Aging is associated with profound remodeling of skeletal muscle composition, which is primarily driven by the loss of type II (fast-twitch) fibers (Cade and Yarasheski, 2006[14]; Domingues-Faria et al., 2014[40]; Phu et al., 2015[93]; Cho et al., 2016[25]). Declines in mRNA expression of myosin heavy chain isoforms IIa and IIx may contribute to this preferential loss of fiber type, and, in turn, to the reductions in muscle strength observed in sarcopenia (Cade and Yarasheski, 2006[14]).

In addition, advancing age is related to a reduced number of motor units (Cade and Yarasheski, 2006[14]), reflecting decreases in motor neuron number and axonal cell body size (Kawamura et al., 1977[64]), which may impair neuronal skeletal muscle activation (Kido et al., 2004[65]) and thereby further promote age-related muscle dystrophy (Wiedmer et al., 2021[128]).

Satellite cells, the resident stem cells of skeletal muscle critical for growth and regeneration, decline in number per myofiber, along with its regenerative capacity, as age advances (Cade and Yarasheski, 2006[14]; Domingues-Faria et al., 2014[40]), particularly those associated with type II fibers (Domingues-Faria et al., 2014[40]).

These changes are accompanied by systemic endocrine dysregulation, characterized by altered skeletal muscle protein turnover, with reduced muscle protein synthesis (MPS) rather than elevated muscle protein degradation (MPD) being the primary driver (Cade and Yarasheski, 2006[14]). With advancing age, MPS declines by approximately 30 %, mainly due to lower synthesis rates of mixed muscle proteins (myofibrillar, mitochondrial, and sarcoplasmic fractions) (Cade and Yarasheski, 2006[14]).

The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis constitutes a main anabolic regulator of skeletal muscle. IGF-1 stimulates MPS and myogenic differentiation primarily via the activation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin complex 1 (PI3K/Akt/mTORC1) cascade (Velloso, 2008[119]; Yoshida and Delafontaine, 2020[135]), whereas age-related declines in GH (~14 % per decade post-puberty; somatopause) and circulating IGF-1 levels attenuate this signaling, favoring net catabolism (Sattler, 2013[101]) (Figure 2(Fig. 2)). Older adults with sarcopenia have been observed to exhibit lower circulating levels of GH, IGF-1, and the IGF-1 splice variant mechano-growth factor (MGF) compared to age-matched controls (Bian et al., 2020[10]). Multivariate analyses confirmed IGF-1 and/or MGF as independent predictors of reduced appendicular skeletal (Bian et al., 2020[10]) and whole-body muscle mass (Walowski et al., 2023[125]), with lower IGF-1 levels also correlated to higher intramuscular fat infiltration in the lumbar region of multifidus and erector spinae muscles (Walowski et al., 2023[125]), reduced handgrip strength (HGS) (Van Nieuwpoort et al., 2018[117]; Walowski et al., 2023[125]), and impaired physical performance (Van Nieuwpoort et al., 2018[117]).

Closely linked to the GH/IGF-1 axis, insulin represents a further key anabolic regulator in skeletal muscle, activating PI3K/Akt/mTORC1 signaling to stimulate protein synthesis while inhibiting forkhead box O-mediated proteolysis (Sakaguchi, 2024[100]) (Figure 2(Fig. 2)). With aging, myocytic insulin sensitivity declines markedly, impairing both glucose and amino acid uptake. Skeletal muscle accounts for ~80 % of insulin-stimulated whole-body glucose disposal (DeFronzo and Tripathy, 2009[34]; Merz and Thurmond, 2020[79]), yet older adults exhibit a 30-35 % reduction compared with younger individuals (Fink et al., 1986[47]), highlighting skeletal muscle as the primary locus of age-related IR. This anabolic resistance may stem from multiple factors blocking PI3K/Akt/mTORC1 signaling, including chronic low-grade inflammation, ectopic lipid accumulation (ceramides/diacylglycerols), mitochondrial dysfunction, endothelial impairment, and reduced autophagy (Shou et al., 2020[108]).

Similarly, age-related declines in circulating sex steroids, including testosterone in men (ap-proximately 1-1.6 % annually for total and 2-3 % for free testosterone from midlife) and es-trogens in women during menopause (Feldman et al., 2002[45]; Burger et al., 2007[13]), are associated with sarcopenia and may contribute to it via reduced anabolic signaling, impaired MPS, and diminished satellite cell activation and proliferation, while upregulating proteolytic signaling pathways. Concurrent fat accumulation may further promote tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) signaling, oxidative stress, and mitochondrial dysfunction, collectively shifting skeletal muscle toward net protein catabolism (Huang and Wang, 2021[59]; Shigehara et al., 2022[106]). Notably, most mechanistic insights into these pathways derive from preclinical in vivo and in vitro models.

Cross-sectional analyses have shown that community-dwelling older men with sarcopenia exhibit lower total and free testosterone levels compared with peers without sarcopenia (Diago-Galmés et al., 2021[39]). Multivariate logistic regression further indicated an association between higher circulating free testosterone and a lower prevalence of sarcopenia in both men and women (Shin et al., 2021[107]). Large epidemiological studies have linked reduced sex steroid concentrations with declines in muscle mass, strength, and physical performance (Vitale et al., 2016[121]). However, longitudinal findings remain inconsistent, as several investigations failed to confirm a clear predictive relationship between baseline testosterone levels and subsequent muscle decline (Roy et al., 2002[99]; Cawthon et al., 2009[16]; Vitale et al., 2016[121]). Evidence regarding circulating estrogens in postmenopausal women is comparatively scarce, limiting firm conclusions about their role in sarcopenia development.

Parallel to the decline in anabolic hormones, aging is accompanied by “inflammaging”, a sterile, chronic low-grade inflammatory state characterized by elevated pro-inflammatory cytokines such as TNF-α and IL-6 as well as increased levels of C-reactive protein (CRP) (Franceschi et al., 2000[48]). These mediators have been implicated in the dysregulation of muscle protein turnover, however, the precise mechanistic links in human sarcopenia are not yet fully clarified (Pan et al., 2021[90]). Evidence indicates that pro-inflammatory cytokines promote muscle loss by activating proteolytic pathways such as the ubiquitin-proteasome system and by impairing anabolic signaling mediated by insulin and IGF-1 (Ji et al., 2022[61]) (Figure 2(Fig. 2)).

In population-based cohorts, older adults with sarcopenia exhibited higher circulating IL-6 and TNF-α concentrations compared with controls (Bian et al., 2017[11]; Kamper et al., 2021[62]; Zhao et al., 2021[137]). In a longitudinal study of 986 individuals followed over three years, elevated IL-6 (> 5 pg/mL) and CRP (> 6.1 µg/mL) independently conferred a two- to threefold increased risk of > 40 % decline in HGS (Schaap et al., 2006[102]). Similarly, among nonagenarians, higher IL-6 and CRP levels were associated with lower HGS and reduced Barthel Index scores, underscoring the detrimental impact of inflammatory burden on physical function in very old adults (Tiainen et al., 2010[115]). Chronic low-grade inflammation in older adults has further been linked to central appetite dysregulation, as elevated cytokines such as TNF‑α and IL‑1β can act on appetite-regulating regions of the central nervous system (Morley et al., 1999[84]; Brown and Bradford, 2021[12]). The resulting reduction in hunger and increased early satiety, collectively termed as “anorexia of aging”, leads to insufficient energy and protein intake and thereby increases the risk of both quantitative and qualitative malnutrition, ultimately facilitating the development of sarcopenia (Wysokiński et al., 2015[131]; Cox et al., 2019[29]) (Figure 2(Fig. 2)).

Within the hallmarks of aging framework (López-Otín et al., 2013[75]), disrupted proteostasis, mitochondrial dysfunction, and inflammatory dysregulation have also been proposed as key mechanisms underlying sarcopenia (Wiedmer et al., 2021[128]).

Most importantly, emerging evidence indicates that age-related epigenetic modifications, particularly DNA methylation drift at cytosine-phosphate-guanine (CpG) dinucleotides, may modulate gene-regulatory programs in human skeletal muscle and thereby contribute to sarcopenia pathogenesis (Figure 3(Fig. 3)) (Voisin et al., 2021[122]; Antoun et al., 2022[2]). In a large epigenome-wide association study meta-analysis (n = 908 skeletal-muscle methylomes from individuals aged 18-89 years), Voisin et al. identified hypomethylation at atrophy-promoting genes, accompanied by an increase in gene expression for histone deacetylase 4 and an increase in protein expression for atrogin-1, while most differentially methylated genes did not alter at the mRNA or protein level but were enriched among genes showing age-related differential transcript and protein expression (Voisin et al., 2021[122]). Complementing these findings, genome-wide DNA methylation profiling (850,000 CpGs) revealed a globally hypermethylated profile in aged human skeletal muscle compared with young adult tissue, with hypermethylated CpG sites enriched in pathways central to muscle mass and function, including PI3K/Akt/mTOR, p53, axon guidance, and Hippo signaling, and across homeobox gene clusters critical for myogenesis and musculoskeletal development (Turner et al., 2020[116]). Moreover, in vastus lateralis muscle biopsies from older men, Antoun et al. observed widespread differential methylation between individuals with and without sarcopenia and identified additional differentially methylated CpGs (dmCpGs) associated with its component measures (grip strength, appendicular lean soft tissue index, and gait speed). Sarcopenia-associated dmCpGs substantially overlapped with those linked to each component and were enriched in genes involved in myotube fusion, oxidative phosphorylation, and voltage-gated calcium channels, suggesting that specific epigenetic alterations may contribute to age-related declines in muscle function (Antoun et al., 2022[2]). Additionally, in peripheral blood, lower fibroblast growth factor 2 levels (FGF2_30) were associated with both the risk and severity of sarcopenia in older adults, with methylation levels below 0.15 conferring approximately ninefold higher odds of sarcopenia compared to those with higher methylation levels (Li et al., 2024[72]).

Furthermore, DNA methylation patterns are highly responsive to sarcopenia risk-associated factors including inflammation (Yamashita et al., 2019[132]) and physical inactivity (Nalli et al., 2026[86]) as well as malnutrition with deficits in energy, protein (methyl-donors), and micronutrients (Hussain et al., 2026[60]) (Figure 3(Fig. 3)).

Taken together, epigenetic alterations may represent a critical frontier in the pathophysiology of MSS, suggesting a mechanistic link between lifestyle- and disease-associated factors and the long-term dysregulation of gene expression that drives skeletal muscle atrophy and metabolic dysfunction in the context of aging.

Current evidence indicates that protein requirements are generally increased in older adults, and that meeting these needs is essential for preventing both age-related malnutrition and sarcopenia (Bauer et al., 2013[3]; Deutz et al., 2014[38]). Recommendations for protein intake are primarily derived from the concept of anabolic resistance, which refers to an attenuated responsiveness of aging skeletal muscle to anabolic stimuli. Key mechanisms contributing to anabolic resistance include increased splanchnic sequestration of amino acids, reduced postprandial delivery of amino acids to the periphery, lower postprandial muscle perfusion, impaired muscle uptake of dietary amino acids, blunted anabolic signaling pathways for protein synthesis, and age-related declines in digestive and absorptive function (Deutz et al., 2014[38]). However, protein intake among community-dwelling older adults is often found to fall below current recommendations (Hengeveld et al., 2020[55]).

Inadequate energy intake promotes a negative energy balance, enhancing the utilization of amino acids for oxidative energy production rather than for MPS and thereby limiting the effectiveness of dietary protein for maintaining muscle mass. Supporting this, data from 940 men and 1,324 women aged ≥ 65 years in the Fourth Korea National Health and Nutrition Examination Survey showed significantly lower energy intake in participants with sarcopenia (Kim et al., 2014[66]).

According to the underlying malnutrition type, the dynamics of protein catabolism can differ, with disease-related malnutrition leading to accelerated MPD and rapid loss of skeletal muscle mass, whereas age-related malnutrition is associated with a slower but progressive decline in muscle mass (Lengelé et al., 2021[71]; Norman et al., 2021[89]).

Micronutrient deficiencies represent an additional and often underrecognized component of malnutrition in older adults, with emerging evidence linking low micronutrient status to impaired muscle health and functional decline (Robinson et al., 2021[97]; Bhattacharya et al., 2022[9]). In particular, suboptimal status of B-vitamins has been associated with impaired skeletal muscle function, including reduced gait speed and lower HGS, potentially reflecting disturbances in energy metabolism, mitochondrial function, and neuromuscular integrity. Vitamin D deficiency is related to muscle pain and weakness, underscoring its role in MPS, calcium homeostasis, and contractile function. Furthermore, inadequate intake or status of minerals such as magnesium, calcium, iron, selenium, and zinc has been associated with impaired excitation-contraction coupling, compromised mitochondrial energy production, reduced antioxidant defense capacity, and diminished neuromuscular performance (Robinson et al., 2021[97]; Bhattacharya et al., 2022[9]), thereby amplifying the negative impact of low protein and energy intake on muscle mass and function. Most of the current evidence, however, arrives from animal studies or observational cohorts. Therefore, large‑scale randomized controlled trials are necessary to confirm these findings and to lay the foundation for the potential adoption of multi‑nutrient supplementation strategies in the management of sarcopenia (Bhattacharya et al., 2022[9]).

Taken together, inadequate dietary intake of energy and protein can initiate malnutrition‑related sarcopenia, while progressive muscle loss in turn impairs physical function and independence, making activities such as food shopping, cooking, and meal preparation more difficult and thereby reinforcing a self‑perpetuating cycle of malnutrition and sarcopenia.

Habitual physical activity declines progressively with age promoting muscle atrophy as well as metabolic and functional impairment (Milanović et al., 2013[81]; Wall et al., 2013[124]; McPhee et al., 2016[78]). Among older adults, meta-analyses demonstrated a 1.7 to 2-fold higher prevalence of sarcopenia in individuals with low and no regular activity compared to active counterparts (Steffl et al., 2017[110]; Gao et al., 2021[50]). Prospective data (n = 2,309) further revealed a 5-year sarcopenia incidence of 14.8 % among the least active versus 9.0 % in the most active (Mijnarends et al., 2016[80]). Continuous exercise from early adulthood through old age was correlated with higher muscle mass (standard deviation (SD) = 0.24, p < 0.001), HGS (SD = 0.18, p < 0.05), and reduced clinically relevant low muscle mass risk in men (OR = 0.36, p < 0.01) (Eibich et al., 2016[42]), underscoring the critical importance of lifelong physical activity maintenance for sarcopenia prevention.

The most commonly employed models to study muscle disuse in humans have been bed rest and limb immobilization/suspension. Prolonged disuse (> 10 days) has been shown to induce rapid skeletal muscle atrophy at approximately 0.5-0.6 % of total muscle mass per day, with strength declining 0.3-4.2 % daily. These changes were primarily attributed to reductions in post-absorptive and post-prandial MPS, while protein breakdown contributed minimally (Wall et al., 2013[124]). Reduced activity further lowers total energy expenditure, which can suppress appetite and dietary intake. Moreover, inactivity is associated with IR and a pro‑inflammatory state, both of which can further impair MPS, promote muscle atrophy, and disturb appetite, energy balance, and nutrient metabolism.

Of potentially greater long-term relevance for the onset of sarcopenia and malnutrition may be the cumulative burden of recurrent short disuse episodes, such as brief hospitalizations or home-based recovery periods due to injury or illness. Successive events, associated with transient increases in MPD and reductions in synthesis, are thought to accumulate over the lifespan, driving net muscle loss with aging (Wall et al., 2013[124]). This effect is exacerbated by delayed and often incomplete recovery in older adults (Suetta et al., 2009[113], 2013[112]).

Acute stressors such as infections, surgery, or trauma trigger a pronounced hyperacute stress response. This response is characterized by elevated pro-inflammatory cytokines, increased release of corticosteroids and catecholamines, insulin and growth hormone resistance, bed rest, and reduced or absent food intake, which together rapidly deplete energy and protein stores and accelerate tissue breakdown (Cederholm et al., 2017[17], 2019[18]). Chronic diseases, including type 2 diabetes mellitus, chronic obstructive pulmonary disease, or chronic kidney disease, act through largely similar mechanisms, but are distinguished by persistent low‑grade inflammation, which, together with altered metabolic demands, sustain protein-energy imbalance and progressive muscle wasting over time. Non-inflammatory conditions, including neurological and psychiatric disorders, cognitive impairment, dementia, and gastrointestinal diseases, compromise nutritional status through appetite dysregulation, malabsorption, and functional dependence (Cederholm et al., 2017[17], 2019[18]).

Beyond these disease-related drivers of malnutrition and sarcopenia, polypharmacy has emerged as an additional key factor in older adults, given the high prevalence of multiple medications. Polypharmacy and sarcopenia are strongly associated in older adults, with those affected by sarcopenia exhibiting a 65 % higher prevalence of polypharmacy and using, on average, 1.39 more medications than their counterparts without sarcopenia (Prokopidis et al., 2023[95]). However, predominantly cross-sectional study designs preclude conclusions regarding causality, direction of causality, and underlying mechanistic links. Nevertheless, multiple biological mechanisms implicated in sarcopenia may also drive its association with polypharmacy, including medication-induced mitochondrial dysfunction, impaired muscle perfusion, electrolyte imbalances, hormonal dysregulation, and acid-base disturbances (König et al., 2018[68]). Likewise, several commonly prescribed drug classes exert direct adverse effects on body composition: proton pump inhibitors, for instance, have been shown to be negatively associated with circulating IGF-1 levels (Maggio et al., 2014[76]); statins, glucocorticoids, and certain antiepileptic, neuroleptic, and antidepressant drugs are known to cause muscle toxicity, while others (e.g., beta blockers, non-steroidal anti-inflammatory drugs) potentially induce detrimental metabolic effects (König et al., 2018[68]). Chemotherapy and cytotoxic anticancer drugs can further directly promote muscle atrophy by suppressing protein synthesis, inducing oxidative damage, depleting cellular energy, and triggering apoptotic or necrotic cell death (Schiessel and Baracos, 2018[103]). Medications may also blunt acute exercise-induced signaling by suppressing key transcription regulators such as mitogen-activated protein kinases and nuclear factor-kappa B (Markworth et al., 2014[77]; Prokopidis et al., 2023[95]), both essential for skeletal muscle adaptations (Kramer and Goodyear, 2007[69]), potentially attenuating strength gains and hypertrophic responses (Lilja et al., 2018[74]).

Furthermore, polypharmacy contributes to sedentary behavior and reduced physical activity, with the likelihood of inactivity increasing alongside the number of medications (Heseltine et al., 2015[56]; de Souza et al., 2023[32]). It is also linked to adverse outcomes such as falls, disability, and impaired physical function, which can further limit activity (de Souza et al., 2023[32]). In addition, older adults taking multiple medications are more vulnerable to drug-related side effects that compromise mobility, including reduced walking speed from anticholinergics, myalgia or muscle weakness induced by statins and corticosteroids, and sedation, dizziness, or orthostatic hypotension from benzodiazepines and antihypertensives (de Souza et al., 2023[32]).

Finally, various types of drugs can induce anorexia due to their side effects contributing to impaired nutritional status or malnutrition (Heuberger and Caudell, 2011[57]; Gálvez et al., 2012[49]; Kok et al., 2022[67]). Polypharmacy further compromises nutrient bioavailability, with deficiency risk increasing with the number and duration of treatment (Zanetti et al., 2023[136]). Undertreatment is also a common issue in older adults with polypharmacy, particularly regarding micronutrients such as vitamin D and calcium, whose insufficiency may exacerbate sarcopenia risk and progression (Chau et al., 2016[21]).

Early identification of MSS is essential, as it enables timely and targeted interventions aimed at slowing disease progression, preserving functional independence, and reducing mortality. Current screening and diagnostic approaches, however, focus primarily on malnutrition or sarcopenia individually, and no standardized framework specifically exists for MSS.

For sarcopenia, the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) recommends initial risk screening using the SARC-F (Strength, Assistance with walking, Rise from a chair, Climb stairs, Falls) questionnaire, a brief self-reported instrument assessing functional limitations related to muscle strength and mobility (Cruz-Jentoft et al., 2019[31]). Its simplicity allows rapid implementation in clinical practice. However, while specificity is high, sensitivity is low-to-moderate, meaning that the tool primarily identifies individuals with more advanced stages of sarcopenia. Patients identified as at risk should subsequently undergo objective assessment of muscle strength, commonly using handgrip dynamometry or chair-stand tests, which are strongly predictive of prolonged hospital stays, increased functional limitations, poor quality of life, and death (Cruz-Jentoft et al., 2019[31]). According to the EWGSOP2, low muscle strength defines probable sarcopenia, with a definitive diagnosis requiring evidence of reduced muscle quantity or quality, while impaired physical performance determines disease severity and guides clinical management.

Parallel to sarcopenia screening, systematic identification of malnutrition is recommended. Several tools have been developed for use in older adults, among which the Mini Nutritional Assessment (MNA) is one of the most widely used instruments (Corcoran et al., 2019[27]). While the MNA offers broad coverage, it may overestimate malnutrition risk, making screening alone unreliable for diagnosis and necessitating a structured assessment (Cereda, 2012[20]). Therefore, complementing MNA screening with GLIM criteria, which provide a standardized, evidence-based framework for diagnosis of malnutrition (de van der Schueren et al., 2020[33]) is necessary.

The GLIM framework proposes a two-step model consisting of initial risk screening using any validated tool, followed by a diagnostic assessment and severity grading (Cederholm et al., 2019[18], 2025[19]). Diagnosis requires the presence of at least one phenotypic criterion, including unintentional weight loss, low body mass index, or reduced muscle mass, together with one etiologic criterion such as reduced food intake/assimilation or the presence of disease burden/inflammation. Among these indicators, reduced muscle mass is strongly supported as a central phenotypic criterion, reflecting the close pathophysiological relationship between malnutrition and skeletal muscle depletion. Although assessment of muscle strength is not part of the formal GLIM diagnostic algorithm, it is recommended as a supportive measure, particularly when sarcopenia is suspected (Cederholm et al., 2019[18], 2025[19]).

Screening for and managing malnutrition is recognized as a crucial early step in the identification and treatment of sarcopenia (Vandewoude et al., 2012[118]), as early nutritional deficits can directly contribute to muscle loss. This link is supported by longitudinal cohort studies demonstrating the prognostic value of GLIM-defined malnutrition for the development of sarcopenia, and consequently for MSS. In community-dwelling older adults, malnutrition according to the GLIM criteria strongly predicted incident sarcopenia over a 14-year follow-up period (Yeung et al., 2021[133]). Similarly, in the SarcoPhAge cohort, individuals classified as malnourished exhibited an approximately threefold higher risk of developing sarcopenia or severe sarcopenia over four years compared with participants with adequate nutritional status (Beaudart et al., 2019[6]). Importantly, subsequent analyses demonstrated that while the GLIM criteria reliably predicted incident sarcopenia, traditional screening tools such as the long and short form of the MNA did not (Lengelé et al., 2021[71]).

Taken together, these findings indicate that screening for malnutrition alone is insufficient to identify older adults at high risk of sarcopenia. Early, integrated assessment strategies that combine nutritional evaluation with objective measures of muscle mass and strength, supported by ongoing monitoring, are essential to track disease progression and optimize management of MSS.

The concurrence of malnutrition and sarcopenia defines a particularly vulnerable subgroup of older adults, often characterized by multimorbidity, frailty, and pronounced functional decline. Effective management therefore requires highly individualized and interdisciplinary approaches that are carefully aligned with the patient's physiological capacity, safety profile, and treatment tolerance. While direct evidence for interventions specifically targeting MSS is lacking, current nutritional and exercise recommendations established for malnutrition alone and sarcopenia alone may offer a pragmatic provisional framework for clinical practice. Nonetheless, their application should remain nuanced and guided by clinical judgment, recognizing that the pathophysiological interplay between malnutrition and sarcopenia may modify therapeutic responsiveness and ultimately demand condition-specific adaptations as empirical data emerge.

The authors declare that they have no conflict of interest.

This research received no external funding.

AI-assisted tools were used only to improve grammar and readability of the human-generated text. No AI tools were used for conceptualization, scientific content generation, data interpretation, conclusion drawing, and preparation of the graphical abstract and figures. The authors have thoroughly proofread the manuscript and take full responsibility for the accuracy, integrity, and originality of its content.

C.O.W. contributed to writing - original draft, visualization (figures 1 to 3(Fig. 1)(Fig. 2)(Fig. 3)), and writing - review & editing. K.N. contributed to conceptualization, visualization (figure 1(Fig. 1)), and writing - review & editing. All authors have read and agreed to the published version of the manuscript.