Fuchs et al. [7] may, in fact, hold a clue to one of the mysteries of the aging field: why do translation-defective mutants live longer? If translation mutants such as ife-2 accumulate amino acids, they would mimic the conditions arising in mitochondrial ETC mutants and IIS pathway mutants. TOR pathway mutants would be predicted to have very similar metabolic profiles to ETC, daf-2 or ife-2 mutants. Analyzing the metabolomes of TOR mutants and translation-defective mutants could therefore shed some light on this problem.
In conclusion, the belief that decreased metabolism leads to longevity is, so far, a generalization that extends beyond the current evidence. We know that genes involved in metabolic control, such as daf-2, regulate life span, but we do not know if overall metabolism is downregulated in these mutants [11]. For instance, daf-2 mutants exhibit decreased carbohydrate metabolism, but gene-expression data suggest that lipid utilization pathways are actually upregulated in these mutants [8].
Life-span-prolonging effects of downregulating protein synthesis might be specific to C. elegans and other invertebrates. The soma of the adult nematode is post-mitotic, and metabolic control might have different effects in C. elegans (where adult cell and tissue replacement does not occur) from those in higher eukaryotes, where compromised cells can be eliminated by apoptosis and replaced. C. elegans cells might have a higher tolerance for cellular insults and decreased metabolism. It is conceivable that translation of new proteins and other cell-maintenance processes may be more important to C. elegans than to higher organisms, as C. elegans somatic cells cannot be replaced.
Although the role of metabolism in aging is not straightforward, the metabolomics of longevity mutants may provide some answers. It is interesting to notice that several classes of long-lived mutants - mitochondrial ETC mutants, IIS mutants, and translation mutants - all have increased levels of branched-chain amino acids [7, 9]. Metabolomic profiles of TOR pathway mutants, dietary restriction mutants and other translation mutants could reveal an under-appreciated function of amino-acid metabolism in longevity.