Researchers have discovered a number of mitochondrial peptides that influence cell and tissue health. Here, it is demonstrated that upregulation of humanin is sufficient to extend life in nematode worms. Since humanin levels decrease with age, and since long-lived families tend to have higher levels of humanin, it is hoped that upregulation can be the basis for therapies to modestly slow the progression of aging. There has been a fair amount of research along these lines in recent years, such as showing that delivery of humanin improves cognition in aged mice. It is an interesting part of the field.

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. Humanin is the first member of this new class of mitochondrial-derived signaling peptides that now includes MOTS-c and SHLP1-6. The humanin gene is found as a small open reading frame within the 16s rRNA gene of the mitochondrial genome. It is highly conserved in chordates but can also be found in species as distant as the nematode, suggesting that humanin is an ancient mitochondrial signal used to communicate to the rest of the organism.

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. Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.