By Deborah Borfitz 

January 21, 2021 | Fundamental aging processes appear to be root-cause contributors to multiple conditions, ranging from heart attacks and cancer to neurodegenerative disorders like Alzheimer’s disease. Oftentimes, chronologic age alone is sufficient to predict disease risk—so much so that all other contributing factors are, on balance, only fractionally relevant, says James Kirkland, M.D., Ph.D., professor of aging research at the Mayo Clinic and director of its Robert and Arlene Kogod Center on Aging. 

Kirkland’s major research focus is the impact of cellular aging, or senescence, on age-related dysfunction and chronic diseases. He is participating in numerous clinical trials that will be running in parallel with others focused on different “pillars of aging,” such as chronic inflammation and sluggish metabolism, all of which are using the same clinical procedures, reference laboratory, and patient questionnaires.

The idea is to learn “quickly, but scientifically and rigorously,” if what has been seen in animals translates to people, says Kirkland. The National Institutes of Health is funding the newly launched, Mayo-led interdisciplinary initiative, called the Translational Geroscience Network, bringing together eight aging research centers to conduct complementary, small-scale, proof-of-concept clinical studies.

Collaborators hail from Harvard University, Johns Hopkins, Wake Forest University, and the universities of Texas (San Antonio), Minnesota, Michigan, and Connecticut, he says. St. Jude Children’s Research Hospital and The Steadman Clinic (Colorado) both participate, as do other groups periodically. 

The aligned effort provides Mayo researchers with an opportunity to test its newly conceived “Unitary Theory of Fundamental Aging Processes” hypothesizing that senolytics— drugs targeting senescence—could affect many or perhaps all other aging mechanisms because they are interlinked, says Kirkland. Further testing is needed to understand the implications of combining interventions, most notably if the therapeutic effects will be synergistic. 

The answer will depend on how tight the relationship is between different aging processes, Kirkland says. When senescent cells are targeted, for example, “essentially all” of the other processes believed to be major contributors to aging are affected.

“Age appears to be a risk factor for many of the major diseases that contribute to the bulk of mortalities and health expenditures and it is also a risk factor for geriatric syndromes—things like frailty, falling, age-related muscle loss, incontinence, mild cognitive impairment—and for loss of resilience [e.g., ability to recover quickly after surgery or from an infection],” says Kirkland.

Additionally, fundamental aging processes seem to predispose people to some acute diseases, he says. For example, higher senescent cell burden has been associated with a more severe course of COVID-19 and bacterial infections.

“All of these fundamental aging processes begin at conception… and tend to be shared across vertebrates and, in some cases, invertebrates as well,” Kirkland notes. “So, there is some hope in the field that interventions effective in mice or rats or monkeys might be somewhat more translatable to humans than mouse models of diseases that are unique to humans.”

The Translational Geroscience Network is also endeavoring to create composite biomarkers to measure whether interventions are targeting fundamental aging processes, Kirkland says. “We’re measuring everything,” including epigenetic clocks and the factors senescent cells produce in the blood. 

Development Path

Senolytics might one day be used to help people improve their healthspan, says Kirkland, but most of the conditions initially being studied by researchers are serious, life-threatening diseases or those without a good treatment. Senolytic drugs could possibly be used in combination with disease-specific drugs to improve treatment outcomes.

“What I really worry about is people taking these drugs or physicians prescribing them off-label because we don’t yet know all the downsides,” Kirkland says. “The place for these kinds of interventions at the moment is in carefully controlled clinical trials with a lot of monitoring.”

The trials being conducted by the Translational Geroscience Network involve investigational new drug applications being filed with the U.S. Food and Drug Administration (FDA) and are being registered on ClinicalTrials.gov prior to launch. “It’s a long process, but the FDA has been extremely helpful,” Kirkland says.

Self-Deleting Cells 

One advantage of senolytics is that they work by inducing bad senescent cells, the ones that damage tissues and the spread of senescence, to “commit suicide” while leaving other nearby cells alone, Kirkland explains. Some senescent cells are beneficial, for example aiding in wound healing and tumor suppression.

Senescent cells are believed to take days or weeks to form, says Kirkland, so one-off insults such as therapeutic radiation for a cancer might be treatable with a single dose of a senolytic drug. But in disease states such as Alzheimer’s and diabetes where senescent cells are being generated continuously, senolytics might best be given intermittently (e.g., once every two to four weeks) to reduce side effects and ensure they do not interfere with the generation of senescent cells when they are needed, he says. 

Kirkland’s research uses senolytic agents with known safety profiles and short elimination half-lives, so they do not persist in the blood to cause off-target effects. The goal is a high peak level of the drug in tissues where the senescent cells are found, he says, and it takes only an hour or two of exposure to these drugs for senescent cells to initiate the process of killing themselves. 

Other types of drugs, including the immune modulator, rapamycin, and anti-diabetic medication, metformin, appear to inhibit the secretory state of senescent cells that contributes to their spread to neighboring cells, says Kirkland. But reduction of senescent cell burden has been demonstrated with continuous rather than intermittent administration. 

It is not particularly important to target a senolytic drug to a specific senescent cell type because of a “threshold phenomenon” associated with senescence, Kirkland explains. “Senescent cells are resistant to dying, and normally only removed by the immune system.” At some point the rate of production of new senescent cells can exceed the rate at which the immune system can remove them. But below that threshold, senolytic agents can kill off as many of the bad actors as possible and the immune system can potentially kick in and get the remaining senescent cells.

“That may not work in some protected areas like the brain,” says Kirkland. “But in general… what really seems to matter is getting people below a particular burden so their immune system can start working better and clear senescent cells faster than they can spread.” 

Human Trials

To date, the Mayo Clinic has registered four studies using senolytic interventions on ClinicalTrials.gov. One is a small, invitation-only study on the effects of the leukemia drug dasatinib and the flavonol quercetin in patients with diabetes and chronic kidney disease. A small, open-label, non-randomized trial previously showed these agents reduced adipose tissue inflammation and decreased circulating factors produced by senescent cells and studies in mice showed such drugs reduced multiple diabetes-related comorbidities—including brain, kidney, liver, and cardiovascular complications. 

Another study is comparing the effectiveness of dasatinib, quercetin, and the flavonol fisetin in improving the bone health of elderly women. 

Two trials are for COVID-19. One invitation-only, placebo-controlled study is examining the effectiveness of fisetin in alleviating dysfunction and inflammation, and the other placebo-controlled study (not yet recruiting) is testing whether fisetin can prevent an increase in the disease's progression and alleviate complications of coronavirus due to an excessive inflammatory reaction in nursing home patients. 

A small, open-label trial validated preclinical findings that senolytic agents reduce frailty in patients with idiopathic pulmonary fibrosis, a progressive fatal lung disease in the elderly that has no good treatment, Kirkland says. This has led to planning for a multi-center, randomized clinical trial. 

Among the trials soon to begin is one looking at the potential of senolytic agents for people with Alzheimer’s disease, he says. Another, in collaboration with St. Jude, will test the agents in childhood cancer survivors in hopes of preventing senescent cells from causing them to prematurely age as adults. 

Studies of senolytics are underway to investigate their efficacy for treating frailty in older women with a gait of less than 0.6 meters per second, among whom the two-year mortality is almost worse than that of most cancers, Kirkland says. Clinical trials of senolytic drugs have started for a variety of other conditions as well, including people with age-related osteoarthritis and bone marrow transplant recipients at risk of premature aging from the chemotherapy or radiation treatment they received prior to surgery.

A trial is also beginning at Mayo and Harvard to try to improve the function of kidneys from old organ donors so they can be used in younger recipients, Kirkland adds. The studies involve discarded organs, he says. “We aren’t actually transplanting them yet.”