Ageing is an intricate biological process affecting all humans, characterised by progressive cellular and molecular changes that influence health and well-being. One of the most pressing age-related conditions is sarcopenia, which entails the gradual decline of muscle mass and function.
This narrative review sheds light on how the hallmarks of ageing, as defined by researchers López-Otín et al., relate to sarcopenia, offering insights into this debilitating condition through a geroscience lens.
What is Sarcopenia?
Sarcopenia is a condition primarily affecting older adults. It manifests as a decline in skeletal muscle mass and strength, often leading to physical disability, fractures, and increased mortality. Researchers classify sarcopenia into two categories: primary sarcopenia, which arises without clear external causes, and secondary sarcopenia, influenced by factors such as chronic illnesses or malnutrition.
The condition’s physiological underpinnings are deeply intertwined with the biological hallmarks of ageing. Understanding these connections may lead to effective preventive measures and targeted therapies.
Hallmarks of Ageing: A Framework for Sarcopenia
López-Otín et al. categorized ageing processes into twelve hallmarks. These can be grouped into primary drivers, antagonistic responses, and integrative markers. Let’s explore their connection to sarcopenia.
1. Primary Drivers
These hallmarks drive cellular dysfunction and ageing:
Genomic Instability:
Genomic damage accumulates with age, leading to mutations and cellular dysfunction. In sarcopenia, higher levels of circulating cell-free DNA (ccfDNA) and mitochondrial DNA (ccf-mtDNA) have been observed, indicating DNA damage. However, studies have yet to establish a direct causal relationship.
Telomere Attrition:
Telomeres protect chromosomes but shorten with cell division. Mixed evidence links shorter telomeres to sarcopenia. Some studies found no association, while others observed correlations in specific groups.
Epigenetic Alterations:
Changes in DNA methylation, histone modifications, and non-coding RNAs can disrupt gene expression. Sarcopenic individuals show altered DNA methylation in muscle-related genes, but the broader implications remain unclear.
Loss of Proteostasis:
The balance of protein synthesis, folding, and degradation is critical. While sarcopenic muscles show altered gene expression related to proteostasis, evidence regarding protein turnover remains inconclusive.
2. Antagonistic Responses
Initially protective, these responses may exacerbate ageing processes over time:
Deregulated Nutrient Sensing:
Pathways like mTOR and AMPK regulate metabolism and nutrient sensing. Sarcopenic individuals often exhibit reduced IGF-1 levels and impaired mTOR signaling, highlighting nutrient dysregulation’s role in muscle decline.
Mitochondrial Dysfunction:
Mitochondria are essential for energy production. In sarcopenic muscles, reduced oxidative phosphorylation (OXPHOS) activity and elevated oxidative stress markers are prevalent. This hallmark strongly correlates with sarcopenia.
Cellular Senescence:
Senescent cells secrete inflammatory molecules, exacerbating tissue damage. Elevated markers like ICAM-1 and p16INK4a suggest a role in sarcopenia, but findings remain inconsistent.
3. Integrative Markers
These arise from interactions between primary damage and compensatory mechanisms:
Stem Cell Exhaustion:
Satellite cells, crucial for muscle repair, decline with age. Sarcopenic individuals exhibit reduced satellite cell activation and circulating progenitor cells, indicating compromised regenerative capacity.
Altered Intercellular Communication:
Disrupted signaling pathways, including increased cortisol and myostatin levels, impair muscle maintenance. The neuromuscular junction (NMJ), essential for muscle contraction, also deteriorates in sarcopenia.
Chronic Inflammation:
Inflammaging, or persistent low-grade inflammation, contributes to sarcopenia. Elevated C-reactive protein (CRP) and IL-6 levels are frequently observed but inconsistently linked to the condition’s progression.
Dysbiosis:
The gut microbiome’s composition changes with age, affecting systemic health. Sarcopenic individuals often exhibit reduced diversity and a decline in butyrate-producing bacteria, potentially impairing muscle function.
Insights from Current Research
Mitochondrial dysfunction emerges as the most closely associated hallmark with sarcopenia. Reduced OXPHOS activity, elevated oxidative stress, and impaired antioxidant defenses are consistently reported. Deregulated nutrient sensing, chronic inflammation, and altered intercellular communication also play pivotal roles.
Meanwhile, evidence connecting primary hallmarks like genomic instability and epigenetic alterations remains limited. Integrative markers such as stem cell exhaustion and NMJ disruption offer promising avenues for understanding sarcopenia but require further investigation.
Challenges and Future Directions
Despite progress, challenges persist in understanding sarcopenia fully:
Standardized Diagnosis:
Variability in diagnostic criteria complicates comparisons across studies. Consistent use of frameworks like the EWGSOP can enhance research reliability.
Age-Related Confounders:
Distinguishing sarcopenia’s effects from general ageing requires careful study design and comparable age groups.
Mechanistic Studies:
Exploring the molecular pathways linking ageing hallmarks to sarcopenia can uncover potential therapeutic targets.
Gut-Muscle Axis:
Investigating the gut microbiome’s influence on muscle health could reveal novel interventions for sarcopenia.
In Conclusion,
Sarcopenia exemplifies the interplay between ageing hallmarks and health. By understanding these biological underpinnings, researchers can develop targeted strategies to mitigate sarcopenia’s impact, improving quality of life for ageing populations. Continued interdisciplinary research is crucial to unraveling the complex biology of sarcopenia and advancing geroscience.
The study is published in the journal Ageing Research Reviews. It was led by researchers from Gerontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, France.
