The role of somatotropic and estrogen signaling in longevity and resistance to oxidative stress

This study investigates the interplay between endocrine signaling and in vivo oxidative stress resistance in mice, examining it in three ways: first, the resistance of pituitary-deficient Ames dwarf mice to oxidative stress was compared with that of phenotypically normal littermates; second, the resistance of Igf1r+/- mice to oxidative stress was compared with that of wildtype littermates; finally, the resistance of gonadectomized estradiol-supplemented mice to oxidative stress was compared with that of gonadectomized, non-supplemented mice and non-gonadectomized mice. In the Ames dwarf study we found that Ames dwarf mice (of both sexes) survived oxidative stress caused by paraquat and diquat for a longer period of time than the control mice. However, we found that when comparing the response of Ames dwarf mouse liver to diquat to that of liver from control mice, Ames dwarf mice were actually more susceptible to apoptosis and loss of cell membrane integrity, indicative of cellular damage. This suggests that though on the whole-animal level, the Ames dwarf mouse is resistant to oxidative stress, the resistance can vary from one organ to another. In the Igf1r +/- study, we found that Igf1r+/- female mice survived paraquat and diquat-induced oxidative stress for longer periods of time than did wildtype females, and there was less diquat-induced liver damage in Igf1r+/- females. However, there was no difference in the survival times of Igf1r +/- and wildtype males, indicating that the Igf1r +/- genotype confers oxidative stress resistance in a sexually dimorphic manner. A study of the Igf1r+/- mouse lifespan had been done by another group previous to this study, but its interpretability is questionable because both the long-lived and non long-lived cohorts lived such a short time compared to accepted standards for baseline longevity of healthy mice. We therefore repeated the Igf1r+/- longevity study with a large sample size and under the optimal husbandry conditions of our facility. We found that the results of the earlier longevity study greatly overstated the true impact that the Igf1r +/- genotype has on longevity. Instead of the widely cited 33% increase in the lifespan of Igf1r+/- females compared to wildtype females, we found only a 6% increase. However in absolute terms, even our shortest-lived group (the wildtype females) substantially outlived the longest-lived group (the Igf1r+/- females) from the earlier study. These results suggest that under non-stressful husbandry conditions where mice have the opportunity to attain their lifespan potential, the oxidative stress resistance conferred by the Igf1r +/- genotype has only a minor additional benefit to longevity. This finding is likely to have a major impact this field of study, because the study we have, for practical purposes, refutes what was widely cited and spawned a number of hypotheses about aging and oxidative stress, which now may have to be re-evaluated. We also found that male Igf1r +/- mice, though not longer lived than male WT mice (in agreement with the earlier study), have a different age-specific mortality rate: Igf1r+/- male mice die at a higher rate than WT male mice at moderately old ages, but at a lower rate than WT male mice at very old ages. This is caused by their having a higher initial rate of mortality, but the rate at which mortality increases is higher for the wildtype males. In the final segment of the study, we directly studied sexual dimorphism of oxidative stress resistance in wildtype mice. We found that ovariectomy shortened the survival of female mice that were exposed to paraquat. However, supplementing ovariectomized mice with a dosage of estradiol approximating average physiological levels improved their survival times to the point where they were indistinguishable from sham-operated control mice. This is strong evidence that estradiol signaling exerts a protective role against oxidative stress in wildtype mice. In contrast, orchidectomy improved the survival times of male wildtype mice that were exposed to paraquat. Supplementation of the orchidectomized male mice with the same amount of estradiol as used for the females had no additional effect on survival. This finding indicates that male mice are less sensitive to the protective role of estradiol and that estradiol is indeed exerting its protection as a hormone rather than as a direct, free-radical scavenger. Furthermore, this finding strongly suggests that unlike estradiol, testosterone may actually suppress oxidative stress resistance.