Aging is the primary risk factor for cardiovascular disease (CVD), and by 2030, 40% of Americans will have some form of CVD incurring a huge economic and human toll on society. Much remains unknown about why cardiovascular dysfunction increases with age. One potential cause of cardiovascular aging is cellular senescence. This complex stress response can be beneficial or detrimental, depending on the physiological context. Two hallmarks of the response are: 1) a permanent arrest of cell proliferation; and 2) development of a senescence-associated secretory phenotype (SASP) -- the transcriptional upregulation and secretion of numerous inflammatory cytokines, chemokines, growth factors and proteases. Senescent cells increase with age in many tissues, including the cardiovascular (CV) system, and the SASP is associated with a variety of age-related pathologies, including cardiac and vascular dysfunction. Senescent cells accumulate with age in the hearts and vasculature of mice and humans, but it is not known if cellular senescence is a cause or consequence of cardiovascular aging. We developed a novel mouse model that permits the visualization and elimination of senescent cells in vivo and their isolation from tissues, making it possible to study the function of integrated systems -- such as the heart and vasculature -- with and without senescent cells. We propose to test the novel hypothesis that senescent cells, and particularly the SASP, are an important mechanistic process driving CV aging. To test this hypothesis, we will develop three specific aims.
Aim 1 : Determine the extent to which senescent cells cause CV system dysfunction in settings of both experimental senescence and natural aging.
This aim will determine when and where senescent cells arise in the cardiovasculature, using an acute model, as well as naturally aged mice. We will employ our novel mouse model, the 3MR mouse in which we can eliminate cells to contrast CV function with and without senescent cells;
Aim 2 : Determine the cellular and molecular mechanisms by which senescent cells negatively impact cardiovascular tissue.
This aim will determine the sensitivity of critical cell types in the CV to senescence, including fibroblasts, endothelial cells, and vascular smooth muscle cells isolated from both arteries and intact hearts. We will determine how secreted factors from senescent cells influence function of other cell types using co-cultures and genetic strategies;
Aim 3 : To identify novel therapeutic targets for age-related CV dysfunction in humans. Having established specific protein and gene expression signatures for different cell types as a result of senescence in aims 1 and 2, in this final aim we will use a novel translational model ? biopsies of endothelial cells from humans to validate our predictions about senescence in different aged humans. Overall our program will provide novel insights into the role of senescence as a major mediator of age- related CVD, and potentially provide new targets of opportunity to combat this devastating disorder.

Public Health Relevance

We will determine the level of cellular senescence in the heart and arteries from mice undergoing induced senescence, as well as in natural aging. We will evaluate how cellular senescence drives cardiotoxic outcomes at both cell and tissue specific levels as well as establishing gene and protein specific signatures of cell types involved in cardiovascular senescence. Finally, we will evaluate how closely signatures of senescence established in the mouse mirror those seen in aging humans through a novel translational aim.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG055822-04
Application #
10105249
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kerr, Candace L
Project Start
2018-06-01
Project End
2023-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945