Does cellular senescence hold secrets for healthier aging?
Disease, injury, and other stress factors harm cells throughout our bodies. Ideally, the damaged cells are cleared by our immune systems through a process called apoptosis. But as we age, our bodies are no longer as effective at removing dysfunctional cells, and this can contribute to a weakened immune system and other less efficient biological processes.
An increasing number of researchers are exploring whether learning to harness a cellular state known as senescence — during which damaged cells resist removal by apoptosis, linger, and harm neighboring normal cells — might hold the key to revitalizing aging tissues and increasing healthy, active years of life.
What is cellular senescence?
Senescent cells are unique in that they eventually stop multiplying but don’t die off when they should. They instead remain and continue to release chemicals that can trigger inflammation. Like the one moldy piece of fruit that corrupts the entire bowl, a relatively small number of senescent cells can persist and spread inflammation that can damage neighboring cells.
However, not all senescent cells are bad. The molecules and compounds expressed by senescent cells (known as the senescent secretome) play important roles across the lifespan, including in embryonic development, childbirth, and wound healing.
How cellular senescence affects the body
The number of senescent cells in a person’s body increases with age. As the aging immune system becomes less efficient, senescent cells accumulate and taint healthy cells. This can affect a person’s ability to withstand stress or illness; recuperate from injuries; and learn new things, since senescent cells in the brain can degrade cognitive functions.
As a result, cellular senescence has been connected to a multitude of age-related conditions, including cancer, diabetes, osteoporosis, cardiovascular disease, stroke, Alzheimer’s disease and related dementias, and osteoarthritis. It has also been linked to declines in eyesight, mobility, and thinking ability. Investigations are underway to see if senescent skin cells may contribute to sagging and wrinkling, and if senescent cells might also be connected to the cytokine storm of inflammation that makes COVID-19 so deadly for older adults.
A scientific curiosity
Cellular senescence has been on scientists’ radar since the early 1960s when Leonard Hayflick, Ph.D., and his colleague Paul Moorhead, Ph.D., overturned the long-held scientific consensus that human cell samples could replicate endlessly in lab cultures. Hayflick and Moorhead showed that there was a limit on the number of division cycles, after which cells entered senescence.
For long after that finding, senescence was believed to be just an odd side effect of laboratory cell culture environments. It was poorly understood and studied by only a few research teams, but in the past 20 years, there has been a spike in interest. Today, it is a still young but promising scientific discipline that has sparked more NIH research as well as private industry support for studies to discover and develop drugs that might give Mother Nature a boost in clearing out senescent cells.
A pioneering pursuit to extend health span
Jim Kirkland, M.D., Ph.D., of the Mayo Clinic, and his former colleague Jan van Deursen, Ph.D., were pioneers of the senescence renaissance. For nearly two decades, Kirkland has studied ways to remove senescent cells. A clinical geriatrician, Kirkland often says he grew tired of prescribing the latest innovations in wheelchairs, walkers, or incontinence control. Instead, he wanted to learn if it was possible to slow down or partially reverse the fundamental aging processes in humans that lead to common health issues as we age.
Kirkland and his team currently focus primarily on a cocktail of two drugs: dasatinib (D), a drug commonly used in leukemia chemotherapy; and quercetin (Q), a pigment found in strawberries, grapes, tomatoes, red wine, onions, and other fruits and vegetables that has natural anti-inflammatory properties. When administered together, D&Q function as senolytics, i.e., drugs that clear out senescent cells.
In 2019 Kirkland and colleagues conducted a very small pilot study of D&Q in 14 volunteers who had idiopathic pulmonary fibrosis (IPF), a fatal, tough-to-treat, and debilitating lung disease. The results showed that the senolytic combination improved physical function in participants, demonstrating the feasibility of testing D&Q for this condition in larger controlled clinical trials. In subsequent small clinical trials, the Mayo Clinic team found that D&Q also cleared senescent cells in research participants with diabetic kidney disease.
In mouse models of IPF, D&Q was shown to clear senescent lung cells, reduce inflammation, and extend health span (the years of life free of major disease and disability), but not longevity. Researchers are currently exploring the potential of senolytics for osteoporosis, glaucoma, macular degeneration, diabetic neuropathy, and other age-related conditions.
Kirkland’s lab has shown that middle-aged mice given a variety of senolytics had delayed onset of several age-related ailments compared to untreated peers. Older mice given D&Q were faster, stronger, and spryer than control groups, and the positive effects lasted until the final months of their natural lifespans. Other studies showed that older mice given D&Q had a 36% longer average lifespan than untreated peers.
Kirkland’s team has also tested the opposite approach, by injecting healthy young or middle-aged mice with a customized senescent cell type. This intervention caused rapid deterioration in their mobility, speed, and strength, and big jumps in frailty rates. What’s more, these negative effects lingered long after the transplanted senescent cells had died off.
A long way to go before safe human use
While these studies pose exciting scientific and medical questions, Kirkland is adamant in underscoring the huge gap between mice and humans. He regularly urges people not to take senolytics or similar supplements or drugs outside of a clinical trial because they have not been confirmed as safe.
“We haven't so far seen serious or severe adverse events in clinical trials with some of these agents, but it doesn't mean they won't happen,” said Kirkland. “They could take a long time to develop, and anything that sounds too good to be true in mouse or cell culture models usually is. We need many more long-term studies and human trials.”
Kirkland, his Mayo colleague Tamar Tchkonia, Ph.D.; and Stefan Tullius, M.D., Ph.D., of Harvard University Medical School, are also looking at other potential benefits of taming senescence to rejuvenate older tissues. One such project is exploring whether treating kidneys or livers from older organ donors with senolytics prior to transplant could help repair the damage accumulated over time and with age. If true, this could make older organs more viable and safer for transplantation, and thus reduce waitlists.
Kirkland emphasized that there are many connections between senescence and age-related conditions, making the field ripe for future discoveries.
Growing interest nationwide
NIA-supported scientists working at NIH and throughout our nation continue to explore the mechanisms that regulate the intersection of senescence, inflammation, aging, and disease. Chronic inflammation seems to be a key to how senescence can turn from helpful to harmful. Healthy tissues normally have a limited type of senescence that suppresses abnormal cell growth that could lead to cancer. But when the healthy cell environment is disrupted by injury or age-related inflammation, this can trigger a loss of control of the body’s natural regulation of senescent cells, which may be linked to the development of cancer and other diseases.
Two top experts in the burgeoning field and frequent collaborators with Kirkland are University of Minnesota researchers Laura Niedernhofer, M.D., Ph.D., and Paul Robbins, Ph.D. Niedernhofer came to senescence from a background in DNA damage and repair.
“Senescence is fascinating to me because a damaged senescent cell can in turn cause damage in healthy cells,” she said, stating further that normal senescence can be helpful, as in wound healing, and that senescence itself is a potent tumor suppressor mechanism.
“Picture a wound on your arm. There is growing evidence that senescent cells may be critical for calling in immune cells to help heal that. But it's just a temporary thing to close that wound and then the signal should go away. The problem comes when you're not able to clear those senescent cells. They are great at spurring the immune system to action, but when your immune system falters as you get older, you get these chronic senescent cells.”
Robbins quipped about the inevitable rise in senescence as we age.
I think I'm chock full of bad senescent cells. They start accumulating when you hit age 60, and from there it's kind of an exponential increase. Toward the end of life, depending how you're aging, up to 10% of certain tissues can have at least some markers of senescence.— Paul Robbins, Ph.D
Senescence science collaboration across NIH
NIH-wide interest in how cellular senescence factors into multiple diseases and conditions is growing as well. The NIH Cellular Senescence Network (SenNet), organized by NIA and the National Cancer Institute, is an NIH Common Fund initiative to coordinate the exploration, identification, and cataloging of differences in senescent cells throughout the body. The network also supports research collaboration and data sharing that could lead to future therapeutics. Through SenNet, researchers aim to create a four-dimensional atlas of senescent cells involved in healthy human aging to find and characterize healthy and unhealthy senescent cells. This could inform investigations into how future senolytic therapies can be customized to only target harmful senescence.
Robbins, Niedernhofer, and their colleagues are energized by the future possibilities.
“Before you go in for surgery, you might want to clear your bad senescent cells to help you recover faster,” Robbins said. “Cancer radiation or chemotherapy treatment at a young age has been shown to drive senescence and aging, so there's a whole group of cancer survivors that may be very appropriate for this sort of treatment.”
Niedernhofer added that the senescence field has exploded since she and others described the first senolytic compounds in 2015.
Now there are more than 20 clinical trials registered for anything from chronic kidney disease or pulmonary fibrosis to frailty in nursing home patients. It's moved very quickly and the thing to be proud of is, it’s really been driven by NIH-funded investigators.— Laura Niedernhofer, M.D., Ph.D.
Sorting out good senescence from bad
Other NIA-funded researchers, like Judy Campisi, Ph.D., of the Buck Institute, see senolytics as a potential routine treatment of the future that could help older adults stave off age-related illness and frailty longer, similar to a dental check-up. In the San Francisco Bay area where she lives, multiple public and private research institutions are looking into future medical applications for senolytics.
Campisi began her career focused on how senescence affected cancer. Eventually, she expanded her research into how it contributes to aging and age-related disease.
“We made a mouse model which allowed us to eliminate senescent cells throughout the lifespan, and it improved a lot of age-related diseases in mice,” she said. “Now the question is, could this happen in humans using senolytics? Well, it does in human cells and in certain human tissues.”
Campisi and her collaborators continue to investigate various aspects and mechanisms of senescence, including how it impacts osteoarthritis and sarcopenia (loss of muscle mass later in life that can lead to disability, frailty, and fall risk) and if senolytic treatments can help reduce the harmful side effects of chemotherapy and HIV/AIDS drugs.
Campisi concedes there are still many unanswered questions.
“We know there are good things senescent cells do in healing, tissue repair, embryonic development, and childbirth. But how are the good guys different from the bad guys? And is there a way we kill the bad guys and not the good guys? We honestly don't know that yet.”
Mapping senescence targets across the body
Myriam Gorospe, Ph.D., and her colleagues in NIA’s in-house labs are examining whether senolytics could tamp down harmful senescence in lab and mice models of Alzheimer’s disease linked to problems with thinking and cognition. They are hoping to map and manipulate senescence-related proteins that are involved with the buildup of beta-amyloid plaques and neuroinflammation, hallmarks of Alzheimer’s disease.
Gorospe’s lab is pursuing the quest for biomarkers — measurable substances in the body that indicate the presence of disease — to better pinpoint and target senescent cells in different types of tissue. Her team also works with senomorphics, a different category of drugs that don’t eliminate senescent cells, but instead repress their harmful secretions. They study senescence’s impact on aging body tissues like the lungs and muscles, and its role in conditions like arteriosclerosis and Alzheimer’s-related neurological decline.
Scientists are just beginning to take a closer look at the role senescence plays in one of the most serious public health crises in recent history, the COVID-19 global pandemic.
“Some of the biomarkers on the membrane of senescent cells function as receptors for the SARS-CoV viruses, so they're critical in understanding the acute pathology of COVID-19 infection,” said Gorospe.
Lessons learned from the pandemic could yield useful knowledge as the scientific community moves forward to someday testing if human use of senomorphics or senolytic treatments could help extend healthy lifespan and ward off disease.
Cautious optimism, support for a young science
In August 2019, NIA convened a workshop attended by academic, industry, and public health scientists to study if it was possible to safely repurpose some drugs or dietary supplements for their senolytic or senomorphic effects to treat or prevent age-related conditions. NIA and the broader NIH offer growing funding opportunities in the field through SenNet and other efforts. Currently, NIA supports a growing portfolio of extramural senescence research, coordinated by program officers including Viviana Perez Montes, Ph.D.
Perez Montes and her NIA colleagues agree the potential for harnessing senescence is vast but echo the cautions of Kirkland that this field is still very young, with a lot of work yet to be done, including building a common research infrastructure and safety standards for human studies.
Above all, it’s important to manage expectations for the public and the medical community that any safe potential health benefits from manipulating senescence will be years if not decades in the future.
“We have to remember that senolytics are going to kill senescent cells and we believe that some of those senescence functions could be beneficial,” said Perez Montes. “If you kill and eliminate cells that are not going to be replaced, we don’t know yet the biological and physiological consequences of this elimination, so we need to be extremely careful in future translational and clinical studies because we're still in the very early stages.”