Evolutionary conservation of regulated longevity assurance mechanisms

Abstract

Background: To what extent are the determinants of aging in animal species universal? Insulin/insulin-like growth factor (IGF)-1 signaling (IIS) is an evolutionarily conserved (public) regulator of longevity; yet it remains unclear whether the genes and biochemical processes through which IIS acts on aging are public or private (that is, lineage specific). To address this, we have applied a novel, multi-level cross-species comparative analysis to compare gene expression changes accompanying increased longevity in mutant nematodes, fruitflies and mice with reduced IIS.

Results: Surprisingly, there is little evolutionary conservation at the level of individual, orthologous genes or paralogous genes under IIS regulation. However, a number of gene categories are significantly enriched for genes whose expression changes in long-lived animals of all three species. Down-regulated categories include protein biosynthesis-associated genes. Up-regulated categories include sugar catabolism, energy generation, glutathione-S-transferases (GSTs) and several other categories linked to cellular detoxification (that is, phase 1 and phase 2 metabolism of xenobiotic and endobiotic toxins). Protein biosynthesis and GST activity have recently been linked to aging and longevity assurance, respectively.

Conclusion: These processes represent candidate, regulated mechanisms of longevity-control that are conserved across animal species. The longevity assurance mechanisms via which IIS acts appear to be lineage-specific at the gene level (private), but conserved at the process level (or semi-public). In the case of GSTs, and cellular detoxification generally, this suggests that the mechanisms of aging against which longevity assurance mechanisms act are, to some extent, lineage specific.

Figure 1

Overlap of differentially expressed functional categories in long-lived nematodes, fruitflies and mice. These Venn diagrams show the number and overlap of significantly differentially regulated functional categories (p < 0.05; GO categories and Interpro domain families) identified in each dataset using Catmap. While most of the differentially expressed categories in each dataset are species-specific, a small number of categories (boxed) show significant changes in expression in response to reduced IIS in all three species. These categories are detailed in Table 5.

Figure 2

Protein synthesis and GST activity are potential semi-public determinants of longevity.

Figure 3

Cellular detoxification (drug metabolism). This process entails two phases: phase 1 (functionalization reactions), and phase 2 (conjugative reactions), which are carried out by several large and diverse gene families, including the CYPs, SDRs and GSTs.

Figure 4

Phylogenetic tree of the GST gene families from worms, flies, and mice. Genes from each species are color-coded, and significantly (q < 0.1) differentially expressed genes in each dataset are shown by closed (up-regulated) or open (down-regulated) circles (see Additional data file 2 for phylogenetic trees for GST, CYP, SDR, and UGT gene families).

Figure 5

Different determinants of longevity may be public, semi-public or private. Our results suggest that public regulators of lifespan regulate semi-public mechanisms of longevity assurance, which may in turn act on a combination of private and public mechanisms of aging. The semi-public character of longevity assurance processes is reflected by the IIS-regulated gene classes. Several are linked to detoxification (such as the GSTs), and are the results of copious lineage-specific expansions.