Ageing Research at King’s (ARK) Special Guest Lecture:
Ageing, Chronic Disease, and Senolytic Agents
Speaker: James L. Kirkland, Noaber Foundation Professor of Aging Research, Director, Mayo Clinic Kogod Center on Aging, Rochester, MN, USA
Fundamental ageing processes including cellular senescence appear to make a “root cause” contribution to multiple chronic diseases, geriatric syndromes, and loss of physiological resilience. Interventions targeting ageing processes such as cellular senescence hold the potential to enhance healthspan by delaying, preventing, or alleviating age-related diseases and conditions as a group, instead of one-at-a-time, the “geroscience hypothesis.” Senescent cells accumulate in many tissues with ageing and at sites of etiology of numerous chronic diseases. Senescent cells are resistant to apoptosis. They can release a range of factors that are pro-apoptotic, pro-inflammatory, cause stem cell dysfunction, disrupt tissues, and spread senescence to normal cells, the senescence-associated secretory phenotype (SASP). Transplanting small numbers of senescent cells around the knees of young mice caused osteoarthritis. Transplanting small numbers of senescent cells into the abdomen of young mice, so that only 1/10,000 cells in the recipients are transplanted senescent cells, is sufficient to cause frailty, the accelerated onset of age-related chronic diseases, and early mortality.
We developed senolytic agents ‒ drugs that selectively clear senescent cells by inhibiting the pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) that prevent these cells from being cleared by apoptosis caused by their own SASP. Intermittent administration of senolytic agents reduced frailty and neuromuscular dysfunction in progeroid mice, enhanced cardiac function in old mice, alleviated Alzheimer-like changes in Tau+ mice, alleviated bleomycin-induced pulmonary fibrosis, reduced age, high fat diet, and shear stress-related vascular dysfunction, restored hepatic function and reduced liver fat and fibrosis in diet-induced liver steatosis, alleviated dysfunction caused by radiation in mice, and restored bone mass and strength by reducing resorption without impeding bone formation in age-induced osteoporosis. Senolytics prevented the frailty, accelerated chronic disease onset, and early death caused by transplanting senescent cells into younger mice. In old mice, senolytics improved physical function, delayed age-related diseases, and extended remaining lifespan by 36%. Thus, senolytics hold promise for delaying, preventing, or treating multiple age- and chronic disease-related disorders if they are safe and effective in humans. Frameworks will be considered for proof-of-concept and later-stage trials of senolytics for targeting age-related chronic diseases, geriatric syndromes, and resilience to stressors.
Speaker bio: James L. Kirkland is Noaber Foundation Professor of Aging Research and Director, Robert and Arlene Kogod Center on Ageing at the Mayo Clinic, Minnesota, USA. The major research focus of his lab is the impact of cellular ageing (senescence) on age-related dysfunction and chronic diseases, especially developing methods for removing these cells and alleviating their effects. Senescent cells accumulate with ageing and in such diseases as dementias, atherosclerosis, cancers, diabetes and arthritis. The goal of Dr Kirkland's current work is to develop methods to remove these cells to delay, prevent, alleviate or partially reverse age-related chronic diseases as a group and extend healthspan, the period of life free of disability, pain, dependence and chronic disease.