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.
Highlights
Mitochondria are central to several theories of aging as they are the major producer of both energy and free radicals, they regulate cell apoptosis, and their dysfunction is central to the observed physiological declines that occur during the aging process [1,2,3,4,5]
After backcrossing the worms to wild-type/N2 worms six times, we examined their lifespan and found that the transgenic worms had a small but consistent and significant (p
We found that the increase in lifespan was dependent on the daf-16/FOXO gene as humanin overexpression does not increase lifespan in a daf-16(mu86) deficient strain (Figure 1B)
Summary
Mitochondria are central to several theories of aging as they are the major producer of both energy and free radicals, they regulate cell apoptosis, and their dysfunction is central to the observed physiological declines that occur during the aging process [1,2,3,4,5]. Perhaps because of the compact nature of the mitochondria and absence of introns, MDPs are encoded in alternative open reading frames within known genes. These MDPs are a novel group of micropeptides encoded within the mitochondrial genome and have been shown to have a large number of biological effects [27,28,29,30,31,32]
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