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
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
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
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
Complete avoidance of calorie intake for anywhere from
one day to several weeks
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
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
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
[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
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.
- Totalhealth magazine: Caloric Restriction Fasting and Nicotinamide Riboside
- Totalhealth magazine: Supplements Target Ketogenesis and Metabolic Flexibility
- 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.
- 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.
- Clouatre, Dallas L. Anti-Fat Nutrients, 4th edition (Basic Health Publications, Spring 2004)
- 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.
- Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends in pharmacological sciences 2010;31:89–98.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Op cit. note 14.
- 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.
- Ludwig DS, Friedman MI. Increasing adiposity: consequence or cause of overeating? JAMA. 2014 Jun 4;311(21):2167–8.