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

Abstract

Summary 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 dietary restriction (DR: 40% reduction in food intake) on mean lifespan of virgin males and females in 41 recombinant inbred (RI) strains of mice. Mean strain-specific lifespan varied 2- to 3-fold 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.

The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster

“…These studies suggest that dietary composition or the ratio of carbohydrate relative to protein is more important than calorie intake in modulating lifespan. In mice, a study of lifespan in approximately 40 recombinant inbred lines under DR condition indicates that DR only extends lifespan in a subset of these mouse lines and even shortens lifespan in some (Liao et al 2010). This suggests that the prolongevity effect of DR depends on genetic background of the organism.…”

Dietary restriction and Sirtuin 1 in metabolic health: connections and divergences

“…Further complicating the picture, the effects of DR might have a strong genetic component. Using one of the largest groups of recombinant inbred strains of mice presently available, the ILSXISS (9) , Liao et al tested the hypothesis that the lifespan response to DR would fluctuate depending on the genetic variations across these genotypes (10) . Contrary to the extensive contemporary literature, at least half of the strains showed lifespan shortening by DR, rather than lifespan lengthening (10,11) .…”

“…Using one of the largest groups of recombinant inbred strains of mice presently available, the ILSXISS (9) , Liao et al tested the hypothesis that the lifespan response to DR would fluctuate depending on the genetic variations across these genotypes (10) . Contrary to the extensive contemporary literature, at least half of the strains showed lifespan shortening by DR, rather than lifespan lengthening (10,11) . Other points that are presently under debate include the degree of severity of the DR regime, the optimal age of onset of such regime and how the basal metabolic state of individuals might affect the effectiveness of the intervention (3) .…”

L’homéostasie métabolique au cœur du vieillissement

“…Afin de répondre à cette question, des cribles génétiques ont été réalisés pour identifier des gènes dont la mutation supprime l'allongement de la durée de vie induite par la restriction calorique. En effet, le génotype d'un individu peut aussi affecter sa réponse à une restriction calorique, pouvant abolir complètement l'allongement de la durée de vie [16]. Parmi les gènes identifiés, plusieurs codent pour des senseurs énergétiques conservés au cours de l'évolution ( Figure 1) tels que l'AMP kinase (AMPK) [17] -dont l'activation dépend des niveaux d'ATP, d'AMP et d'ADP -, la déacétylase SIRT1 (sirtuine, homologue chez la levure de silent information regulator 2 [Sir2]) [18] -qui a pour cofacteur le NAD -, et la sérine thréonine kinase TOR (target of rapamycin) [19].…”