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.

Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue

“…Thus, the inverse relationship observed between FGF21 and FGF19 in obesity and diabetes—upregulation of FGF21 and downregulation of FGF19—(Gallego‐Escuredo et al, 2015) did not occur in healthy elderly individuals, despite the significant increase in FGF21 (Figure 1a). Despite the absence of overt diabetes, our population of aged individuals showed an increase in glycemia and insulinemia relative to young individuals (Table 1), an observation previously reported and considered an indication of impaired functionality of general metabolic homeostasis with age (Barzilai, Huffman, Muzumdar, & Bartke, 2012). In fact, FGF21 levels were positively correlated with glucose levels ( r  = 0.197, p  = 0.048), insulin levels ( r  = 0.224, p  = 0.038), and insulin resistance, measured as HOMA‐IR, ( r  = 0.427, p  = 0.005) in the studied cohort.…”

Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

“…Clearly, disruption of the insulin/IGF‐1 signaling pathway in lower organisms extends lifespan, while a decrease in growth, and hence body size in mammals, is also linked to longevity (Barzilai et al ., 2012; Brown‐Borg & Bartke, 2012). However, while low peripheral IGF‐1 is linked to less cancer (Renehan et al ., 2004), it is associated with increased risk for other age‐related diseases in humans (Sonntag et al ., 2012).…”

“…Diminished growth hormone/insulin‐like growth factor‐1 (GH/IGF‐1) signaling improves longevity across nature, including mice heterozygous for the IGF‐1 receptor (IGF‐1R) (Holzenberger et al ., 2003; Barzilai et al ., 2012). Moreover, low IGF‐1 action is relevant to humans because of its link to less cancer risk (Renehan et al ., 2004), an observation that spurred the development of IGF‐1R antagonists as a clinical cancer treatment (Pollak, 2012).…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…It has been observed that the decreased activity, low concentrations, and small amounts of mRNA of insulin‐degrading enzyme in brains of patients with AD and knockout mice that lack the enzyme have reduced degradation of Aβ and insulin in brain (Lam & Lu, 2007; Li et al, 2002; Shanley, Irving, & Harvey, 2001). Similarly, insulin resistance is commonly observed in older adults (Barzilai, Huffman, Muzumdar, & Bartke, 2012; Morley, 2008). Insulin resistance usually caused the unrestrained hepatic gluconeogenesis, adipose lipogenesis, and defective glycogen synthesis and glucose uptake in skeletal muscle.…”