Uncovering cellular and molecular adaptations for whole-organism rejuvenation

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.

Grant Number: 1DP2AG093210-01
NIH Institute/Center: NIH
Principal Investigator: Blair Benham-Pyle