As cells age, they can experience senescence, a condition in which they stop growing but continue to release inflammatory and tissue-degrading molecules. When a person is young, the immune system reacts and eliminates aging cells, often called zombie cells. However, zombie cells persist and contribute to a variety of age-related health problems and diseases. Mayo Clinic researchers shed light on the biology of aging cells in two studies.
In a study published in Aging Cell, Mayo Clinic researchers analyzed zombie cells to explain aging at the cellular level.
“We know that people age at different rates and that a person’s chronological age does not always match their biological age,” said Dr. Jennifer St. Sauver, lead author of the study and scientific director of the Population Health Science Scholars Program at the Center for Health Care Delivery Science Robert D. and Patricia E. Kern of the Mayo Clinic. “We discovered that a group of different proteins secreted by zombie cells can serve as biomarkers of aging and can predict health outcomes in older people. We also found that measuring these biomarkers in the blood can help predict mortality beyond the combination of a person’s chronological age, gender, or the presence of a chronic disease.”
The study included 1,923 adults aged 65 and older with one or no health conditions. The group included 1,066 women and 857 men, with 68% of study participants having no chronic disease and 32% having one disease.
“What’s so unique about this study is that even in the absence of disease, the biomarkers are highly predictive of poor health outcomes in the future,” says Nathan LeBrasseur, PhD, director of the Robert and Arlene Kogod Center on Aging and Aging author of the study. Dr. LeBrasseur studies the biological processes that drive aging.
The researchers noted that the most common chronic conditions in the group were arthritis, high cholesterol and a history of cancer.
The researchers found that higher levels of specific aging biomarkers, such as GDF15, VEGFA, PARC and MMP2, were associated with an increased risk of death. Some of these biomarkers are associated with the development of chronic diseases. For example, research shows that people with heart disease and certain types of cancer have higher levels of GDF15 and VEGFA. Ongoing studies are investigating how lifestyle factors, including diet, physical activity and drugs that appear to help clear senescent cells, affect circulating levels of the biomarkers.
Dr. LeBrasseur envisions using these biomarkers as clinical practice tools to find people at risk for health challenges. In addition, research could benefit from identifying subjects who may be most responsive to emerging ways to target senescent cells and assess their response to treatment.
Dr. St. Sauver emphasizes the need to include more diversity in future studies, ensuring that diverse populations are included in current aging research.
“We did see differences in the levels of these biomarkers between men and women, and we also know that race and ethnicity affect many biological processes,” says Dr. St. Sauver. “For future studies, we need to consider these factors in aging research.”
Discovery of an unknown phenomenon in zombie cells
Mayo Clinic researcher Dr. Joao Passos, who also studies the biology of aging, sees his primary goal as working to improve vitality and health span — the length of time one lives without the effects 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 cell’s tiny powerhouses, are responsible for producing energy, but they also play a critical role when the cell suffers excessive damage. They can initiate a self-destructive mechanism called apoptosis, which leads to cell death. Senescent cells that do not die are known to be resistant to apoptosis. These two processes, apoptosis and senescence, are often viewed as opposite cell fates.
However, Dr. Passos, Dr. Victorelli and team unexpectedly observed a small group of “rogue” mitochondria attempting to initiate apoptosis in senescent cells. When they do, these mitochondria release their DNA into the cell’s cytosol, the “soup” inside the cell. Mitochondria were once independent bacteria, so the cell perceives mitochondrial DNA as foreign, triggering inflammation that can damage tissues and lead to disease.
The researchers also found that if they blocked this process in mice equivalent to the age of a 70-year-old person, they could reduce tissue inflammation and significantly improve their health, including improving their strength, balance and bone structure.
This newfound knowledge of the inner workings of senescent cells may open the door to new types of therapies, beyond senolytics that eliminate senescent cells, to improve human health.
“Inflammation is one of the main ways we think senescent cells cause deleterious effects in aging-related diseases. So it’s exciting to find a way to target a pathway that reduces inflammation,” explains Dr. Victorelli.
Outline the big picture
Dr Passos and colleagues, in collaboration with researchers from the US, are part of an ambitious project to map senescent cells in different tissues. The project is called the Cellular Senescence Network (SenNet) and is funded by the General Fund of the National Institutes of Health. Its main goal is to compile a comprehensive atlas of aging cells in the human body throughout life. Dr. Passos recently led an effort published in Nature Aging to highlight emerging technologies and challenges in spatial mapping of cellular aging.
“By targeting these fundamental mechanisms driving the aging process, rather than fighting each disease individually, we have the potential to fight not just one disease of aging, but all of them,” says Dr. Passos.