Episode 59: Stephen Cunnane discusses the role of ketones in human evolution and Alzheimer’s

// Mar 13, 2018

Nearly five million people in the United States have Alzheimer’s disease. In 30 years, that number is estimated to be 16 million

In today’s episode, Ken and Dawn interview Dr. Stephen Cunnane, a Canadian physiologist whose extensive research into Alzheimer’s disease is showing how ketones can be used as part of a prevention approach that helps delay or slow down the onset of Alzheimer’s.

Cunnane is a metabolic physiologist at the University of Sherbrooke in Sherbrooke, Quebec. He is the author of five books, including” Survival of the Fattest: The Key to Human Brain Evolution,” which was published in 2005, and “Human Brain Evolution: Influence of Fresh and Coastal Food Resources,” which was published in 2010.

He earned his Ph.D. in Physiology at McGill University in 1980 and did post-doctoral research on nutrition and brain development in Aberdeen, Scotland, London, and Nova Scotia. From 1986 to 2003, he was a faculty member in the Department of Nutritional Sciences at the University of Toronto where his research focused on the role of omega-3 fatty acids in brain development and human health. He also did research on the relation between ketones and a high-fat ketogenic diet on brain development.

In 2003, Dr. Cunnane was awarded a senior Canada Research Chair at the Research Center on Aging and became a full professor at the University of Sherbrooke. He has published more than 280 peer-reviewed research papers and was elected to the French National Academy of Medicine in 2009.


Lower Brain 18F-Fluorodeoxyglucose Uptake:

Castellano et al AD dPET J Alz Dis 2015

Brain glucose and acetoacetate metabolism:

Nugent et al dPET YE Neurobiol Aging 2014

Energetic and nutritional constraints on infant brain development:

Cunnane & Crawford J Human Evol 2014

Inverse relationship between brain glucose and ketone metabolism in adults:

Courchesne-Loyer et al PET KD JCBFM 2016

A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults:

Croteau et al. AD MCI CMR Exper Gerontol 2017

A 3-Month Aerobic Training Program Improves Brain Energy Metabolism in Mild Alzheimer’s Disease:

Castellano et al. exercise ketones JAD 2017

Show notes:

3:33: Dawn mentions that Stephen was born in London but that his family emigrated to Canada when he was an infant. She asks him about growing up in a suburb of Montreal.

4:02: Ken mentions that he has been told by a reliable source that as soon as Stephen got into high school he spent a lot of time in the chemistry lab, where sometimes created mischief.

4:58: Dawn asks if it is true that Stephen nearly flunked out of college when he first started.

5:16: Dawn comments that Stephen got his PHD in physiology at McGill University which is when his interest in science really caught on and asks how that came about.

5:55: Stephen talks about communicating with Desmond Morris while Stephen was working on his post-doc.

8:03: Dawn asks about Stephen’s post-doctoral research, for which he traveled to Aberdeen London and Nova Scotia; as well as what prompted his interest in nutrition in the brain.

9:01: Dawn mentions that in 1986 Stephen became a faculty member in the department of nutritional sciences at the University of Toronto. She asks how he ended up teaching nutrition when he didn’t have a degree in nutrition.

10:33: Stephen talks about accepting a senior Canada Research Chair at the Research Center of Aging and a full professorship at the University of Sherbrooke.

11:57: Ken talks about Stephen’s interest in human evolution how it eventually led him to research the nutritional importance of shore-based foods and omega-3 fatty acid in particular in the development of human’s brains. He asks Stephen to talk about his work leading up to the hypothesis that humans evolved near the water.

16:32: Dawn asks which of the various forms and sources of omega-3 are optimal for overall wellness and brain health, and what are the differences between them.

18:50: Dawn asks Stephen if there was any pushback against his research into the importance of ketones and fat in the brain development of infants? Dawn points out that Stephen was working on this during the middle of the low-fat craze in the U.S. and Canada.

20:33: Dawn mentions that there is evidence that intermittent fasting improves cognition, and asks if there is any evolutionary basis for that?

21:49: Dawn asks if it was Stephen’s research into the metabolism of omega-3 fatty acids and the importance of ketones that lead him to write his book Survival of the Fattest?

23:04: Dawn notes that it seems as if ketones are at the core of Stephen’s way of thinking about infant brain development. She asks him to elaborate on this.

24:15: Dawn asks Stephen to talk about what it’s going to take to transition to the therapeutic use of ketones.

26:06: Ken mentions how Stephen has noted the importance of ketosis in postnatal life for a number of reasons, including brain development and survival and early breast milk availability. Ken asks about the effect of women consuming a ketogenic diet while breastfeeding children, and if this inadvertently lowers ketone levels in the infant due to lower medium chain triglyceride (MCT) levels in the breast milk, a phenomenon found in rodents fed a ketogenic diet during lactation.

28:36: Dawn comments how Stephen has said that certain brain-selective nutrients — such as DHA, iodine, iron, selenium, zinc and copper — would be best supplied by a shore-based diet. She asks which shores humans would have evolved close to and which types of food made up this diet during human evolution?

32:29: Dawn mentions that at Sherbrooke, Stephen’s research has been focused on the use of brain imaging techniques to study changing brain fuel metabolism and cognitive function during aging. She asks if he can give an overview of what he is finding.

34:08: Dawn comments on the increasing interest in exogenous ketones for treatment of neurological disease. She further mentions that these ketone esters can elevate Beta-hydroxybutyrate (BHB) levels far beyond what is normally attained during the ketogenic diet. She asks Stephen for his thoughts on the initiation of ketosis through MCTs versus exogenous ketones (salts or esters) versus carbohydrate restriction versus fasting. She asks about mechanistic differences between each of these methods of initiating ketosis.

35:39: Ken mentions that Stephen’s tracer work has used 11c acetoacetate in the setting of endogenous ketones and neurological disease. He asks if there are any key differences in brain ketone metabolism between endogenous and exogenesis ketosis after mentioning how BHB and acetoacetate appear in a relatively predictable 1:1 ratio when ketosis is induced through diet.

37:28: Ken mentions that it has been noted that ketones are 10% more efficient than glucose as a brain fuel. He asks Stephen about his understanding of cerebral fuel selection given ample availability of both glucose and ketones.

38:25: Dawn asks if there are areas of the brain that are particularly high users of ketone bodies, and if so, could that have any link to some of the functional or behavioral changes, such as mood, that are seen in some cases of animals or people adhering to a ketogenic diet.

39:16: Dawn asks Stephen to talk about his research into how and why omega-3 fatty acid homeostasis changes during aging.

40:21: Dawn asks for Stephen’s opinion on what are the primary challenges that our brains face as we age.

41:12: Dawn mentions how that Stephen is currently focused on Alzheimer’s research and ketones. She asks for an overview of his research that’s looking into how ketones can be used to the advantage of a person suffering from Alzheimer’s disease.

43:21: Dawn comments on how we know that APOE4 carriers have an increased risk of development of late onset familial Alzheimer’s disease. She asks if there is a link between the genotype and a change in brain metabolism.

44:42: Ken asks if substrate utilization differs between healthy subjects and those with neurological conditions, such as mild cognitive impairment or Alzheimer’s disease.

45:18: Dawn asks Stephen what other metabolic interventions he thinks have promise for a neurodegenerative disease.

46:01: Dawn mentions that exercise helps to get more ketones into the brain. She inquires as to how much exercise is needed to do this effectively.

46:49: Dawn asks Stephen to elaborate on his recommendation that older people who might not be able to exercise effectively should consider consuming a ketone drink made from MCTs that people can make in their kitchen.

48:31: Ken comments how he envisions it not being too long before studies can be done with powerful ketone ester drinks, and that exogenous ketones will become more readily available and more potent, giving people more effective options to elevate their level of circulating ketones.

50:09: Dawn asks Stephen if chronically high systemic inflammations contribute to neuroinflammation and cognitive decline. She also asks if targeting systemic inflammation with nutritional ketosis would be an acceptable strategy to enhance and also preserve cognitive function and brain longevity.

51:15: Dawn mentions that we know ketones increase brain blood flow and metabolism. She goes on to ask if Stephen thinks that some of the beneficial effects might be working through the newly discovered brain lymphatic system or glymphatic system.

51:41: Dawn points out there are about five million people with Alzheimer’s disease in the U.S., and that the number of Americans with AD is estimated to swell to 16 million in the next 30 years. She asks if Stephen thinks this dramatic increase in the prevalence of Alzheimer’s is related to the Western diet which has created an epidemic of type-2 diabetes and other chronic diseases.

52:42: Ken mentions that a number of recent papers show dramatic improvements in both health span and life span of rodents that are fed a ketogenic diet. While humans are not rats, he asks Stephen for his thoughts on the effects of prolonged ketosis as a promoter of human healthspan and perhaps even longevity.

53:51: Dawn concludes the interview by asking Stephen’s about his interests outside of work.