HiTS Seminar: James Kirkland, MD, PhD 10:00 AM, Thursday, December 19, 2019
Noaber Foundation Professor of Aging Research
Director, Mayo Clinic Kogod Center on Aging, Rochester, MN, USA
Aging, Chronic Disease, and Senolytic Agents
Fundamental aging processes
including cellular senescence appear to make a “root cause” contribution to
multiple chronic diseases, geriatric syndromes, and loss of physiological
resilience. Interventions targeting aging 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 aging 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, 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.
10:00 am – 11:00 am
Thursday, December 19, 2019
Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, Room 563
Boston, MA 02115
Hosted by Kenichi Shimada, Ph.D.