Abstract
Recent studies have revealed a variety of genes and mechanisms that influence the rate of aging progression. In this study, we identified cell cycle factors as potent regulators of health and longevity in C. elegans. Focusing on the cyclin-dependent kinase 2 (cdk-2) and cyclin E (cye-1), we show that inhibition of cell cycle genes leads to tolerance towards environmental stress and longevity. The reproductive system is known as a key regulator of longevity in C. elegans. We uncovered the gonad as the central organ mediating the effects of cell cycle inhibition on lifespan. In particular, the proliferating germ cells were essential for conferring longevity. Steroid hormone signaling and the FOXO transcription factor DAF-16 were required for longevity associated with cell cycle inhibition. Furthermore, we discovered that SKN-1 (ortholog of mammalian Nrf proteins) activates protective gene expression and induces longevity when cell cycle genes are inactivated. We conclude that both, germline absence and inhibition through impairment of cell cycle machinery results in longevity through similar pathways. In addition, our studies suggest further roles of cell cycle genes beyond cell cycle progression and support the recently described connection of SKN-1/Nrf to signals deriving from the germline.
Highlights
The nematode Caenorhabditis elegans has been invaluable to biological research of mechanisms that slow aging processes and may prevent age-related diseases
We found that post-developmental inactivation of cdk-2 had a strong effect on lifespan with an increase of 28% compared to wild type control (24.1 d in cdk-2(RNAi) vs 18.8 d control (RNAi)) (Figure 1A and Table 1)
To determine if an intact germline is necessary for lifespan regulation by cell cycle genes, we examined the effect of cye-1 and cdk-2 knockdown in glp-1 mutant worms. glp-1 encodes a Notch family receptor that is essential for mitotic proliferation of germline stem cells [33, 34]
Summary
The nematode Caenorhabditis elegans has been invaluable to biological research of mechanisms that slow aging processes and may prevent age-related diseases. The role of germline signaling in the regulation of health and longevity has been shown to be evolutionarily conserved in several species, including C. elegans, D. melanogaster, and mice [1,2,3,4]. The lifespan extension associated with ablation of the germline in C. elegans is caused by loss of proliferating germline stem cells and requires the preservation of the somatic gonad [1, 7]. These findings suggest that longevity is not a result of sterility but is regulated by counterbalancing signals produced by the germline and somatic gonad.
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