Elamipretide was formerly known as SS-31, and is a mitochondrially targeted antioxidant molecule that improves mitochondrial function, and may or may not achieve that result through the antioxidant mechanism. For many of the current stable of small molecules known to improve mitochondrial function, it isn't entirely clear as to whether their known mechanisms of action are actually the important ones. Here, researchers demonstrate that elamipretide improves muscle function in old mice, an expected outcome, but does not affect epigenetic age, which is perhaps surprising. Epigenetic clocks that assess biological age based on changing patterns of epigenetic modifications to DNA are known to have some blind spots, but mitochondrial function should not be one of them, given the importance of mitochondria in the aging process.
Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways.
We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation.
Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.
Link: https://doi.org/10.1111/acel.70026
View the full article at FightAging
