ABSTRACT Reversing the negative effects of aging has the potential to delay age-related diseases and significantly improve the quality of life in old age. In recent findings, we reported that sexual planarians of Schmidtea mediterranea have evolved a natural solution to age reversal at the whole-body level. However, the underlying molecular and cellular mechanisms behind this phenomenon remain unclear. In this proposal, we aim to investigate two mechanisms that could potentially globally reverse the aged states of most cells within an organism. The first involves examining asymmetrical age distribution during stem cell division and differentiation, which plays a critical role in replacing differentiated and aged cells during tissue homeostasis and regeneration. The second involves investigating epigenetic regulators that can globally modify chromatin states, leading to gene expression changes and functional impacts on cellular physiology. Our collective goal is to identify the molecular regulators of these processes and examine their impact on whole-body age reversal. The proposed experiments have the potential to identify genes that are evolutionarily conserved in mammals and could ultimately contribute to improving or inspiring anti-aging medicine in humans

PROJECT NARRATIVE Age reversal in an entire organism can postpone age-related diseases and enhance the well-being during the later stages of life. Our research has revealed that sexual planarians of Schmidtea mediterranea have evolved a natural solution to age reversal at the whole-body level, and here we propose to investigate the underlying molecular and cellular mechanisms that drive age reversal. Successful completion of the project holds the promise of providing valuable insights to advance anti-aging medicine for humans.