The research interests of Darren J. Baker, M.S., Ph.D., are focused on the involvement of senescent cells in the processes of aging and cancer.
Cellular senescence, a state of irreversible cell cycle arrest that limits the ability of cells to divide, is a potent anti-tumor mechanism that is also a common feature of aged tissue. Instead of simply being resident cells within a tissue, senescent cells promote various age-related phenotypes due to components that they secrete.
Studying the role of cellular senescence in vivo, however, has been difficult due to the lack of reliable markers and the inability to selectively manipulate these cells in animals.
Dr. Baker's research team has developed a transgenic mouse model, termed INK-ATTAC, in which senescent cells can be selectively eliminated in an inducible fashion. By using the INK-ATTAC model in combination with an accelerated aging model, Dr. Baker has demonstrated the ability to significantly delay age-related pathologies and phenotypes, including cataract formation, by removing senescent cells.
Senescent cells in natural aging. Dr. Baker's team has demonstrated that removal of senescent cells from a prematurely aged mouse model is effective at delaying a variety of phenotypes that are dependent on the acquisition of senescent cells. The team is now interested in extending these studies into the normal aging process that occurs in mice. The expression of p16 increases in many tissues with age, but whether this causes age-related pathologies is unclear.
Using INK-ATTAC, Dr. Baker's team is able to test, for the first time, whether a wide variety of aging-related conditions can be prevented or attenuated by clearing senescent cells from chronologically aged wild-type mice, leading to improved health span and extended life span. Since the team's approach is to interfere with senescent cell viability rather than with senescent cell formation, team members expect to fully preserve the tumor suppressive functions of the senescence program.
The role of senescent cells in Alzheimer's disease and dementia. Alzheimer's disease, which is characterized by the presence of neurofibrillary tangles and amyloid plaques, is the leading cause of dementia in older adults. However, it is unknown whether and how these deposits contribute to Alzheimer's.
Dr. Baker is working to exploit the observation that both neurofibrillary tangles and neuritic components of plaques of patients with Alzheimer's disease show strong immunoreactivity to the cyclin-dependent kinase inhibitor p16, but not to other members of p16's cell cycle regulatory family of proteins. The p16 biomarker also exhibits increased expression in a variety of tissues with age, but not in terminally differentiated neurons.
Using mouse models of Alzheimer's, Dr. Baker uses the INK-ATTAC transgenic mice to remove p16-expressing cells. His goal is to improve understanding of how p16-expressing cells contribute to AD.
Significance to patient care
If the novel treatment strategy of eliminating p16-expressing cells is effective in preclinical models, it will open an entirely new avenue for exploration in the treatment of Alzheimer's disease.