R01AG076515

Defining the interactions of senescent immune cells and skeletal cells - Cellular senescence is now recognized as one of the fundamental aging mechanisms contributing to multiple age-related degenerative conditions, including osteoporosis. In previous studies, we have systematically identified senescent cells in the bone microenvironment and demonstrated a causal role for senescent cells in mediating age-related bone loss in mice.

In recent studies, we used a novel transgenic mouse model, P16-LOX-ATTAC, capable of temporal- and cell-specific senescent cell clearance, and found that in contrast to global clearance of senescent cells using the (P16)-INK-ATTAC model, clearance specifically of senescent osteocytes only partially replicated the beneficial skeletal effects of global senescent cell clearance, suggesting an important role for other cells in the bone microenvironment (e.g., immune cells) in contributing to skeletal aging.

In addition, in our previous work, we demonstrated a dramatic upregulation of the senescence-associated secretory phenotype (SASP) in bone marrow myeloid cells with aging, and more recent studies by our investigative team have shown that with aging, activated neutrophils can induce senescence in multiple tissues in a paracrine manner. Conversely, senescent cells are capable of attracting neutrophils, which then further propagate senescence to other cells.

Collectively, these studies point to previously unexplored cross-talk between skeletal and immune cells, specifically in the context of cellular senescence. Thus, our central hypothesis is that senescence of immune cells contributes to skeletal deterioration and conversely, senescent skeletal cells attract and contribute to an inflammatory and/or senescent phenotype of immune cells.

We will test this hypothesis by examining the effects of senescent immune cells on bone and in the reverse experiment, evaluating the effects of senescent skeletal cells on immune cells. Our proposed studies make use of novel mouse models: P16-LOX-ATTAC mice, developed in the Khosla/Monroe laboratory, which are capable of temporal- and cell-specific (when crossed with a CRE mouse) senescent cell clearance; and ERCC1-/FL mice, developed by Drs. Niedernhofer and Robbins (co-Is), where we can induce a tissue-specific DNA repair defect leading to premature cellular senescence only in that tissue (e.g., immune or skeletal cells).

Collectively, our studies will address a number of fundamental questions relevant to osteoimmunology: (1) What are the specific populations of bone marrow immune cells that undergo senescence with aging using strictly defined criteria for cellular senescence (rather than the much broader umbrella of "immunosenescence" that includes inflammatory, but not necessarily senescent cells)? (2) Does chronological or premature aging of the immune system cause skeletal deterioration? (3) Conversely, do senescent skeletal cells lead to senescence, or at least inflammation, in bone marrow immune cells and does this further propagate senescence to other skeletal cells and perhaps systemically? (4) What are the potential mediators of the cross-talk between senescent skeletal cells and senescent/inflammatory immune cells?

Mayo Clinic

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Rochester, Minnesota 559050001 United States

Single Zip Code

Aging Effects on Osteoimmunology (R01 Clinical Trials Not Allowed) (RFA-AG-22-002)

Amendment Since initial award the total obligations have increased 281% from $490,477 to $1,870,085.