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

TLDR

Dietary restriction is a well‑established life‑extending intervention, yet evidence shows it can also shorten lifespan in certain genotypes, and a comprehensive genetic screen of this response has been missing. The study assessed the impact of a 40 % reduction in food intake on mean lifespan in 41 recombinant inbred mouse strains, comparing virgin males and females under ad libitum and restricted feeding. Across strains, DR produced a 6‑ to 10‑fold increase in lifespan variability, shortened life in more strains than it extended, and showed no correlation with baseline food intake, fertility, or ad libitum lifespan, indicating that the genetic determinants of DR response are distinct and that life extension by DR is not universal.

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.