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

• Published in: Aging (Albany, NY.) NY.), 2020-06, Vol.12 (12), p.11185-11199
• Main Authors: Yen, Kelvin, Mehta, Hemal H, Kim, Su-Jeong, Lue, YanHe, Hoang, James, Guerrero, Noel, Port, Jenna, Bi, Qiuli, Navarrete, Gerardo, Brandhorst, Sebastian, Lewis, Kaitlyn Noel, Wan, Junxiang, Swerdloff, Ronald, Mattison, Julie A, Buffenstein, Rochelle, Breton, Carrie V, Wang, Christina, Longo, Valter, Atzmon, Gil, Wallace, Douglas, Barzilai, Nir, Cohen, Pinchas
• Format: Article
• Language: English
• Subjects: Adult; Aged, 80 and over; Alzheimer Disease - blood; Alzheimer Disease - metabolism; Animals; Animals, Genetically Modified; Caenorhabditis elegans - genetics; Caenorhabditis elegans Proteins - metabolism; Case-Control Studies; Child; Cohort Studies; DNA, Mitochondrial - genetics; Female; Forkhead Transcription Factors - metabolism; Gene Dosage; Humans; Infant, Newborn; Intracellular Signaling Peptides and Proteins - blood; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Longevity - physiology; Macaca mulatta; MELAS Syndrome - blood; MELAS Syndrome - metabolism; Mice; Middle Aged; Mitochondria - metabolism; Models, Animal; Mole Rats; Pregnancy; Priority Research Paper; Young Adult
• ISSN: 1945-4589
• DOI: 10.18632/aging.103534

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 the overexpression of humanin is sufficient to increase lifespan, dependent on . 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.