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. 2001 Jun 5;98(12):6736-41.
doi: 10.1073/pnas.111158898. Epub 2001 May 22.

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

Affiliations

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

K Flurkey et al. Proc Natl Acad Sci U S A. .

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 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.

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Figures

Figure 1
Figure 1
Snell dwarf mice live longer than sibling controls. The triangles indicate control mice and the circles indicate mice of the dwJ/dw genotype on the (C3H/HeJ × DW/J)F1 background, housed at the University of Michigan. (Upper) Survival. Each symbol corresponds to a mouse dying at the age indicated. (Lower) Mortality rates, starting, for each genotype, as the age at which 20% of the mice have died. The lines are fitted by linear regression.
Figure 2
Figure 2
Age-dependent change in collagen denaturation time is slowed in dwarf mice. The vertical axis represents time, in minutes, for breakage of a weighted tendon in a denaturing urea solution. Each bar shows mean and SEM for n = 5 mice on the (DW/J × C3H/HeJ)F1 background, housed at The Jackson Laboratory.
Figure 3
Figure 3
Lifespan of (DW/J × C3H/HeJ)F1-Pit1dw/dwJ mice is not diminished by pituitary graft implantation at 3 months of age. Each bar shows mean ± SEM for mice of the indicated gender, treatment, and genotype. The numbers of mice per group were (left to right) 3, 4, 5, 4, 4, 4, 3, 4, 3, and 4. ANOVA including all grafted and sham-operated animals showed a significant effect of genotype (P < 0.0001), but no significant effects for gender or grafting and no significant interaction effects.
Figure 4
Figure 4
Extended lifespan of Ghrhr-defective lit/lit mice. (Upper) The survival curve for 35 mice of the C57BL/6J-Ghrhrlit/lit genotype and 31 lit/+ littermate control mice; genders were not significantly different and are pooled. Each symbol represents one mouse. (Lower) Smoothed monthly mortality rates, starting, for each genotype, at the age at which 20% of the mice had died. The lines are fitted by linear regression.
Figure 5
Figure 5
Body weight and serum leptin concentrations in (DW/J × C3H/HeJ)F1 dwarf and control mice at two age ranges. The bars indicate mean weight ± SEM; n = 7–20 mice for each point. Values written over the bars show leptin concentrations in ng/ml; standard errors were 2–3 ng/ml except for the aged dwarf males, which had a standard error of 9 ng/ml. n = 7–11 mice/point except n = 3 for the aged control males. For the leptin data, two mice have been omitted (one control male and one dw/dwJ female, both old) because they had leptin levels 6 and 19 standard deviations above the mean for the group as a whole. Excluding the outlier, the difference in leptin levels between old dwarf and old control mice is significant (P = 0.007) in males but not in females.

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