Targeting multiple hallmarks of mammalian aging with combinations of interventions.

Aging is currently viewed as a result of multiple biological processes that manifest themselves independently, reinforce each other and in their totality lead to the aged phenotype. Genetic and pharmaceutical approaches targeting specific underlying causes of aging have been used to extend the lifespan and healthspan of model organisms ranging from yeast to mammals. However, most interventions display only a modest benefit. This outcome is to be expected if we consider that even if one aging process is successfully treated, other aging pathways may remain intact. Hence solving the problem of aging may require targeting not one but many of its underlying causes at once. Here we review the challenges and successes of combination therapies aimed at increasing the lifespan of mammals and propose novel directions for their development. We conclude that both additive and synergistic effects on mammalian lifespan can be achieved by combining interventions that target the same or different hallmarks of aging. However, the number of studies in which multiple hallmarks were targeted simultaneously is surprisingly limited. We argue that this approach is as promising as it is understudied.