Episode 120: Gordon Lithgow on alpha-ketoglutarate’s potential to affect healthspan and lifespan

// Mar 17, 2021

Ever since Cell Metabolism published a study that found the naturally occurring metabolite alpha-ketoglutarate reduces inflammatory signaling as well as chronic inflammation, listeners have been asking Ken and Dawn for their take on the paper. Today, we have the author of the paper, Dr. Gordon Lithgow, as our guest on STEM-Talk. We talk with Gordon in-depth about his study and the potential of alpha-ketoglutarate to have positive effects on lifespan and healthspan.

Gordon is a professor and vice president of Academic Affairs at the Buck Institute in Novato, California, where his research focuses on uncovering genes and small molecules that prolong lifespan through enhanced molecular stability. Today we cover Gordon’s research into alpha-ketoglutarate in the second part of a two-part interview. In part one, episode 119, we asked Gordon about his fascination with C elegans, a microscopic worm that Gordon and other geneticists study and often use for their research. He particularly covered two of his studies involving C elgans: one that looked at the role that protein homeostasis plays in aging;  and another study that found vitamin D3 improves protein homeostasis and slows aging.

A native of Scotland, Gordon researched the biology of aging at the University of Manchester in England before moving to the Buck Institute in 2000. Gordon is married to Dr. Julie Andersen, who was our guest on episodes 117 and 118 and who also is a researcher at the Buck Institute.

Show notes:

00:03:20 Dawn opens part two of our interview with Gordon by mentioning his most recent paper on alpha-ketoglutarate, which has generated a lot of buzz. This study suggests there is a metabolite that one can buy in a health food store that may have a positive effect on lifespan as well as healthspan. Dawn goes on to mention that alpha-ketoglutarate (AKG), is a naturally occurring metabolite. She notes that previous studies on it have shown that blood plasma levels of AKG can drop up to 10-fold as we age. Dawn asks Gordon to explain what AKG is and how it is involved in so many of our fundamental physiological processes.

00:07:41 Ken mentions that in the study, Gordon fed the mice calcium AKG. Ken asks why Gordon chose calcium AKG as opposed to arginine AKG, which is a dietary supplement often used by athletes and bodybuilders to improve their performance and reduce muscle fatigue.

00:09:22 Dawn mentions that when Gordon’s paper came out in Cell Metabolism, Gordon was quoted as saying, “The nightmare scenario has always been life extension with no reduction in disability.” Dawn goes on to state that this study showed that the middle-aged mice who were treated got healthier over time, and that even the mice that died early saw improvements in their health. Dawn asks Gordon to elaborate on this apparent extension in healthspan.

00:12:41 Dawn asks Gordon about the significance of the finding in his study that calcium AKG reduced inflammatory signaling, as well as chronic inflammation, as it relates to degenerative aging.

00:14:57 Ken asks if Gordon’s study has been replicated in any other strains of mice.

00:18:54 Dawn mentions that Ponce De Leon Health, which is based in Florida, is marketing a formulation of calcium AKG under the brand name Rejuvant. She goes on to mention that Gordon and his colleagues at the Buck worked with Ponce De Leon Health to develop the product and that Gordon owns stock in the company. Dawn asks Gordon to give an overview of this partnership and address the concerns that some people may have about a potential conflict of interest.

00:21:17 Ken asks Gordon to explain how the dose of calcium AKG used in the mouse study compares to the dose recommended for humans via the commercial supplement, noting that the dose seems to be substantially and proportionally higher for mice.

00:22:03 Ken asks why Ponce De Leon Health is marketing different formulations of its product for men and women, and what the difference is between the two formulations.

00:24:53 Dawn asks with regard to the consistent positive longevity effects of AKG in C elegans and now mice, if these positive effects are translational to humans.

00:27:39 Ken mentions that there are several biomarkers for determining biological age, and goes on to mention that Ponce De Leon Health distributes a product called “True Age,” a test of biological age based on epigenetic markers. Ken asks if Gordon has any thoughts on this, and what biomarker does he use to evaluate biological age in his research and why.

00:31:09 Dawn mentions that an article published in the Mercury News in San Jose, Calif.,  interviewed a number of scientists who were very impressed by Gordon’s AKG study and its results. A handful of scientists, however, were quoted as saying that while “AKG is likely to be safe, it is possible there are side effects.” Dawn asks Gordon if he knows of any side effects of AKG that people need to be aware of.

00:32:37 Dawn mentions a paper published in Nature communications by Gordon and some international colleagues titled “Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction”which used a genetic model of dietary restriction in C elegans. Dawn goes on to mention that the paper shows that dietary restriction results in increased levels of long chain omega 6 and 3 polyunsaturated fatty acids including linoleic acid and EPA, which are known to signal increased expression of cytoprotective and detox genes that increase lifespan. Dawn asks Gordon to talk about how genetic models of dietary restriction both do and don’t reflect true dietary restriction in animal models and humans.

00:36:01 Ken follows up on the previous question by asking Gordon if he thinks that the metabolic reprogramming seen in the C elegan model gives any insight into how intakes of dietary polyunsaturated fatty acids (PUFAs) might alter health outcomes in humans. Ken goes on to mention that Gordon noted in his paper that supplementing C elegans with monounsaturated fats decreased lipid peroxidation, but exogenous fish oil both increases peroxidation and decreases lifespan. Ken notes that this seems to be in stark comparison to humans, where much time, research and money has been poured into creating various fish oil formulas to improve human health. Gordon provides his thoughts on this matter.

00:39:38 Dawn mentions that when Gordon first joined the Buck institute and started looking at aging and disease, the word geroscience did not exist. She goes on to mention that today there are hundreds of companies around the world devoting themselves to the idea of geroscience. Gordon discusses how he and his colleagues came up with this word and what it refers to.

00:42:07 Dawn says that it is an exciting time to be in the field of aging. She asks Gordon where he thinks the future of aging research is headed, and what are some questions that he and his colleagues at the Buck will be addressing in the years to come.

00:45:31 Dawn closes the interview by mentioning that Gordon’s wife, Julie Andersen (episodes 117 and 118), said Gordon was the cook in the house. Dawn goes on to note that she understands Gordon makes a turmeric curry about every week. Dawn asks if there is any special reason for this fondness of curry, and why the choice of turmeric.


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