Regulation of metabolism in Caenorhabditis elegans longevity

Abstract

The nematode Caenorhabditis elegans is a favorite model for the study of aging. A wealth of genetic and genomic studies show that metabolic regulation is a hallmark of life-span modulation. A recent study in BMC Biology identifying metabolic signatures for longevity suggests that amino-acid pools may be important in longevity.

See research article http://www.biomedcentral.com/1741-7007/8/14.

Aging in Caenorhabditis elegans seems to be intimately tied to the modulation of metabolism. The first genes identified for their ability to affect life span were age-1, which encodes a phosphatidylinositol kinase [1], and daf-2 (constitutive dauer formation), which encodes a receptor tyrosine kinase similar to the mammalian insulin and insulin-like growth factor 1 (IGF1) receptors [2]. Although complete loss of daf-2 function is lethal [3], partial loss of function extends adult life by two- to threefold. daf-2 and age-1 specify steps in the insulin/insulin-like signaling (IIS) pathway, thereby influencing metabolism. IIS signaling inactivates the FOXO (forkhead box O) transcription factor DAF-16, which controls genes that mediate a wide variety of functions, including metabolism, innate immunity, stress response, and translation (reviewed in [4]). The modulation of life span by the IIS pathway seems to result from an intricate network of physiological changes primarily mediated by unregulated DAF-16 activity, including major shifts in both energy and fat metabolism.

In addition to the IIS pathway, two other main groups of genes have profound effects on life span and are linked to metabolic control: genes involved in dietary restrictio and mitochondrial function. Dietary restriction has been associated with increased life span in a wide variety of species (including mammals) and appears to be universally associated with longevity (reviewed in [5]). Increased longevity resulting from mutations in genes that regulate mitochondrial function is more problematic, although, at least superficially, it is related to metabolic slow-down. Work in nematodes and other invertebrates seems to support the notion that reducing the rate of oxidative phosphorylation (OXPHOS) leads to increased life span in two major ways: by decreasing the metabolic rate, and by reducing the level of reactive oxygen species, which are an obligate byproduct of OXPHOS. However, mutations that reduce mitochondrial function are beneficial for C. elegans longevity, but have deleterious and often lethal effects in mammals [6]. The reason for this discrepancy is not understood.

Given the large number of genes that have been shown to regulate life span through different pathways, it is reasonable to ask whether there are any physiological changes conducive to longevity that are common in all long-lived mutants. A recent metabolomic study on five different long-lived mutants published in BMC Biology by Fuchs et al. [7] suggests that the answer to this question may be yes. Fuchs et al. report that mutants carrying three different alleles of daf-2, one allele of the insulin-like gene daf-28 or one allele of ife-2 (translational initiation factor 4E) have similar metabolic signatures, which cluster away from those of wild-type worms. These metabolic signatures are consistent with previous findings that assessed gene expression in daf-2 mutants [8]. In particular, they showed that long-lived daf-2 worms upregulate the glyoxylate cycle, gluconeogenesis and starch metabolism.

Fuchs et al. [7] detected a common metabolic signature for IIS mutants and ief-2. All five of the long-lived mutants had increased pools of amino acids, especially of the branched-chain amino acids isoleucine, leucine and valine, together with phenylalanine and tyrosine. A similar increase in branched-chain amino acids has been found in animals carrying mutations in components of the mitochondrial electron transport chain (ETC) complexes I, II and III [9]. At least some of these ETC mutants are long-lived. The increase in branched-chain amino acids in long-lived worms is intriguing for two reasons. First, it opens the possibility that protein metabolism plays an important role in life-span determination. Second, branched-chain amino acids are known to stimulate protein synthesis and inhibit protein degradation in higher eukaryotes [10], a phenomenon mediated by the TOR (target of rapamycin) pathway.