The Well Studied Mutations that Extend Life in Mammals

Mutations affecting growth hormone metabolism and insulin metabolism, and that lead to extended life, are comparatively well studied in mammals. The longest lived mice are those in which growth hormone receptor is knocked out. Unfortunately this, like many interventions related to growth, nutrient sensing, and the like, produces a much greater effect on life span in short-lived species than in long-lived species. Humans with analogous loss-of-function mutations in growth hormone receptor may be resistant to some common age-related diseases, but do not live meaningfully longer than the rest of us.

In 1996, a report of extended longevity in mice homozygous for a mutation producing growth hormone (GH) deficiency was quickly followed by the demonstration of extensive homology between one of the key longevity genes in a worm, Caenorhabditis elegans, and genes coding for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor in mammals. Since GH is the key determinant of hepatic IGF-1 expression and circulating IGF-1 levels, and has major impact on insulin signaling, these findings led to an exciting conclusion that the insulin/insulin-like growth factor signaling (IIS) is an evolutionarily conserved mechanism which controls aging in organisms ranging from yeast and worms to insects and mammals.

Subsequent work provided much evidence in support of this exciting realization, and this has led to a focus on IIS, rather than GH signaling, in analyzing genetic control of mammalian aging. This is an important distinction. Although biosynthesis and blood plasma levels of GH and IGF-1 are closely linked, the actions of these hormones are not identical and, in some cases, opposite. For example, IGF-1 mimics some of the insulin actions and promotes insulin sensitivity, while GH is anti-insulinemic and promotes insulin resistance; IGF-1 promotes fat deposition, while GH is lipolytic. Actions of GH not shared with IGF-1 include other effects relevant to aging such as impact on reactive radicals production and anti-oxidative defenses, DNA damage and repair, macrophage reprogramming, ovarian primordial follicle reserve, bone resorption and turnover, kidney dysfunction, and cognitive functioning.

In contrast to the remarkable extension of longevity in female and male mice lacking GH or GH receptors, the impact of reduced IGF-1 signaling on longevity of IGF1R ± mice and mice treated with an antibody to IGF-1 receptor is modest and seen only in one sex. This difference between the effects of reduced IGF-1 and GH signaling is likely related to IGF-1 exerting both beneficial and detrimental effects on aging and age-related disease (including opposite effects on the risk of type 2 diabetes vs cardiovascular disease and cognitive decline) and GH having primarily "pro-aging" effects. Both hormones impact growth, but the metabolic effects of GH are significantly greater.


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