Understanding of mechanisms that control lifespan is among the most challenging biological problems. Although not viewed as a medical condition to be treated, aging is the most prevalent disease-related state. Many complex human diseases are associated with aging, which is both the most significant risk factor and the process that drives the development of these diseases. Clinically, extending lifespan would mean delaying the onset of age-related diseases, such as cancer, neurodegenerative diseases, type II diabetes and sarcopenia. Studies of model organisms and centenarians as well as the use of compounds that extend lifespan in model organisms (e.g., rapamycin) as drugs for multiple human diseases associated with aging suggest that these approaches are feasible. It is also clear that the aging process can be naturally accelerated and delayed (e.g., mammals are characterized by >100-fold difference in lifespan, and it can both increase and decrease during evolution). These differences in lifespan and other traits among mammals are much larger than those among natural isolates of the same species of model organisms, between centenarians and controls, or between wild type and longer-lived mutant organisms identified in various laboratories. Moreover, the observed variation in mammalian lifespan occurs naturally, in contrast to laboratory mutants characterized by extended lifespan but unable to compete in the natural setting. We propose to employ this diversity in lifespan and associated life-history traits to uncover mechanisms that regulate species lifespan in mammals. For this, we will utilize methods of comparative genomics to examine pairs of genomes of closely related short- and long-lived organisms, carry out analysis of lifespan, life-history and other traits across a panel of mammalian tissues and cells using RNA-seq and metabolomics, identify key regulators of lifespan, develop interventions that simultaneously target these regulators, and directly apply these findings to cells and organisms in order to shift short-lived species toward the state of related longer-lived species. We suggest that a better understanding of causal relationships and molecular mechanisms of lifespan control will lead to a better understanding of human diseases of aging and will allow development of treatments that delay the aging process, thereby delaying the onset of human diseases associated with aging.

Public Health Relevance

Many human diseases, including the most devastating, are the diseases of aging - a consequence of an inevitable process that drives the transition from young to old. Species lifespan is linked to life-history and other traits in mammals: we will characterize these traits, identify key longevity determinants by high-throughput and integrative approaches, and use this information to extend lifespan of model organisms.

National Institute of Health (NIH)
National Institute on Aging (NIA)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZRG1)
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Guo, Max
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Brigham and Women's Hospital
United States
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Golubev, Alexey; Hanson, Andrew D; Gladyshev, Vadim N (2017) Non-enzymatic molecular damage as a prototypic driver of aging. J Biol Chem 292:6029-6038
Lee, Sang-Goo; Kaya, Alaattin; Avanesov, Andrei S et al. (2017) Age-associated molecular changes are deleterious and may modulate life span through diet. Sci Adv 3:e1601833
Petkovich, Daniel A; Podolskiy, Dmitriy I; Lobanov, Alexei V et al. (2017) Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions. Cell Metab 25:954-960.e6
Podolskiy, Dmitriy I; Lobanov, Alexei V; Kryukov, Gregory V et al. (2016) Analysis of cancer genomes reveals basic features of human aging and its role in cancer development. Nat Commun 7:12157
Gladyshev, Timothy V; Gladyshev, Vadim N (2016) A Disease or Not a Disease? Aging As a Pathology. Trends Mol Med 22:995-996
Gladyshev, Vadim N (2016) Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell 15:594-602
Podolskiy, Dmitriy I; Gladyshev, Vadim N (2016) Intrinsic Versus Extrinsic Cancer Risk Factors and Aging. Trends Mol Med 22:833-834
Ma, Siming; Upneja, Akhil; Galecki, Andrzej et al. (2016) Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity. Elife 5:
Seim, Inge; Ma, Siming; Gladyshev, Vadim N (2016) Gene expression signatures of human cell and tissue longevity. NPJ Aging Mech Dis 2:16014
Carlson, Bradley A; Tobe, Ryuta; Yefremova, Elena et al. (2016) Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol 9:22-31

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