Sarcopenia and Genetics: Why Muscle Mass Loss Varies with Age

After age 40, muscle mass and strength gradually change, but the speed and extent of these changes vary from person to person. In some people they remain barely noticeable for a long time, while in others a decline in muscle strength, the amount or quality of muscle tissue, and physical function becomes clinically significant. This combination of changes, defined by specific clinical criteria, is described as sarcopenia (Kirk et al., Age and Ageing, 2024; Cruz-Jentoft et al., Age and Ageing, 2019).

How muscles change with age is influenced by physical activity, nutrition, hormonal and metabolic status, coexisting conditions, and genetic factors. No single one of these determines the individual course on its own: age-related changes in the muscular system are shaped by their combined effect.

How Sarcopenia Differs From Age-Related Muscle Changes

Sarcopenia is a clinical condition defined by a combination of several parameters of the muscular system. Under the conceptual definition from the Global Leadership Initiative in Sarcopenia (GLIS), sarcopenia comprises three components: muscle mass, muscle strength, and specific muscle strength — that is, strength per unit of muscle mass. GLIS classifies impaired physical function as a consequence of the condition rather than one of its components (Kirk et al., Age and Ageing, 2024).

The European consensus EWGSOP2 considers reduced muscle strength the key sign of sarcopenia: it is what warrants further work-up (Cruz-Jentoft et al., Age and Ageing, 2019). The diagnosis is confirmed when a reduced amount or quality of muscle tissue is additionally found, while impaired physical function indicates a more severe stage of the condition (Cruz-Jentoft et al., Age and Ageing, 2019).

There is not yet a single agreed set of diagnostic criteria. Besides the European consensus, clinical practice and research also use the criteria of the Asian Working Group for Sarcopenia (AWGS) (Chen et al., J. Am. Med. Dir. Assoc., 2020), the Foundation for the National Institutes of Health project (Studenski et al., J. Gerontol. A Biol. Sci. Med. Sci., 2014), and the Sarcopenia Definition and Outcomes Consortium (Bhasin et al., J. Am. Geriatr. Soc., 2020), which weigh muscle mass, strength, and gait speed differently. As a result, prevalence estimates for sarcopenia in the same group of people can differ several-fold depending on the definition used (Sánchez-Sánchez et al., J. Clin. Med., 2024).

This distinction has practical significance. Age-related muscle mass loss is a common phenomenon that is not, by itself, a diagnosis. Sarcopenia is diagnosed only when muscle strength, the amount or quality of muscle tissue, and physical function meet clinical criteria.

Why It Becomes Harder to Maintain Muscle Tissue With Age

Muscle tissue is constantly renewed: protein synthesis and breakdown occur continuously, and the balance between them determines whether muscle mass is maintained or lost. With age, the muscle protein synthesis response to dietary protein intake weakens: the same amount of protein produces a smaller increase than at a younger age. In the scientific literature this phenomenon is called anabolic resistance (Aragon et al., Nutr. Rev., 2023).

In parallel, changes take place in the neuromuscular system: the number of motor units that control muscle fibers decreases, and some fibers lose their connection to the nervous system. Surviving neurons partly compensate for this by sprouting new branches toward the orphaned fibers, but this capacity for remodeling declines with age (Jones et al., J. Physiol., 2022). These changes are compounded by declining physical activity levels, shifts in hormonal and metabolic status, and the accumulation of coexisting conditions that affect the structure and function of muscle tissue.

Age-related changes do not come down to a single linear mechanism of muscle loss. Age alters the conditions under which muscle tissue is maintained rather than triggering one single process of its breakdown.

What Affects Muscle Mass and Strength

People of the same age can differ substantially in muscle mass and strength because many factors act on these measures at the same time. Training history and the current level of physical activity determine how regularly muscles receive a stimulus for protein synthesis. Nutrition — in particular, adequate protein and energy intake — supplies the material for protein synthesis. Sleep and recovery create the conditions for muscle tissue repair and adaptation. Coexisting conditions and medication use can further accelerate or slow these changes.

Genetic variability is also part of this list, but it is not the only factor and does not always outweigh the rest. Twin and family studies estimate the heritability of muscle mass at roughly 50% (Pei et al., Commun. Biol., 2020), while the remainder is explained by environmental and behavioral factors.

How Genetics Affects Muscle Mass and Strength

Muscle mass and strength are quantitative traits influenced by thousands of genetic variants, each with a small effect (Pei et al., Commun. Biol., 2020). These variants are located across different regions of the genome.

Such variants are identified in genome-wide association studies (GWAS), which compare the genomes of large groups of people and pinpoint regions linked to a trait. A polygenic risk score (PRS) combines the cumulative contribution of these variants into a single measure and shows how strongly the predisposition is expressed compared with what is typical for people of the same ancestry.

What Genetic Studies of Muscle Mass and Strength Show

One of the largest studies to date of appendicular (arm and leg) muscle mass, covering more than 450,000 UK Biobank participants, identified 1,059 independent variants at 799 loci that together explain about 15.5% of the variation in this trait (Pei et al., Commun. Biol., 2020). A study of grip strength in more than 223,000 UK Biobank participants identified 101 loci associated with this measure (Tikkanen et al., Sci. Rep., 2018).

Sample size directly affects how many loci can be detected: a 2017 meta-analysis of 38,000 participants found five loci linked to muscle mass, whereas a 2020 study of more than 450,000 participants found 799 (Zillikens et al., Nat. Commun., 2017; Pei et al., Commun. Biol., 2020).

Genetic Predisposition Is Not a Forecast of Muscle Mass Loss

Genetic features, the current state of muscle tissue, and the development of sarcopenia are three different aspects that should not be equated. Genetic predisposition describes a person's relative position on traits related to muscle mass or strength within a reference population. Current status is assessed using functional tests, body composition analysis, and laboratory data. A given person's actual muscle mass, strength, and physical function are shaped by genetic, age-related, behavioral, and clinical factors.

A study in the FinnGen cohort of more than 342,000 people assessed the association between a polygenic score for grip strength and long-term health outcomes: a higher score was linked to a 2–10% reduction in the risk of several common diseases and in mortality, and the difference between the highest and lowest score quintiles was 5–23% (Herranen et al., J. Gerontol. A Biol. Sci. Med. Sci., 2024). The study shows that genetic predisposition to grip strength is associated with long-term health outcomes, but on its own it does not make it possible to predict exactly how sarcopenia will develop in a given person. The most informative approach is a comprehensive assessment of risk and current muscular status that combines genetic data with measures of muscle mass, strength, physical function, and clinical factors.

How Lifestyle Can Influence the Expression of Genetic Predisposition

Genetic predisposition does not change over a lifetime and is only one of the factors affecting the state of the muscular system. At the same time, age-related changes in muscle are influenced by modifiable factors:

• strength training, which remains one of the main ways to maintain and restore muscle strength,
• adequate dietary caloric intake and optimal protein intake matched to the body's needs and level of physical activity,
• adequate sleep and recovery, needed for muscle tissue to adapt to training loads,
• managing coexisting diseases and conditions that can accelerate the loss of muscle function.

A systematic review and meta-analysis of studies in people aged 60 and older with sarcopenia found that combining protein supplementation with strength training significantly improves measures of muscle mass and strength (Whaikid & Piaseu, Epidemiol. Health, 2024). The effect was observed even among people with sarcopenia, showing that muscle mass and strength can be influenced even in the presence of pronounced age-related changes.

The Role of a Genetic Profile in Assessing the State of the Muscular System

Functional strength tests, body composition assessment using DXA (dual-energy X-ray absorptiometry) or bioimpedance analysis, and laboratory indicators reflect the current state of the muscular system. The measures assessed by these methods change with age and depend on physical activity, nutrition, and health status. A genetic profile describes stable genetic features associated with the formation and characteristics of muscle mass, strength, and other measures of the muscular system.

Apixmed Prism DNA tests assess genetic features associated with sports characteristics, musculoskeletal function, and recovery, and make it possible to evaluate polygenic predisposition to specific traits. A genetic test does not diagnose sarcopenia and does not replace functional tests, body composition assessment, or laboratory studies. It supplements data on the body's current state with a stable genetic context that can be taken into account when planning training and nutrition and when preventing age-related muscle loss.

Learn more about Apixmed Prism genetic tests and panels →

The results of a genetic test are not a diagnosis and do not replace a doctor's consultation. The Apixmed Prism report provides genetic context that supplements examination results and helps in making decisions together with a doctor.

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