Identification of novel regulators of late-life longevity in the worm C. elegans
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Abstract
Ageing is a ubiquitous, detrimental phenomenon experienced by almost every known uni- and multi-cellular species. The hallmarks of ageing are conserved from worm to man and suggest an origin deep in evolutionary history. However, how such an obviously detrimental process could be maintained, despite the obvious negative selection it would be subjected to, has been a much-debated topic for over a century. The most widely accepted explanation is that ageing is a consequence of evolution. It arises from the preferential selection of alleles with positive fitness effects early in life even if those alleles lead to degeneration later in life. This antagonistic pleiotropy (AP) theory of ageing has received some experimental support but to date, no investigation has found genes with detrimental effects specific to the later life period.
To address this insufficiency I developed a novel age-synchronous liquid culture technique for the worm C. elegans that allowed for the reliable production of large quantities of old worms absent of the use of sterile strains or drugs to inhibit reproduction. With this technique, I screened an RNAi library of nearly 800 genes involved in gene or chromatin regulation in the post-reproductive worm. This screen identified 31 novel candidate AP longevity genes including pha-4. The transcription factor PHA-4 (FOXA) is essential to survival and longevity in young worms. Remarkably, however, its inhibition post-reproduction extended lifespan by 33%. PHA-4 transcriptionally regulates the expression of two essential autophagy genes bec-1 and unc-51. Late-life inhibition of these genes extended lifespan by an even greater degree than pha-4, up to 63%. Both bec-1 and pha-4 display AP characteristics including a switch from pro- to anti-longevity as the worm ages and a delay in the onset of ageing hallmarks only when inhibited late in life. The mechanism of this lifespan extension is independent of the major canonical life extension pathways and is likely routed in the autophagic function of these genes.
The results described in this study demonstrate a simple novel protocol for the generation of aged C. elegans samples that will greatly facilitate large-scale analysis of the late age period. The efficiency of the RNAi screen suggests that many more AP genes remain to be discovered. This could open a new path to the treatment of ageing and age-related disease through the targeting of detrimental AP factors outside of the development window. Furthermore, autophagy is generally considered to be a beneficial and required process throughout life. The identification of autophagy genes as a detrimental force in late-life could radically redefine our understanding of this process.