The Endocrine Regulation of Aging by Insulin-like Signals

Science -- Tatar et al. 299 (5611): 1346: "Pituitary Endocrine Deficiency in Mammals Of the half-dozen genetic models that retard murine aging, four involve deficiency of pituitary endocrine action. The mutations Prop1df (42) and Pit1dw impede pituitary production of growth hormone (GH), thyroid stimulating hormone (TSH), and prolactin; reduce growth rate and adult body size; and increase adult life-span by 40 to 60% (43, 44). Small adults with similar improvement in longevity are also produced by a knockout of growth hormone receptor (GHR-KO) (45). Expressed throughout life, these mutations produce many secondary alterations in endocrine systems. Without GH, the synthesis of circulating IGF-1 is suppressed, as is plasma insulin as a result of enhanced sensitivity in the liver combined with altered pancreatic islet development (46). Thyroid function is reduced in Prop1df and Pit1dw mutants deficient for TSH (45); GHR-KO mice are mildly hypothyroid, presumably as a result of impaired development (47). The challenge is to identify which of these hormones regulate aging and at which stage of life.

In invertebrates, reduced insulin/IGF signaling increases longevity, but it remains unclear whether or how reduction in GH and IGF-1 directly affects aging in rodents (Fig. 1C). In addition to its impact on IGF-1, GH influences somatic metabolism--for instance, by inducing adipocyte lipolysis. IGF-1 itself may affect aging in both beneficial and detrimental ways. In rodents as in humans, levels of GH and IGF-1 decline with adult age. Short-term GH supplementation in aged adults restores some aspects of body composition and cognition (48, 49). Thus, the withdrawal of GH and IGF-1 has been suggested to be a cause of senescence rather than a condition that retards aging. On the other hand, because it stimulates metabolism and cell growth, GH may hasten tissue pathology. Indeed, chronic treatment of GH-deficient dwarf rats with GH increased tumor incidence in response to a carcinogen (50). High IGF-1 titers in young wild-type animals may produce a trade-off between current benefits to reproduction and later costs in senescence (51).

Powerful evidence for the direct role of IGF-1 signaling in the control of mammalian aging was provided by mice mutant for the IFG-1 receptor Igf1r (52): Igf1r+/ females, but not males, live 33% longer than wild-type controls. These mutants exhibit minimal reduction in growth with no alterations in the age of sexual maturation, fertility, metabolism, food intake, or temperature. Life extension is associated with increased tolerance of oxidative stress and reduced phosphorylation of Shc, a gene previously implicated in the control of longevity and stress resistance in mice (53). Mouse longevity is also increased 18% by fat-specific disruption of the insulin receptor gene (54). These mice have normal caloric intake yet retain leanness and glucose tolerance with age. Multiple intriguing changes in adipocytes underlie these effects, including elevated plasma leptin relative to adipose tissue mass, reduced lipolysis, and polarization of adipocytes into populations with altered expression of fatty acid synthase (55). Thus, insulin at adipose tissue may affect aging through impacts on neural-targeted hormones as well as through regulation of intermediary metabolism."

Science, Vol 299, Issue 5611, 1346-1351 , 28 February 2003