Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer.

Two theories of how energy metabolism should be associated with longevity, both mediated via free-radical production, make completely contrary predictions. The 'rate of living-free-radical theory' (Pearl, 1928; Harman, 1956; Sohal, 2002) suggests a negative association, the 'uncoupling to survive' hypothesis (Brand, 2000) suggests the correlation should be positive. Existing empirical data on this issue is contradictory and extremely confused (Rubner, 1908; Yan & Sohal, 2000; Ragland & Sohal, 1975; Daan et al., 1996; Wolf & Schmid-Hempel, 1989]. We sought associations between longevity and individual variations in energy metabolism in a cohort of outbred mice. We found a positive association between metabolic intensity (kJ daily food assimilation expressed as g/body mass) and lifespan, but no relationships of lifespan to body mass, fat mass or lean body mass. Mice in the upper quartile of metabolic intensities had greater resting oxygen consumption by 17% and lived 36% longer than mice in the lowest intensity quartile. Mitochondria isolated from the skeletal muscle of mice in the upper quartile had higher proton conductance than mitochondria from mice from the lowest quartile. The higher conductance was caused by higher levels of endogenous activators of proton leak through the adenine nucleotide translocase and uncoupling protein-3. Individuals with high metabolism were therefore more uncoupled, had greater resting and total daily energy expenditures and survived longest - supporting the 'uncoupling to survive' hypothesis.