The insulin/IGF-1 signaling in mammals and its relevance to human longevity.

Hormones, like insulin and insulin-like growth factor 1 (IGF-1), are thought to be deeply involved with longevity. Lower species have been the source for most of our current knowledge on the role of the insulin/IGF-1 signaling in modulating lifespan. This hormonal system may have originated from a very early common ancestor and is involved in many functions that are necessary for metabolism, growth, and fertility in animal models like flies, nematodes and mammalians. Disruption of the insulin/IGF-1 receptor in nematodes and flies increases lifespan significantly. With evolution, mammals developed two well characterized hormonal systems: insulin and growth hormone (GH)/IGF-1, with different metabolic and developmental functions. Abnormalities in the insulin signaling pathway generate age-related diseases and increased mortality, whereas the GH/IGF-1 axis could potentially modulate longevity in many species. In this review we briefly describe the lifespan regulatory role of the insulin/IGF-1 signaling of nematodes, flies and rodent models and compare it with the human equivalent.

Differential responses of visceral and subcutaneous fat depots to nutrients.

Increased visceral adiposity is a pivotal component of the metabolic syndrome. Differential gene expression patterns of fat-derived peptides (FDPs) in visceral fat and subcutaneous fat have been characterized in the fasting state. Here we examined whether delivery of nutrients differentially affects the expression of FDPs in visceral fat versus subcutaneous fat (in the fed state). We increased the rate of glucose flux into adipose tissue of normal rats (n = 16) by hyperglycemia or hyperinsulinemia using the clamp technique. Glucose uptake was associated with increased expression of FDPs, including resistin ( approximately 5-fold), adiponectin ( approximately 2-fold), leptin ( approximately 15-fold), plasminogen activating inhibitor-1 ( approximately 10-fold), and angiotensinogen ( approximately 4-fold) in visceral fat, but markedly less in subcutaneous fat. Cytokine expression derived mainly from vascular/stromal/macrophage components of adipose tissue was less dramatically increased. Infusion of glucosamine amplified the results obtained by increasing glucose uptake into adipose tissue, suggesting that flux through the hexosamine biosynthetic pathway may serve as a mechanism for "nutrient sensing." Nutrient-dependent expression of FDPs in visceral fat was also associated with increased plasma levels of several FDPs. Because a biologic sensing pathway can dynamically couple daily food intake to abnormal plasma levels of important FDPs, we challenge the practice of obtaining plasma levels after fasting to assess risk factors for metabolic syndrome.

Inflammatory peptides derived from adipose tissue.

The low-grade inflammation seen with aging is noted particularly in subjects with the metabolic syndrome of aging. Insulin resistance, obesity/abdominal obesity, and risks for many age-related diseases characterize this common syndrome. It is becoming clear that this increased adipose tissue is not simply a reservoir for excess nutrients, but rather an active and dynamic organ capable of expressing several cytokines and other fat-derived peptides (FDP). Some, but not all, FDP may have a role in development of the metabolic syndrome but there is no evidence that these FDP are causing inflammation directly. We suggest that high levels of inflammatory peptides are markers for obesity/abdominal obesity seen with aging, but some may not necessarily have a causative role in the development of inflammation.