How Studying Cellular Senescence Can Help Researchers Learn to Delay Aging – Yale School of Medicine

Reaching the golden years doesn’t always feel so golden. Growing older introduces a range of health challenges, including being at increased risk for developing chronic diseases and having reduced immunity to infection. But while scientists have traditionally viewed the unpleasant aspects of aging as inevitable, new research could reveal how to substantially delay aging and improve the health of older individuals.

Chronic inflammation, one of the major hallmarks of aging, is thought to be partly caused by senescent cells that may accumulate in older individuals. Now, Yale researchers have received a grant [U54-AG079759] from the National Institutes of Health (NIH) Common Fund’s Cellular Senescence Network Program(SenNet) to study these specialized cells. The grant will further scientists’ knowledge of the mechanisms behind aging and potential therapies for dampening inflammation associated with old age. The SenNet is based on ‘Geroscience,’ an approach that intersects basic aging biology, chronic disease, and health to understand the cellular mechanisms that make aging a major risk factor for common chronic conditions of older people. Support by the NIH Common Fund shows the NIH’s commitment to Geroscience as a complex, high priority topic in biomedical research.

“A number of diseases that increase in older people may have a unifying underlying mechanism having to do with senescence,” says Ruth Montgomery, PhD, professor of medicine and of epidemiology (microbial diseases), and co-PI of the project. “If we are able to understand and address this, we may be able to reduce the incidence of a number of diseases, including cancers and heart diseases.”

Senescent Cells May Cause Inflammation in Older Adults

As we age, a small number of cells in tissues throughout our body become senescent. These cells undergo irreversible cell cycle arrest—in other words, they can no longer divide. The unique cells may have some evolutionary benefit. Rapid cell division, for example, can lead to cancer, and senescence may be an evolutionary adaptation that reduces the risk of certain cells becoming cancerous. However, senescent cells also produce inflammatory cytokines that accelerate the process of aging.

Researchers hypothesize that through targeting senescent cells, they could potentially reign in chronic inflammation in aging individuals. But they still have a poor understanding of the characteristics of senescent cells.

“These cells occur in extremely small numbers in organs. So the question is, how can so few cells which have these uncertain biomarkers be so important for inflammation?” says Vishwa Deep Dixit, PhD, Waldemar Von Zedtwitz Professor of pathology, professor of immunobiology, director of the Yale Center for Research on Aging, and co-PI.

The NIH awarded Yale a grant last year to study cellular senescence in lymphoid organs. Studying human tissue, however, poses some important limitations. The latest grant will allow Yale to launch a second center to study senescence in mouse models.

“If we want to treat patients, human tissues are the ultimate truth. But of course, access is difficult and limited,” says Stephanie Halene, MD, PhD, Arthur H. and Isabel Bunker Associate Professor of Medicine, professor of pathology, and co-PI of the human tissue project. “With mice, not only is access to tissues easy, but scientists can create mice that are epigenetically and genetically the same so that they can very cleanly study specific variables.”

“This is a perfect opportunity for Yale—having two senescence centers in the same institution,” says Rong Fan, PhD, professor of biomedical engineering. “With these two centers on campus, we are in the best position across the entire country to understand senescence. Not only are we studying it in humans, but our animal models will allow us to dive deeper into the mechanism.”

Determining Senescence Biomarkers Could Lead to New Therapies

To study senescence in mice, the researchers will mark various cells with fluorescent markers to track how the cells age over time and to see if they become senescent. Next, they will use unbiased transcriptional sequencing and spatial sequencing approaches—techniques used to help researchers generate a map of the cell they are sequencing—to try and discover new markers that are unique to senescent cells.

“Molecular characterization of senescent cells and their effect on neighboring cells is very challenging and requires the development of new ways of looking at data,” says Yuval Kluger, PhD, professor of pathology. “From the mathematical side, it’s very exciting.”

The team hopes their work will lead to the development of approaches to target senescent cells in a way that reduces the inflammation they produce. Some researchers, for example, are studying ways to eliminate senescent cells using drugs known as senolytics. However, the use of these drugs is controversial because current senolytic drugs aren’t specific to just getting rid of senescent cells and may harm other cells as well. The work at Yale could potentially help scientists identify senescent cells causing chronic inflammation and develop newer, more precision drugs targeting these cells.

“The older population in the world is growing, so it is imperative for us to understand the health issues that affect this group,” says Montgomery. “We are very excited that this research is going forward and that so many strong investigators from Yale can contribute to this effort.”

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