Abstract
SummaryThe RNA‐binding protein LIN‐28 was first found to control developmental timing in Caenorhabditis elegans. Later, it was found to play important roles in pluripotency, metabolism, and cancer in mammals. Here we report that a low dosage of lin‐28 enhanced stress tolerance and longevity, and reduced germline stem/progenitor cell number in C. elegans. The germline LIN‐28‐regulated microRNA let‐7 was required for these effects by targeting akt‐1/2 and decreasing their protein levels. AKT‐1/2 and the downstream DAF‐16 transcription factor were both required for the lifespan and germline stem cell effects of lin‐28. The pathway also mediated dietary restriction induced lifespan extension and reduction in germline stem cell number. Thus, the LIN‐28/let‐7/AKT/DAF‐16 axis we delineated here is a program that plays an important role in balancing reproduction and somatic maintenance and their response to the environmental energy level—a central dogma of the ‘evolutionary optimization’ of resource allocation that modulates aging.
Highlights
Aging can be caused by a limited capacity of somatic maintenance and repair
Germline stem cell and lifespan effects of lin-28 RNAi are both abolished in let-7, akt-1, akt-2, and daf-16 mutant worms, indicating that the LIN-28/ let-7/AKT/DAF-16 axis is a program that plays an important role in balancing reproduction and somatic maintenance
We found that knockdown of lin-28 in germline showed a similar effect on the germline progenitor cell number to that of whole-body knockdown of LIN-28 (21.9% reduction in rrf-1 vs. 22.4% in wild-type, Fig. 3A, equal lin-28 RNAi efficiency is observed in N2 and rrf-1 strains by q-PCR, Figs S2E,F, Table S2) while lin-28 RNAi in the soma only RNAi strain, ppw-1(pk2505), hardly reduced number of germline progenitor cells (Fig. 3B), suggesting that LIN-28 mainly acts in the germline to regulate germline stem/progenitor cell number
Summary
Aging can be caused by a limited capacity of somatic maintenance and repair. Germline stem cells, as the only immortal cells in an organism, need elevated levels of maintenance and repair. As an organism and a species, the plastic ‘evolutionary optimization’ process has shaped an Accepted for publication 17 August 2016 intricate balance between reproduction (or germline progenitor pool size) vs aging (or somatic maintenance and repair) under limited resources and energy availability to the organism (Kirkwood, 2005). It is unclear whether there exists a genetic program that determines this balance. By RNA-seq and PCR of dissected gonads, Jungkamp et al confirmed germline expression of lin-28 mRNA in young adult worms, implicating that LIN-28 may play roles in adult worms in addition to developmental timing (Jungkamp et al, 2011)
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