Mitochondrial-derived peptides in aging and age-related diseases
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ORIGINAL ARTICLE
Mitochondrial-derived peptides in aging and age-related diseases Su-Jeong Kim & Brendan Miller & Hiroshi Kumagai & Ana R. Silverstein & Melanie Flores & Kelvin Yen
Received: 15 July 2020 / Accepted: 28 August 2020 # American Aging Association 2020
Abstract A decline in mitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Here, we review the evidence that a decline in the levels of mitochondrial-derived peptides contributes to aging and age-related diseases. In particular, we discuss how mitochondrial-derived peptides, humanin and MOTS-c, contribute to specific aspects of the aging process, including cellular senescence, chronic inflammation, and cognitive decline. Genetic variations in the coding region of humanin and MOTS-c that are associated with age-related diseases are also reviewed, with particular emphasis placed on how mitochondrial variants might, in turn, regulate MDP expression and agerelated phenotypes. Taken together, these observations suggest that mitochondrial-derived peptides influence or regulate a number of key aspects of aging and that strategies directed at increasing mitochondrial-derived peptide levels might have broad beneficial effects. Keywords Mitochondrial-derived peptides . Mitochondria . Humanin . MOTS-c . Aging . Age-related diseases S.G polymorphism is located in the coding region of humanin and is associated with lower circulating levels of humanin and higher cognitive decline in the African-American population [57]. These results are well aligned with previous studies that show that humanin administration improves cognitive function. Another mitochondrial SNP in the MOTS-c coding region, the MT-1382 A>C polymorphism, which causes a K14Q amino acid replacement, was found in 5–10% of the East-Asian populations [71]. We found that the C allele carriers of this SNP showed a significantly higher visceral fat area, which is a risk factor for T2D, than the A allele carriers in a small Japanese cohort. Additionally, a meta-analysis of three independent Japanese cohorts (n = 27,527) demonstrated that male subjects with
GeroScience Fig. 2 MDPs are associated with some hallmarks of aging
the C allele of MT-1382 A>C polymorphism exhibited a higher prevalence of T2D than those with the A allele of the same polymorphism [72]. Interestingly, men with the C allele of the MT-1382 A>C polymorphism exhibited a 65% greater rate of T2D only in the sedentary group, demonstrating a kinesio-genomic interaction [72]. Moreover, SNP carriers exhibited dramatically elevated circulating MOTS-c levels in Japanese populations, implying that K14Q MOTS-c acts as a bioinactive form of MOTS-c, which is similar to bioinactive leptin associated with obesity and bioinactive insulin leading to MODY diabetes [73, 74]. To support these human observations, MOTS-c administration in high-fat-fed mice resulted in reduced weight and improved glucose tolerance in male mice, but not in K14Q MOTS-c–treated mice
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