The loss of tissue homeostasis and regenerative capacity with age underlies some of the most challenging health issues in the elderly. A major contributor to age-related decline in the structure and function of many tissues is the loss of stem cell function that occurs during the aging process. To be able slow, arrest, or even reverse those age-related declines in stem cell function holds would represent a major therapeutic advance in the growing field of regenerative medicine. The primary focus of this Program is to understand the molecular basis of age-related changes in stem cell function with the underlying premise that such an understanding is likely to reveal ways to target those changes in order to enhance aged stem cell function. Based largely on the work from the laboratories of this Program, there is increasing evidence of profound epigenetic changes that occur in stem cells as they age and that underlie many functional changes. A central conceptual theme that is woven throughout the proposal is the notion that these changes are not only mediators of cellular function but are amenable to being restored to a more youthful state through the process we call ?epigenetic rejuvenation?. In addition, we explore how the epigenetic changes confer upon stem cells the characteristics that may be responsible for selection of subsets of cells across the lifespan by an ever changing adaptive landscape and result in a population of distinct stem cells in the aged milieu. To examine those concepts experimentally, this Program includes three Projects that focus on somatic stem cells from three different tissues that differ in terms of their homeostatic turnover and regenerative capacity ? blood (high turnover, highly regenerative), muscle (low turnover, highly regenerative), and brain (low homeostatic, minimally regenerative). The Projects are integrated in their shared approaches to understanding the epigenetics of stem cell aging using cutting-edge technologies, including single cell transcriptome and epigenome analysis, modified CRISPR/cas9 technology for locus-specific epigenetic modifications, and in vivo lineage studies to explore the dynamics of stem cell populations during aging. These Projects are supported by three essential Cores ? an Administrative Core to facilitate the interactions among the laboratories, a ?Rejuvenation Strategies? Core for our shared animal studies to explore epigenetic rejuvenation, and a Bioinformatics Core to serve as the essential hub for storing, processing, visualizing, analyzing, and sharing data from the three Projects. Overall, the investigators who are Project Leaders and Core Directors are internationally recognized experts in these areas and bring to the Program the full breadth of expertise, creativity, and records of accomplishment to assure an integrated, innovative, and highly successful Program to explore the molecular mechanisms of stem cell aging.

Public Health Relevance

The mechanisms that control stem cell function are fundamental determinants of how tissues are maintained during normal activity, adapt in response to stress, and are repaired in response to injury. One of the hallmarks of aging is the decline in the ability of tissues to perform all of these functions. Therefore, understanding how stem cells change with age may provide insights into the basic mechanisms of aging. The studies of this proposal are designed to examine the molecular mechanisms that regulate stem cell functions in adult mice and how those mechanisms change with age, examining stem cells from three different tissues ? muscle, brain, and blood. We will focus on the epigenetic changes influence how functional the stem cells are in terms of tissue homeostasis and repair. Ultimately, our goal is to indentify ways to prevent the age-related decline in stem cell function and to restore youthful function to aged stem cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG036695-06
Application #
9211407
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (O2))
Program Officer
Kohanski, Ronald A
Project Start
2011-07-01
Project End
2022-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
6
Fiscal Year
2017
Total Cost
$2,211,523
Indirect Cost
$384,749
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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Leeman, Dena S; Hebestreit, Katja; Ruetz, Tyson et al. (2018) Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359:1277-1283

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