The critical role of metabolic pathways in aging

Abstract

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 (GH), 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.

FIG. 1.

Major metabolic pathways that regulate mammalian longevity. Life span has been verifiably modulated by genetic, pharmacologic, and dietary interventions in model systems. 1: CR represents the most robust intervention to extend both mean and maximum life span in mammals, perhaps due to the magnitude of pathways affected by CR, including reduced cytokine levels, adiposity, IIS signaling, thyroid hormone levels, and increased adiponectin. 2: In response to these changes, numerous downstream cellular pathways are engaged, including SIRT1 activation (gray), IIS/phosphatidylinositol 3-kinase (PI3K)/Akt signaling (yellow), AMPK/mTOR signaling (purple), and extracellular signal-regulated kinase 1/2 (Erk1/2) signaling (green). 3: The collective response of these pathways to CR is believed to promote cellular fitness and ultimately longevity via activation of autophagy, stress defense mechanisms, and survival pathways while attenuating proinflammatory mediators and cellular growth. Furthermore, there is evidence supporting that life span extension can be achieved with pharmacologic approaches, such as rapamycin, via mTOR signaling blockade, resveratrol, by activating SIRT1 activity, and metformin, which seems to be a robust stimulator of AMPK activity. Arrows indicate a directional and stimulatory relationship, whereas blunt-ended lines indicate an inhibitory effect. Please note that there is some evidence that Akt activation of NF-κB may be mTOR-dependent, whereas SIRT1 may be a direct stimulator of AMPK activity and autophagy (not shown). TNFα, tumor necrosis factor-α; IL-6, interleukin-6; NF-κB, nuclear factor-κB; PAI-1, plasminogen activator inhibitor 1; IRS-1, insulin receptor substrate-1.

FIG. 2.

The frequency and trends of favorable longevity genotypes with aging. These data were obtained in ∼700 unrelated subjects from the longevity genes project at Albert Einstein College of Medicine, of which ∼350 were over the age of 95 years. Because in the U.S. approximately half of the population die by the time they reach age ∼80 years, subjects are selected for exceptional longevity. A polymorphism for longevity will be rather rare in individuals ∼60 years old but will be monotonically increased and overrepresented in centenarians. AdipoQ-del/del, homozygous deletion in the 3′-untranslated region adiponectin gene; Apo C3-CC, apolipoprotein C-3 genotype; CETP-VV, homozygosity genotype in CETP; FOXO3a-T, polymorphisms in the FOXO3A gene; IGFr, polymorphisms in the IGF-1 receptor gene; TSHr-G, polymorphisms in the TSH receptor gene (see text for references). Adapted from Barzilai et al. (74).