Buck Institute professors Judith Campisi, PhD and Lisa Ellerby PhD, have been awarded a $14.3 million grant from the NIH's National Institute of Aging to study cellular senescence, one of the major hallmarks of aging, as a driver of Alzheimer's disease and other age-related dementias.
"Age is the largest risk factor for Alzheimer's disease and other dementias," said Campisi, who is recognized as a pioneer in studying cellular senescence, a stress response which has been linked to numerous age-related diseases. "We are extremely excited to bring our expertise in cellular senescence to efforts to study brain aging in the context of dementia. Our objective is to uncover new mechanisms that can be developed into interventions to treat patients."
Senescent cells spew out a panoply of inflammatory molecules (known collectively as the SASP – the senescence-associated secretory phenotype) that can have profound effects on tissue structure and function by promoting chronic low-level inflammation. The SASP is of great interest to researchers who study aging biology; several biotech companies are developing therapeutics aimed at quelling the damaging effects of senescent cells.
The need for new approaches to Alzheimer's and other age-related neurodegeneration is clear, given that there are no therapeutics that effectively treat or prevent these conditions."
Judith Campisi, PhD, Professor, Buck Institute
An estimated 6.2 million Americans age 65 and older are currently living with dementia.
The five-year grant consists of three research projects and involves other Buck faculty. One project, led by Campisi, will characterize in depth the senescent responses of human and mouse astrocytes, microglia and neurons. A second project, led by Buck President and CEO, Eric Verdin, MD, will focus on changes in systemic and cellular metabolism as they relate to neurodegeneration and inflammation. Recent research from the Verdin and Campisi labs show an increasing burden of senescent cells causes the degradation of NAD+ (nicotinamide adenine dinucleotide), a key metabolite central to an efficient and healthy metabolism.
A third project, under the leadership of Lisa Ellerby, will study the SASP in the context of cell-cell interactions, particularly between neurons and non-neuronal support cells in the brain. Buck research in mouse models of Parkinson's disease and Huntington's disease suggest cellular senescence plays a significant role in the pathology and progression of those incurable neurodegenerative diseases. The senescent features of neurons in patient-derived Huntington's disease neurons is also found in Alzheimer's. .
Much of the research will call on the expertise of Ellerby, a neuroscientist who is co-principal investigator on the grant. Her team will derive neurons, astrocytes, microglia and neurons from induced pluripotent stem cells generated from all of the models used in the project, including those from patients who had Alzheimer's. Ellerby's team will also grow brain organoids, so-called "mini brains" that recapitulate the cellular integrity, structure and function of the brain. "This will allow for three-dimensional research so that we can track and understand the interactions between brain cells in a very complex environment," she said. "It will also allow us to 'seed' these organoids with senescent cells to see what happens in real time. The advances in technology make this a really exciting time to embark on this project." Ellerby's group will also grow cells that recapitulate the blood-brain barrier, which has been an impediment to developing treatments that can get into the brain.
"This program project is a quintessential example of the Buck's strength," said Verdin. "It brings together researchers with diverse expertise, all of whom are acknowledged leaders in contemporary aging research and have a history of productive collaborations. I could not be more proud of this team and am thrilled that the NIH is bringing research on aging into the fight against Alzheimer's and age-related dementia."
Frailty may predict dementia risk years before onset, study finds