The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan

Kelvin Yen, Hemal H. Mehta, Su Jeong Kim, Yan He Lue, James Hoang, Noel Guerrero, Jenna Port, Qiuli Bi, Gerardo Navarrete, Sebastian Brandhorst, Kaitlyn Noel Lewis, Junxiang Wan, Ronald Swerdloff, Julie A. Mattison, Rochelle Buffenstein, Carrie V. Breton, Christina Wang, Valter Long, Gil Atzmon, Douglas WallaceNir Barzilai, Pinchas Cohen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)11185-11199
Number of pages15
JournalAging
Volume12
Issue number12
DOIs
StatePublished - Jun 30 2020

Keywords

  • Aging
  • Humanin
  • Mitochondria
  • Peptides

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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  • Cite this

    Yen, K., Mehta, H. H., Kim, S. J., Lue, Y. H., Hoang, J., Guerrero, N., Port, J., Bi, Q., Navarrete, G., Brandhorst, S., Lewis, K. N., Wan, J., Swerdloff, R., Mattison, J. A., Buffenstein, R., Breton, C. V., Wang, C., Long, V., Atzmon, G., ... Cohen, P. (2020). The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Aging, 12(12), 11185-11199. https://doi.org/10.18632/aging.103534