Caloric restriction (CR), undernutrition without malnutrition, offers a powerful way to explore mechanisms of delayed aging. CR is the only environmental intervention that repeatedly and strongly increases maximum lifespan and delays biological aging in laboratory rodents. The rhesus monkey provides an extremely valuable model in which to test the ability of CR to extended healthspan and lifespan in a primate species. By proving that CR extends healthspan and lifespan in rhesus monkeys we have validated an outstanding model for physiological, systemic, and molecular aging studies that is directly translational to human aging. In 1989, we began a study to test the overall hypothesis that adult-onset CR could slow the aging process in a primate species. Importantly, these studies are not yet complete as 17% of the monkeys are alive. Thus, the major goals of this application are active data collection from remaining animals, integrative longitudinal analysis of 25+ years of study data, and expansion of studies into the mechanisms of CR. There has been renewed emphasis in biology and medical research on the impact of adiposity in health and disease vulnerability. Our preliminary molecular profiling data demonstrate that adipose tissues respond to aging and CR in a manner that is not simply reflective of adiposity. We will test the hypothesis that adipose tissue contributes to age- related disease vulnerability and its prevention by CR in a depot specific manner in nonhuman primates. We propose two Specific Aims: 1) To perform and facilitate in-depth, longitudinal analyses of the biology of aging and effects of moderate (30%) adult-onset CR in a primate species. Health, biometric and clinical measures of the long-term CR study animals will be conducted to ultimately determine the effects of CR on maximal lifespan. Data will be combined to create an integrative perspective on health outcomes in response to CR. All data and the inventory of available tissues will be made available through a newly created curated online accessible database to extend studies on aging and the mechanisms of CR to a broad collaborative research network. 2) To determine the adipose tissue depot specific response to age and CR. We will determine the signature of age and CR through high resolution molecular profiling, elucidate the contribution of adipose tissue to lipid and metabolite profiles in serum, and identify novel systemic indices of health status with potential clinical value. Using banked specimens of subcutaneous and visceral (mesenteric) adipose tissues (44 males and females, median age 26 years, age range: 13-33 years), we propose to derive the molecular signature of CR in terms of metabolomics, lipidomics, and transcriptomics, and use these data to identify depot specific processes and pathways associated with the enhanced resilience to age-related disease conferred by CR. This study will advance biology of aging research by defining fully the influence of CR on maximal lifespan under tightly controlled conditions in a long-lived primate species, and provide unparalleled mechanistic insights into age-related disease vulnerability in this highly translatable model.

Public Health Relevance

Our rapidly growing aging population deems interventions that delay or prevent age-associated disease to be of huge public health significance. Caloric restriction (less calories eaten but without a shortage of essential nutrients) opposes a broad array of age-associated health problems in monkeys. This 25-year-long project will establish the impact of CR on lifespan and discover how CR extends healthy aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Fridell, Yih-Woei
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University of Wisconsin Madison
Veterinary Sciences
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United States
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Rhoads, Timothy W; Burhans, Maggie S; Chen, Vincent B et al. (2018) Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys. Cell Metab 27:677-688.e5
Colman, Ricki J (2018) Non-human primates as a model for aging. Biochim Biophys Acta Mol Basis Dis 1864:2733-2741
Yamada, Yosuke; Kemnitz, Joseph W; Weindruch, Richard et al. (2018) Caloric Restriction and Healthy Life Span: Frail Phenotype of Nonhuman Primates in the Wisconsin National Primate Research Center Caloric Restriction Study. J Gerontol A Biol Sci Med Sci 73:273-278
Schneider, Augusto; Dhahbi, Joseph M; Atamna, Hani et al. (2017) Caloric restriction impacts plasma microRNAs in rhesus monkeys. Aging Cell 16:1200-1203
Mattison, Julie A; Colman, Ricki J; Beasley, T Mark et al. (2017) Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 8:14063
Maegawa, Shinji; Lu, Yue; Tahara, Tomomitsu et al. (2017) Caloric restriction delays age-related methylation drift. Nat Commun 8:539
Balasubramanian, Priya; Howell, Porsha R; Anderson, Rozalyn M (2017) Aging and Caloric Restriction Research: A Biological Perspective With Translational Potential. EBioMedicine 21:37-44
Balasubramanian, Priya; Mattison, Julie A; Anderson, Rozalyn M (2017) Nutrition, metabolism, and targeting aging in nonhuman primates. Ageing Res Rev 39:29-35
Martin, Stephen A; DeMuth, Tyler M; Miller, Karl N et al. (2016) Regional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction. Aging Cell 15:100-10
Polewski, Michael A; Burhans, Maggie S; Zhao, Minghui et al. (2015) Plasma diacylglycerol composition is a biomarker of metabolic syndrome onset in rhesus monkeys. J Lipid Res 56:1461-70

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