It is widely known that caloric restriction (CR) remains the only nongenetic and most robust intervention that reproducibly extends both average and maximal lifespan in a wide variety of species, including mammals (1 ). An important distinction to be drawn is that CR, unlike other approaches, increases both average and maximal lifespan. A number of different interventions can act to extend average lifespan in both animals and humans. Consider that average lifespan for men and women has increased remarkably since the early 1900s in developed countries from about 40 yr then to 80 yr today. This is mostly attributable to a reduction in early mortality due to improvements in medical care (antibiotics,

From: Methods in Molecular Biology: Biological Aging: Methods and Protocols Edited by: T. O. Tollefsbol © Humana Press Inc., Totowa, NJ

vaccinations, and so on), nutrition, and improvements in overall health. Despite notable increases in the average human lifespan, the maximal (presumably genetically determined) lifespan has remained fixed around 120 yr. It can be argued that interventions that affect average lifespan do so by altering pathologies associated with aging and age-related disease, whereas interventions such as CR that also increase maximal lifespan fundamentally alter the underlying biology of aging. As such, CR is not only the most robust intervention for lifespan extension and retardation of aging, but may also be an important tool available to scientists to explore fundamental biological mechanisms of aging.

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