Comparative genetics of aging

The past few decades have seen the emergence of insulin/IGF-1-like signaling, target of rapamycin (TOR) signaling, sirtuins, and dietary restriction as important and evolutionarily conserved regulators of aging and longevity. Pharmacological agents that target components of these pathways, such as resveratrol and rapamycin, are being developed and tested for agingrelated activities in model organisms. This chapter deals with these models. Clinical trials for some of these agents are already under way for treatment of cancer and diabetes and will probably be expanded to other age-related disorders. These trials mark the first clinical benefits derived from comparative genetics of aging in model organisms. As key players in these conserved aging pathways continue to be uncovered and characterized using model systems, one also gain a better understanding of how they function and interact to integrate environmental signals into cellular responses that modulate aging. It has become apparent that, although longevity interventions can be mapped to genetically distinct pathways through epistasis and other types of studies, in reality most (or all) of these conserved longevity modifiers interact within cells as part of a complex network. For example, TOR activity both modulates and is modulated by insulin-like signaling, while DR alters signaling through both pathways. In future studies, it will be important to consider not only which proteins play a conserved longevity role, but which interactions between longevity factors have also been conserved. Such an approach should make it possible to develop a more comprehensive picture of the overarching longevity network and may resolve lingering questions and controversies in the field while providing more effective routes toward therapies for improving human health span and longevity.