The Critical Role of Metabolic Pathways in Aging

Aging is characterized by a deterioration in the maintenance of homeostatic processes over time, leading to functional decline and increased risk for disease and death. The aging process is characterized metabolically by insulin resistance, changes in body composition, and physiological declines in growth hormone (GM), insulin-like growth factor-1 (IGF-1), and sex steroids. Some interventions designed to address features of aging, such as caloric restriction or visceral fat depletion, have succeeded in improving insulin action and life span in rodents. Meanwhile, pharmacologic interventions and hormonal perturbations have increased the life span of several mammalian species without necessarily addressing features of age-related metabolic decline. These interventions include inhibition of the mammalian target of rapamycin and lifetime deficiency in GH/IGF-1 signaling. However, strategies to treat aging in humans, such as hormone replacement, have mostly failed to achieve their desired response. We will briefly discuss recent advances in our understanding of the complex role of metabolic pathways in the aging process and highlight important paradoxes that have emerged from these discoveries. Although life span has been the major outcome of interest in the laboratory, a special focus is made in this study on healthspan, as improved quality of life is the goal when translated to humans. Diabetes 61:1315-1322, 2012