Episode 173: Anurag Singh on urolithin-A’s ability to optimize mitochondrial efficiency

Our guest today is Dr. Anurag Singh, the chief medical officer at Timeline Nutrition, a Swiss life-science company that focuses on ways to improve mitochondrial and cellular health. Anurag is particularly known for his research into the gut metabolite, urolithin-A, which has been shown to improve muscle strength, protect immune systems and optimize mitochondrial efficiency.

Anurag is an MD in internal medicine with a Ph.D. in immunology. He has led more than 50 randomized clinical trials, many of them focusing on urolithin-A over the past decade.

In today’s episode we talk to Anurag about his investigations into urolithin-A and the role it plays as a postbiotic that enhances mitochondrial function. Foods that contain the polyphenols needed to produce urolithin-A include pomegranates, strawberries, raspberries and walnuts.

Show notes:

[00:02:48] Marcas starts the interview by mentioning that Anurag grew up in India, in Lucknow, and asks what Anurag’s childhood was like.

[00:03:56] Marcas follows up, asking Anurag what he was like as a kid, given the competitive environment he grew up in.

[00:04:47] Ken asks Anurag if it is true that, at an early age, his parents noticed he was gifted in biology and encouraged him to think about pursuing medical school.

[00:05:47] Ken asks if Anurag started medical school at only 18 years of age.

[00:06:28] Marcas explains that Anurag went to India’s Armed Forces Medical College for training in internal medicine and asks if it is true that this is one of India’s top medical schools.

[00:07:07] Marcas explains that it is typical for graduates from the India Armed Forces Medical College to serve a few years in the Indian army after graduation. Marcas asks Anurag to tell the story of how he was able to go to the U.S. post-graduation rather than serving time in the army.

[00:08:00] Ken asks if Anurag’s interest in medical research led him to pursue a Ph.D. in immunology.

[00:08:56] Ken asks Anurag what his Ph.D. research was on.

[00:09:37] Marcas mentions that in 2009, Anurag accepted a position at Nestlé at a time when the company was entering into the space between food and pharma. Marcas asks Anurag how this move came about.

[00:11:20] Ken explains that Anurag quickly became medical director at Nestlé and started initiating clinical trials around food and allergies, as well as research on aging and how the immune system declines with age. Ken asks Anurag to explain what his time at Nestle was like.

[00:12:53] Marcas mentions how the shift from practicing physician to research scientist is an interesting course and asks Anurag to talk about a mentor who gave him the advice that led to his career shift.

[00:13:55] Ken mentions that in 2014 Anurag joined a Swiss company, Amazentis, as chief medical officer, and later became the lead for their medical and clinical research strategies. Ken asks Anurag to talk about the company and the work he does.

[00:15:00] Ken asks Anurag to describe the relationship between Amazentis and Timeline.

[00:15:42] Marcas asks Anurag to elaborate on his biotech approach to nutrition science, and how hard biology is used in his nutritional approaches at Amazentis.

[00:18:02] Marcas asks Anurag to give listeners an overview of the function and importance of mitochondria.

[00:19:15] Ken asks Anurag if there are any other benefits to good mitochondrial health, other than an increased energy supply.

[00:20:24] Ken asks Anurag to define the terms “mitochondrial biogenesis” and “mitophagy.”

[00:22:13] Marcas pivots to discuss age-related frailty and healthspan, specifically bringing up a study Anurag conducted on a Dutch population comparing active seniors to sedentary seniors.

[00:25:09] Ken mentions that Marcas likes to refer to exercise as medicine, given its potent effects on a wide variety of biomarkers. Ken asks Anurag to discuss the importance of exercise.

[00:26:59] Following up on the Dutch study, Marcas mentions that there is an explosion of research into healthspan, resilience, and even lifespan, and asks Anurag to discuss the core principles of healthy aging.

[00:29:14] Ken asks Marcas to give a brief aside as to the capacity, capabilities, and aims of IHMC’s new Healthspan Resilience and Performance complex.

[00:31:36] Ken mentions that poor metabolic health continues to be a growing global issue. Ken asks Anurag to share his thoughts on the issue.

[00:33:25] Marcas circles back to Anurag’s work at Timeline investigating natural compounds that target mitochondrial health. Marcas notes that Anurag and his colleagues found that urolithin-A outperformed every other molecule tested with respect to mitochondrial health. Urolithin-A is a natural compound produced by gut bacteria from metabolizing ellagitannins and ellagic acid, complex polyphenols found in foods such as pomegranates berries and nuts. Marcas asks Anurag to explain what these compounds are in detail.

[00:35:25] Marcas asks if there are lifestyle changes one can make to improve their gut microbiome population to increase how much urolithin A one can pull from food sources.

[00:37:07] Ken asks, assuming the hypothetically perfect microbiome and the perfect ellagitannin conversion, if it is possible through diet alone to produce enough urolithin A to observe considerable benefit.

[00:38:51] Marcas asks if any factors, other than chronic antibiotic use, have been shown to negatively affect the gut microbiome and its ability to produce urolithin-A.

[00:41:09] Marcas moves on to discuss Anurag’s 2016 paper titled “Urolithin-A induces mitophagy and prolongs lifespan in c-elegans and increases muscle function in rodents” Marcas asks Anurag to discuss the origins of this paper and the impact of its findings.

[00:44:18] Ken asks if the professor that Anurag partnered with on his 2016 paper ever investigated rapamycin as opposed to metformin.

[00:45:08] Ken asks if the primary mechanism of action regarding urolithin-A’s effect on mitophagy is known or if we have only seen a strong association with other mechanisms of mitophagy and autophagy.

[00:46:14] Marcas explains that in the progression of aging and a sedentary lifestyle, there is a decline in a cell’s ability to eliminate dysfunctional elements through autophagy and mitophagy. This decreased capacity specifically in skeletal muscle has been associated with poor muscle health and quality in older adults. Marcas asks about a 2019 paper Anurag wrote that detailed the results of his first human clinical trial in which he administered urolithin-A to sedentary but otherwise healthy adults.

[00:49:35] Marcas mentions that exercise also activates mitophagy, and asks if there are any key cellular, or mechanistic, differences between exercise and urolithin-A in their effects on mitochondrial health.

[00:50:49] Ken mentions that Anurag’s research on urolithin-A led to the development of Mitopure, which is the first postbiotic nutrient that has been shown to trigger mitophagy by targeting cellular decline. Ken goes on to mention that in 2022, Anurag published the paper “Urolithin-A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle aged adults” in which subjects were given oral doses of Mitopure. Ken asks Anurag to discuss this paper and its findings.

[00:54:37] Ken asks Anurag to discuss the specific contents of each package of Mitopure.

[00:56:19] Ken mentions that many therapies targeting mitochondrial health seem to only be effective when there is some defect or problem with the mitochondria. Ken asks Anurag’s why it seems that mitochondrial therapies can only return mitochondrial functioning to baseline rather than increase performance above baseline.

[00:58:15] Maras asks Anurag if he thinks that Mitopure is best used as a supplement to healthy lifestyle choices such as exercise, rather than a replacement for them.

[00:59:42] Ken pivots to talk about the sources of urolithin A, one of which being Iberian pigs, which consume a diet almost exclusively of acorns, which are rich in ellagitannins. Ken asks if the urolithin-A in Iberian pigs can be found in the ham meat itself.

[01:01:45] Marcas mentions Anurag’s paper published in the journal Aging Cell, which showed that Mitopure supplementation had potential to improve mitochondrial functioning in human cartilage. In this study, Anurag demonstrated that Mitopure supplementation for eight weeks, protected against osteoarthritic disease progression. Marcas asks Anurag to talk about this potential.

[01:04:03] Ken mentions that much of the research on urolithin-A has been conducted on its effects on skeletal muscle; however, urolithin-A also would be expected to have effects on other mitochondrially dense tissue as well. Ken asks if there has been any research on urolithin-A’s effects on tissues like liver or cardiac tissue.

[01:06:23] In response to Anurag mentioning the Buck institute’s research with urolithin-A, Ken mentions that we discussed urolithin-A at length with Buck institute researcher Julie Andersen on episode 118.

[01:07:34] Moving on to Anurag’s current research, Marcas asks about a randomized controlled trial in collaboration with the Buck Institute to see if urolithin-A can improve the immune health of middle-aged adults by improving mitochondr