Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening

Abstract

Chronic dietary restriction (DR) is considered among the most robust life-extending interventions, but several reports indicate that DR does not always extend and may even shorten lifespan in some genotypes. An unbiased genetic screen of the lifespan response to DR has been lacking. Here, we measured the effect of one commonly used level of DR (40% reduction in food intake) on mean lifespan of virgin males and females in 41 recombinant inbred strains of mice. Mean strain-specific lifespan varied two to threefold under ad libitum (AL) feeding and 6- to 10-fold under DR, in males and females respectively. Notably, DR shortened lifespan in more strains than those in which it lengthened life. Food intake and female fertility varied markedly among strains under AL feeding, but neither predicted DR survival: therefore, strains in which DR shortened lifespan did not have low food intake or poor reproductive potential. Finally, strain-specific lifespans under DR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of DR exhibits wide variation amenable to genetic analysis. They also show that DR can shorten lifespan in inbred mice. Although strains with shortened lifespan under 40% DR may not respond negatively under less stringent DR, the results raise the possibility that life extension by DR may not be universal.

Fig. 1

Strain variation in mean lifespan of ILSXISS recombinant inbred (RI) mice under ad libitum (AL) and dietary restriction (DR) diets. Lifespans were typically obtained from 10 AL and 10 DR mice from each strain (5 males & 5 females per treatment group); sample sizes in a few strains were either greater or less than 10 (details in Supplementary Table S1). The mean lifespans in the upper two panels are shown for each strain [AL (□) and DR (■)], ranked in ascending order according to the AL means (A: males, 41 strains; B: females, 39 strains). The lower two panels illustrate the deviation (positive and negative) of the mean DR lifespan from the mean AL for the same strains, ranked from the strain with the greatest increase in lifespan under DR to the strain with the greatest decrease (C: males; D: females). Error bars represent SEM. * p < 0.05, ** p < 0.01, *** p < 0.001 by t-test (no experiment-wise Bonferroni correction).