A protein better known for its role in immune checkpoint signaling may help harmful aging cells, or senescent cells, remain hidden from the immune system, allowing them to accumulate in tissues and contribute to age-related dysfunction, according to a new study from Cedars-Sinai Health Sciences University investigators.
The study is titled “Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction.” The findings, published in Cell Metabolism, point to programmed cell death ligand 2, or PD-L2, as a possible target for therapies designed to help clear senescent cells, as well as a potential blood marker for tracking their presence. Senescent cells are damaged cells that stop dividing but do not die. Instead, they can persist in tissues, where they release inflammatory factors and disrupt the function of nearby cells. Their buildup has been linked to metabolic dysfunction, impaired physical fitness, and other health problems associated with aging.
“Our findings suggest that PD-L2 may help aging cells stay in the body when they would normally be removed by the immune system,” said Selim Chaib, PhD, research assistant professor of medicine at Cedars-Sinai and first and co-corresponding author of the study.
Immune checkpoint proteins have been studied extensively in cancer, where they can help tumor cells escape immune attack. In the new study, the researchers examined whether a similar process might allow senescent cells to evade immune clearance during aging. They found that PD-L2 was increased in isolated senescent human cells and rose with age in some human tissues. Circulating soluble PD-L2 also increased with aging and declined after senolytic treatment in humans, according to the study’s highlights.
The team then tested the effects of removing or blocking PD-L2 in mice. Older mice lacking PD-L2 accumulated fewer senescent cells than older wild-type mice. They also showed greater insulin sensitivity and grip strength, two measures tied to metabolic function and physical fitness. In aged wild-type mice, anti-PD-L2 therapy restored insulin sensitivity and increased physical strength.
Together, the results suggest that PD-L2 may act as an immune checkpoint on senescent cells, helping them avoid removal and promoting their persistence during aging. The work also adds to the growing interest in senescence-targeted approaches, including senolytics, that aim to reduce the burden of dysfunctional cells rather than treating one age-related disease pathway at a time.
“If we can find a way to block this protein, we may be able to help the immune system get rid of these cells and potentially improve health problems linked with aging,” said James Kirkland, MD, PhD, director of the Center for Advanced Gerotherapeutics and senior author of the study.
The authors cautioned that more research is needed to determine whether blocking PD-L2 can safely produce health benefits in people.
