Mammalian aging is associated with functional defects in numerous tissues that require cellular renewal during life. These tissues are replenished by tissue stem cells as differentiated cells are lost throughout life. Accumulating evidence indicates that defects in aging tissues can be explained in part by impaired stem cell function or alterations in the stem cell niche. A greater understanding of how stem cell regulation is altered in aging is required in order to devise approaches to improve or reverse defects in renewing tissues with advancing age. We have found that two pathways with critical roles in stem cell survival and self-renewal - telomerase and Wnt signaling - are intimately connected. Synthesis of telomeres by telomerase is required for stem cell self-renewal. In addition, telomerase serves as a co-factor in the Wnt signaling pathway by modulating the transcriptional output of the Wnt axis. Wnts are known to be crucial for stem cell proliferation and survival in diverse tissue contexts. Thus, telomerase serves to connect two critical aspects of stem cell function, telomere maintenance and extracellular signaling. Our hypothesis is that telomerase is a critical node in aging mammals by virtue of controling telomere synthesis and Wnt signaling - two pathways implicated in stem cell aging. To test this hypothesis, we will pursue the following aims: 1) To understand the role of TERT in Wnt signaling and epithelial stem cell function; 2) Understanding epigenetic control of stem cell aging by telomerase and Wnts using ChlP-Seq and 3) To study the mechanisms by which Wnts regulate telomerase
Emerging evidence indicates that altered stem cell function can contribute to human aging. However, the precise changes that occur in stem cells with advancing age and the pathways that govern these changes remain obscure. We find that two pathways - telomerase and Wnts - work together to regulate stem cells. An improved understanding of these processes will greatly enhance our ability to intervene in the aging process.
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