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 exploration of the molecular basis for age-related changes in cell and tissue function and for the pathophysiology of age-dependent diseases. We show here 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 relatively 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-sensitive indices of immune system status. These findings thus demonstrate that a single 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 not due to lowered prolactin levels. In contrast, homozygosity for the Ghrhr(lit) mutation, which like the Pit1(dw) mutation lowers plasma growth hormone levels, does lead to a significant increase in longevity. Male Snell dwarf mice, unlike calorically restricted mice, become obese and exhibit proportionately high leptin levels in old age, showing that their exceptional longevity is not simply due to alterations in adiposity per se. Further studies of the Pit1(dw) mutant, and the closely related, long-lived Prop-1(df) (Ames dwarf) mutant, should provide new insights into the hormonal regulation of senescence, longevity, and late life disease.
Flurkey
K
K
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Papaconstantinou
J
J
Miller
R A
RA
Harrison
D E
DE
D000375:Aging; D000818:Animals; D001835:Body Weight; D003094:Collagen / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D013006:Growth Hormone / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D020738:Leptin / Q000097:blood; D008136:Longevity; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D010902:Pituitary Gland / Q000637:transplantation; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000502:physiology*; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D003094:Collagen; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D007334:Insulin-Like Growth Factor I; D020738:Leptin; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C494185:Pou1f1 protein, mouse