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.

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In multi-cellular organisms, the control of gene expression is key not only for development, but also for adult cellular homeostasis, and gene expression has been observed to be deregulated with aging. In this review, we discuss the current knowledge on the transcriptional alterations that have been described to occur with age in metazoans. First, we discuss age-related transcriptional changes in protein-coding genes, the expected functional impact of such changes, and how known pro-longevity interventions impact these changes. Second, we discuss the changes and impact of emerging aspects of transcription in aging, including age-related changes in splicing, lncRNAs and circRNAs. Third, we discuss the changes and potential impact of transcription of transposable elements with aging. Fourth, we highlight small ncRNAs and their potential impact on the regulation of aging phenotypes. Understanding the aging transcriptome will be key to identify important regulatory targets, and ultimately slow-down or reverse aging and extend healthy lifespan in humans.

Aging is the leading risk factor for multiple non-communicable chronic diseases. Age-related physiological deterioration is underlined by a progressive loss of cellular homeostasis and physical capacity. Healthy aging can be promoted by preemptively enhancing physical capacity and metabolic fitness. Mitochondria are chief metabolic organelles with strong implications in aging.In addition to their prominent role in bioenergetics, mitochondria also coordinate broad physiological functions by communicating to other cellular compartments or distal cells, using multiple factors including peptides that are encoded within their own independent genome.However, it is unknown if aging is actively regulated by factors encoded in the mitochondrial genome. MOTS-c is a mitochondrial-encoded peptide that regulates metabolic homeostasis, in part, by translocating to the nucleus to regulate adaptive nuclear gene expression in response to cellular stress. Here, we report that MOTS-c is an exercise-induced mitochondrial-encoded peptide that significantly enhanced physical performance when administered to young (2 mo.), middle-aged (12 mo.), and old (22 mo.) mice. In humans, we found that endogenous MOTS-c levels significantly increased in response to exercise in skeletal muscle (5-fold) and in circulation (1.5fold). Systemic MOTS-c treatment in mice significantly enhanced the performance on a treadmill of all age groups (~2-fold). MOTS-c regulated (i) nuclear genes, including those related to metabolism and protein homeostasis, (ii) glucose and amino acid metabolism in skeletal muscle, and (iii) myoblast adaptation to metabolic stress. Notably, a statistical enrichment analysis on our RNA-seq data, from both mouse skeletal muscle and myoblasts, revealed heat shock factor 1 (HSF1) as a putative transcriptional factor that could regulate gene expression upon MOTS-c treatment. Indeed, siRNA-mediated HSF1 knockdown reversed MOTS-c-dependent stress resistance against glucose restriction/serum deprivation. Ultimately, late-life initiated intermittent MOTS-c treatment (23.5 months; 3x/week) improved overall physical capacity and trended towards increasing lifespan. Our data indicate that aging is regulated by genes that are encoded not only in the nuclear genome, but also in the mitochondrial genome. Considering that aging is the major risk factor for multiple chronic diseases, our study provides new grounds for further investigation into mitochondrial-encoded regulators of healthy lifespan that could also provide novel therapeutic targets of mitochondrial basis.3 Main Text:The progressive loss of metabolic homeostasis is a hallmark of aging, which impedes parenchymal function and ultimately diminishes physical capacity 1,2 . In fact, aging is a leading risk factor for a myriad of non-communicable chronic diseases 3-9 . Organismal fitness requires continuous adaptive cellular stress responses to the ever-shifting internal and external environment. Mitochondria not only produce the bulk of cellular energy, but also coordinate adaptive cell...