Science is on the cusp of realizing an age-old ambition: to impede or reverse the hands of time. Cedars-Sinai’s new Center for Advanced Gerotherapeutics houses investigations exploring the biological aging process and medications that could slow its pathological elements long in advance of disease and death.

The center, launched with the recruitment of its director James Kirkland, MD, PhD—a founder of the rapidly emerging field of senolytics—advances Cedars-Sinai’s burgeoning geroscience enterprise alongside the Center for Translational Geroscience and Center for Diabetes and Aging. Expert investigators are leveraging robust networks of molecular and biotechnology tools, advanced computing, and AI to reveal the mysteries of cellular senescence. Their collective efforts are building a formidable landscape of research that could upend aging as we define it today.

Ongoing trials harness escalating knowledge of how cells decay throughout our lives to regain control over the most urgent diseases of aging, including Alzheimer’s disease, cancer, diabetes, and diseases of the heart, skin, kidney, lung, liver, eye and bone. Researchers will match patients with their safest, most effective gerotherapeutics.

"Ultimately, we wish to delay, prevent, alleviate or treat multiple disorders at once," Kirkland said. "If these interventions work, they could impact many medical disciplines."

At Cedars-Sinai, Kirkland continues pioneering work developing novel therapies and refining the first generation of senolytics, including fisetin, dasatinib and quercetin. These drugs directly eliminate stubbornly resilient senescent cells that amass in skin, bone, heart and brain tissues. The cells accumulate throughout older and even younger adults’ bodies, especially in those who are immunocompromised, have diabetes, are overweight, or have undergone chemotherapy or radiation. In a 2020 report in the Journal of Internal Medicine, Kirkland found that approximately 30% to 70% of senescent cells are destructive to surrounding tissues and trigger inflammation and fibrosis.

Senolytics have shown promise in reducing senescent cell burden, improving symptoms, and stalling onset or progression of more than 70 age-related conditions, even the most fatal and serious. These drugs can be dosed periodically because of the time it takes for the age-damaged cells to develop and build up again between treatments.

In a landmark 2018 study, Kirkland and center co-director Tamar Tchkonia, PhD, led a team of researchers who determined that the presence of even one transplanted senescent cell in 10,000 cells caused frailty and younger onset of all natural causes of death in mice. Further, they found that combining dasatinib and quercetin (D+Q)—a regimen discovered by Kirkland’s team—successfully removed highly resistant senescent cells without serious off-target effects, curbing cellular deterioration and frailty to improve healthspan and lengthen lives.

The body of evidence supporting the use of senolytics is accelerating faster than Kirkland expected, with human benefits coming into view. As principal investigator of the Translational Geroscience Network, he is ushering the international consortium through nearly 90 active clinical trials. In December 2024, the collaborators found in a pilot study that a six-week regimen of D+Q significantly bolstered cognition in older adults with mild cognitive impairment and slow gait.

In a paper in Nature Medicine, UNITY Biotechnology investigators found a high volume of senescent cells in the retinas of patients with diabetes-induced vision loss and supported the use of UBX1325, another senolytic. Kirkland and Tchkonia’s recent research sheds new light on how senescence impacts the structure of blood, fat, skin, bone and other cells, including tissue integrity and rigidity. Their insights could guide tissue-preserving treatments for conditions such as age-related osteoporosis.

Investigators are also eyeing senolytic combinations to enhance effects of existing, disease-specific treatments, as well as innovative anti-inflammatory agents and immune-modulating drugs and immunotherapies that more precisely target cell surface molecules highly released during senescence. The molecularly targeted therapy could reduce the risk of toxic side effects in some patients.

Therapies such as the common diabetes drug metformin, ruxolitinib (a treatment for a rare bone marrow disorder) and rapamycin (an antifungal frequently used to suppress the immune system) are senomorphic: They potentially suppress secreted pro-inflammatory proteins to strengthen metabolism and extend both health and life.

Sara Espinoza, MD, director of the Center for Translational Geroscience, conducted the first randomized, controlled trial of metformin in older adults for an aging indication. The study builds on her earlier research into metformin’s ability to prevent frailty among older adults who have prediabetes, exploring the drug’s influence on senescence, mitochondrial function and other “pillars of aging.” In turn, investigators will connect the dots between those hallmarks and healthspan measures such as physical function, muscle strength and cognition.

Tchkonia, who oversees the gerotherapeutic center’s Facility for Geroscience Analysis, is examining samples from ongoing geroscience research across Cedars-Sinai and the global Translational Geroscience Network. The facility is centering its efforts on biomarkers indicative of aging processes such as senescence, epigenetic changes and mitochondrial dysfunction.

The establishment of biomarkers in the blood, urine, saliva, hair, fingernails, or microbiome or by imaging would enable investigators to identify populations best suited to specific therapies. Biomarkers could also help clinicians create diagnostic tools to better prescribe individualized care based on underlying aging mechanisms.

Tchkonia is attempting to identify signals suggestive of aging, independent of the condition and intervention. Her lab has quickly narrowed down from over 200 molecular and cellular biomarkers to 100 tests of proteins, nucleotides and senescent cells. Higher levels of certain proteins are linked to senescence, depending on the cell and tissue type, as well as cancer and many other serious conditions.

This approach to simultaneously treat multiple illnesses through shared pathways “requires a complete rethink,” Kirkland emphasized, central to measuring the drugs’ impact.

"These fundamental aging processes are interconnected,” Tchkonia said. “If you manipulate one, you effectively impact others, too."

Approximately 80% of adults above age 65 worldwide develop at least one chronic condition, such as arthritis, diabetes and dementia. More than half of those age 60 and older have multiple illnesses. By 2050, current models foresee the number of U.S. adults age 50 and older with more than one chronic disease swelling by more than 90% to nearly 15 million people. Researchers have begun building a clinical trial paradigm that includes them, by design.

"Clinical trials are overwhelmingly conducted in middle-age people who have just one condition and are otherwise healthy, and they evaluate one outcome, but that’s not the real world," Kirkland said.

Cooperative studies focus on diabetes, dementia, and other diseases of aging and geriatric syndromes. Kirkland and Tchkonia collaborated with Mitzi Gonzales, PhD, director of Translational Research in the Jona Goldrich Center for Alzheimer’s and Memory Disorders, and Diabetes and Aging Center Director Nicolas Musi, MD, on among the first human studies of senolytics. Their study in Alzheimer’s disease found that dasatinib safely penetrated the central nervous system in early-stage Alzheimer’s patients, while a trial in idiopathic pulmonary fibrosis (IPF) found signs of improved physical function and alterations in senescent secretion.

Investigators are studying lifestyle interventions to modulate aging, as well. In a large federally funded trial, Musi, who is the Kathi and Gary Cypres Chair in Diabetes Research at Cedars-Sinai, is delving into whether clearing senescent cells through exercise and nutrition could aid in glucose metabolism and physical function, while Gonzales and Espinoza are beginning to untangle the effects of intermittent fasting on brain health.

"We want to cover the bases from preclinical development of potential interventions in the laboratory to applications in the gym and for clinical trials," Espinoza said.

Looking to the future, gerotherapeutic leaders are planning senolytic approaches in cancer, which affects approximately 17.4 million people in the U.S. and is among the most prevalent fatal diseases of aging. Kirkland and Tchkonia plan to test new medications in adaptive trials for the most severe, treatment-resistant forms of cancer, including glioblastoma and triple-negative breast cancer, sequenced with chemotherapy and radiation.

Another research emphasis is the potential of senolytics to unburden the U.S. organ shortage. More than 24,000 kidneys are discarded annually, in large part due to the older age of donors. Preclinical and animal findings suggest the drugs can rehabilitate aged hearts, kidneys, livers and other organs. If the benefits translate, physicians could quickly make more organs viable for transplant and reduce the three- to five-year average wait for kidneys for over 100,000 individuals in the queue.

The center intends to launch clinical trials into cancer and organ preservation in the coming years. Additionally, they are poised to explore senolytics alongside antifibrotic drugs in systemic scleroderma—a severe autoimmune condition survived by just half of patients, on average—along with other forms of fibrosis, including IPF and heart failure associated with cardiovascular fibrosis.

"There needs to be a long-term, in-depth view," Kirkland said, "not just the one-year horizon, but for the next five, 10 and 20 years."