In flies and worms, loss-of-function mutations in insulin and insulin-related cell signaling pathways have led to increase in life span of the species studied. In order to evaluate these pathways in a mammalian specie, the present investigators developed mice with hemizygous loss of one insulin-like growth factor-1 receptor (IGF-IR) allele and studied their longevity. The hemizygous IGF-I+/- mice were generated by deletion of exon 3 of the gene encoding IGF-IR; these mice had 50% of the IGF-IR levels that intact animals had. Homozygous inactivation of the gene encoding the IGF-IR (IGF-IR-/-) was lethal. During nursing, IGF-IR+/- and intact (IGF-IR+/+) mice grew identically; after weaning there was a slight decrease in growth (-6% to -8%) in hemizygous mice relative to intact animals through 11 weeks of age. IGF-IR+/- female mice lived 33% longer and males 16% longer than did IGF-IR+/+ mice, and female hemizygous mice outlived their male counterparts. (Figure) As anticipated, serum IGF-I concentrations were higher in IGF-IR+/- mice than with control animals, while insulin levels were normal. Glucose tolerance was impaired in IGF-IR+/- male but not female mice. Energy balance in mutant and control animals was similar in food intake, body temperature, physical activity, metabolic rate and fertility. The ability to withstand an oxidative stress was greater in mutant than control animals both in vivo and vitro. In cultured fibroblasts, the amounts of several signal transduction molecules downstream of the IGF-IR were decreased relative to the activity of control fibroblasts. In particular, levels of phosphorylated p66 shc, an activator of mitogen activated protein (MAP) kinase, were reduced by one-half, suggesting that perhaps a decrease in the rate of cell division might be an important factor in increasing longevity. The investigators conclude that in mice the partial inhibition of IGF-I signaling leads to increase in life span.
Bluher et al demonstrated that in mice in which there has been localized “knock out” of fat specific insulin-receptors (FIRKO) (in contrast to generalized loss of IRS which leads to insulin resistance, diabetes mellitus, and obesity), there was extension of life span despite normal caloric intake and without clinical or biochemical abnormalities. FIRKO mice were approximately 20% lighter and their body fat content approximately 60% lower than control animals, despite eating similar quantities of food. Control animals lived an average of 753 days, while FIRKO mice lived 887 days (+134 days, +18%); median life span in FIRKO was increased by +3.5 months and maximum life span by +5 months. Fertility of the FIRKO mice was not reported. The investigators concluded that low body fat content (leanness) rather than decreased food intake was the primary factor contributing to increase in life span of the FIRKO mice.
Holzenberger M, et al. IGF-I receptor regulates lifespan and resistance to oxidative stress in mice. Nature 2003;421:182-186.
Bluher M, et al. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 2003;299:572-574.
Editor’s Comment: There is increasing evidence that insulin, growth hormone (GH), and IGF-I are intimately involved with the duration of life. Experimentally, partial caloric deprivation increases life span while decreasing serum concentrations of IGF-I. Mice with GH deficiency (GHD) such as Ames (Propdf/df) and Snell (Pit1dw/dw) mice are extremely long-lived albeit dwarfed and infertile, as are mice in which the GH receptor has been "knocked-out."
The manuscripts present several interesting observations in addition to those on longevity. Thus, partial inactivation of the IGF-IR gene led to slightly subnormal growth in mice, suggesting that variants of this gene might play a role in the diversity of height in man. Also of interest were the gender specific effects of partial loss of IGF-IR which was more pronounced in females than males which indicated that sex-specific factors may modulate the effects of IGF-IR.
While it is not possible to transpose these data to man, they make one wonder whether we may be adversely affecting life span by treating our GHD adult patients with rhGH. Perhaps it might be less risky to treat the cardiovascular and skeletal abnormalities of the adult with GHD with agents other than rhGH.
Allen W. Root, MD