My research interests 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.
We have recently developed a transgenic mouse model, termed INK-ATTAC, in which these cells can be selectively eliminated in an inducible fashion. By using this model in combination with one of accelerated aging, we have demonstrated the ability to significantly delay age-related pathologies and phenotypes, including cataract formation, by removing senescent cells.
Specific Research Topics
Senescent cells in natural aging
We have 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. We are 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 we will be 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 healthspan and extended lifespan. Since our approach is to interfere with senescent cell viability rather than with senescent cell formation, we 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 (AD), which is characterized by the presence of neurofibrillary tangles and amyloid (senile) plaques, is the leading cause of dementia in the elderly. However, it is unknown whether or not; and how these deposits contribute to AD.
I plan to exploit the observation that both neuorfibrillary tangles and neuritic components of plaques of patients with AD show strong immunoreactivity to the cyclin-dependent kinase inhibitor p16, but not other members of this cell cycle regulatory family. This biomarker also exhibits increased expression in a variety of tissues with age, but not in terminally differentiated neurons.
Using mouse models of AD, I will remove p16-expressing cells using our INK-ATTAC transgenic mice to get an improved understanding of how these cells contribute to AD.
Finding that this novel treatment strategy is effective in this pre-clinical model would open an entirely new avenue for exploration in the treatment of this currently incurable disease that affects a growing segment of the United States.