R01AG073341

Reverse Engineering of Cell Senescence - Abstract

Cellular senescence is not just a symptom of aging, but a contributor to aging pathologies. Recent experiments in mice show that elimination of senescent cells (a.k.a. senolysis) can reverse several features of the aging process and extend life- and health-span. This has stimulated interest in cell senescence and in finding ways to suppress it that can be easily ported from mouse to human and made even more effective. This implies looking for such drugs as an early senolytic candidate – a kinase inhibitor dasatinib, whose mode of action is unclear.

Taking senolytic therapies into humans will also require a better understanding of the cell type-specific progression towards senescence and diverse sub-types of senescence. In addition to aging per se, cells respond to insults such as DNA damage, cell cycle arrest, or oncogene activation by expressing aging phenotypes, such as hypertrophy, cell cycle arrest markers, and by secreting growth factors and chemokines, which are thought to produce degenerative responses in nearby cells.

Hypertrophy may be one of the most pervasive senescent cell responses but has been hard to study, as until recently we have not had accurate enough means to measure cell mass and cell size, protein and lipid content. Yet, hypertrophy is of special interest because it is deeply connected to cell growth, which is normally under strict control in normal cells.

We propose to study how cells, prompted by stressors like radiation or drugs or simply by age, become hypertrophic and how they come to express senescence markers. We have three goals: 1) to trace the progression of cell senescence in molecular terms by quantitative mass spectrometry and phospho-mass spectrometry, and in physiological terms by Raman microscopy, 2) to identify protein circuits responsible for cell senescence, and 3) to find drugs that will prevent, reverse, or eliminate senescent cells.

As our tools of perturbation, we have chosen kinase inhibitors. Employing a machine learning approach, we will probe senescent cell development and senescent cell viability via a small set of well-characterized poly-specific kinase inhibitors; then regress a phenotype, such as senescence-specific signaling and senescent cell formation or death, to the activity of key kinases and their downstream circuits. Kinases implicated that way will be independently validated using siRNA knockdowns and CRISPR. Additionally, extensive phospho-proteomic profiling will identify the phosphorylation sites on key proteins that most contribute to the phenotypes of senescence and which could be druggable by other means.

Taken together, these methods will produce insight into the mode of action of already identified senolytic drugs and suggest new targets and new drugs for seno-therapies. This combination of pharmacology, machine learning, quantitative proteomics, and new forms of microscopy can provide fresh insights into aging and suggest potential therapies for aging-related diseases.

President And Fellows Of Harvard College

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]

Boston, Massachusetts 021155701 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 416% from $638,421 to $3,296,807.