Abstract
The mechanisms underlying biological aging are becoming recognized as therapeutic targets to delay the onset of multiple age-related morbidities. Even greater health benefits can potentially be achieved by halting or reversing age-associated changes. C. elegans restore their tissues and normal longevity upon exit from prolonged adult reproductive diapause, but the mechanisms underlying this phenomenon remain unknown. Here, we focused on the mechanisms controlling recovery from adult diapause. Here, we show that functional improvement of post-mitotic somatic tissues does not require germline signaling, germline stem cells, or replication of nuclear or mitochondrial DNA. Instead a large expansion of the somatic RNA pool is necessary for restoration of youthful function and longevity. Treating animals with the drug 5-fluoro-2'-deoxyuridine prevents this restoration by blocking reactivation of RNA metabolism. These observations define a critical early step during exit from adult reproductive diapause that is required for somatic rejuvenation of an adult metazoan animal.
Highlights
While many interventions that delay age-associated declines have been described in laboratory studies, instances of pausing or even reversing aging are relatively rare and generally do not preserve or restore youthful function in all tissues of an animal (Kaeberlein et al, 2015)
We found that somatic tissues of homozygous cye-1 animals recover from adult reproductive diapause (ARD) normally and that this recovery is blocked by FUDR (Figure 2F,G,H)
We propose that a strong inhibitory effect of the drug on RNA metabolism underlies its effect on post-ARD recovery
Summary
While many interventions that delay age-associated declines have been described in laboratory studies, instances of pausing or even reversing aging are relatively rare and generally do not preserve or restore youthful function in all tissues of an animal (Kaeberlein et al, 2015). Diapause states have been discovered in C. elegans that apparently preserve or restore functionality of chronologically old tissues after diapause exit One example of such a state is the adult reproductive diapause (ARD), which is induced in developmentally mature animals by starvation. Depending on the developmental point at which C. elegans face starvation, animals can enter diapause at either the first larval stage L1 (L1 arrest), the second larval stage L2 (dauer), or, in the case of ARD, just after the transition from the fourth larval stage (L4) to young adulthood (Angelo and Van Gilst, 2009; Johnson et al, 1984; Klass and Hirsh, 1976). Dauer worms undergo significant anatomical transformations, such as synthesis of the specialized cuticle and mouth plug (Frezal and Felix, 2015; Hu, 2007) These morphological changes make it difficult to investigate aging at the cellular
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