Role of the mitochondrial peptide humanin in regulating aging and stress resistance

$277,339P01FY2016AGNIH

University Of Southern California, Los Angeles CA

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Abstract

Role of the Mitochondrial Peptide Humanin in Regulating Aging and Stress Resistance Aging and longevity are regulated by multiple pathways, but two of the most potent regulators of the aging process are diet and the GH/IGF axis, which are themselves inter-related. Over the last funding period we studied the effects of dietary interventions and GH/IGF-axis modulation on longevity and diseases of aging, and we have also identified a remarkable relationship between these interventions and the novel mitochondrial-derived peptide, humanin, which is encoded from a small open reading frame (sORF) within the mitochondrial genome (16S rRNA gene). Dietary restriction (DR), GH/IGF reduction, and H2S lead to increases in humanin levels, while humanin suppresses IGF-I and dramatically raises the levels of IGFBP-1. Humanin levels fall with age and humanin overexpression or administration to various organisms leads to healthspan and lifespan extension. Similarly to DR, humanin protects from a variety of insults, and its administration prevents the development of diseases of aging. These studies suggest a DR-mimetic role for humanin. In this project we will consider the central hypotheses that (1) humanin is a DR-mimetic whose expression is regulated by aging-modulating interventions such as dietary manipulations, H2S, and IGF- reduction, and (2) humanin administration can act similarly to DR and periodic fasting or protein restriction cycles (PFC, PRC), H2S, and GH/IGF-blockade, to promote longevity and healthspan. We will study the mechanisms by which diet, IGF, and H2S regulate humanin expression;? and study the transcriptional and post-transcriptional regulation of the humanin-sORF. We will propose to demonstrate using several mouse models and in vitro systems that humanin treatment or over-expression delays aging and aging-related diseases acting as a physiological DR-mimetic (and that humanin knock-down has opposite effects) and elucidate the mechanisms involved, including IGF-1 suppression in hepatocytes. Together, these proposed studies will demonstrate the dietary-restriction-like effects of humanin and will advance our understanding of its regulation by diet and GH and its mechanisms of action. If successful, our work will set the stage for clinical advancement of new diagnostic and therapeutic interventions for diseases of aging.

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