MOTS-c is one of several recently identified hormones known to mimic the effects of exercise. However, MOTS-c is unique because it is encoded in the small genome of mitochondria rather than the larger genome in a cell’s nucleus. This opens up a whole new genome to target for new interventions, says Lee and researchers at USC. His subsequent studies showed how mitochondrial-encoded MOTS-c instructs proteins to interact with the nuclear genome and plays important roles in regulating cell metabolism and stress responses.
Injections of MOTS-c affected mice of different ages by measuring physical capacity and performance in young (2 months), middle-aged (12 months), and old (22 months) mice. Mice of all ages who had received MOTS-c treatment fared significantly better than untreated mice of the same age.
The human equivalent of 65 and above doubled their running capacity on the treadmill and outperformed human equivalent middle-age mice.
In muscle cells, levels of MOTS-c significantly increased nearly 12-fold after exercise and remained partially elevated after a four-hour rest, while MOTS-c levels in blood plasma also increased by approximately 50% during and after exercise and then returned to baseline after the rest period. The findings suggest that the exercise itself induced the expression of the mitochondrial-encoded regulatory peptides.
Mitochondria are strongly implicated in aging at multiple levels and MOTS-c may contribute to longevity by promoting cellular homeostasis. Here, we present evidence that the mitochondrial genome encodes for instructions to maintain physical capacity (i.e. performance and metabolism) during aging and thereby increase healthspan. MOTS-c treatment initiated in late-life, proximal to the age at which the lifespan curve rapidly descends for C57BL/6N mice, significantly delayed the onset of age-related physical disabilities, suggesting “compression of morbidity” in later life66. Interestingly, an exceptionally long-lived Japanese population harbors a mitochondrial DNA (mtDNA) SNP that yields a functional variant of MOTS-c.
The study shows that exogenously treated MOTS-c enters the nucleus and regulates nuclear gene expression, including those involved in heat shock response and metabolism. Thus, age-related gene networks are comprised of integrated factors encoded by both genomes, which entails a bi-genomic basis for the evolution of aging. Although the detailed molecular mechanism(s) underlying the functions of MOTS-c is an active field of research we provide a proof-of-principlevstudy that realizes the mitochondrial genome as a source for instructions that can regulate physical capacity and healthy aging.
Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.
SOURCES- Nature Communications, USC
Written By Brian Wang, Nextbigfuture.com
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