Deletion of the p66shc gene promotes longevity in laboratory mice but reduces survival rate under natural conditions

Deletion of the p66Shc gene results in lean and healthy mice, retards aging, and protects from aging-related pathologies, raising the question of why p66Shc is still part of our genome, and what is its physiological role. We have investigated survival and reproduction of p66Shc -/- mice in a population living in a large outdoor enclosure for one year, subjected to food competition and exposed to winter temperatures. Under these conditions, the p66Shc-/- phenotype was strongly counterselected. Laboratory studies revealed that knock-out subjects have defects in fat accumulation, thermoregulation and reproduction, suggesting that p66Shc has been evolutionarily selected because of its role in energy metabolism. These findings suggest that the health impact of targeting aging genes might depend on the specific energetic niche and caution should be taken against premature conclusions regarding gene functions that have only been observed in protected laboratory conditions.