Episode 122: James Kirkland on targeting senescent cells to reverse age-related diseases

STEM-Talk

In today’s episode, we talk about zombie cells, a term used to describe senescent cells because of their refusal to die. Our guest on this topic is Dr. James Kirkland, a geriatrics specialist and researcher at the Mayo Clinic in Rochester, Minnesota, who is known for his research into the role that senescence and senescent cells have on age-related dysfunction and chronic disease.

As senescent cells build up in the body, they promote cellular aging and a host of chronic conditions related to aging, such as dementia, cancer, atherosclerosis, diabetes and arthritis. In today’s interview, we focus on Jim’s 2015 study where he and his colleagues at Mayo were the first to report on the potential of senolytic drugs to selectively kill zombie senescent cells. Jim’s paper in Aging Cell has been hailed as a major breakthrough in aging research.

Jim is the director of the Robert and Arlene Kogod Center of Aging at Mayo and the president of the American Federation for Aging Research. The goal of James’ lab and research is to develop methods to remove senescent cells to delay, prevent, alleviate or partially reverse age-related chronic diseases. Jim and his colleagues believe that doing this will help extend people’s health span, and, more important, prolong the period of life where people can live free of disabilities caused by chronic disease.

Show notes:

00:03:20 Jim starts the interview talking about growing up in Canada.

00:03:31 Dawn asks him when he became interested in science.

00:04:05 Ken mentions that he understands that Jim had an interest in becoming a physician at a very early age, and given Jim’s previous comments, asks if it was Jim’s childhood observations of his grandparents’ aging that drove his interest in geriatrics.

00:04:39 Dawn asks how Jim ended up at the University of Toronto.

00:04:51 Dawn mentions that Jim received his medical degree in 1977 and completed his residency at Toronto General Hospital. Dawn goes on to ask why, after this, did Jim decide to go overseas to study at the University of Manchester.

00:05:37 Dawn mentions that after Jim’s experience in Manchester, he moved back across the Atlantic to work at the National Institutes of Health (NIH), where he mainly studied adipose tissue.

00:06:11 Dawn asks what role Jim’s research at NIH played in his Ph.D., which he earned from the University of Toronto in 1990.

00:07:19 Dawn mentions that in 2007 Jim became the director of the Kogod Center on Aging at the Mayo Clinic and asks how Jim ended up at that position.

00:07:54 Dawn asks Jim to clarify the difference between lifespan and healthspan.

00:09:26 Ken mentions that Jim’s research throughout his career has focused on cellular aging and senescent cells. Ken asks what initially triggered Jim’s interest in senescence.

00:11:42 Dawn mentions Jim’s 2015 paper in Aging Cell, where Jim and his colleagues at the Mayo Clinic were the first to report on the potential of senolytic drugs, which selectively kill senescent cells. Dawn goes on to ask Jim about his research leading up to this breakthrough paper.

00:14:47 Dawn asks Jim to talk about two senolytic compounds that he and his colleagues identified called dasatinid and quercetin, and what the significance of their discovery is.

00:17:20 Ken mentions the senolytic agent called fisetin, which is another agent showing benefit in rodent studies and is now being used in human clinical trials. Ken mentions that some authors have described fisetin as having roughly twice the senolytic potency as quercetin. Ken asks Jim to explain where fisetin fits into the senolytic landscape.

00:19:18 Dawn mentions that Jim began his aforementioned 2015 paper by writing about how the research shows that the healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Jim goes on in that paper describing how a series of experiments by he and his colleagues demonstrated the efficacy of senolytics to alleviate symptoms of frailty and extend health span. Dawn asks Jim to explain the process and results of these experiments.

00:22:13 Dawn mentions that not only did Jim’s findings support the idea that senescent cells could one day be used for treating cardiovascular disease and frailty, but also raised the possibility that these agents have the potential to target a multitude of disorders. Dawn asks Jim to explain this potential and why he believes that the clinical application of senolytic agents could be transformative.

00:24:31 Dawn explains that Jim followed up on his 2015 paper with a clinical trial involving a small group of diabetic kidney patients. This trial led to the publishing of “Senolytics Decrease Senescent Cells in Humans” in The Lancet. Jim explains how this study was designed.

00:27:38 Ken brings up Jim’s 2018 paper in Nature Medicine titled “Senolytics improve physical function and increase lifespan in old age.” Ken asks Jim to describe how he was able to demonstrate that with senolytic drugs he could delay the onset of virtually all age-related diseases that kill mice.

00:31:52 Dawn mentions that despite the promising potential of senolytic drugs, Jim cautions that there could be dangerous side effects, and that people should not be taking these drugs yet. Jim explains his safety concerns, as well as his estimated length of time it will take to test the safety of such anti-aging drugs.

00:33:42 Ken mentions that some STEM-Talk listeners have been experimenting with fisetin on themselves, using the Mayo protocol, which involves taking 20 mg/kg body weight of oral fisetin on two consecutive days and repeating the same dose, one month later. Ken asks if this is the same protocol used in the human clinical trials of fisetin.

00:36:02 Dawn mentions that diabetes and obesity are also associated with the accumulation of senescent cells in fat and other tissues. She mentions that Jim’s paper in Aging Cell in 2019 implicated cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements. Jim explains how he was able to demonstrate that senolytic agents show promise in terms of treating obesity-related metabolic dysfunction and its complications.

00:37:59 Jim talks about a more recent paper he published in Nature Communications that explored the possibility of transplanting organs from older doners to younger recipients. In this study Jim did heart transplants from old mice to young mice as well as young mice to old mice. Jim explains what he found in this study and what its potential significance is.

00:41:39 Ken mentions that Jim’s lab has a number of human clinical trials underway and asks Jim to share the range of conditions which these trials are reviewing.

00:43:36 Ken explains that at IHMC researchers are very interested in skeletal muscle, both in the context of aging and human spaceflight. Ken talks about the declines in physical functioning Jim mentioned in his aforementioned 2018 paper. Ken wonders if after transplantation of senescent cells into mice, if there were a direct or local role for senescence in skeletal muscle cells in the mechanisms of frailty with aging. If so, Ken asks if there is any evidence so far that specific tissues can be targeted with senolytics.

00:45:27 Ken asks if senescence plays a possible role in muscle atrophy associated with human spaceflight.

00:46:49 Ken asks if bedrest increases senescence.

00:48:28 Dawn mentions that Jim’s 2017 paper in the Journal of American Geriatrics Society titled “The Clinical Potential of Synolytic Drugs” is a good primer for those listeners interested in learning more about these agents. Dawn mentions that since this paper is more than four years old, she wonders if there is anything new Jim would add to it.

00:51:26 Dawn closes the interview asking if Jim feels good about the work his lab is doing and if he feels like he is making progress toward his goal of slowing down and even reversing the symptoms of aging.

Links:

James Kirkland bio

Robert and Arlene Kogod Center of Aging

Mayo Clinic

Learn more about IHMC

STEM-Talk homepage

Ken Ford bio

Ken Ford Wikipedia page

Dawn Kernagis bio