The efficiency of stem cell-dependent processes declines with age, largely owing to a decline in stem cell capacities, but the mechanisms remain unclear. Using the C. elegans germline stem cells (GSCs) as model, we found that two general mechanisms underlie stem cell activity decline during aging: a passive decline that results from aging, and an active induction of quiescence to meet stem cell progeny needs. The adult C. elegans germline can be viewed as a biological assembly line, with stem cells as the raw material that is turned, in a stepwise manner, into mature oocytes. Under replete growth conditions, the two gonad arms produce about 300 oocytes over three days in self-fertilizing hermaphrodites, but can produce more if they mate with males. We found that the accumulation of unfertilized oocytes, which occurs after sperm depletion, triggers a feedback signal leading to a reversible complete germline arrest, including the induction of stem cell quiescence. Accumulation of intermediate differentiation products or sperm does not trigger the feedback, which once induced, is able to strongly suppress stem cell proliferation throughout the gonad. The active induction of stem cell quiescence in otherwise healthy and well-fed adults only occurs when there is an accumulation of terminally-differentiated stem cell progeny (oocytes) and requires a localized, daf-16-independent down-regulation of insulin signaling in the germline. This in turns locally activates the energy-sensing kinase AMPK, which can then phosphorylate regulators of the ERK/MAPK pathway, including MPK-1 itself, to inhibit MPK-1 activity and shut down GSC proliferation and differentiation. Our results demonstrate that stem cell assembly units (from the stem cells to their terminally-differentiated progeny) can function as self-regulated, independent entities within multi-cellular organisms. This allows different stem cell populations, across and within tissues, to differentially respond to systemic information according to the local needs.
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