So what actually is metabolic damage?


Obligatory disclaimer: I am not a medical doctor, and the content of this website was created for informational purposes only. Such content is not intended as a substitute for medical advice, treatment or diagnosis.

Last week we went over a couple of definitions on metabolic damage. Those definitions were rather vague, and seemingly inconsistent among themselves, so in this post we will attempt to understand if a thing called metabolic damage exists, and what it actually is. As a reminder, last week’s definitions on metabolic damage can be condensed into something like this: “metabolic damage is a slowdown in metabolic rate due to long-term caloric restriction”. With that in mind, let’s get started.

To begin this task, we first need to understand what metabolism is. Let’s keep this short and simple, and head straight for Wikipedia:

Metabolism is the set of life-sustaining chemical reactions in organisms. The main purposes of metabolism are: the conversion of food to energy to run cellular processes; the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and some carbohydrates; and the elimination of nitrogenous wastes.

That’s quite a simple definition, and it essentially deals with the way our body gets and uses energy. As an aside, consider that a quick search for the word damage in that Wiki page doesn’t bring up any results. Interesting.

If metabolic damage is metabolism slowing down, then we also need to understand what the metabolic rate is. Again, Wikipedia comes to the rescue:

Basal metabolic rate (BMR) is the rate of energy expenditure per unit time by endothermic animals at rest. It is reported in energy units per unit time ranging from watt (joule/second) to ml O2/min or joule per hour per kg body mass J/(h·kg). Proper measurement requires a strict set of criteria be met. These criteria include being in a physically and psychologically undisturbed state, in a thermally neutral environment, while in the post-absorptive state (i.e., not actively digesting food).

Presumably, if the BMR is the rate of energy expenditure at rest, then the metabolic rate (MR) would just be the rate of energy expenditure for a period of time. Furthermore, and just to be pedantic about it, BMR is the amount of energy per unit of time that is required to keep an organism functioning while at rest, any less and we go back to our starvation mode/response post and any more and we begin gaining weight. That having been said, searching for the word damage in Wiki’s page for BMR brings up no results. That’s also interesting.

On the other hand, by searching for metabolic damage on Google Scholar we get about 5 thousand hits. However, just by taking a quick glance at some of the search results, it’s a little obvious that it’s not what we’re looking for. Consider the first result that comes up, (Pfluger, P. T., Herranz, D., Velasco-Miguel, S., Serrano, M., & Tschöp, M. H. (2008). Sirt1 protects against high-fat diet-induced metabolic damage. Proceedings of the national academy of sciences105(28), 9793-9798):

The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome.

So now we’re talking about a thing called metabolic syndrome, and this syndrome is believed to be caused by high-fat diets? Clearly we’re looking in the wrong direction: we went from caloric restriction to high-fat diets and from metabolic damage to metabolic syndrome.  Let’s try searching for something different: what about metabolic adaptation to caloric restriction? That search gets us a couple of very nice results: Leonie K Heilbronn, Eric Ravussin; Calorie restriction and aging: review of the literature and implications for studies in humans, The American Journal of Clinical Nutrition, Volume 78, Issue 3, 1 September 2003, Pages 361–369 and Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-Month Calorie Restriction on Biomarkers of Longevity, Metabolic Adaptation, and Oxidative Stress in Overweight IndividualsA Randomized Controlled TrialJAMA.2006;295(13):1539–1548.

From the first paper (it’s a long quote, but a good one):

CR [caloric restriction] is hypothesized to lessen oxidative damage by reducing energy flux and metabolism, or the “rate of living,” thereby influencing the aging process. We know that CR results in a loss of weight and tissues and a reduction in the rate of metabolism. A portion of this decline is the result of reduced energy intake and the consequent decrease in the thermic effect of food, whereas another portion is due to the reduced size of the metabolizing mass. However, whether there is also a “metabolic adaptation,” defined here as a reduction in the metabolic rate that is out of proportion to the decreased size of the respiring mass, is a subject of continued debate. In their investigation of the biology of semistarvation, Keys et al defined metabolic adaptation as “a useful adjustment to altered circumstances.” More recently, a 1985 FAO/WHO/UNU report proposed a definition of adaptation as “a process by which a new or different steady state is reached in response to a change or difference in the intake of food or nutrients”. In this context, the adaptation can be genetic, metabolic, social, or behavioral. The important question is whether CR reduces energy expenditure (EE) more than would be expected to result from the changes observed in FM [fat mass] and fat-free mass (FFM).


In summary, there is evidence that a metabolic adaptation develops in response to CR and loss of weight in humans. The reason for the apparently paradoxical difference between rodents and humans with regard to an adaptation in EE in response to CR may be related to the erroneous way in which physiologists express rodent energy metabolism data (60) or to differences in metabolism between rodents and humans. Other possible reasons are that the methods for measuring human EE are more sensitive than are those for measuring rodent EE, and investigators can obtain the full cooperation of the subjects.

In other words, there is a reduction in metabolic rate because of caloric restriction, and such a reduction is due to

  • the lesser intake of energy and the associated reduction in specific dynamic action (also known as the thermic effect of food, we’ll talk about it in a later post)
  • a lesser amount of body mass involved in energy consumption, which is caused by weight loss
  • lower hormone concentrations in the thyroid (which the authors of the second paper call metabolic adaptation, and they also attribute it to energy deficit rather than caloric restriction)

From the second of those three factors it’s clear that if the weight loss is maintained constant, then the reduction in metabolic rate will also remain constant, all else being equal. This would be akin to hiking a given distance without a backpack and with a 100 Kg weight, the larger weight requires more energy. This was confirmed by the second phase of of the CALERIE studies (Redman, L. M., Smith, S. R., Burton, J. H., Martin, C. K., Il’yasova, D., & Ravussin, E. (2018). Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging. Cell metabolism27(4), 805-815):

Phase 1 CALERIE or the Comprehensive Assessment of the Long-Term Effects of Reducing Intake of Energy studies were the first randomized controlled trials to test the metabolic effects of CR in non-obese humans. Then, the phase 2 CALERIE study, a 2-year 25% CR prescription in non-obese volunteers, was shown to be safe and without any untoward effects on quality of life. Importantly, the study confirmed the presence of a CR-induced decrease in total daily energy expenditure (EE) measured by doubly labeled water after 12 and 24 months (measured CR was 12% on average), indicating a decrease in physical activity and/or a metabolic adaptation. However, in the CR group compared with the control group, resting metabolic rate adjusted for loss of fat-free and fat masses was only lower during the weight loss phase, i.e., at 12 months of intervention, but not a year later.

So far this metabolic damage doesn’t seem so damaging, unless you are willing to say that a reduction in the metabolic rate, whatever its magnitude, constitutes metabolic damage.

Now, let us consider what would happen if the caloric restriction were to be halted and the individual were to return to their original dietary habits. Both the second and third factors would necessarily mean an increased metabolic rate, since some energy would be required to digest the ingested food, and, because the individual would return to their original weight, a greater body mass would require greater amounts of energy to function.

In other words, even if the term metabolic damage were accurate, then the process could be reversed by simply stopping what caused it in the first place.

Let’s recap what we’ve learned so far:

  • Metabolism is the series of chemical reactions that sustain life in an organism. Those reactions essentially deal with how an organism manages energy: how it gets it, how it puts it to use, and how it deals with waste.
  • The basal metabolic rate is the rate at which we use energy when at rest. It basically is the amount of energy that an organism at rest requires to survive during a period of time.
  • The metabolic rate is decreased when going through caloric restrictions. This is because by ingesting less food, it takes less energy to digest that food; because a long term caloric restriction causes weight loss, and a lesser amount of body mass requires a reduced amount of energy to survive; and because of lower hormone concentrations are present in the thyroid.
  • Such metabolic adaptation is only permanent if the caloric restriction becomes the “new normal”, all else being equal. For example, going from eating 5,000 kcal per day to a permanent diet of 4,000 kcal would cause a permanent metabolic rate decrease. However, if the caloric restriction were removed, then the metabolic rate would go back to its original level.

Final thoughts: I would like to know how the label of damage came to be pasted on metabolic adaptation. When it came to starvation response/mode, I could easily understand how some marketing guru or a normal person would use the label of mode instead of response by mistake or to make things sound more interesting. The use of the label damage, however, implies some level of dishonesty beyond simple ignorance, as well as an attempt at dissuasion.

In any case, next week we’ll talk about the thermic effect of food.

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