Enhancing Innate Immune Surveillance of Senescent Cells

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Buck Institute for Research on Aging & SENS Research Foundation Research Center

Principal Investigator: Judith Campisi
Research Team: Abhijit Kale (Buck Institute), Amit Sharma (SRF-RC)

When normal cells lose their ability to replicate, they become senescent cells. Over time, senescent cells accumulate in aging tissues, spewing off a cocktail of inflammatory and growth factors, as well as enzymes that break down surrounding tissue (the “senescence-associated secretory phenotype” (SASP)). The charge sheet against senescent cells has now expanded into a remarkable litany of the diseases of aging.

Multiple studies have now, on a more encouraging note, documented that “senolytic” drugs and gene therapies that destroy senescent cells exert sweeping rejuvenating effects in aging, both in laboratory animals and animal models of multiple diseases of aging. But in theory, senolytic therapies shouldn’t be necessary. The body’s immune system is on continuous patrol against senescent cells: our natural killer (NK) cells, recognize senescent cells as abnormal, bind to them, and release substances that trigger the senescent cells to self-destruct.

In a Foundation-donor-funded collaboration between Dr. Judith Campisi’s lab at the Buck Institute and the SRF Research Center, this project seeks to answer the critical question of why senescent cells accumulate with age, and what might we do to enhance immune surveillance and elimination of these cellular saboteurs?

Research Highlights:

Dr. Campisi has found that about ten percent of senescent cells are resistant to being killed, even by fresh NK cells, suggesting that these resistant cells are the ones that escape immunosurveillance and accumulate in aging tissues. Her research team and other scientists have developed preliminary data suggesting mechanisms whereby senescent cells can make themselves invisible to NK cells, thus protecting themselves from destruction.

The Buck-SRF-RC collaboration is now seeking to drill further down into these questions and test possible means to intervene in the process. The Campisi lab is looking into further elaborating the biology of one of senescent cells’ two self-protective mechanisms, and also testing a potential role for another kind of immune cell (macrophages) in defending the body against senescent cell accumulation.

At the SRF-RC, we are currently perfecting the method of co-culturing NK and senescent cells and controlling the killing process, and will begin testing two potential therapeutic targets identified in the Campisi lab. The SRF-RC scientists are also working for the first time with NK cells derived directly from aged human donors (rather than long-cultured lines of NK cells, or NK cells artificially “aged” by exposure to oxidative stress or extensive replication in culture, as has been done in the past). Using these cells will allow them for the first time to observe any direct effects of aging on NK cell senolytic activity. The team is also developing an algorithm for the SRF-RC’s automated microscope imaging system to rapidly analyze stained plates of cells for quantitative analysis of senescent cell-killing ability — a job hitherto done by laborious human visual microscopy.

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