Basic Biology of Aging: Mitochondrial-Derived Peptides and their Role in Aging and Disease
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Pinchas Cohen, MD
USC Leonard Davis School of Gerontology
Mitochondrial-Derived Peptides and their Role in Aging and Disease
Mitochondria are involved in energy metabolism and apoptosis, and are central to the pathogenesis of multiple diseases, including diabetes, cancer, neurodegeneration, and aging. Our lab cloned humanin, a novel 24-amino-acid peptide encoded from the 16S rRNA region of the mtDNA that was shown to be a potent cytoprotective factor. Humanin is protective, in vitro and in vivo, in models of atherosclerosis, diabetes, and Alzheimer’s. Humanin is inhibited by GH/IGF signaling and is induced by caloric restriction (CR). Humanin administration leads to a CR-mimetic effect that includes suppression of IGF-I as well as extension of lifespan and healthspan in model organisms. We also identified six additional peptides encoded from open reading frames (ORFs) within the 16S rRNA, which we named SHLPs (small humanin-like peptides). SHLPs 2 acts as a potent neuroprotective, glucose-regulating peptide. SHLP6 has opposing actions, potently inducing apoptosis in cancer cells. Recently, we cloned an additional mitochondrial peptide named MOTS-c, which is a potent metabolic regulator with relevant effects in aging-related diseases. MOTS-c acts by activating the AMPK pathway and leads to an exercise mimetic effect on fat and muscle and induces weight-loss in mice fed a high fat diet. These observations reveal that the mitochondria possess previously unappreciated roles in the regulation of metabolism and cellular functions that occur via the production of mitochondrial-derived peptides (MDPs). We propose that the mitochondrial peptidome could explain important new aspects of mitochondrial biology and dysfunction with, relevance to human biology and disease, with a particular interest in aging; and that the novel MDPs we describe here may represent retrograde communication signals from the mitochondria.
The Basic Biology of Aging seminar series is sponsored by The Nathan Shock Center of Excellence in the Basic Biology of Aging, the Genetic Approaches to Aging Training Grant, and the UW Healthy Aging and Longevity (HALo) Research Institute. The seminar features guest speakers presenting the latest research in the basic biology of aging.