PROJECT SUMMARY Organismal aging and age-associated diseases, including many cancers, are driven by the slow accumulation of damage in cells and tissues over time. In some instances, accumulation of deleterious mutations increases genomic instability in dividing cells and disrupts the proliferation and regenerative capacity of adult stem cells that maintain tissue function. Repeated injuries can also stimulate wound- induced inflammation that accelerates aging across an entire organism. Interventions that increase regenerative capacity of injured and aging tissues have the potential to improve quality of live and disease outcomes. However, they require an ability to both detect and rejuvenate aging tissues without increasing risk of disease. While researchers have discovered genes and signaling pathways that can expand life span in short-lived organisms like mice, flies, nematodes, and yeast, there are relatively few studies of anti-aging mechanisms in regenerative organisms with resistance to age-associated disease. This proposal exploits a highly regenerative flatworm, Schmidtea mediterranea, to address this gap. Asexual S. mediterranea undergo indefinite repeated cycles of clonal expansion through asexual reproduction and whole-body regeneration, but do not outwardly appear to suffer from age-associated tissue degradation. We have discovered that planarian tissues do accumulate age-associated damage during growth, but this damage does not result in stem cell exhaustion or a decline in regenerative capacity across clonal generations. Therefore, the central goals of this proposal are to (1) determine how age-associated damage manifests in asexual planaria throughout the animal lifecycle and (2) Identify the cell types and signaling pathways that regulate cellular aging, detection of aged tissues, and tissue rejuvenation. We will use a combination of well-established assays for conserved aging hallmarks, unbiased genomics and transcriptomics methods, and RNAi gene depletion studies to achieve these goals. Together, our proposed work will produce the most complete functional characterization age-associated signaling in asexual S. mediterranea to date and rigorously establish planaria as a tractable discovery model for anti-aging research. By expanding our understanding of adaptations for anti-aging and whole-organism rejuvenation in planaria, we can build a foundation of knowledge that will ultimately improve anti-cancer and anti-aging therapies in humans.

PROJECT NARRATIVE Aging is driven by accumulated damage in cells over time that disrupts normal tissue function. Often, this process is exacerbated by repeated injuries that stimulate proliferation and wound-induced inflammation. This proposal leverages a highly aging-resistant organism that reproduces solely through asexual reproduction and whole-body regeneration to uncover the cellular and molecular basis for whole-organism rejuvenation and anti-aging.