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

Kevin Flurkey, John Papaconstantinou, Richard A. Miller, David E. Harrison

Research output: Contribution to journalArticle

585 Scopus citations

Abstract

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 × DW/J)F1 background. Mutant dwJ/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 Ghrhrlit mutation, which like the Pit1 1dw 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 Pit 1dw mutant, and the closely related, long-lived Prop-1df(Ames dwarf) mutant, should provide new insights into the hormonal regulation of senescence, longevity, and late life disease.

Original languageEnglish (US)
Pages (from-to)6736-6741
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number12
DOIs
StatePublished - Jun 5 2001

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Keywords

  • Ghrhr
  • Longevity
  • Pit1
  • Snell dwarf
  • T lymphocytes

ASJC Scopus subject areas

  • General

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