The majority of gerontological research is focused on understanding biological mechanisms of aging, with a primary goal to develop interventions that slow the aging process in order to enhance healthspan and lifespan. While this approach has proven quite successful in laboratory models, an alternative, and potentially much more powerful strategy, is to focus on interventions that promote rejuvenation of aged cells or animals toward a more youthful state. Mechanisms of rejuvenation have been understudied, however, largely because of the lack of robust and tractable biological models. We believe that we have overcome this barrier by developing a model for rejuvenation of aged somatic cells and regeneration of a youthful reproductive system in the nematode Caenorhabditis elegans. Adult reproductive diapause can be induced by removing the bacterial food source from C. elegans at the transition from L4 to adulthood. ARD animals survive at least 3-fold longer than normal adult C. elegans, but still age as indicated by morphological and structural changes to organelles, cells, and tissues. Upon exit from ARD, these aged animals show a remarkable rejuvenation of both reproductive and somatic tissues that we hypothesize is mediated by protected germline stem cells. Rejuvenated animals go on to have a full lifespan as if they were day 1 adults. The goal of this proposal is to understand the mechanisms underlying this rejuvenation process, in particular the signals emanating from the protected germline stem cells to restore somatic tissues to their youthful state. Understanding and harnessing these mechanisms will lead to novel strategies to restore aged tissues to a more youthful state in people, thereby promoting healthy aging by preventing age- related pathology that drives disease.
During adult reproductive diapause in C. elegans, animals are developmentally arrested but continue to show molecular and morphological changes associated with aging. We have shown that upon release from this diapause there is a rejuvenation of both the reproductive and the somatic tissues that is associated with preservation of germline stem cells, and we hypothesize that a signal from these stem cells promotes the rejuvenations process. This proposal will define the mechanisms underlying rejuvenation following release from adult reproductive diapause, with promise to provide novel approaches to restore youthful properties to aged cells and tissues in order to prevent age-associated pathologies in people.
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