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 f mammalian tissues and cells using RNA-seq and metabolomics, identify key regulators of lifespan, develop interventions that simultaneously target these regulators,
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.
| Zhao, Yang; Tyshkovskiy, Alexander; Muñoz-Espín, Daniel et al. (2018) Naked mole rats can undergo developmental, oncogene-induced and DNA damage-induced cellular senescence. Proc Natl Acad Sci U S A 115:1801-1806 |
| Seluanov, Andrei; Gladyshev, Vadim N; Vijg, Jan et al. (2018) Mechanisms of cancer resistance in long-lived mammals. Nat Rev Cancer 18:433-441 |
| Ma, Siming; Avanesov, Andrei S; Porter, Emily et al. (2018) Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity. Aging Cell :e12740 |
| Sziráki, András; Tyshkovskiy, Alexander; Gladyshev, Vadim N (2018) Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell 17:e12738 |
| Carlson, Bradley A; Lee, Byeong Jae; Tsuji, Petra A et al. (2018) Selenocysteine tRNA[Ser]Sec, the Central Component of Selenoprotein Biosynthesis: Isolation, Identification, Modification, and Sequencing. Methods Mol Biol 1661:43-60 |
| Ke, Zhonghe; Mallik, Pramit; Johnson, Adam B et al. (2017) Translation fidelity coevolves with longevity. Aging Cell 16:988-993 |
| Ma, Siming; Gladyshev, Vadim N (2017) Molecular signatures of longevity: Insights from cross-species comparative studies. Semin Cell Dev Biol 70:190-203 |
| Lee, Sang-Goo; Mikhalchenko, Aleksei E; Yim, Sun Hee et al. (2017) Naked Mole Rat Induced Pluripotent Stem Cells and Their Contribution to Interspecific Chimera. Stem Cell Reports 9:1706-1720 |
| 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 |
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