhance satellite stem cell regenerative capacity, and senolytic drugs to remove the toxic byproducts of senescent cells.
The author acknowledges Andrea Loewendorf, PhD, for creating the figures.
Name: Marie E. Csete, MD, PhD.
Contribution: This author conceived of and wrote the manuscript.
This manuscript was handled by: Robert Whittington, MD.
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