Over the last decade, two related types of eating patterns—caloric restriction / fasting diets and ketogenic diets—have begun to attract ever greater attention among university researchers. In this magazine, the first is discussed in "Caloric Restriction, Fasting and Nicotinamide Riboside" (TotalHealth, February 2015).1 The second is examined in "Supplements Target Ketogenesis and Metabolic Flexibility for Sports and Health" (TotalHealth, June 2016).2 Neither of these approaches to influencing aging and health is new, of course. R. H. Weindruch and R. L. Walford already by 1979 had begun publishing major findings on caloric restriction and they were hardly the first to pursue the topic in a serious manner.3,4 As for ketogenic diets, many will remember Robert C. Atkins, Dr. Atkins' Diet Revolution (Bantam, 1972), which was immensely popular for years. Its predecessor was developed in the 1920s for the quite different purpose of treating pediatric epilepsy and was widely used until the introduction of effective anticonvulsant drugs. Outside of epilepsy, until recently the medical world strongly resisted even studying ketogenic diets. A discussion of the use of high-fat/low carbohydrate diets in the early 20th Century for diabetes can be found in my book, Anti-fat Nutrients.5

Taming the CR/Fasting Interventions
Caloric restriction (CR) / fasting and ketogenic dietary interventions exhibit both overlaps and differences. One major overlap arises from the fact that caloric restriction, just as does the ketogenic diet, encourages ketogenesis. Both diets, in their more pure forms, are quite hard to follow. Caloric restriction generally involves a 20 to 40 percent reduction in energy intake. Even at this level, caloric restriction can lead to undesirable consequences, such as general malnutrition, muscle weakness and wasting, a failure to adapt to environmental challenges, neurological deficits, dizziness, irritability, lethargy, and depression.6

Ketogenic diets have different adverse effects, several of which are linked to a tendency to avoid almost all fruits and vegetables, hence losing adequate access to most phytonutrients and even to many of the canonical vitamins and minerals, such as vitamin C and potassium. Adverse consequences can include unwanted weight loss, constipation, kidney stones, calcium deficiency and other vitamin and mineral deficiencies. At 20 to 50 grams of carbohydrates per day (80 to 200 calories), a medical-style ketogenic diet is difficult to follow. A common failing on ketogenic diets is eating too much protein and too little fat. This defeats at least one of the major goals of ketogenic dieting, which is to reduce insulin-like growth factor 1 (IGF-1).7

Fasting and reduced caloric intake are practices in many of the world's medical systems, whether for healing or for preserving health. As but one example, consuming most food only during a restricted time window, in practice an eight–ten hour window, and avoiding all solid food after approximately 4 or 5 p.m. is an ancient Buddhist recommendation for health. For most individuals, versions of caloric restriction and/or fasting are far easier to follow over the long term than is any version of the ketogenic diet. Furthermore, there are quite a few flexible eating plans that have been developed to achieve at least some of the benefits of classic calorie restriction and fasting without requiring that the adherent become an ascetic.

Approaches to Caloric Restriction and Fasting

Below are some of the defined approaches that have been worked out by various researchers and writers. For readers interested in a much more elaborate discussion of these and related options, an excellent overview can be found in "Running on Empty: Fasting Diets Are Increasingly Popular, But Do They Really Work?"8

Calorie Restriction
Reduction in calorie intake by 20 to 40 percent (1200 calories for women versus 1400 calories for men per day) over an extend period of time ranging from weeks to months

Intermittent Calorie Restriction
Reduction in calorie intake by 50 to 70 percent (600– 1000 calories per day) for short periods of time, for instance, once or twice per week

Fasting
Complete avoidance of calorie intake for anywhere from one day to several weeks

Intermittent Fasting
Alternating a fasting day with a normal energy intake day or fasting once or twice per week; typically, there are no food restrictions on eating days, although eating should be moderate rather than compensatory; there are many versions of this plan, such as eating five days a week and fasting for two

Daily Partial Fasting
Complete avoidance of calorie intake for 14–18 hours daily; meals are resumed at the start of each day, but all meals are eaten within a defined period of approximately eight to ten hours9

Alternate-Day Dieting
Alternating a normal eating day with a calorie restriction day of approximately 20 percent of typical calorie intake; some writers call this alternate-day fasting

What Diets Do the Researchers Themselves Follow?
The author of the article mentioned above, "Running on Empty," very helpfully queried caloric restriction and fasting researchers as to the eating plans they practice themselves. The following are some of the responses that he received. Researchers give their rationales for various practices in the body of the article.

  • Valter Longo, University of Southern California: Eats twice per day (skipping lunch) and practices a periodic fast for five days every six months
  • Mark Mattson, National Institute on Aging: Eats within a six-hour window every day and does trail running
  • Satchidananda Panda, Salk Institute: Eats within a 12-hour window every day and practices an extended water-only fast of five days once per year
  • Krista Varady, University of Illinois at Chicago: Practices alternate-day fasting one or two months per year, "usually after Christmas to shed the five pounds of holiday weight."

Back to Ketogenesis
Lean tissue loss with caloric restriction quite clearly is an issue, especially in anyone past middle age, at which point regaining lean muscle tissue becomes much more difficult. Fasting, of course, is ketogenic and some version of fasting would appear to be more practical over the long term, keeping mind, however, that those who are insulin resistant have difficulty in accessing fat stores for fuel and thus will, again, sacrifice lean tissues for access to protein in order to fuel the glucose requirements that are required even with a ketogenic diet. A nice point about a ketogenic diet is that there is greater freedom to consume essential nutrients than is true of more extreme forms of fasting.

Recent research in animals suggests that, at least in this model, a ketogenic diet extends longevity and healthspan even when begun in adult animals.10 Similarly, a ketogenic diet in this model promotes better memory in this model.11 Interestingly, although rodents typically are quite poor choices for testing high-fat diets due to their inappropriate metabolism of high-fat diets compared to humans, nevertheless, after animals made obese on a high-fat diet had transitioned to a ketogenic diet, they lost all excess body weight, exhibited improved glucose tolerance and displayed increased energy expenditure.12 Likewise, there is improved antioxidant and free radical protection under ketogenic diet conditions.13 Short- and long-term ketogenic dieting improves select markers of liver oxidative stress compared to standard rodent chow feeding, although long-term ketogenic diet feeding may negatively affect skeletal muscle mitochondrial physiology. The picture is not entirely unmixed in the animal model (there are contradictory outcomes regarding the impact on skeletal muscle mitochondria), yet overall conclusions seem positive.14,15

Next month in these pages, it will be noted that even in elite athletes of approximately 30 years of age, it can take three months or more to adjust adequately to a ketogenic diet. (See "Sports Supplements For Better Metabolic Flexibility and Performance," May 2018 TotalHealth.) For those who are older and not so physically elite, the transition might well run six to twelve months, which is quite a long time for a diet that is, frankly, difficult to follow except for Eskimos and Tibetan nomads!

In light of these considerations, the question arises as to whether there are alternatives to following a ketogenic diet. Again, last month it was pointed out that many of the benefits of a ketogenic diet, including the ability to produce and metabolize ketones, likely can be achieved by means of a combination of diet and selected dietary supplements to achieve metabolic fitness / metabolic flexibility. The other alternative considered was the consumption of ketone salts and/or esters. Although this route in animal research and in actual human trials has been shown thus far to be inferior for both general and athletic purposes to a sustained ketogenic diet,16 evidence is accumulating, at least in an animal model, that consumed ketone bodies may mimic at least in part the lifespan-extending properties of caloric restriction. Indeed, the argument is being made that calorie restriction extends lifespan at least in part through increasing the levels of ketone bodies.17

Conclusion
[B]illions of dollars have been spent on research into the biological factors affecting body weight, but the near-universal remedy remains virtually the same, to eat less and move more. According to an alternative view, chronic overeating represents a manifestation rather than the primary cause of increasing adiposity. Attempts to lower body weight without addressing the biological drivers of weight gain, including the quality of the diet, will inevitably fail for most individuals.

"Increasing adiposity: consequence or cause of overeating?"18

The primary focus of this and related articles have been the concepts of metabolic fitness and metabolic flexibility. Human physiology and metabolism can adapt to a quite wide range of circumstances and can be "tweaked," likewise, with a broad number of approaches. Enhancing healthspan, even if perhaps not absolute lifespan, can be achieved through caloric restriction, fasting and dietary interventions involving properly balanced and selected foods combined with nutrients / dietary supplements. Some of these approaches are more easily sustainable under modern conditions and habits than are others. Regardless of the approach selected, basic physiology, not willpower, needs to be the guiding principle. For most individuals, no dietary program will succeed in the long run that does not address both biological drivers and the constraints of life (personality, work, family, social obligations, etc.) as it actually is lived.

Endnotes:

  1. Totalhealth magazine: Caloric Restriction Fasting and Nicotinamide Riboside
  2. Totalhealth magazine: Supplements Target Ketogenesis and Metabolic Flexibility
  3. Weindruch RH, Kristie JA, Cheney KE, Walford RL. Influence of controlled dietary restriction on immunologic function and aging. Fed Proc. 1979 May;38(6):2007–16.
  4. Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cance incidence. Science. 1982 Mar 12;215(4538):1415–8.
  5. Clouatre, Dallas L. Anti-Fat Nutrients, 4th edition (Basic Health Publications, Spring 2004)
  6. Keys A, Brozek J, Henschels A & Mickelsen O & Taylor H. The Biology of Human Starvation, 1950, Vol. 2, p. 1133. University of Minnesota Press, Minneapolis.
  7. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends in pharmacological sciences 2010;31:89–98.
  8. https://www.the-scientist.com/?articles.view/articleNo/49462/title/Running-on-Empty/
  9. Gill S, Panda S. A Smartphone App Reveals Erratic Diurnal Eating Patterns in Humans that Can Be Modulated for Health Benefits. Cell Metab. 2015 Nov 3;22(5):789–98.
  10. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, Imai DM, Griffey SM, Kim K, Hagopian K, Haj FG, Baar K, Cortopassi GA, Ramsey JJ, Lopez-Dominguez JA. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab. 2017 Sep 5;26(3):539–46.e5.
  11. Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP, Huang Y, Haldar S, Verdin E. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. Cell Metab. 2017 Sep 5;26(3):547–57.e8.
  12. Kennedy AR, Pissios P, Otu H, Roberson R, Xue B, Asakura K, Furukawa N, Marino FE, Liu FF, Kahn BB, Libermann TA, Maratos-Flier E. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1724–39.
  13. Salomón T, Sibbersen C, Hansen J, Britz D, Svart MV, Voss TS, Møller N, Gregersen N, Jørgensen KA, Palmfeldt J, Poulsen TB, Johannsen M. Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis. Cell Chem Biol. 2017 Aug 17;24(8):935–43.e7.
  14. Kephart WC, Mumford PW, Mao X, Romero MA, Hyatt HW, Zhang Y, Mobley CB, Quindry JC, Young KC, Beck DT, Martin JS, McCullough DJ, D'Agostino DP, Lowery RP, Wilson JM, Kavazis AN, Roberts MD. The 1-Week and 8-Month Effects of a Ketogenic Diet or Ketone Salt Supplementation on Multi-Organ Markers of Oxidative Stress and Mitochondrial Function in Rats. Nutrients 2017 Sep 15;9(9). pii: E1019.
  15. Hyatt HW, Kephart WC, Holland AM, Mumford P, Mobley CB, Lowery RP, Roberts MD, Wilson JM, Kavazis AN. A Ketogenic Dietin Rodents Elicits Improved MitochondrialAdaptationsin Response to Resistance Exercise Training Compared to an Isocaloric Western Diet. Front Physiol. 2016 Nov 8;7:533.
  16. Op cit. note 14.
  17. Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017 May;69(5):305–14.
  18. Ludwig DS, Friedman MI. Increasing adiposity: consequence or cause of overeating? JAMA. 2014 Jun 4;311(21):2167–8.

Dallas Clouatre, PhD

Dallas Clouatre, Ph.D. earned his A.B. from Stanford and his Ph.D. from the University of California at Berkeley. A Fellow of the American College of Nutrition, he is a prominent industry consultant in the US, Europe, and Asia, and is a sought-after speaker and spokesperson. He is the author of numerous books. Recent publications include "Tocotrienols in Vitamin E: Hype or Science?" and "Vitamin E – Natural vs. Synthetic" in Tocotrienols: Vitamin E Beyond Tocopherols (2008), "Grape Seed Extract" in the Encyclopedia Of Dietary Supplements (2005), "Kava Kava: Examining New Reports of Toxicity" in Toxicology Letters (2004) and Anti-Fat Nutrients (4th edition).

Website: www.dallasclouatre.com