The Sir2-p53-IGF link in mammalian life-span control

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DESCRIPTION (provided by applicant): Metabolic reprogramming in response to malnutrition early in life impedes cell division, organ growth, and differentiation, and can lead to permanent growth deficits, as well as decreased life span. The "thrifty phenotype" hypothesis proposes that poor fetal nutrition imposes growth and developmental constraints and changes upon the fetus, which may be considered as achieving metabolic thrift. However, adaptive changes that are beneficial to survival under conditions of poor nutrition may be detrimental under conditions of nutritional abundance and lead to reduced health--‐ and life span. In the second cycle of funding for our grant entitled, ¿The Sir2¿p53¿IGF link in mammalian life span control,¿ we will pursue studies to delineate the molecular mechanism underlying the thrifty phenotype and how metazoan size and life span are coupled. Our hypothesis is that they require the coordinated activity of growth factor driven pathways on the one hand and metabolic pathways on the other, and that what links the two is the activity of the tumor suppressor p53. Specifically, we propose that metabolic flexibility is the function of Delta40p53, an embryonic isoform of p53 that can ¿sense¿ the environment and modulate the activity of full-length p53 on key metabolic target genes in response. The information we glean from the experiments to be undertaken in a second cycle of funding will have important applications in assisted reproductive technology (ART) and in healthy aging. Enormous advances over the past several decades have made it possible for babies to be conceived by and born to couples previously deemed infertile. Emerging evidence indicates, however, that individuals born using ART are prone to decrements in mid-life health associated with cardiovascular and metabolic dysfunction and might be at risk for reduced life expectancy. The overlap in phenotype between humans conceived by ART and experimental animals subjected to nutrient stress early in development is striking and needs to be understood, not just for its own sake, but also because not doing so represents a missed opportunity for designing more rational strategies to optimize the health and well being of all humans. The focus of our new experiments is on events occurring during an early developmental window, when stem cells first arise, that could permanently affect the trajectories of size and life span. We will be using our unique mouse strains with one, two, or three copies of Delta40p53 to develop the notion that events that occur (very) early in life can predispose individuals to changes that occur much later in life, even in old age. This distinct and virtually unexplored field of aging biology has particular relevance to eutherian mammals, including humans. PUBLIC HEALTH RELEVANCE: Paradoxically, robust growth and bigger size are not necessarily good predictors of a long and healthy life span. Despite the obvious significance of this observation, the mechanism that couples longevity and body size is poorly understood. We propose that it is the tumor suppressor p53 that links these two traits by controlling the switch from anaerobic to aerobic metabolism in stem cells.