Genetic Adaptation to Diet Preserves Longevity
Authors: Albertha J.M. Walhout
Journal: Cell Metabolism (2014)

Diet affects cellular metabolism and organismal life history traits. Pang and Curran, 2014Pang S. Curran S.P. Cell Metab. 2014; (in press)Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar use Caenorhabditis elegans and its bacterial diets to unveil genetic perturbations in proline catabolism that shorten lifespan, but, only on specific Escherichia coli diets, thereby unveiling a genome-encoded adaptive response to different nutritional states. Diet affects cellular metabolism and organismal life history traits. Pang and Curran, 2014Pang S. Curran S.P. Cell Metab. 2014; (in press)Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar use Caenorhabditis elegans and its bacterial diets to unveil genetic perturbations in proline catabolism that shorten lifespan, but, only on specific Escherichia coli diets, thereby unveiling a genome-encoded adaptive response to different nutritional states. Our diet not only affects our daily functioning and tendency to get sick, it may also contribute to how long we live. The nematode C. elegans is a prime model organism to study the genetics of aging as it shares many key developmental, physiological, and metabolic pathways with humans, and many genes have been identified that can prolong or shorten the animal's lifespan (Tissenbaum, 2012Tissenbaum H.A. J. Gerontol. A Biol. Sci. Med. Sci. 2012; 67: 503-510Crossref PubMed Scopus (75) Google Scholar). More recently, the worm has also emerged as a powerful system to gain insight into the effects different diets and nutrients exert on major life history traits such as developmental rate, fertility, and aging. For instance, when fed a diet of Comamonas bacteria, wild-type C. elegans develop faster, have reduced fertility, and die younger than when fed the standard laboratory diet of E. coli OP50 or HT115 (MacNeil et al., 2013MacNeil L.T. Watson E. Arda H.E. Zhu L.J. Walhout A.J.M. Cell. 2013; 153: 240-252Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). The response to Comamonas depends on intact metabolism of branched-chain and other amino acids in the worm. While E. coli diets elicit similar life history traits in wild-type worms, important differences between them are unveiled in C. elegans mutants. For instance, animals harboring mutations in nhr-114, a nuclear hormone receptor transcription factor, are sterile when fed E. coli OP50 but not E. coli HT115, and this effect is rescued by supplementation of tryptophan (Gracida and Eckmann, 2013Gracida X. Eckmann C.R. Curr. Biol. 2013; 23: 607-613Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Pang and Curran, 2014Pang S. Curran S.P. Cell Metab. 2014; (in press)Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar expand on this theme by identifying that alh-6 mutant C. elegans exhibit a diet-specific reduction in lifespan on the E. coli OP50 diet. How do different bacteria elicit distinct and specific effects in either wild-type or mutant C. elegans? Understanding this requires (1) elucidating the mechanisms by which the worm responds to particular diets and (2) identifying what the bacteria provide or lack that elicit a response in the worm. C. elegans genes responsible for this remarkable adaptive response to various diets can be identified by forward genetics or by systematic, genome-scale RNAi perturbations (Watson et al., 2013Watson E. MacNeil L.T. Arda H.E. Zhu L.J. Walhout A.J.M. Cell. 2013; 153: 253-266Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). While searching for genetic perturbations that activate SKN-1, the worm NRF transcription factor that protects the animal from a variety of stresses (Pang and Curran, 2014Pang S. Curran S.P. Cell Metab. 2014; (in press)Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), the authors identified alh-6 mutants and fortuitously discovered that these animals are much healthier when fed the E. coli HT115 strain than when fed the E. coli OP50 strain. In fact, alh-6 mutant animals exhibited a 40% reduced lifespan when fed the OP50 strain compared to wild-type animals, as well as diminished egg laying and reduced fertility. However, developmental rate was unaffected. Remarkably, the life-shortening effect of alh-6 mutations requires exposure to the E. coli OP50 diet between the L3 and L4 larval stages, as well as continued exposure during adulthood, suggesting that an unknown developmental component is involved. Altogether these results led the authors to propose that a wild-type copy of alh-6 is required for an adaptive response to diet: it is necessary to prolong lifespan of C. elegans on a diet of E. coli OP50, but not HT115. The key question is: how does alh-6 protect against the life-shortening effect of the E. coli OP50 diet? alh-6 encodes a metabolic enzyme that is involved in the two-step breakdown of proline. Specifically, ALH-6 converts the intermediate metabolite 1-pyrroline-5-carboxylate (P5C) into glutamate. Antioxidants such as N-acetylcysteine and vitamin C reverse the accelerated aging effect of E. coli OP50 bacteria, suggesting that the effect occurs via the buildup of reactive oxygen species (ROS) and an associated impairment of mitochondrial function. Remarkably, the activation of skn-1 expression by alh-6 mutations is independent of the lifespan reduction caused by these mutations. Since ROS is known to activate skn-1 expression (Hoeven et al., 2011Hoeven Rv. McCallum K.C. Cruz M.R. Garsin D.A. PLoS Pathog. 2011; 7: e1002453Crossref PubMed Scopus (154) Google Scholar), this suggests that skn-1 activation is a secondary effect. Insulin signaling and dietary restriction (DR) are well-known regulators of aging (Tissenbaum, 2012Tissenbaum H.A. J. Gerontol. A Biol. Sci. Med. Sci. 2012; 67: 503-510Crossref PubMed Scopus (75) Google Scholar). Remarkably, as with Comamonas bacteria (MacNeil et al., 2013MacNeil L.T. Watson E. Arda H.E. Zhu L.J. Walhout A.J.M. Cell. 2013; 153: 240-252Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), the effect of E. coli OP50 bacteria detected in this study is independent of insulin signaling. Rather, alh-6 acts via the DR pathway, as an eat-2 mutation, which causes reduced feeding, fails to increase lifespan in alh-6 mutant animals. The activation of the adaptive response to E. coli OP50 occurs, at least in part, at the level of gene expression because, although alh-6 levels are unaffected in animals fed this diet, they do express higher levels of prodh/B0513.5, which converts proline into P5C. Since the activation of SKN-1 by alh-6 mutations can be uncoupled from the accelerated aging on the E. coli OP50 diet, other transcription factors are likely involved in mediating this response. The compounds provided by the bacteria that elicit the effects in the worm remain unknown. E. coli OP50 and HT115 do not exhibit large differences in most macronutrients, with the exception of carbohydrate levels, which are higher in HT115 bacteria (Brooks et al., 2009Brooks K.K. Liang B. Watts J.L. PLoS ONE. 2009; 4: e7545Crossref PubMed Scopus (202) Google Scholar, MacNeil et al., 2013MacNeil L.T. Watson E. Arda H.E. Zhu L.J. Walhout A.J.M. Cell. 2013; 153: 240-252Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Given the molecular function of ALH-6, it is tempting to speculate that E. coli OP50 bacteria provide larger quantities of proline, P5C, or both. This is supported by the observation that alh-6 mutant animals fed E. coli HT115 supplemented with excess proline exhibited a reduced lifespan, whereas supplementing proline to E. coli OP50 had no additional adverse effects on longevity. However, it is likely that the intermediate P5C and not proline itself is toxic to the animal, because the detrimental effect of alh-6 mutation is lost when the conversion of proline into this compound is prevented by a perturbation of PRODH/B0513.5. In the future, mass spectrometry of different bacteria may reveal whether they harbor different levels of proline or P5C. Since both are E. coli strains, it is unlikely that such differences would result from major differences in metabolic pathways. Rather, variations in metabolic pathway genes may underlie the observed effects. Exploring variation in proline metabolism and other gene activity or expression, bacterial genetic screens, or targeted mutagenesis of candidate genes will be useful to unravel the precise mechanism involved. Altogether, this study provides an important step forward in our appreciation of the effect different amino acids can exert, whether it is the conversion of proline central to this study, tryptophan in nhr-114 mutants on the E. coli OP50 diet (Gracida and Eckmann, 2013Gracida X. Eckmann C.R. Curr. Biol. 2013; 23: 607-613Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar), or branched-chain amino acid metabolism in response to the Comamonas diet (Watson et al., 2013Watson E. MacNeil L.T. Arda H.E. Zhu L.J. Walhout A.J.M. Cell. 2013; 153: 253-266Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). C. elegans and its bacterial diets will no doubt continue to provide a powerful interspecies paradigm to dissect the interactions between specific genes and nutrients, and their effects on development, fertility, and aging. As with many other key findings from the nematode, results may illuminate how particular nutrients, such as amino acids, affect cellular and organismal physiology in health and disease in humans as well. Adaptive Capacity to Bacterial Diet Modulates Aging in C. elegansPang et al.Cell MetabolismJanuary 16, 2014In BriefAnimals adapt to diverse diets by sensing different food sources for survival. Pang and Curran show that, in C. elegans, a conserved proline metabolism enzyme, ALH-6, confers adaptive capacity to different diets by protecting animals against diet-induced mitochondrial defects, which in turn delays aging. Dietary restriction also requires alh-6 to induce longevity. Full-Text PDF Open Archive