From Cells to Mice: Mutations Conferring Oxidative Stress-resistance on Longevity Phenotypes in the Mouse

Oxidative stress is one of the drivers of the aging process and resistance to oxidative stress is a common characteristic of long-lived organisms. For these reasons, stress resistance has been recognized as a surrogate marker of longevity. Efforts to promote stress resistance through boosting the antioxidant system did not extend lifespan, suggesting that other uncharacterized pathways mediate the relationship of stress resistance and longevity. To identify mammalian genes that enhance oxidative stress resistance and thus slow aging, our group developed a high-throughput platform for screening and selecting novel genetic mutants in the mouse. In the studies outlined here we report on the longitudinal assessment of healthspan and lifespan of two genetic mutant mice, Pigl and Tiam1, that were selected from our screening platform. We assessed two metrics of healthspan, body weight (BW) and grip strength (GS), across the lifespan in both male and female mice. BW and GS are measures of general and neuromuscular health and are commonly assessed in mice and humans. We found that Pigl and Tiam1 mice had lower BWs than control mice at younger ages, the Tiam1 mice reached comparable BWs to controls whereas the Pigl mice remained smaller. BW at 350 days was not predictive of lifespan, but maximal BW and age at maximal BW were. GS declined more slowly in Pigl and Tiam1 mice compared to controls, and GS at 350 days was predictive of lifespan. In general, male mice increased BW more quickly and lost GS more slowly than female mice. These characteristics are consistent with extended lifespan; however, we observed minimal longevity effects. The heterozygous Pigl female mice were longer lived than wildtype littermates and the Tiam1 mice regardless of genotype were shorter lived than controls. These studies are some of the few that longitudinally evaluate healthspan and lifespan in male and female mice of different genetic backgrounds. Collectively, our results show that genetic mutations conferring oxidative stress resistance slowed GS decline and reduced BW but did not extend lifespan. This suggests that increased stress resistance may preserve physiological function thereby extending healthspan and highlights the complex relationship between stress-resistance and longevity.

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