Wide‐scale comparative analysis of longevity genes and interventions

Abstract

SummaryHundreds of genes, when manipulated, affect the lifespan of model organisms (yeast, worm, fruit fly, and mouse) and thus can be defined as longevity‐associated genes (LAGs). A major challenge is to determine whether these LAGs are model‐specific or may play a universal role as longevity regulators across diverse taxa. A wide‐scale comparative analysis of the 1805 known LAGs across 205 species revealed that (i) LAG orthologs are substantially overrepresented, from bacteria to mammals, compared to the entire genomes or interactomes, and this was especially noted for essential LAGs; (ii) the effects on lifespan, when manipulating orthologous LAGs in different model organisms, were mostly concordant, despite a high evolutionary distance between them; (iii) LAGs that have orthologs across a high number of phyla were enriched in translational processes, energy metabolism, and DNA repair genes; (iv) LAGs that have no orthologs out of the taxa in which they were discovered were enriched in autophagy (Ascomycota/Fungi), G proteins (Nematodes), and neuroactive ligand–receptor interactions (Chordata). The results also suggest that antagonistic pleiotropy might be a conserved principle of aging and highlight the importance of overexpression studies in the search for longevity regulators.

Gray whale transcriptome reveals longevity adaptations associated with DNA repair and ubiquitination

“…In regard to this, it was previously suggested that upregulation of stress response genes could result in pro-longevity effects 18 . This is further supported by our previous study showing that overexpression of stress-related LAGs results in most cases in lifespan extension 27 . Remarkably, in the gray whale transcriptome, a great portion of the pro-longevity LAGs found through overexpression experiments (19 out of 30) are stress-related genes, which display expression values higher than average or median.…”

“…A noteworthy finding is the lower than expected number of LAG homologues found both for anti-and prolongevity genes in the gray whale, particularly in view of the assumed high evolutionary conservation of LAGs 27 . This however has a technical explanation, namely the fact that the gray whale did not have a reference genome until now, and that the transcriptome analysis was performed de novo, whereas for model organisms, there are already numerous well annotated transcriptomes and genomes.…”

“…Two additional points should be stressed in this context: 1) first, as we previously showed, despite high evolutionary distances, the lifespan effects obtained when manipulating orthologous LAGs in different model organisms leads mostly to concordant results 27 , and 2) second, the experiments resulting in lifespan extension, and even more so, those where overexpressing a LAG results in lifespan extension, are more definite in terms of evaluating the impact of a given gene on longevity than those resulting in lifespan reduction 27 . This means that focusing on LAGs from overexpression studies will be more definite and unambiguous.…”

“…The above-mentioned processes are well known to be involved in anti-cancer mechanisms, for preventing cell transformation or elimination of potentially cancerogenous or cancer cells 12,24 , and in a larger sense in determining mammalian longevity 1,[25][26][27] . This is highly relevant, because while the bowhead whale is known for its resistance to cancer 12,19 , for the gray whale, such data is still absent.…”

“…With regards to longevity determination, hundreds of genes have been identified to have an impact, when genetically manipulated, on the lifespan of model organisms like yeast, worm, fruit fly and mouse. These genes have been previously defined as longevity-associated genes (LAGs) and include two categories: a) LAGs which promote longevity, and b) LAGs which reduce lifespan and promote an accelerated aging phenotype (a phenotype that along with shorter lifespan includes features of premature aging) 27,28 .…”