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

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
United States
Zip Code
de Morrée, Antoine; van Velthoven, Cindy T J; Gan, Qiang et al. (2017) Staufen1 inhibits MyoD translation to actively maintain muscle stem cell quiescence. Proc Natl Acad Sci U S A 114:E8996-E9005
Rando, Thomas A (2017) Fleeting factors, turning back time. Nat Biotechnol 35:218-220
van Velthoven, Cindy T J; de Morree, Antoine; Egner, Ingrid M et al. (2017) Transcriptional Profiling of Quiescent Muscle Stem Cells In Vivo. Cell Rep 21:1994-2004
Dulken, Ben W; Leeman, Dena S; Boutet, Stéphane C et al. (2017) Single-Cell Transcriptomic Analysis Defines Heterogeneity and Transcriptional Dynamics in the Adult Neural Stem Cell Lineage. Cell Rep 18:777-790
Rodgers, Joseph T; Schroeder, Matthew D; Ma, Chanthia et al. (2017) HGFA Is an Injury-Regulated Systemic Factor that Induces the Transition of Stem Cells into GAlert. Cell Rep 19:479-486
Stearns-Reider, Kristen M; D'Amore, Antonio; Beezhold, Kevin et al. (2017) Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16:518-528
Quarta, Marco; Cromie, Melinda; Chacon, Robert et al. (2017) Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss. Nat Commun 8:15613
Brunet, Anne; Rando, Thomas A (2017) Interaction between epigenetic and metabolism in aging stem cells. Curr Opin Cell Biol 45:1-7
Luo, Dan; de Morree, Antoine; Boutet, Stephane et al. (2017) Deltex2 represses MyoD expression and inhibits myogenic differentiation by acting as a negative regulator of Jmjd1c. Proc Natl Acad Sci U S A 114:E3071-E3080
Du, Hongqing; Shih, Chung-Hsuan; Wosczyna, Michael N et al. (2017) Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nat Commun 8:669

Showing the most recent 10 out of 80 publications