Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production

Single-gene mutations that extend lifespan provide valuable tools for the e xploration of the molecular basis for age-related changes in cell and tissu e function and for the pathophysiology of age-dependent diseases. We show h ere that mice homozygous for loss-of-function mutations at the Pit1 (Snell dwarf) locus show a > 40% increase in mean and maximal longevity on the rel atively long-lived (C3H/HeJ x DW/J)F-1 background. Mutant dw(J)/dw animals show delays in age-dependent collagen cross-linking and in six age-sensitiv e indices of immune system status. These findings thus demonstrate that a s ingle gene can control maximum lifespan and the timing of both cellular and extracellular senescence in a mammal. Pituitary transplantation into dwarf mice does not reverse the lifespan effect, suggesting that the effect is n ot due to lowered prolactin levels, In contrast, homozygosity for the Ghrhr (lit) mutation, which like the Pit1(dw) mutation lowers plasma growth hormo ne levels, does lead to a significant increase in longevity. Male Snell dwa rf mice, unlike calorically restricted mice, become obese and exhibit propo rtionately high leptin levels in old age, showing that their exceptional lo ngevity is not simply due to alterations in adiposity per se. Further studi es of the Pit1(dw) mutant, and the closely related, long-lived Prop-1(df) ( Ames dwarf) mutant, should provide new insights into the hormonal regulatio n of senescence, longevity, and late life disease.