The aging muscle: sarcopenia, mitochondrial function, and redox biology| JOURNAL OF GERONTOLOGY AND GERIATRICS

Abstract

Sarcopenia, age-related skeletal muscle loss and weakened strength, hinders functional independence, elevates mortality risk, and strains healthcare systems. Diagnosis varies among working groups, leading to diverse prevalence estimates. Recent meta-analyses suggest a 10% overall prevalence, increasing with age and peaking at 50% for those aged 80 or older. Standardized diagnostic criteria are essential for addressing this significant health concern. Sarcopenia is associated with structural and functional muscle changes, including mitochondrial alterations and disruptions in redox balance. Given the pivotal role of mitochondria in the pathogenesis of sarcopenia, further preclinical and clinical studies are needed to gain a deeper comprehension of redox signaling pathways and to identify targeted therapeutic strategies.

INTRODUCTION

Sarcopenia is characterized by low muscle strength as the primary parameter, with a diagnosis confirmed by the presence of low muscle quantity or quality, and considered severe when low muscle strength, low muscle quantity/quality, and low physical performance are all detected ¹. This condition exerting a negative effect on functional autonomy due to muscle weakness and disability, and increasing the risk of mortality ^2-4. Furthermore, sarcopenic subjects show a higher mortality rate as well as a considerable economic burden for healthcare systems ^5,6. Even though a decrease in skeletal muscle mass is frequently indicated as the “primum movens” of sarcopenia, strength reduction can occur even several years before muscle mass loss ⁷. Age-related loss of muscle strength without involvement of muscle mass is named dynapenia ⁷. From a clinical perspective, sarcopenia can be diagnosed by applying different criteria related to skeletal muscle mass, strength and performance. Procedures of working groups on sarcopenia are constantly updated, resulting in a loss of uniformity in diagnostic criteria without universal consensus. Indeed, diagnosis of sarcopenia according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), the Asian Working Group for Sarcopenia (AWGS), the Sarcopenia Definition and Outcomes Consortium (SDOC), and the Foundation for the National Institute of Health (FNIH) relies on different diagnostic criteria ^1,8-10. Use of different criteria and diagnostic methods leads to different prevalence values in the same population ^11,12.

Indeed, according to a recent meta-analysis, the overall prevalence among individuals aged ≥ 60 may range from 10 to 27% ¹³. Of note, the prevalence of sarcopenia increases with age, peaking to 50% in people aged 80 years or older ¹⁴.

SKELETAL MUSCLE CHANGES DURING AGING

Aging is associated to changes in body composition, represented by an increase in fat mass and a decrease in lean mass and bone mineral density ¹⁵. From 20 to 80 years of age, bout 30% of skeletal muscle mass and 20% of cross-sectional area (CSA) are lost ¹⁶. In community-dwelling individuals aged 75 years or older, longitudinal studies report the rate of skeletal muscle mass loss at 0.64-0.70% per year in women and 0.80-0.98% per year in men, this rate is worsened by muscle unloading in inactive old people ^3,17. Several underlying mechanisms drive this change, with a network of interacting dysfunctional systems involving protein turnover, reactive species, reduced number of satellite cells, neuromuscular and mitochondrial changes, and inflammation ³ (Fig. 1). These processes may promote a decrease in the number of skeletal muscle fibers and CSA, and impaired regeneration, as described in older humans ³. In old age, both size and contractile function of fibres expressing slow myosin heavy chain (MHC) I are preserved, whereas there is a marked decrease of these features in fibres expressing the MHC II isoforms ¹⁸.

Progression of aging is associated with a significant reduction in the regenerative capacity of the muscle. Importantly, capillarization is crucial in this scenario. Trained aged animals showed a greater capillarization as compared to aged sedentary counterparts, suggesting that early revascularization may facilitate improved recovery in regenerative response. In fact, muscle capillarization not only facilitates a direct interaction between endothelial cells and satellite cells, but also allows for the distribution of growth factors from other cell types. Exercise can improve muscle capillarization in animal models ¹⁹.

AGING AND SKELETAL MUSCLE METABOLISM

Skeletal muscle mass depends on proteostasis, defined as the dynamic balance between muscle protein synthesis (MPS) and breakdown (MPB), folding and trafficking, in turn influenced by two main factors: food intake and physical activity ²⁰. One of the most important pathways involved in the muscle protein synthesis is modulated by the PI3K/Atk (PKB)/mechanistic target of rapamycin (mTOR) signalling ²¹. The mammalian target of rapamycin complex 1 (mTORC1) is an essential site of integration for anabolic signals, such as amino acids, insulin, and resistance exercise, to stimulate protein synthesis in human skeletal muscle via ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) ²². Skeletal muscle protein degradation depends by four major proteolytic pathways: the ubiquitin-proteasome system (UPS), calpains, caspases, and the autophagy-lysosomal pathway ²¹. In particular, the UPS plays a pivotal role in degradation of misfolded and aggregated proteins that accumulate during aging in skeletal muscle ²³.

Loss of skeletal muscle mass during aging is associated to unbalance between proteostasis. Increased catabolism may be attributed to differences in health status, insulin sensitivity, physical activity, and/or dietary habits in elderly subjects as compared to young ^24-26. In old people, basal total protein levels of mTOR, S6K1, and 4E-BP1 are downregulated as compared to young individuals ²⁷. Also, changes in mitochondrial DNA and ATP production affect muscle energy metabolism in older people. Aging is associated to reduction in mitochondrial mass, activity of tricarboxylic acid cycle enzymes, O2 consumption, and ATP synthesis ^28,29. Furthermore, age-related changes in tissue metabolism lead to impaired glucose, fat, protein uptake and utilization, and finally energy production. A natural decline in sex hormones, including androgens and estrogens, is a common aspect of aging. In men, bioavailable testosterone tends to decrease by approximately 2 to 3% annually after the age of 30. Women experience a reduction in estrogen levels during menopause. The observed variations in skeletal muscle metabolism and distinctions between males and females may be influenced, in part, by the age-related changes in sex hormones ³⁰. The disparities between males and females stem from the impact of sex hormones, contributing to greater skeletal muscle loss and increased visceral fat in males. This is accompanied by a prevalent reduction in capillarization of type II glycolytic myofibers ³¹. Estrogen, particularly estradiol, plays a crucial role in modulating skeletal muscle strength through various pathways involving immune cells and satellite cells ³². During menopause, the decline in estrogen levels is associated with a reduction in lean body mass and a decline in the regenerative capacity of muscles. Similarly, testosterone has a significant impact on muscle mass growth, and diminishing testosterone levels during aging are linked to a decrease in both muscle mass and strength. Studies have shown that testosterone supplementation in hypogonadal men can increase muscle mass and reduce fat content, possibly by elevating the number of satellite cells and promoting subsequent hypertrophy ³³. Low skeletal muscle capillarization may contribute to sarcopenia and reduced exercise capacity in older adults by limiting diffusion of substrates, oxygen, hormones, and nutrients ³⁴. Transcapillary transport of insulin is a major determinant of glucose uptake in metabolically active tissues, so that the age-related alterations of skeletal muscle capillarization contribute to insulin-resistance. In fact, impaired glucose tolerance or type 2 diabetes increase with advancing age ³⁵. Transporters involved in glycolysis and glycogen metabolism, as well as glucose transporter-4 (GLUT4), are downregulated ³¹. Several other age-related alterations in insulin signalling were reported in skeletal muscle, contributing to systemic insulin resistance and impaired glucose metabolism ³¹. As regards the proteolytic pathways in aged skeletal muscle, recent evidence attributes to E3 ubiquitin ligases (e.g., Parkin, UBR4, and Mib1) a key role in the development of proteostasis alterations. The reduction of E3 ubiquitin ligases may have detrimental effects on muscle homeostasis and function, although an accumulation in other E3 ubiquitin ligases can be just as deleterious ²³.

AGING, MUSCLE FIBERS, AND NEUROMUSCULAR CHANGES

During aging, several changes occur in the structure of skeletal muscle characterized by decreased satellite cell and fiber number, reduced fiber size, and decline in the expression of myosin heavy chain (MHC) isoform IIa (MHC IIa) ³⁶. Satellite cells (SCs) play a key role in repair and regeneration of skeletal muscle. However, aging affects the ability of SCs to regenerate muscle and replace lost myofibers. This impaired function appears to be mediated by changes in growth factors and cytokines present in the surrounding connective tissue microenvironment ^37,38. Impaired SCs function contributes to the development of sarcopenia ³⁹. Aging is associated with muscle fiber size reduction ³⁶. This reduction mostly involves type II fibers, with a 10-40% reported increase in the ratio of type I to type II fibres in humans ^3,40. Changes in fiber size seem to be related to fewer SCs in type II fibers and lower protein synthesis, which reduce the speed of skeletal muscle growth and repair ³⁶. SCs alteration in fast type II fibers suggests that stem cell depletion is prevalent in sarcopenia and may facilitate age-associated fast-to-slow transition ⁴¹.

Also, a key role for the development of sarcopenia is played by age-induced loss of motor units (MU). In fact, loss of MU may lead to fiber denervation and consecutively increased risk of muscle atrophy. Denervated fibers may be reinnervated by nearby axons in a process named MU remodelling ²⁰. In turn, aged MU remodelling is linked to the preferential denervation of fast-twitching type II fibers, characterizing faulty patterns of reinnervation by smaller motor neurons that establish slower-contracting type I MU ⁴¹. A failure to reinnervate fibers characterizes sarcopenic from no-sarcopenic aged subjects ²⁰.

However, conflicting data exist demonstrating no changes in the percentage of type I and type II fibres with age in humans ^3,42. These contradictory findings are most probably dependent on a slight number of younger participants in studies ³.

AGING AND MUSCLE ARCHITECTURE

Muscle architecture is one of the most important determinants of muscle strength and power performance ⁴³. Muscle architecture relies on muscle thickness, fiber fascicle length, and pennation angl ^44,45. Larger pennation angle is associated with higher skeletal muscle strength as well as higher CSA, leading to an improved ability of the muscle to develop strength ⁴⁶. Elderly people show decreased muscle thickness, fascicle length (FL), and pennation angle (PA) as compared to young adults ^47,48. Data show a reduction of 19.1% for cross-sectional area (CSA), 10.2% for FL, and 13.2% for PA in the gastrocnemius medialis muscle in old subjects as compared to young controls ⁴⁸. Magnitude of age-related decline expressed as percentage of muscle thickness appears to change across the different lower-limb and trunk muscles as compared to young ⁴⁹. Changes in muscle performance may precede alteration in muscle mass. Strength is lost more rapidly with a rate of 3-4% per year in men and 2.5-3% per year in women; indeed, the latest guidelines from EWGSOP2 have centered the diagnostic pathway for sarcopenia primarily on muscle loss ^17,49. Muscle composition has been correlated to maximal strength, independently of muscle size ⁵⁰. However, muscle power, defined as the product of the force and speed of muscle contraction, declines earlier and more markedly with aging as compared to muscle strength ^51,52. Indeed, patients affected by sarcopenia with reduced muscle CSA and volume exhibit changes in the spatial arrangement of muscle fibres, including alterations in fibre fascicle length, pennation angle, and muscle thickness. A decrease in fascicle length predicts a loss of sarcomere in series and a decrease in pennation angle, as well as a loss of sarcomeres arranged in parallel ⁴⁴.

AGING, SKELETAL MUSCLE AND INFLAMMATION

As individuals age, the immune system experiences significant changes, often referred to as immune senescence ⁵³. Inflammation represents a key factor in the development of sarcopenia and, interestingly, skeletal muscle has emerged as a regulator of immune function ^53,54. Aging is associated with higher levels of circulating cytokines and acute-phase proteins, characterizing a condition of chronic low-grade inflammation defined as “inflamm-aging” ^54,55. Circulatory cytokines contribute in activating or blocking signalling pathways involved in protein synthesis and proteolysis ⁵⁶. In fact, inflammatory mediators affect muscle protein metabolism, and elevated level of interleukin (IL)-6, tumor necrosis factor (TNF) and C-reactive protein (CRP) are associated with sarcopenia ^53,57. Data in elderly people show a significant association between high level of circulant IL-6 and sarcopenia, as well as high level of Il-6 and muscle strength reduction ⁵⁶. IL-6 exerts a complex biological profile with both pro- and anti-inflammatory effects, and further promotes skeletal muscle anabolism or catabolism, depending on the target structure. IL-6 facilitates skeletal muscle atrophy by blunting muscle anabolism and energy homeostasis, and it may also directly mediate muscle catabolism ⁵³. However, IL-6 knockout mice showed no significant difference in muscle catabolism as compared to wild type mice in an experimental model, so it can be assumed that the sole action of IL-6 is not sufficient to induce muscle wasting; indeed, the catabolic effect of IL-6 is dependent on the synergistic interaction with other factors that mediate the inflammatory response such as TNF-α ^53,58. TNF plays a crucial role in the loss of skeletal muscle mass by promoting protein degradation and decreasing protein synthesis ⁵⁶. Recently, Wu et al. demonstrated how TNF contributes to sarcopenia by triggering gasdermin E (GSDME)-mediated pyroptosis in myotubes. This occurs through the activation of caspase-8 and caspase-3, and they utilized caspase-8 and caspase-3 inhibitors for their study. Specifically, TNF-α activates caspase-8 and caspase-3 via TNF Complex IIb, leading to pyroptosis in myotubes. Consequently, pyroptotic myotubes show reduced expression of MHC1 and subsequent muscle fiber loss, which culminates in sarcopenia ⁵⁹. These pieces of evidence suggest that chronic low-grade inflammation can induce muscle wasting, while the homeostasis of skeletal muscle plays a role in maintaining healthy immune function. This interplay suggests that age-related disturbances in the balance between muscle and the immune system could be central to conditions like sarcopenia, where both systems potentially amplify each other’s dysfunctions ⁵³.

EPIGENETICS AND MUSCLE AGING

The regulation of gene expression significantly influences the phenotype of every tissue, and play a role in the aging process ⁶⁰. One hallmark of aging is the alteration in the epigenetic landscape, with DNA methylation being the most extensively studied epigenetic modification. DNA methylation can lead to heritable changes in gene expression without modifying the nucleotide sequence. Both genetic and environmental factors contribute to individual DNA methylation patterns, leading to variability of muscle aging ^61,62. Specifically, DNA methylation in aged skeletal muscle affect tissue-specific genes and, compared to young skeletal muscle, shows genome-wide hypermethylation. Early exposure to inflammatory stress during proliferative phases can lead to sustained hypermethylation of certain muscle regulatory factors ⁶². Past research, has highlighted both an age-related rise in DNA methylation and a decline in gene expression, underscoring the influence of DNA methylation on crucial metabolic genes in muscle and its potential involvement in age-associated metabolic diseases ^63,64. Notably, recent studies by Antoun et al., revealed extensive changes in muscle methylation associated with sarcopenia and related factors such as grip strength, lean mass, and gait speed. Their findings demonstrated that inhibiting Enhancer of Zeste Homologue 2 in human primary myoblast altered key cellular processes and methylation patterns. These insights emphasize the central role of epigenetics in muscle functionality and propose potential strategies for enhancing ATP production in sarcopenic muscle cells through targeted interventions ⁶¹. Additionally, consistent physical activity, encompassing endurance and resistance training, is associated with a reduction in genome methylation in young muscle, contrasting the hypermethylation observed with age, suggesting that increased activity levels might mitigate some age-related DNA methylation changes ⁶².

MITOCHONDRIAL FUNCTION IN SKELETAL MUSCLE

Mitochondria are organelles serve as the primary source of energy for cells. Mitochondrial respiration and ATP synthesis primarily rely on ADP sourced from ATP-consuming reactions occurring in the cytosol ⁶⁵.

Skeletal muscle mitochondria form an interconnected three-dimensional reticulum within and between skeletal muscle fibers, able to distribute energy and metabolites throughout the cell ⁶⁶. Almost two types of mitochondria subpopulation can be recognized, with differing morphology and biochemical properties: subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria ⁶⁷. A third mitochondrial subpopulation, called perinuclear, is located around the nucleus as a continuation of SS, even though it is less characterized than SS and IMF ³¹. SS mitochondria provide ATP for membrane active transport, while IMF mitochondria provide ATP to the contractile filaments within muscle to facilitate contraction. Also, the location of IMF mitochondria between the myofibrils adjacent to Z-line of sarcomere and in direct contact with transverse tubules, accounts for their key role in Ca2+ signalling within the cell ⁶⁷. Through regulation of Ca2+ levels, mitochondria in skeletal muscle modulate not only contraction, but also metabolism and intracellular signalling ^31,67. The different fiber types that compose human skeletal muscle (type I, IIa, and IId/x fibers) present with a different metabolic profile. Type I slow-twitch and IIa fast-twitch fibers are characterized by an oxidative profile with higher expression of oxidative enzymes, mitochondria, and capillary supply; on the contrary, type IId/x fibers exhibit a glycolytic metabolic profile, with prevalent expression of glycolytic enzymes, less mitochondria and capillary supply ⁶⁸.

Whole-body aerobic capacity depends mostly on skeletal muscle mitochondrial respiration ⁶⁹. However, the aerobic capacity, defined as the maximal ability to use oxygen to meet the energy demand of physical activity, tends to decline with age, especially after 50 years ²⁸.

MITOCHONDRIA DURING SKELETAL MUSCLE AGING

Mitochondrial dysfunction is a hallmark of aging and is associated with changes in skeletal muscle energy metabolism ^31,70. In addition, mitochondrial dysfunction is associated with skeletal muscle apoptosis ⁷¹. In aged skeletal muscle, mitochondria appear enlarged and more rounded in shape, with matrix vacuolization and smaller cristae when compared with skeletal muscle mitochondria from young subjects ²⁹. With advancing age, there is a decrease in mitochondrial content in skeletal muscle. This reduction is associated with a decrease in mitochondrial number and density, as well as a decreased mitochondrial deoxyribonucleic acid (DNA) copy number and protein expression ⁷⁰. Such decline in mitochondrial content may contribute to the loss of skeletal muscle mass, resulting from reduced mitochondrial biogenesis, an imbalance of mitochondrial dynamics, and impaired mitophagy ^70,72. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), an important gene regulating mitochondrial biogenesis and skeletal muscle insulin sensitivity, is decreased in skeletal muscle of aged rodent models 70. Also, PGC-1α modulates the crosstalk of signalling pathways related to mitochondrial quality in old age, such as expression of mitofusin 2 (Mfn2) that plays a significant role in fusion dynamics and mitophagy, and expression of sirtuin (SIRT) 3 involved in deacetylation of key mitochondrial metabolic and antioxidant enzymes ²¹. Mitochondrial dynamics is related to the ability of these organelles to quickly modulate their size, shape, and distribution by fission and fusion events ³¹. Alterations in mitochondria dynamics were observed in skeletal muscle aging. Dynamin-related protein 1 (DRP1) content tends to significantly increase with age, together with mitochondrial network reorganization and reduced mitochondrial DNA copy number. Also, activation of the dsRNA-dependent protein kinase/eukaryotic initiation factor 2/fibroblast growth factor 21 pathway by Drp1 overexpression leads to decreased skeletal muscle protein synthesis and downregulation of the growth hormone pathway. In a mouse model, Mfn2 expression decreases with skeletal muscle aging. Selective Mfn2 knockout in mouse skeletal muscle reduces mitophagy and decreases mitochondrial function. The reduction in Mfn2 expression associated to aging can lead to skeletal muscle metabolic disorders and sarcopenia ⁷⁰. AMP-activated protein kinase (AMPK) disrupts defective and fragmented mitochondria through FoxO3-dependent mitophagy. Dysfunctional mitochondria with exaggerated sensitivity to mitochondrial permeability transition pore (MPTP) opening tends to accumulate in aged skeletal muscle due to impaired mitophagy, resulting in a progressive accumulation of a non-degradable and polymeric material called lipofuscin in lysosomes. Lipofuscin has been suggested to contribute to the functional impairment in skeletal muscle with advanced age ⁷¹.

MITOCHONDRIAL PRODUCTION OF REACTIVE SPECIES DURING SKELETAL MUSCLE AGING

Generation of reactive oxygen and nitrogen species (ROS and RNS), with associated oxidative damage and/or defective redox signalling, is one of the major mechanisms involved in the development of sarcopenia ²¹. Metabolic reactions produce both reactive oxygen and nitrogen species (ROS and RNS, respectively), globally termed as reactive species or oxidants ⁷³. Redox signalling changes are observed during aging process, with increased exposure or modulation of mitochondrial reactive species. Furthermore, aged skeletal muscle is vulnerable to oxidative damage to DNA, lipids, and proteins ²⁹. Excessive production of mitochondrial ROS/RNS is associated with altered mitochondrial energy metabolism and sarcopenia ⁷⁴. With age, skeletal muscles show a decline in mtDNA and mRNA abundance, mitochondrial ATP production and oxygen consumption ⁷¹. Complexes I and IV activities are decreased in aged muscles, probably due to their content in subunits encoded by the mtDNA, which is more vulnerable to ROS/RNS derived from the respiratory chain. Also, increase in ROS/RNS production affects mitochondrial content and protein expression of PGC-1α with a rise of mitochondrial apoptotic susceptibility. These alterations are potentially involved in the development of age-related sarcopenia ⁷¹. Furthermore, AMPK and SIRT1 can directly affect PGC-1α activity through phosphorylation and deacetylation, respectively. Data from in vivo transgenic models show that AMPK, SIRT1, and PGC-1α might act as a network to control cellular energy expenditure and to improve metabolic fitness ⁷⁵. Elevated levels of ROS such as H2O2 can inhibit phosphorylation of Akt, mTOR, and the downstream mTOR targets 4E-BP1 and p70S6K ^13,21. Excess ROS/RNS produced in aged muscles may inhibit key components of the Akt/mTOR pathway, thereby limiting their capacity to respond to exercise stimul ²¹.

The insulin-like growth factor-1/phosphatidylinositol 3-kinase/protein kinase B (IGF-1/PI3K/PKB) is one of the main pathways that promote protein synthesis 76. ROS/RNS activate the IGF-1/Akt/mTOR pathway in myocytes, stimulating protein synthesis and cellular hypertrophy. However, increased resistance to IGF-1-mediated signalling occurs during muscle aging ⁷⁷. Conversely, Akt phosphorylates FoxOs, affecting their nuclear translocation and transcription, and counteracting the FoxO1-mediated protein catabolism in skeletal muscle ⁷⁸.

During muscle aging, a close connection is also present between ROS/RNS and inflammation. In fact, ROS/RNS induce the release of TNF that in turn activates the NF-κB-mediated signalling which induces an increase in muscle protein degradation ⁷⁹. TNF-α signaling pathways are involved in the healing process consequent to muscle injury and are predominantly associated with tissue degradation ⁸⁰. TNF-α plays an important role in sarcopenia through its complex signalling pathways, mostly interconnecting different types of programmed cell death. TNF-α is released by inflammatory cells as well as skeletal muscle cells, activating complex cell death signalling by binding to TNF receptor 1. In a murine model of sarcopenia, a pro-inflammatory state and higher levels of TNF-α were associated with loss of skeletal muscle mass and grip strength ⁵⁹.

During aging, both mitochondrial dysfunction and oxidative stress enhance myonuclear apoptosis ⁷⁵. In rodent models, skeletal muscle aging is associated with increased apoptosis as well as mono- and oligonucleosome fragmentation. Both mitochondria-independent and mitochondria dependent pathways may be involved in the apoptotic process ³¹. Changes in mitochondrial structure decrease aerobic energy efficiency and may result into apoptosis ⁸¹.

MITOCHONDRIA-TARGETED THERAPY FOR THE PREVENTION AND TREATMENT OF SARCOPENIA

Therapeutic strategies targeting both the quality and function of mitochondria can be categorized based on either molecular size and type, or by taking into account the molecular mechanism. Considering the structural features, the most effective approach for targeting mitochondria to treat sarcopenia includes particles ranging from 1 to 1000 nm in size, which can directly activate myotubes or inflammatory cells. According to the mechanism of action, both passive and active mechanisms are outlined. Passive targeting depends on the physical and chemical properties of carrier systems, whereas active targeting relies on specific interactions (such as ligand-receptor or antigen-antibody) at mitochondrial sites. However, to date, exercise is the only proven therapy for sarcopenia, as it can limit changes induced by muscle aging ⁸². Whole-body resistance exercises are suggested for targeting the major muscle groups in older adults. Exercises focusing on the lower body muscles should be the main part of the program because they help with everyday tasks like walking, standing up, and climbing stairs. It’s also important to work on muscles such as the quadriceps, hamstrings, glutes, calves, and the muscles of the foot and ankle. Strengthening upper-body muscles is key for tasks like dressing, cooking, and taking care of oneself ⁸³.

Studies are underway to assess treatments aimed at reducing the loss of muscle mass, targeting various factors. Anti-myostatin antibodies have been developed and tested in humans, showing positive effects on lean mass and, in some cases, evidence of improved physical performance. Recently, the inhibition of activin A in primates has shown improved muscle growth. Testosterone also exerts important effects on muscle trophism through Akt/mTOR activation, reduction in adipose stem cells, and activation of satellite cell recruitment. In accordance with this, evidence shows an increase in skeletal muscle mass after treatment with testosterone, although there is some conflicting data regarding the effect on physical function and muscle strength. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis tends to decline with age, and it has been demonstrated that administering human GH to older, healthy individuals can increase muscle mass ⁸⁴. Recently, growing evidence has highlighted the role of ECM remodeling in muscle health, as well as in the development and progression of sarcopenia, and the potential association between ECM remodeling and mitochondrial function in muscle tissue. In this context, the ECM/mitochondrial pathway could be a potential target to counteract the onset and progression of sarcopenia ⁸⁵.

CONCLUSIONS

Mitochondria play a key role during skeletal muscle aging. In recent years, significant progress has been made in understanding the different pathways involved in muscle changes with age. Age-associated dysregulation of redox signaling appears to be one of the major mechanisms involved in the mitochondrial alterations observed in aged muscle. However, while further preclinical, and clinical studies are essential to discern the exact role of different pathways in the age-related sarcopenia, it’s pivotal to differentiate between immediate clinical implications and the typical geriatric multidimensional ones. Addressing this differentiation becomes even more critical when considering the development of molecules tailored for skeletal muscle mitochondria. In addition to this, we must also acknowledge the complexities introduced by the challenges of routine health assessments in non-gerontologic settings. These settings may not always be equipped or trained to recognize subtle geriatric nuances or the intricate interactions between muscle aging and overall health. As a result, there’s a risk of oversight or misinterpretation of early signs of age-related conditions. Such targeted interventions hold promise not only in enhancing efficacy but also in minimizing the associated toxicity, thereby presenting potential solutions to challenges observed in current therapies.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

ALB, FB: writing – original draft preparation; GV: writing – review and editing. All authors have read and agreed to the published version of the manuscript.

Ethical consideration

Not applicable.

Figures and tables

Figure 1.Mechanisms underlying the changes associated with muscle aging.Several interconnected mechanisms underlie muscle aging, such as impaired protein turnover, increased production of reactive species, reduced numbers of satellite cells, dysfunctional neuromuscular and mitochondrial changes, and an elevation in circulating pro-inflammatory mediators. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license ().

References

1. Cruz-Jentoft AJ, Bahat G, Bauer J. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019; 48:16-31. DOI
2. Seene T, Kaasik P. Muscle weakness in the elderly: Role of sarcopenia, dynapenia, and possibilities for rehabilitation. Eur. Rev. Aging Phys. Act. 2012; 9:109-117. DOI
3. McCormick R, Vasilaki A. Age-related changes in skeletal muscle: changes to life-style as a therapy. Biogerontology. 2018; 19:519-536. DOI
4. Sakuma K, Aoi W, Yamaguchi A. Molecular mechanism of sarcopenia and cachexia: recent research advances. Pflugers Arch. 2017; 469:573-591. DOI
5. Beaudart C, Zaaria M, Pasleau F. Health outcomes of sarcopenia: a systematic review and meta-analysis. PLoS One. 2017; 12:E0169548. DOI
6. Bruyère O, Beaudart C, Ethgen O. The health economics burden of sarcopenia: a systematic review. Maturitas. 2019; 119:61-69. DOI
7. Manini TM, Clark BC. Dynapenia and aging: an update. J Gerontol A Biol Sci Med Sci. 2012; 67A:28. DOI
8. Chen L-K, Woo J, Assantachai P. Asian Working Group for Sarcopenia: 2019 Consensus Update on sarcopenia diagnosis and treatment. J Am Med Dir Assoc. 2020; 21:300-307.E2. DOI
9. Kirk B, Zanker J, Bani Hassan E. Sarcopenia Definitions and Outcomes Consortium (SDOC) criteria are strongly associated with malnutrition, depression, falls, and fractures in high-risk older persons. J Am Med Dir Assoc. 2021; 22:741-745. DOI
10. Studenski SA, Peters KW, Alley DE. The FNIH Sarcopenia Project: rationale, study description, conference recommendations, and final estimates. J Gerontol A. 2014; 69:547-558. DOI
11. Meza-Valderrama D, Marco E, Dávalos-Yerovi V. Sarcopenia, malnutrition, and cachexia: adapting definitions and terminology of nutritional disorders in older people with cancer. Nutrients. 2021; 13:761. DOI
12. Cao M, Lian J, Lin X. Prevalence of sarcopenia under different diagnostic criteria and the changes in muscle mass, muscle strength, and physical function with age in Chinese old adults. BMC Geriatr. 2022; 22:889. DOI
13. Petermann-Rocha F, Balntzi V, Gray SR. Global prevalence of sarcopenia and severe sarcopenia: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2022; 13:86-99. DOI
14. von Haehling S, Morley JE, Anker SD. An overview of sarcopenia: facts and numbers on prevalence and clinical impact. J Cachexia Sarcopenia Muscle. 2010; 1:129-133. DOI
15. St-Onge M-P, Gallagher D. Body composition changes with aging: the cause or the result of alterations in metabolic rate and macronutrient oxidation?. Nutrition. 2010; 26:152-155. DOI
16. Evans WJ. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am J Clin Nutr. 2010; 91:1123S-1127S. DOI
17. Mitchell WK, Williams J, Atherton P. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front Physiol. 2012; 3:260. DOI
18. Grosicki GJ, Zepeda CS, Sundberg CW. Single muscle fibre contractile function with ageing. J Physiol. 2022; 600:5005-5026. DOI
19. Nederveen JP, Betz MW, Snijders T. The importance of muscle capillarization for optimizing satellite cell plasticity. Exerc Sport Sci Rev. 2021; 49:284-290. DOI
20. Wilkinson DJJ, Piasecki M, Atherton PJJ. The age-related loss of skeletal muscle mass and function: measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans. Ageing Res Rev. 2018; 47:123-132. DOI
21. Foreman NA, Hesse AS, Ji LL. Redox signaling and sarcopenia: searching for the primary suspect. Int J Mol Sci. 2021; 22:9045. DOI
22. Francaux M, Demeulder B, Naslain D. Aging reduces the activation of the mTORC1 pathway after resistance exercise and protein intake in human skeletal muscle: potential role of REDD1 and impaired anabolic sensitivity. Nutrients. 2016; 8:47. DOI
23. Hughes DC, Baehr LM, Waddell DS. Ubiquitin ligases in longevity and aging skeletal muscle. Int J Mol Sci. 2022; 23:7602. DOI
24. Fry SC, Rasmussen B. Skeletal muscle protein balance and metabolism in the elderly. Curr Aging Sci. 2011; 4:260-268. DOI
25. Tieland M, Trouwborst I, Clark BC. Skeletal muscle performance and ageing. J Cachexia Sarcopenia Muscle. 2018; 9:3-19. DOI
26. Koopman R, Van Loon LJC. Aging, exercise, and muscle protein metabolism. J Appl Physiol. 2009; 106:2040-2048. DOI
27. Cuthbertson D, Smith K, Babraj J. Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J. 2005; 19:1-22. DOI
28. McGregor RA, Cameron-Smith D, Poppitt SD. It is not just muscle mass: a review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life. Longev Heal. 2014; 3:9. DOI
29. Seo DY, Lee SR, Kim N. Age-related changes in skeletal muscle mitochondria: the role of exercise. Integr Med Res. 2016; 5:182-186. DOI
30. Gheller BJF, Riddle ES, Lem MR. Understanding age-related changes in skeletal muscle metabolism: differences between females and males. Ann Rev Nutr. 2016; 36:129-156. DOI
31. Bellanti F, Lo Buglio A, Vendemiale G. Mitochondrial impairment in sarcopenia. Biology (Basel). 2021; 10:31. DOI
32. Larson AA, Baumann CW, Kyba M. Oestradiol affects skeletal muscle mass, strength and satellite cells following repeated injuries. Exp Physiol. 2020; 105:1700-1707. DOI
33. Haizlip KM, Harrison BC, Leinwand LA. Sex-based differences in skeletal muscle kinetics and fiber-type composition. Physiology. 2015; 30:30-39. DOI
34. Prior SJ, Ryan AS, Blumenthal JB. Sarcopenia is associated with lower skeletal muscle capillarization and exercise capacity in older adults. J Gerontol A Biol Sci Med Sci. 2016; 71:1096-1101. DOI
35. Landers-Ramos RQ, Prior SJ. The microvasculature and skeletal muscle health in aging. Exerc Sport Sci Rev. 2018; 46:172. DOI
36. Papa EV, Dong X, Hassan M. Skeletal muscle function deficits in the elderly: current perspectives on resistance training. J Nat Sci. 2017; 3:E272.
37. Hikida SR. Aging changes in satellite cells and their functions. Curr Aging Sci. 2011; 4:279-297. DOI
38. Parker MH. The altered fate of aging satellite cells is determined by signaling and epigenetic changes. Front Genet. 2015; 6:59. DOI
39. Alway SE, Myers MJ, Mohamed JS. Regulation of satellite cell function in sarcopenia. Front Aging Neurosci. 2014; 6:246. DOI
40. Nilwik R, Snijders T, Leenders M. The decline in skeletal muscle mass with aging is mainly attributed to a reduction in type II muscle fiber size. EXG. 2013; 48:492-498. DOI
41. Dowling P, Gargan S, Swandulla D. Fiber-type shifting in sarcopenia of old age: proteomic profiling of the contractile apparatus of skeletal muscles. Int J Mol Sci. 2023; 24:2415. DOI
42. Lexell J, Taylor CC, Sjöström M. What is the cause of the ageing atrophy? Total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men. J Neurol Sci. 1988; 84:275-294. DOI
43. Bartolomei S, Nigro F, Ciacci S. Relationships between muscle architecture and performance in division I male Italian field hockey players. Appl Sci. 2021; 11:4394. DOI
44. Narici M, McPhee J, Conte MF. Age-related alterations in muscle architecture are a signature of sarcopenia: the ultrasound sarcopenia index. J Cachexia Sarcopenia Muscle. 2021; 12:973. DOI
45. Lo Buglio A, Bellanti F, Serviddio G. Impact of nutritional status on muscle architecture in elderly patients hospitalized in internal medicine wards. J Nutr Health Aging. 2020; 24:717-722. DOI
46. Strasser EM, Draskovits T, Praschak M. Association between ultrasound measurements of muscle thickness, pennation angle, echogenicity and skeletal muscle strength in the elderly. Age (Dordr). 2013; 35:2377-2388. DOI
47. Kubo K, Kanehisa H, Azuma K. Muscle architectural characteristics in young and elderly men and women. Int J Sports Med. 2003; 24:125-130. DOI
48. Narici MV, Maganaris CN, Reeves ND. Effect of aging on human muscle architecture. J Appl Physiol. 2003; 95:2229-2234. DOI
49. Ikezoe T. Age-related change in muscle characteristics and resistance training for older adults. Phys Ther Res. 2020; 23:99-105. DOI
50. Perkisas S, De Cock A, Verhoeven V. Physiological and architectural changes in the ageing muscle and their relation to strength and function in sarcopenia. Eur Geriatr Med. 2016; 7:201-206. DOI
51. Auyeung TW, Lee SWJ, Leung J. Age-associated decline of muscle mass, grip strength and gait speed: a 4-year longitudinal study of 3018 community-dwelling older Chinese. Geriatr Gerontol Int. 2014; 14:76-84. DOI
52. Reid KF, Fielding RA. Skeletal muscle power: a critical determinant of physical functioning in older adults. Exerc Sport Sci Rev. 2012; 40:4-12. DOI
53. Nelke C, Dziewas R, Minnerup J. Skeletal muscle as potential central link between sarcopenia and immune senescence. EBioMedicine. 2019; 49:381-388. DOI
54. Peake J, Della Gatta P, Cameron-Smith D. Aging and its effects on inflammation in skeletal muscle at rest and following exercise-induced muscle injury. Am J Physiol Regul Integr Comp Physiol. 2010; 298:R1485-R1495. DOI
55. Romano AD, Lo Buglio A, Bellanti F. Diagnostic reliability of the procalcitonin serum marker in septic frail patient. Aging Clin Exp Res. 2019; 31:727-732. DOI
56. Wang J, Leung KS, Chow SKH. Inflammation and age-associated skeletal muscle deterioration (sarcopaenia). J Orthop Transl. 2017; 10:94-101. DOI
57. Dalle S, Rossmeislova L, Koppo K. The role of inflammation in age-related sarcopenia. Front Physiol. 2017; 8:1045. DOI
58. Williams A, Wang JJ, Wang LI. Sepsis in mice stimulates muscle proteolysis in the absence of IL-6. Am J Physiol. 1998; 275:R1983-R1991. DOI
59. Wu J, Lin S, Chen W. TNF-α contributes to sarcopenia through caspase-8/caspase-3/GSDME-mediated pyroptosis. Cell Death Discov. 2023; 9:76. DOI
60. Gensous N, Bacalini MG, Franceschi C. Age-related DNA methylation changes: potential impact on skeletal muscle aging in humans. Front Physiol. 2019; 10:996. DOI
61. Antoun E, Garratt ES, Taddei A. Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS). J Cachexia Sarcopenia Muscle. 2022; 13:240-253. DOI
62. Turner DC, Gorski PP, Maasar MF. DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity. Sci Rep. 2020; 10:15360. DOI
63. Ling C, Poulsen P, Simonsson S. Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest. 2007; 117:3427-3435. DOI
64. Rönn T, Volkov P, Davegårdh C. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet. 2013; 9:E1003572. DOI
65. Carter HN, Chen CCW, Hood DA. Mitochondria, muscle health, and exercise with advancing age. Physiology. 2015; 30:208-223. DOI
66. Philp AM, Saner NJ, Lazarou M. The influence of aerobic exercise on mitochondrial quality control in skeletal muscle. J Physiol. 2021; 599:3463-3476. DOI
67. Hood DA, Memme JM, Oliveira AN. Maintenance of skeletal muscle mitochondria in health, exercise, and aging. Ann Rev Physiol. 2019; 81:19-41. DOI
68. Yan Z, Okutsu M, Akhtar YN. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. J Appl Physiol. 2011; 110:264-274. DOI
69. Heden TD, Johnson JM, Ferrara PJ. Mitochondrial PE potentiates respiratory enzymes to amplify skeletal muscle aerobic capacity. Sci Adv. 2019; 5:eaax835a. DOI
70. Li J, Wang Z, Li C. Impact of exercise and aging on mitochondrial homeostasis in skeletal muscle: roles of ROS and epigenetics. Cells. 2022; 11:2086. DOI
71. Boengler K, Kosiol M, Mayr M. Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue. J Cachexia Sarcopenia Muscle. 2017; 8:349-369. DOI
72. Ritov VB, Menshikova EV, Kelley DE. High-performance liquid chromatography-based methods of enzymatic analysis: electron transport chain activity in mitochondria from human skeletal muscle. Anal Biochem. 2004; 333:27-38. DOI
73. Bellanti F, Lo Buglio A, Vendemiale G. Redox homeostasis and immune alterations in coronavirus disease-19. Biology (Basel). 2022; 11:159. DOI
74. Sanchez-Roman I, Gómez A, Pérez I. Effects of aging and methionine restriction applied at old age on ROS generation and oxidative damage in rat liver mitochondria. Biogerontology. 2012; 13:399-411. DOI
75. Ferri E, Marzetti E, Calvani R. Role of age-related mitochondrial dysfunction in sarcopenia. Int J Mol Sci. 2020; 21:5236. DOI
76. Léger B, Cartoni R, Praz M. Akt signalling through GSK-3β, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy. J Physiol. 2006; 576:923-933. DOI
77. Thomson DM, Gordon SE. Impaired overload-induced muscle growth is associated with diminished translational signalling in aged rat fast-twitch skeletal muscle. J Physiol. 2006; 574:291-305. DOI
78. Stitt TN, Drujan D, Clarke BA. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell. 2004; 14:395-403. DOI
79. Zhou LZ-H, Johnson AP, Rando TA. NFκB and AP-1 mediate transcriptional responses to oxidative stress in skeletal muscle cells. Free Radic Biol Med. 2001; 31:1405-1416. DOI
80. Stratos I, Behrendt A-K, Anselm C. Inhibition of TNF-α restores muscle force, inhibits inflammation, and reduces apoptosis of traumatized skeletal muscles. Cells. 2022; 11:2397. DOI
81. Dirks AJ, Hofer T, Marzetti E. Mitochondrial DNA mutations, energy metabolism and apoptosis in aging muscle. Ageing Res Rev. 2006; 5:179-195. DOI
82. Bellanti F, Lo Buglio A, Vendemiale G. Muscle delivery of mitochondria-targeted drugs for the treatment of sarcopenia: rationale and perspectives. Pharmaceutics. 2022; 14:2588. DOI
83. Hurst C, Robinson SM, Witham MD. Resistance exercise as a treatment for sarcopenia: prescription and delivery. Age Ageing. 2022; 51:afac003. DOI
84. Coen PM, Musci RV, Hinkley JM. Mitochondria as a target for mitigating sarcopenia. Front Physiol. 2019; 9:1883. DOI
85. Melouane A, Yoshioka M, St-Amand J. Extracellular matrix/mitochondria pathway: a novel potential target for sarcopenia. Mitochondrion. 2020; 50:63-70. DOI