Sarcopenia in the Elderly: From Pathogenic Mechanisms to Dietary Interventions—New Insights for Muscle Health

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Sarcopenia in the Elderly: From Pathogenic Mechanisms to Dietary Interventions—New Insights for Muscle Health

Sarcopenia is a syndrome characterized by the progressive decline in skeletal muscle mass, muscle strength, and function, which severely impairs the quality of life of the elderly. Its pathogenic mechanisms involve a variety of intrinsic factors (such as age, hormone levels, and genetic background) and extrinsic factors (such as malnutrition and lack of exercise). At the molecular level, it is closely associated with abnormalities in the PI3K-AKT-mTOR signaling pathway, transcription factors including FOXO, SMAD2/3, and NF-κB, as well as branched-chain amino acid (BCAA) metabolism. Currently, there are no clearly effective pharmacological treatments, making dietary intervention a crucial strategy. This includes supplementation with proteins, vitamin D, n-3 fatty acids, and antioxidants. In recent years, studies have found that natural products such as trigonelline and oleuropein can significantly enhance muscle function by improving mitochondrial function, promoting NAD+ synthesis, and facilitating calcium ion uptake. These findings provide new research directions for the prevention and treatment of sarcopenia. The application of multi-models (e.g., nematodes, cells, and mice) helps to systematically evaluate the effectiveness of intervention measures.

1. Definition and Development of Sarcopenia

1.1 Physiological Role and Structural Characteristics of Skeletal Muscle

Skeletal muscle accounts for approximately 40% of the total human body weight, making it the largest organ in the human body. It not only plays a role in supporting the body but also participates in various physiological activities such as balance maintenance, movement execution, and energy metabolism. However, with aging, the function of skeletal muscle gradually declines significantly. Studies have shown that skeletal muscle aging is a major cause of disability and physical frailty in the elderly, seriously affecting their quality of life.

The structure and function of skeletal muscle are highly conserved across different species. It is composed of highly differentiated muscle fibers, which are rich in contractile proteins and organized into sarcomeres—the basic functional units. The contraction process is initiated by nerve electrical signals, which are transmitted to the muscle fiber membrane through the neuromuscular junction. The extracellular matrix is responsible for transmitting and integrating the contractile force generated by muscle fibers to the tendons, thereby driving bone movement.

Skeletal muscle contains various types of muscle fibers, ranging from slow-twitch (Type I) to fast-twitch (Type II). The contraction speed of these fibers is determined by specific myosin isoforms and other contractile proteins. Muscle fiber contraction relies on ATP as an energy source, and ATP is produced through different metabolic pathways. Typically, Type I muscle fibers mainly use lipid oxidation for energy supply, while Type II muscle fibers depend on glycogen or glucose breakdown.

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1.2 Concept Evolution and Diagnostic Criteria of Sarcopenia

The term "sarcopenia" was proposed in the late 1980s and officially defined for the first time in 1993. Although its definition has evolved over time, it has always centered on three core indicators: the progressive and systemic decline in skeletal muscle mass, muscle strength, and muscle function (e.g., walking speed and physical activity capacity). In humans, a decline in muscle mass and strength usually begins after the age of 50. In rodents, sarcopenia often occurs at 15 months of age (equivalent to middle adulthood in humans) and becomes significant at 24 months of age. After that, individual differences increase, often accompanied by tumors and other comorbidities.

Currently, there are differences in the diagnostic criteria for sarcopenia among different organizations. Taking the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) as an example, its diagnosis is mainly based on three indicators: muscle mass (e.g., the appendicular lean mass of men should not be less than 20 kg), muscle strength (grip strength should not be less than 27 kg), and gait speed (should not be less than 0.8 m/s).

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2. Risk Factors of Sarcopenia and Common Animal Models

2.1 Classification of Risk Factors: Intrinsic and Extrinsic

The risk factors of sarcopenia are complex and diverse, which can be divided into non-modifiable intrinsic factors and modifiable extrinsic factors. Age is the most important risk factor. Muscle mass and strength usually reach their peak in early adulthood, start to decline gradually around the age of 40, and enter an accelerated decline phase after the age of 50. Intrinsic factors also include the decrease in sex hormone (e.g., testosterone) levels, the peak muscle mass and loss rate affected by genetic background, and various disease states—especially metabolic diseases such as diabetes, which can significantly accelerate muscle loss and functional decline.

Modifiable extrinsic factors involve various aspects of nutrition and lifestyle. Insufficient protein intake can lead to negative nitrogen balance and promote muscle breakdown. Vitamin D deficiency is associated with decreased muscle strength, impaired balance function, and increased risk of falls. Significant weight loss often directly reflects muscle loss. In sarcopenic obesity (i.e., the coexistence of sarcopenia and obesity), inflammatory factors and adipokines secreted by adipose tissue further deteriorate muscle mass and function. Inadequate physical activity or long-term immobilization is a key trigger for muscle loss. Studies have confirmed that even short-term bed rest can quickly lead to a decrease in muscle strength. In addition, smoking, excessive alcohol consumption, and the use of certain drugs (e.g., glucocorticoids) can also cause direct damage to muscle health.

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2.2 Overview of Sarcopenia Research Models

In terms of research models, common models for sarcopenia include zebrafish, nematodes, mice, rats, rabbits, non-human primates, and cell models. Among them, mouse models are widely used, and various models can be constructed based on different pathogenic mechanisms, such as natural aging, gene editing, high-fat diet induction, tail suspension, tumor burden, chronic heart failure, and drug induction. The high-fat diet-induced model is particularly suitable for the exploration of metabolic mechanisms and nutritional intervention studies.

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3. Tissue and Molecular Changes During the Development of Sarcopenia

At the histopathological level, sarcopenia is mainly characterized by inflammatory infiltration, extracellular matrix remodeling, abnormal innervation, and changes in the vascular network. At the molecular mechanism level, the growth or atrophy state of muscles is mainly regulated by the PI3K-AKT-mTOR signaling pathway. This pathway regulates cell division in most cells, while in terminally differentiated muscle cells, it mainly maintains muscle mass by promoting overall protein synthesis and inhibiting degradation. Specifically, the activation of the PI3K-AKT signal can inhibit the FOXO transcription factor, thereby enhancing the net protein accumulation.

In addition, a variety of transcription factors play key roles in muscle atrophy, including glucocorticoid receptors, SMAD2/3, and NF-κB. Inhibiting the activity of these factors can delay the atrophy process to varying degrees. Among them, SMAD2 and SMAD3 mediate the proteolytic signals downstream of myostatin, activin A, and other members of the TGF-β family, promoting a hypercatabolic state. As a core regulator of inflammation and apoptosis, NF-κB plays an important role in various muscle atrophy models. Although its specific mechanism has not been fully clarified, recent studies have shown that it may be an effective inducer of myostatin. In addition, branched-chain amino acid (BCAA) catabolism dysfunction has been identified as a potential therapeutic target for sarcopenia, and relevant studies were published in Nature Aging in 2025.

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4. Dietary Intervention Measures and Mechanisms for Sarcopenia

4.1 Current Status of Pharmacological Research and Core Dietary Interventions

Currently, no drugs have been proven to have clear clinical benefits for the treatment of human sarcopenia. However, intervention strategies targeting mitochondrial dysfunction have shown potential therapeutic value. For example, urolithin A has shown preliminary positive effects in small-scale randomized controlled trials. In addition, other drug classes such as troponin activators and ryanodine receptor modulators are currently being studied for other myopathies and may also be applicable to the exploration of sarcopenia treatment in the future.

In terms of dietary intervention, common measures include supplementation with proteins, vitamin D, n-3 polyunsaturated fatty acids, and antioxidants. Dietary protein not only provides amino acids required for muscle synthesis but also acts as an anabolic signal to directly promote protein synthesis. Vitamin D deficiency is common in the elderly population, and it may affect muscle strength and function through mechanisms mediated by the vitamin D receptor (VDR), although the specific pathway has not been fully clarified. n-3 fatty acids can directly promote muscle protein synthesis by regulating the mTOR signaling pathway.

4.2 Natural Products as Novel Intervention Agents: Trigonelline and Oleuropein

In recent years, a number of high-level studies have focused on exploring the role of natural products in the prevention and treatment of sarcopenia. A study published in Nature Metabolism in 2024 showed that trigonelline can act as a NAD+ precursor to promote mitochondrial energy metabolism. This study first found through cohort analysis that the serum trigonelline level in sarcopenia patients was significantly reduced, and confirmed that its supplementation can effectively improve NAD+ biosynthesis. Mechanistic studies revealed that trigonelline promotes NAD+ synthesis mainly through the Preiss-Handler pathway, and significantly improves muscle function and mitochondrial activity in mouse and nematode models.

In addition, another study published in Cell Metabolism in 2025 reported that oleuropein enhances energy metabolism by activating mitochondrial calcium uptake. The researchers found that the decrease in mitochondrial calcium ion levels in elderly sarcopenia patients is related to abnormal calcium regulation mediated by the MCUR1 protein, leading to reduced pyruvate dehydrogenase (PDH) activity and decreased ATP production. Through high-throughput screening of 5,571 natural products, oleuropein showed the strongest ability to activate mitochondrial calcium uptake. Its effect of improving mitochondrial function and the underlying molecular mechanism were verified in primary human muscle cells and in vivo experiments.

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