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Do you know what senescent (zombie) cells are and how cellular senescence and senolytics impact health? In this episode of Longevity by Design, hosts Ashley Reaver and Dr. Gil Blander are joined by Dr. James Kirkland from the Mayo Clinic, one of the world's leading figures in aging research. This episode is a deep dive into aging research, cellular senescence, and senolytics. Dr. Kirkland discusses the impact of cellular aging (senescence) on healthspan and his discovery of the first senolytic agents that remove senescent cells and extend healthspan, illuminating his pioneering work in aging research.
Dr. Kirkland shares insights into the science of cellular senescence and how targeting these cells could revolutionize the treatment of age-related chronic diseases. He sheds light on the mechanisms behind senolytics and their promise for extending healthspan. The conversation also touches on the importance of lifestyle factors like diet and exercise in managing senescent cells.
Dr. Kirkland also discusses geroscience, a research paradigm that seeks to understand the mechanisms that make aging a major risk factor for and driver of common chronic conditions and diseases of older people. This knowledge can be used to slow the rate of aging, reverse its effects, delay or even cure age-related diseases, and extend healthspan. The conversation also highlights the emerging evidence and potential of using gerotherapeutics (treatments) that target aging biology to combat aging-related diseases and increase healthspan and lifespan. Dr. Kirkland also covers the challenges and opportunities in translating these scientific discoveries into clinical applications, emphasizing the critical role of interdisciplinary efforts in advancing our understanding and management of aging.
This is an enlightening episode with Dr. Kirkland on aging research and the opportunities to revolutionize healthcare by combating aging-related diseases and increasing people’s healthspan and lifespan.
Episode highlights
James L. Kirkland, M.D., Ph.D., is the Noaber Foundation Professor of Aging Research at Mayo Clinic and a board-certified specialist in internal medicine, geriatrics, and endocrinology and metabolism. Dr. Kirkland’s research is on the contribution of fundamental aging processes, particularly cellular senescence, to age-related chronic diseases and development of gerotherapeutics: agents and strategies for targeting fundamental aging mechanisms to treat age-related diseases and conditions. Dr. Kirkland's journey into geriatrics and the biology of aging began at a young age, with his first memory being of his grandfather looking down at him. This early connection sparked a lifelong interest in understanding the clinical and research aspects of the aging process.
Dr. Kirkland’s laboratory published the first article about agents that selectively eliminate senescent cells—senolytics. Dr. Kirkland demonstrated that senolytic agents enhance healthspan and delay, prevent, or alleviate multiple age-related disorders and diseases in mouse models. He published the first composite biomarker gerodiagnostic score of senescent cell burden that is sensitive to drug interventions in humans and the first clinical trials of senolytic drugs. He is preparing or conducting clinical studies of senolytics, including for COVID-19, frailty in elderly women, Alzheimer’s disease, diabetes/obesity, osteoporosis, childhood cancer survivors, restoring function of organs from old donors to enable transplantation, idiopathic pulmonary fibrosis, pre-eclampsia, glioblastoma, and others.
Dr. Kirkland is Principal Investigator of the Translational Geroscience Network, which brings together multiple academic institutions in the US to translate healthspan interventions, including senolytics and other drugs that target fundamental aging processes. He is also the President of the American Federation for Aging Research (AFAR).
At the core of Dr. Kirkland's work are the "fundamental aging mechanisms" or "pillars of aging"—a set of interrelated processes that begin at or before conception and can drive a wide range of acute and chronic conditions across the lifespan. These include cellular senescence, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
When these fundamental aging processes are accelerated, often due to factors like family history, radiation exposure, obesity, diabetes, or stress, they can channel through these various pillars and result in the development of multiple age-related diseases and conditions simultaneously—a phenomenon known as "multimorbidity." This underscores the importance of targeting the root causes of aging rather than simply treating individual diseases as they arise.
This has led to the emergence of geroscience, a research paradigm that seeks to understand the mechanisms that make aging a major risk factor for and driver of common chronic conditions and diseases of older people. This knowledge can be used to slow the rate of aging, reverse its effects, delay or even cure age-related diseases, and extend healthspan. As a result, this has subsequently led to the coining of the term “gerotherapeutics” for the use or development of agents and strategies that target fundamental aging mechanisms to prevent or delay multiple diseases and extend healthspan and lifespan with a single therapy.
One of the key areas of focus in Dr. Kirkland's research is on the role of cellular senescence and "senolytics"—agents that selectively eliminate senescent cells. While cellular senescence was first described decades ago, in 1961, by Leonard Hayflick and Paul Moorhead, it wasn't until more recently that researchers began to unravel the profound implications of these cells. Senescent cells are cells that have lost the ability to divide further and have mechanisms to resist cell death and removal from the body and tend to increase with age. However, far from being inert, these cells produce various factors, known as the senescence-associated secretory phenotype (SASP), that can have both local and systemic effects.
The SASP is characterized by the secretion of a complex mixture of proteins, peptides, and other bioactive molecules that can profoundly impact the surrounding tissue environment and even have systemic effects throughout the body. The nature of the SASP varies depending on the type of cell that became senescent, how long it has been senescent, and what triggered the senescence process—be it repeated cell division, mechanical stress, high blood sugar levels, or exposure to radiation or chemotherapy.
Some of the factors secreted by senescent cells can be beneficial, such as temporarily reinforcing the senescence growth arrest in nearby cells to prevent the development of cancer. However, many of the SASP components are pro-inflammatory and can negatively impact neighboring cells and tissues.
Importantly, while senescent cells are relatively rare even in aged tissues, their ability to spread throughout the body allows them to exert outsized local and systemic influences, Dr. Kirkland explained. This means that even a small number of senescent cells can contribute to chronic inflammation, tissue dysfunction, and the development or progression of various age-related diseases. The systemic impact of the SASP helps explain the development of multimorbidity.
While senescent cells play important roles, such as in cancer prevention, wound healing, embryonic development, and giving birth, their accumulation can also contribute to a wide range of age-related diseases. Dr. Kirkland's laboratory was the first to identify senolytics and publish research on them. They discovered that by temporarily disabling the defense mechanisms of senescent cells, they could selectively eliminate the senescent cells that were causing damage while leaving non-senescent cells unharmed. "Senolytics don't kill every senescent cell. They only kill the senescent cells that are doing damage. They only kill the ones that are producing factors that are damaging cells around them by taking away their ability, the senescent cells' ability, to resist those factors", explains Dr. Kirkland.
One of the earliest and most well-studied senolytics is a combination of the natural products quercetin and dasatinib. Quercetin is a flavonoid found in fruits and vegetables, while dasatinib is a chemotherapy drug initially developed to treat certain leukemias. Together, this senolytic cocktail targets multiple pro-survival pathways in senescent cells. Other examples of senolytics are compounds like the cancer drug navitoclax and fisetin, a natural product found in strawberries, cucumbers, and other plants, is another example of a senolytic. Additionally, exercising and eating a healthy diet are important factors that can also have a senolytic effect and reduce or prevent the accumulation of senescent cells. Beyond these examples, many other potential senolytics are being explored, including natural products, repurposed drugs, and new chemical entities.
Senolytics work through diverse mechanisms, targeting different defense mechanisms of a senescent cell. Sometimes a combination of products is required to have a senolytic effect. However, senescent cells have varying defense mechanisms depending on their tissue of origin and the triggers that induced senescence. Because of this, not all senolytics will eliminate all of the same senescent cells, and a combination of senolytics may be required.
A cell can become senescent quickly because of infection, chemotherapy, or radiation, but under normal circumstances, it takes between one to six weeks. For this reason, and because senolytics act quickly to eliminate senescent cells, studies have shown that everyday treatment using senolytics is not required and is effective when administered intermittently. For example, administering a senolytic one time per month for three consecutive days is one such protocol shown to be effective for eliminating senescent cells.
The ability of senolytics to delay, prevent, or alleviate multiple age-related disorders and diseases in animal models and initial trials in humans looking at safety and efficacy has been promising. Some examples of the first Dr. Kirkland and his team are now conducting a range of human clinical trials to explore further the effects of senolytics on conditions such as COVID-19, frailty, Alzheimer's disease, cardiovascular disease, diabetes, and various types of cancer, among others.
While the initial findings on senolytics and other gerotherapeutics are exciting, Dr. Kirkland cautions that translating these results to humans is a complex and challenging process. He emphasized the importance of personalized approaches, the need for reliable biomarkers, an interdisciplinary approach, and the appropriate navigation of regulatory and ethical considerations.
To help address these challenges, Dr. Kirkland is the principal investigator of the Translational Geroscience Network, a collaborative effort that brings together multiple academic institutions to support the translation of healthspan interventions, including senolytics and other drugs targeting fundamental aging processes. The network provides guidance on trial design, coordinates sample analysis and data management, and works to establish standardized procedures and biorepositories to support the broader research community.
As researchers continue to unravel the mechanisms of aging, the potential impact of successful gerotherapeutic interventions could be profound. Dr. Kirkland speculated that, if proven safe and effective, these treatments could transform healthcare in ways even more profound than the introduction of antibiotics. While he acknowledges the significant challenges ahead, he remains cautiously optimistic about the future, urging continued investment and a multidisciplinary approach to this critical field of research.
The insights shared by Dr. James Kirkland in this podcast episode highlight the exciting frontiers of aging research and the promise of targeting cellular senescence and fundamental aging processes to improve healthspan. As we navigate the complexities of translating these findings to the clinic, the work of the Translational Geroscience Network and the dedication of researchers like Dr. Kirkland offer promise for a future where we can delay, prevent, and alleviate the age-related diseases that impact so many lives and extend healthspan and lifespan.
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