The primary challenge in the matter of understanding aging is not the generation of data - there is far more data on any aspect of aging than any one research group is capable of assimilating. Production of data is a great deal easier than making something of that data, and so the databases continue to grow at a faster pace than the understanding of that data. The primary challenge is to build bridges of established, comprehensible cause and effect between the various bodies of data, to show that age-related biochemical change A causes unfortunate consequence B, and that A is more important in the progression of B than any of the countless other biochemical changes observed to correlate with B. This is hard.
One first step along this path is to take what is known of the causes of aging (such as those outlined in the SENS view of rejuvenation biotechnology) and try to fix them, observing the results. This is not as popular an approach as might be imagined! More effort goes instead to taking what is known of observed outcomes in aging, and attempting to gain insight into their relationships to to one specific age-related condition. Since the publication of the Hallmarks of Aging paper, a lot of this latter sort of exploration has been undertaken. Today's open access paper is one example of the type, in which researchers give direction for others to explore more deeply the links between specific hallmarks of aging and the age-related loss of muscle mass and strength that leads to sarcopenia.
Research on how molecular and cellular processes - referred to as the hallmarks of aging - are linked to clinically diagnosed sarcopenia and its muscular components. Understanding the biological mechanisms underlying sarcopenia and identifying signature biomarkers are essential for developing preventive strategies that could delay its onset. Among aging hallmarks, mitochondrial dysfunction appears to be the most closely associated with sarcopenia. This dysfunction is characterized by decreased electron transport chain (ETC) expression and activities, changes in metabolites from the TCA cycle, compromised OXPHOS, heightened oxidative stress, and lower antioxidant defenses. These findings were consistently observed across various populations.
Additionally, sarcopenia was associated with deregulated nutrient sensing, indicated by lower IGF-1 and insulin levels in sarcopenic individuals, alongside diminished mTOR signaling and potential influences from specific amino acids. Inflammatory indicators included elevated cortisol levels and oxidative stress markers, while CRP and other cytokines were not consistently associated with sarcopenia. Direct muscle evaluation also revealed no significant increase in inflammatory pathways. Lastly, a decrease in butyrate-producing bacteria and an increase in pathogenic flora were indicatives of gut dysbiosis in individuals with sarcopenia.
Additional connections between sarcopenia and other aging hallmarks, though indicative of potential links, are based on limited or inconsistent evidence. This applies to most of the primary hallmarks. Indicators suggest that genomic instability occurs in sarcopenia, evidenced by increased levels of cell-free mitochondrial and nuclear DNA, as well as epigenetic alterations. However, a deeper understanding of the specific pathways influenced by methylation in various DNA regions and other epigenetic processes is essential. There is a rationale supporting the influence of proteostasis on muscle function, and evidence of transcriptional changes in sarcopenia is apparent. However, the available information is not sufficient to confirm their direct link to sarcopenia. Moreover, lower concentrations of circulating progenitor cells and reduced activation of myosatellite cells in sarcopenic individuals indicate that stem cell exhaustion may contribute to the disease. More research, including mechanistic preclinical investigations, as well as longitudinal human studies, is necessary to explore how these factors relate to the development of sarcopenia.
The field of sarcopenia has witnessed significant advancements, evolving from establishing disease criteria to deepening our understanding of its mechanisms and exploring potential interventions. Despite this progress, the primary management strategies for sarcopenia are solely strength exercise training and nutritional support, as current evidence does not support the efficacy of pharmacological treatments. A recent systematic review examining both current and investigational medications for sarcopenia found no conclusive evidence to support the effectiveness of testosterone replacement or vitamin D supplementation in improving sarcopenia outcomes, reinforcing the findings of our review, which also did not find a consistent relationship between these endocrine networks and sarcopenia. Current preclinical research is investigating the roles of exerkines - molecules secreted by skeletal muscle fibers - and senolytic drugs in muscle health. Based on our findings, enhancing oxidative phosphorylation pathways and restoring energetic balance are also promising future targets for developing treatment options for sarcopenia.
View the full article at FightAging
