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.
|Number of pages||15|
|State||Published - 23 Jun 2020|
Bibliographical noteFunding Information:
Funding: The centenarian study was funded in part by grants from the NIH [(P01AG021654 to N.B.), (1R01AG042188 to G.A.), and (1R01AG 034430 and 1P01AG034906 to P.C.)], the Nathan Shock Center of Excellence for the Biology of Aging (P30AG038072 to N.B.), and the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation Grant to N.B. and P.C.). The monkey studies were funded by the National Institute on Aging Intramural Research Program, NIH to J.A.M. Human mitochondrial copy number experiments were supported by NIH grant R21 ES025870 to C.V.B. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). CSF samples were provided by the UCLA AD Center.
© Yen et al.
ASJC Scopus subject areas
- Cell Biology