Senescence, or the state where cells stop growing and release harmful molecules, leads to various age-related diseases, with Mayo Clinic research uncovering the biology behind aging cells and identifying specific biomarkers that can predict health outcomes. A study on “rogue” mitochondria in senescent cells revealed a new phenomenon that could potentially improve health in older adults by reducing tissue inflammation and enhancing vitality.
As individuals age, their cells may undergo senescence, a condition in which cell growth halts, yet these cells persist in emitting molecules that promote inflammation and break down tissues. In youth, the immune system effectively targets and removes these so-called zombie cells. Over time, these zombie cells accumulate, playing a significant role in the onset of numerous health issues and diseases associated with aging. Researchers from Mayo Clinic have conducted two studies, offering insights into the cellular mechanisms that underpin aging.
In a study published in Aging Cell, Mayo Clinic researchers analyzed zombie cells to explain aging at the cellular level.
“We know people age at different rates and that a person’s chronological age doesn’t always match their biological age,” says Jennifer St. Sauver, Ph.D., the lead author of the study and scientific director of the Population Health Science Scholars Program at Mayo Clinic’s Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. “We found that a group of diverse proteins secreted by zombie cells can serve as biomarkers of senescence and can predict health outcomes in older adults. We also found that measuring these biomarkers in the blood can help predict mortality beyond the combination of a person’s chronologic age, sex or presence of a chronic disease.”
The study included 1,923 adults aged 65 and older with one health condition or none. The group included 1,066 women and 857 men, with 68% of study participants having no chronic conditions and 32% having one condition.
The researchers noted that the most common chronic conditions in the group were arthritis, high cholesterol, and a history of cancer.
Researchers found that higher levels of specific senescent biomarkers, such as GDF15, VEGFA, PARC, and MMP2, were all associated with an increased risk of death. Some of these biomarkers have been associated with developing chronic diseases. For example, research has shown that people with heart disease and some types of cancers have higher levels of GDF15 and VEGFA. Ongoing studies are investigating how lifestyle factors, including diet, physical activity, and medications that appear to help clear senescent cells, influence the circulating levels of the biomarkers.
Uncovering unknown phenomena in zombie cells
Mayo Clinic researcher Joao Passos, Ph.D., who also studies the biology of aging, sees his main purpose as working to enhance the vitality and health span—the period of life free from the consequences of disease and disability—in older people.
In a new study published in Nature, he, along with postdoctoral researcher Stella Victorelli, Ph.D., and a large interdisciplinary team of collaborators, uncovered a previously unknown phenomenon that occurs in zombie cells.
Mitochondria, the tiny powerhouses within a cell, are responsible for producing energy but also play a crucial role when a cell incurs excessive damage. They can initiate a self-destruct mechanism called apoptosis, which leads to a cell’s death. Senescent cells, which do not die, are notorious for resisting apoptosis. These two processes, apoptosis, and senescence, have often been regarded as opposite cell fates.
However, Dr. Passos, Dr. Victorelli, and the team unexpectedly observed a small group of “rogue” mitochondria attempt to initiate apoptosis in senescent cells. When they do so, these mitochondria release their DNA into the cell’s cytosol, the “soup” inside a cell. Mitochondria were once independent bacteria, so the cell perceives the mitochondrial DNA as foreign, which sparks inflammation that can damage tissues and lead to disease.
Furthermore, the researchers found that if they blocked this process in mice equivalent in age to a 70-year-old human, they could reduce tissue inflammation and significantly boost their health, including improving their strength, balance, and bone structure.
References: “Biomarkers of cellular senescence and risk of death in humans” by Jennifer L. St. Sauver, Susan A. Weston, Elizabeth J. Atkinson, Michaela E. Mc Gree, Michelle M. Mielke, Thomas A. White, Amanda A. Heeren, Janet E. Olson, Walter A. Rocca, Allyson K. Palmer, Steven R. Cummings, Roger A. Fielding, Suzette J. Bielinski and Nathan K. LeBrasseur, 06 October 2023, Aging Cell.
DOI: 10.1111/acel.14006
“Apoptotic stress causes mtDNA release during senescence and drives the SASP” by Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S. Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B. Lagnado, Lilian Sales Gomez, Joshua N. Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C. Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A. Porritt, Huijie Huang, Timothy Y. Huang, Derek A. Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H. Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K. LeBrasseur, Xue Lei, Alva G. Sainz, Viktor I. Korolchuk, Peter D. Adams, Gerald S. Shadel, Stephen W. G. Tait and João F. Passos, 11 October 2023, Nature.
DOI: 10.1038/s41586-023-06621-4
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