Davis Englund, Ph.D., assistant professor in the UAB Department of Medicine. Although senescent cells no longer divide, these “zombie”-like cells can still wreak havoc in muscles during aging or as diseases develop, according to a new review article from investigators at the University of Alabama at Birmingham. Published in The American Journal of Physiology-Cell Physiology, the article explains how senescent cells can damage skeletal muscle and how researchers are developing therapies to stop it.
As individuals age, the muscles used to walk up stairs and carry groceries gradually weaken, making everyday tasks more difficult. That same decline can happen because of illnesses like muscular dystrophies or infections, or when older adults have prolonged hospital stays. Understanding how muscle deteriorates could help researchers extend the human health span.
“When you ask most older adults what their biggest fear is, it’s not dying — it’s loss of functional independence,” said Davis Englund, Ph.D., assistant professor in the UAB Department of Medicine. “The field is shifting away from simply extending lifespan and toward prioritizing health span — developing strategies that help people remain disease-free, functional and independent as they age.”
The undead cells
In the review, Englund’s team explains that it has been challenging to determine the molecular mechanisms behind muscle weakening, but the scientific evidence points strongly toward an accumulation of senescent cells.
When cells experience extreme or prolonged damage, they usually die through a process called apoptosis. But if the stressor is less severe or does not occur for too long, cells can put the brakes on cell division to give them time to repair the damage. However, a subset of these damaged cells become permanently locked down and enter a senescent state — they never divide again, but they do not die.
“These damaged cells hang around in tissues and secrete deleterious pro-inflammatory factors that negatively influence the cells around them,” Englund said. “In this way, they can drive inflammation throughout the body and reduce overall health.”
Multiple cell types in muscle can undergo senescence, including muscle fibers, as well as stem cells and fibro-adipogenic progenitors, both of which are key players in regeneration. Even macrophages, the immune cells responsible for clearing debris after injury, can become senescent, as shown in animal models.
How to stop a zombie apocalypse — in muscle
To resist death, senescent cells activate anti-apoptotic signaling pathways that can be targeted with drugs. Senolytic medications inhibit anti-apoptotic pathways, enabling senescent cells to finally undergo apoptosis and die. These medications are currently being tested in clinical trials.
A potential limitation is that current pharmacologic strategies are not specific, so they kill senescent cells throughout the body, not just in muscle. “With new advanced technologies, the field is working toward developing cell- and tissue-specific strategies to target these cells,” Englund said.
Other approaches target the biological effects of senescent cells instead of killing them. Senomorphic drugs may work by inhibiting the activity of SASP — the pro-inflammatory cytokines, chemokines, growth factors and proteases that senescent cells secrete — or by interfering with metabolic and inflammatory signaling.
Lifestyle changes, such as exercising and eating a nutritious diet, could prevent cells from undergoing senescence in the first place. These interventions may also support immune function and tissue homeostasis, potentially helping limit the accumulation and effects of senescent cells.
Future directions
Although researchers have made great strides, there are many directions left to pursue. For example, more data on how senescent cells spread damage locally and throughout the body are needed, Englund says. In addition, the exact molecular stimulus that sets off senescence is still unclear.
Currently, Englund’s team is focusing on skeletal muscle senescence in response to infection and traumatic injury. He recently partnered with Robert Mankowski, Ph.D., associate professor in the UAB Department of Medicine; and Preston Hewgley, M.D., assistant professor, and Jillian Richter, Ph.D., associate professor, both with the UAB Department of Surgery, to obtain muscle samples from hospital patients with an infection or a traumatic injury. This research will help the team achieve their ultimate goal of translating their findings from animal models to humans, while helping them go in the reverse direction. Findings from human samples may raise questions that the team can then address in the lab with studies on animal models and cells that are not possible with humans.
To move toward studies with less invasive samples, Englund is investigating blood-based biomarkers that senescent cells release. As a postdoctoral fellow, Englund showed that taking stock of these biomarkers allowed him to develop an index of senescent cell burden that predicted how a group of older adults responded to exercise.
“The idea is to develop a similar senescence index in disease populations based on their blood profiling, which could predict the progression of disease or, potentially, their response to therapies,” he said.
The American Journal of Physiology-Cell Physiology review article, “Cellular senescence in skeletal muscle: myogenic and nonmyogenic cell populations, mechanisms, and therapeutic opportunities,” was led by corresponding authors Englund and Cory M. Dungan, Baylor University.
Co-authors are Konstantinos Papanikolaou and Robert T. Mankowski, UAB Department of Gerontology; Angad Yadav, UAB Department of Cell, Developmental and Integrative Biology; Matthew S. Alexander, UAB Department of Pediatrics and UAB Center for Exercise Medicine; Jorge L. Gamboa, UAB Department of Medicine; and Anna E. Thalacker-Mercer, UAB Department of Cell, Developmental and Integrative Biology and Birmingham Department of Veterans Affairs.