Reviewing Mitochondria-Derived Peptides in Aging

Researchers have explored a number of mitochondria-derived peptides as a basis for treatments in the context of aging. These peptides are created from fragments of genes in the mitochondrial DNA, released from the cell, and appear to be involved in a range of mechanisms relevant to declining function in aging. Is it possible to supply such peptides as a therapy in order to produce benefits in an aged metabolism? A number of groups working towards that goal, on the basis of data in animal studies and humans patients.

The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1-6.

MDPs have been extensively studied in the context of aging. Three MDPs have been studied in the context of age-related diseases: humanin, MOTS-c, and SHLP2. Humanin has been shown to mitigate Alzheimer's disease pathology in rodents, and its levels and genetic variation associate with age and cognition. MOTS-c has been described as an exercise mimetic and prevents muscle atrophy in mice, and its levels and genetic variation associate with age and type 2 diabetes (T2D). SHLP2 functions as a mitochondrial modulator and protein chaperone, and its levels associate with age and prostate cancer.

In addition to their ability to attenuate age-related diseases, MDPs have promoted lifespan and healthspan. Humanin is the best-conserved MDP and is found in as diverse species as humans, naked mole rats, and nematodes. Overexpression of humanin increased lifespan in nematodes, and this was dependent on FOXO. Additionally, humanin has increased autophagy in cells, and this increase in autophagy was also required for the lifespan extension in the transgenic worms. The second approach was to initiate a longevity experiment in mice in which we injected middle-aged (18-month-old) female mice with humanin twice a week. Although lifespan was not increased - likely because of humanin's short half-life of approximately 20 minutes - healthspan measures such as memory and metabolic parameters improved. Thus, humanin is sufficient to increase lifespan and healthspan in model organisms, and an optimized dosing of humanin may lead to increases in lifespan in more complex organisms.

Link: https://doi.org/10.1172/JCI158449