Role of the Mitochondrial Peptide Humanin in Regulating Aging and Healthspan Diet and the GH/IGF axis are central to aging and longevity. We identified a key role for the novel mitochondrial- derived peptide (MDP), humanin, which is encoded from a small open reading frame (sORF) within the mitochondrial genome (16S rRNA gene) in this regard. Dietary manipulations, administration of H2S-donors, and IGF-I reduction lead to increases in humanin levels, while humanin itself mimics dietary restriction (DR) in multiple ways including suppressing IGF-I, increasing IGFBP-1, improving insulin sensitivity, and reducing weight. Humanin levels fall with age and correlate with lifespan, and humanin overexpression or administration to various organisms leads to healthspan and lifespan extension. Similarly to dietary interventions and H2S, humanin protects from a variety of insults, and its administration prevents the development of diseases of aging. Our collaborative studies with Projects 1 & 3 indicate that humanin is a central connecting link between dietary restriction, IGF reduction, and H2S expression, integrating stress resistance and fitness during aging. Our central hypotheses are (1) humanin is a mitochondrial hormone whose expression is directly regulated by aging-modulating interventions such as dietary manipulations, H2S, and IGF-reduction, (2) Humanin regulates circulating IGF-I (mimicking DR) by direct activity on the hypothalamus leading to a central-hepatic effect that inhibits IGF-I production in liver (3) humanin administration can act similarly to DR and fasting mimicking diets or protein restriction cycles, H2S, and GH/IGF-blockade, to promote healthspan and possibly longevity. We will study the mechanisms by which diet, IGF-I, and H2S regulate humanin expression; and study the transcriptional and post-transcriptional regulation of the humanin-sORF. We will decipher the mechanisms involved in the DR-mimetic effects of humanin action through hypothalamic-mediated suppression of hepatic IGF-I; as well as through direct protective effects on target tissues. We will characterize the effects of humanin on healthspan and identify the mechanisms involved, using novel humanin-transgenic mouse models, GP130- inhibitors, and IGF-add-back experiments. Together, this project will demonstrate the physiological significance of humanin as a mediator and regulator of healthspan and longevity pathways including those related to diet, IGF-I, and H2S. We hope to demonstrate that HN is necessary and sufficient for healthspan/lifespan enhancement.

Public Health Relevance

Role of the Mitochondrial Peptide Humanin in Regulating Aging and Healthspan Aging and longevity are regulated by multiple pathways, but two of the most potent regulators of the aging process are diet and the growth hormone system, which themselves are inter-related. We identified a remarkable relationship between these interventions and the novel mitochondrial-derived peptide, humanin, which is encoded within the mitochondrial genome. Both dietary manipulations, as well as growth hormone reduction lead to increase in humanin levels. In this project we will evaluate if humanin is a diet restriction-like hormone and will advance our understanding of its regulation by diet. If successful, our work will set the stage for clinical advancement of new diagnostic and therapeutic interventions for diseases of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG055369-01A1
Application #
9417792
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2018-02-15
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Yen, Kelvin; Wan, Junxiang; Mehta, Hemal H et al. (2018) Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans. Sci Rep 8:14212
Henning, Susanne M; Galet, Colette; Gollapudi, Kiran et al. (2018) Phase II prospective randomized trial of weight loss prior to radical prostatectomy. Prostate Cancer Prostatic Dis 21:212-220
Mao, Kai; Quipildor, Gabriela Farias; Tabrizian, Tahmineh et al. (2018) Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice. Nat Commun 9:2394
Kim, Su-Jeong; Mehta, Hemal H; Wan, Junxiang et al. (2018) Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY) 10:1239-1256
Xiao, Jialin; Cohen, Pinchas; Stern, Mariana Carla et al. (2018) Mitochondrial biology and prostate cancer ethnic disparity. Carcinogenesis 39:1311-1319
Nencioni, Alessio; Caffa, Irene; Cortellino, Salvatore et al. (2018) Fasting and cancer: molecular mechanisms and clinical application. Nat Rev Cancer 18:707-719
Nashine, Sonali; Cohen, Pinchas; Nesburn, Anthony B et al. (2018) Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration. Sci Rep 8:15175
Guidi, Novella; Longo, Valter D (2018) Periodic fasting starves cisplatin-resistant cancers to death. EMBO J 37:
Liang, Pei; Henning, Susanne M; Guan, Johnny et al. (2018) Role of Host GPR120 in Mediating Dietary Omega-3 Fatty Acid Inhibition of Prostate Cancer. J Natl Cancer Inst :
Qin, Qing; Mehta, Hemal; Yen, Kelvin et al. (2018) Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice. Am J Physiol Heart Circ Physiol 315:H1127-H1136