Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans

Eric L Greer,Anne Brunet

doi:10.1111/j.1474-9726.2009.00459.x

Abstract

Dietary restriction (DR) has the remarkable ability to extend lifespan and healthspan. A variety of DR regimens have been described in species ranging from yeast to mammals. However, whether different DR regimens extend lifespan via universal, distinct, or overlapping pathways is still an open question. Here we examine the genetic pathways that mediate longevity by different DR regimens in Caenorhabditis elegans. We have previously shown that the low-energy sensing AMP-activated protein kinase AMPK/aak-2 and the Forkhead transcription factor FoxO/daf-16 are necessary for longevity induced by a DR regimen that we developed (sDR). Here we find that AMPK and FoxO are necessary for longevity induced by another DR regimen, but are dispensable for the lifespan extension induced by two different DR methods. Intriguingly, AMPK is also necessary for the lifespan extension elicited by resveratrol, a natural polyphenol that mimics some aspects of DR. Conversely, we test if genes previously reported to mediate longevity by a variety of DR methods are necessary for sDR-induced longevity. Although clk-1, a gene involved in ubiquinone biosynthesis, is also required for sDR-induced lifespan extension, we find that four other genes (sir-2.1, FoxA/pha-4, skn-1, and hsf-1) are all dispensable for longevity induced by sDR. Consistent with the observation that different DR methods extend lifespan by mostly independent genetic mechanisms, we find that the effects on lifespan of two different DR regimens are additive. Understanding the genetic network by which different DR regimens extend lifespan has important implications for harnessing the full benefits of DR on lifespan and healthspan.

Highlights

Restricting nutrients without malnutrition extends lifespan and reduces age-dependent decline and diseases in virtually all species (Masoro, 2005)
We find that while AMPK and FoxO are necessary for longevity induced by sDR and by peptone dilution in plates, these genes are not absolutely required for eat-2 and bacteria in liquid cultures (bDR) to extend lifespan
AMPK/aak-2 and FoxO/daf-16 are necessary for sDR-induced lifespan extension across a gradient of bacteria on plates

Summary

Introduction

Restricting nutrients without malnutrition extends lifespan and reduces age-dependent decline and diseases in virtually all species (Masoro, 2005). A single term [dietary restriction (DR)] is often used to refer to this intervention, there exist a number of methods of restricting nutrients that all result in lifespan extension in species ranging from yeast to mice (Goodrick et al, 1990; Mair et al, 2005; Masoro, 2005; Dilova et al, 2007; Mair & Dillin, 2008; Piper & Bartke, 2008; Skorupa et al, 2008). There exist eight distinct methods of manipulating the diet that all extend lifespan to varying degrees in C. elegans, allowing comparison across DR regimens (Table 1). The DR methods in worms are: (i) a genetic mutation (eat-2) that reduces the pharyngeal pumping rate of the worms, thereby decreasing food intake (Avery, 1993; Lakowski & Hekimi, 1998); (ii and iii) two different methods of diluting the bacteria in liquid cultures (bacterial DR: bDR and liquid DR: lDR) (Klass, 1977; Houthoofd et al, 2003; Bishop & Guarente, 2007; Panowski et al, 2007); (iv and v) two chemically defined liquid medias that induce DR-like phenotype in C. elegans (axenic medium and chemically defined liquid medium: CDLM) (Houthoofd et al, 2002a; Szewczyk et al, 2006); (vi) the dilution of peptone in the agarose plates, which reduces the growth of bacteria (DP: dilution of peptone) (Hosono et al, 1989); (vii) the total absence of bacteria on plates (dietary deprivation: DD) (Kaeberlein et al, 2006; Lee et al, 2006); and (viii) a method that we recently described where bacteria are serially diluted on plates (solid DR: sDR) (Greer et al, 2007)

Methods

Results

Discussion

Conclusion