Intermittent Stem Cell Cycling Balances Self-Renewal and Senescence of the C. elegans Germ Line

• DOI: 10.1371/journal.pgen.1005985
• Publication Date: 2016-04-14T18:48:13Z
• Authors: Amanda Cinquin; Michael Chiang; Adrian Paz; Sam Hallman; Oliver Yuan; Indre Vysniauskaite; Charless C. Fowlkes; Olivier Cinquin
• Keywords: 0301 basic medicine; Aging; DNA Repair; 1.1 Normal biological development and functioning; Apoptosis; 612; QH426-470; Regenerative Medicine; 03 medical and health sciences; Underpinning research; Stem Cell Research - Nonembryonic - Human; Replication Protein A; Genetics; Animals; Cell Self Renewal; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cellular Senescence; Contraception/Reproduction; Reproduction; Stem Cells; Ovary; Biological Sciences; Stem Cell Research; DNA-Binding Proteins; Starvation; M Phase Cell Cycle Checkpoints; Stem Cell Research - Nonembryonic - Non-Human; Female; Generic health relevance; Developmental Biology; Research Article; DNA Damage; Transcription Factors

Self-renewing organs often experience a decline in function in the course of aging. It is unclear whether chronological age or external factors control this decline, or whether it is driven by stem cell self-renewal-for example, because cycling cells exhaust their replicative capacity and become senescent. Here we assay the relationship between stem cell cycling and senescence in the Caenorhabditis elegans reproductive system, defining this senescence as the progressive decline in "reproductive capacity," i.e. in the number of progeny that can be produced until cessation of reproduction. We show that stem cell cycling diminishes remaining reproductive capacity, at least in part through the DNA damage response. Paradoxically, gonads kept under conditions that preclude reproduction keep cycling and producing cells that undergo apoptosis or are laid as unfertilized gametes, thus squandering reproductive capacity. We show that continued activity is in fact beneficial inasmuch as gonads that are active when reproduction is initiated have more sustained early progeny production. Intriguingly, continued cycling is intermittent-gonads switch between active and dormant states-and in all likelihood stochastic. Other organs face tradeoffs whereby stem cell cycling has the beneficial effect of providing freshly-differentiated cells and the detrimental effect of increasing the likelihood of cancer or senescence; stochastic stem cell cycling may allow for a subset of cells to preserve proliferative potential in old age, which may implement a strategy to deal with uncertainty as to the total amount of proliferation to be undergone over an organism's lifespan.