Aging is broadly defined as the deterioration of bodily tissues over time. Excluding death due to infectious disease or accidents, aging is what ultimately places finite limits on lifespan and healthspan, the time in which in individual remains active and in good health. Although healthspan and lifespan are intimately linked, it is the extension of human healthspan that is a major goal of gerontological research. Such an achievement would have broad social and economic benefits and importantly would mitigate the dire consequences of the predicted future rise in the prevalence of age-related diseases due to the growing proportion of the population that is of advanced age (65yr and over). A broad understanding of the physiological, metabolic, hormonal, cellular and molecular factors that contribute to aging and lifespan determination will allow for the development of strategies to extend healthspan.

The work presented herein describes the use of three unique mouse models of extended healthspan and maximum lifespan, including calorie restricted (CR), Snell Dwarf and rapamycin-treated mice, to investigate several factors linked to healthspan and lifespan determination in mammals. These factors include reduced insulin-like growth factor-1 (IGF-1) expression, reduced cell proliferation, reduced protein synthesis and enhanced proteome stability. Using these three models the following conclusions have been drawn: 1) Physiological adaptations to CR previously suggested to confer the healthspan and lifespan benefits of CR in rodents cannot account for the global cell proliferation rate-lowering effect of CR; 2) Fibroblast growth factor 21 (FGF21) is not necessary for the reduction in IGF-1 or the reduction in global cell proliferation rates in response to moderate CR in adult mice; 3) A reduction in global cell proliferation rates is not a consistent predictor of maximum lifespan extension in mice; 4) A reduction in hepatic protein replacement rates is a sensitive and early predictor of maximum lifespan extension in mice and likely reflects a more stable and functional proteome.