STM Commentary v02

C R E D IT : A . F O ST E R INTRODUCTION Age is the greatest risk factor for most major chronic diseases in the industrialized world and to an increasing degree in the developing world. After adolescent development, functionality declines progressively with age (1), and mortality rates increase exponentially, doubling roughly every 7 to 8 years after puberty. This exponentiality manifests as a progressive, roughly synchronous rise in the incidence of disease, disability, and death from chronic diseases beginning after midlife (examples in Fig. 1) and suggests a causal—rather than a casual— relationship. The physiological basis of these phenomena lies in the progressive lifelong accumulation of deleterious changes in the structure of the body at the molecular, cellular, and tissue levels. These changes (aging damage) arise primarily as damaging side effects of normal metabolism, aggravated by environmental toxins and unhealthy lifestyle. Aging damage contributes to pathology either directly (by impairing the function of specific biomolecules) or indirectly [by eliciting cellular or systemic responses that generally serve near-term protective functions but ultimately are deleterious (2, 3)]. As damage accumulates, organisms suffer progressively diminished functionality, homeostasis, and plasticity, reducing the capacity to survive and recover from environmental challenge. These changes both contribute etiopathologically to specific age-related diseases and increase the organism’s vulnerability to other insults that contribute to them, leading to increasing morbidity and mortality. The surprising conclusion from the past two decades of research on biological aging is that aging is plastic: Within a species, maximum life span is not fixed but can be increased by dietary manipulation [particularly calorie restriction (CR) (4)] or genetic manipulation [particularly dampened insulin/insulin-like growth factor–1 signaling (IIS) (5)]. These interventions generally reduce the generation, enhance the repair, and/or increase the tolerance of the molecular and cellular damage of aging. Although our ability to assess “health span” in model organisms remains incomplete (6), these interventions generally preserve “youthful” functionality in regard to tested parameters and reduce the incidence of age-related disease. There have long been calls (7, 8) for greater efforts to translate this research into clinical interventions to expand the healthy, productive period of human life. By targeting the aging damage that is responsible for the age-related rise in disease vulnerability, such interventions would reA g I N g