Priority Research Paper Volume 12, Issue 12 pp 11185—11199
The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan
- 1 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
- 2 Department of Medicine, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
- 3 Department of Physiology, The Barshop Institute, University of Texas Health at San Antonio, TX 78229, USA
- 4 Translational Gerontology Branch, National Institute on Aging, Dickerson, MD 20892, USA
- 5 Calico Life Sciences, South San Francisco, CA 94080, USA
- 6 Department of Preventive Medicine, Keck School of Medicine, USC, Los Angeles, CA 90089, USA
- 7 Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- 8 Department of Human Biology, Faculty of Natural Science, University of Haifa, Haifa, Israel
- 9 Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Received: April 8, 2020 Accepted: June 11, 2020 Published: June 23, 2020
https://doi.org/10.18632/aging.103534How to Cite
Copyright © 2020 Yen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo. Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer’s disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.