In this article I will look into the possibility of calorie restriction or intermittent fasting, which is just an alternative strategy to induce a caloric deficit, effective nutritional therapeutic strategies to prevent, alleviate or even eliminate some of the so-called “age-related diseases”, thus contributing for a better and longer life. It is important to note that most studies on the effects of calorie restriction or intermittent fasting (or intermittent calorie restriction) on life expectancy are mechanistic, and conducted in animal and / or in vitro models. It is understandable that there are fewer human intervention studies in this area. If we think about it, it is not easy to conduct studies with humans on calorie restriction to study its effects on life expectancy and the incidence of “age-related diseases”. Not only it is not easy to recruit people to voluntarily incur in a calorie restriction period, it is also not practical to study in humans (in a randomized controlled manner) the effects of calorie restriction or fasting on life expectancy, because they simply “live a long time”. ” In order to obtain timely results, it is essential to conduct studies on species with a shorter life expectancy. However, observational studies and some human intervention studies (discussed later) appear to confirm the same health benefits and molecular mechanisms as those observed in animals.

It should also be noted that, in the experimental context, caloric restriction is defined as “reduced food intake without malnutrition”. In other words, nutritional interventions imply a 10-40% reduction in daily caloric requirements in which only calories, and not nutrients, are restricted (in most controlled studies this is ensured with vitamin and mineral supplementation) (Kitada & Koya, 2013b; Robertson & Mitchell, 2013). This notion is important! Caloric deficit does not imply nutrient deficit and caloric surplus does not imply that nutrient requirements are met. Intermittent fasting will be no more than an alternative method of calorie restriction in which food intake is restricted for a certain period of time (usually 16 to 24 hours) followed by an unrestricted intake period and has been touted as producing beneficial health effects similar to more constant calorie restriction protocols (Martin, Mattson, & Maudsley, 2006; Robertson & Mitchell 2013).

Part 1
Should we accept being “sick” just because we get older?

It is recurrent to hear that the disease is something that “comes with the age package.” In fact, getting older is a drag! The general perception of a progressive decline of all our capabilities as we age is, unfortunately, not an illusion. There are several theories about aging. While certainly a very interesting topic, a detailed description of the various theories of aging is not the purpose of this article. These are some of mechanisms underlying the aging process which are generally pointed out as the main ones:

  • The “Hayflick limit” (phenomenon discovered by Leonard Hayflick) determines that human cells have a replication limit number, after which they become senescent. Telomeres (i.e. a kind of protective “helmets” at the end of each chromosome) become progressively shorter with each cell division (Shay & Wright 2000). However, DNA methylation (an essential and repairing process consisting of the addition of methyl groups to DNA and which can be promoted by the abundance of dietary methyl donors for example) is said to be protective of telomere length and that way to postpone cell death and aging. For example, in animal models, hypomethylation of the enzyme telomerase reverse trancriptase has led to the preservation of leukocyte telomere length (Zhang et al. 2003; 2014). In this example, it is plausible to infer that delaying leukocyte senescence (through methylation and consequent telomere length conservation) may contribute to a stronger immune system and thus positively influence longevity.
  • This theory suggests that unresolved chronic inflammation induces the human organism not to allocate resources for the functioning of other body functions (as they are permanently allocated to unresolved inflammation) and thus leading to early aging of various organs and tissues, and the early onset of “age-related diseases”.
  • This theory, originally proposed by Dr. Denham Harman in 1956, is based on the premise that the aging process is mediated by free radical damage. Theoretically, by reducing free radical accumulation (e.g. reactive oxygen species) and at the same time increasing the antioxidant capacity of the organism (increasing glutathione, and antioxidant enzymes such as SOD and catalase), tissue damage can be prevented (by slowing down aging process) and to prevent the occurrence of “age-related diseases” and consequently contribute to increase functional longevity (Harman, 1988; 2006).

Very well, getting older is inevitable! We already know that. However, if we give it a little thought, all the mechanisms mentioned have an environmental root, that is, we can, to some extent, control them through decisions that we make every day. Namely decisions about what we eat and how we move. And this is good news! It is in fact in our hands to slow down the process of senescence and prevent the onset of the so-called ‘’age-related diseases’’. Note that if for us (Westernized world) it is statistically “normal” to grow old with diabetes, hypertension, cancer, dementia, sarcopenia, osteoporosis, cardiovascular disease, insulin resistance, obesity and chronic inflammation (because the population studied incurs in a lifestyle that leads to disease), in other contemporary (non-Westernized) populations such diseases are rare or even non-existent. In this context, I invite the reader to consult what I consider to be one of the best books I know about nutrition and lifestyle, and its relation to the incidence of so-called “Western” diseases: Food and Western Disease: Health and Nutrition from an Evolutionary Perspective by Staffan Lindeberg. In fact, if we want to aim at maximizing health and lifespan potential, we should not just look at what is ‘’normal’’ in a given population, because that may be a sick population. Rather, we should look for what is “biologically normal” for a human being! A species that is designed (evolutionarily) to deal with a range of environmental stimuli that include certain levels of physical activity, nutrition, sun exposure and sleep. And, although aging is a normal process, it should not be “biologically normal” to age with chronic disease.

In this context, the Okinawa Centenarian Study is also frequently cited. The Okinawan population has the highest ratio of (healthy) centenarians on the planet (50 / 100,000 vs 10-20 / 100,000 in the USA) and as such is of greatest interest to study the factors that potentiate this kind of longevity. One of the factors identified (in addition to an appreciable level of physical activity and social interaction) was the fact that populations over 70 eat about 11% of calories below (about 1785kcal / day, which is a very moderate level of calorie restriction) than would be recommended for maintaining body weight (according to the Harris-Benedict equation), however on a nutrient-rich diet (Wilcox et al., 2006).

*Okinawan residents expected to have the highest ratio of centenarians worldwide with 50 / 100,000.

What we can do to live longer and better is one of my main interests. As I mentioned, our choices regarding the type of exercise, food we eat and other lifestyle factors can affect how long we live and, perhaps most importantly, how healthy and functional we live. In Part 2 of this article I will discuss some mechanisms by which nutritional interventions such as calorie restriction or intermittent fasting can lead to health benefits. And in Part 3 I will address the possible implications and practical applications of the practice of calorie restriction or fasting, as well as which populations can benefit most from these nutritional strategies and whoshould avoid them.

Stay around!

Nuno Correia


Dröge W., 2009. Avoiding the First Cause of Death. New York, Bloomington. iUniverse, Inc.

Harman D., 1988. Free radicals in aging. Mol Cell Biochem. Dec; 84(2), pp.155-161.

Harman D., 2006. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci. May;1067, pp.10-21.

Kitada, M. & Koya, D., 2013b. SIRT1 in Type 2 Diabetes: Mechanisms and Therapeutic Potential. Diabetes & metabolism journal, 37(5), pp.315–25.

Lindeberg, S., 2010. Food and Western Disease: Health and Nutrition from an Evolutionary Perspective. Oxford, United Kingdom: Wiley-Blackwell.

Martin, B., Mattson, M.P. & Maudsley, S., 2006. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing research reviews, 5(3), pp.332–53.

Masoro.E. L., 2002. Caloric Restriction: A Key to Understanding and Modulating Aging. Texas, USA: ELSEVIER.

Robertson, L.T. & Mitchell, J.R., 2013. Benefits of short-term dietary restriction in mammals. Experimental gerontology, 48(10), pp.1043–8.

Shay J.W., Wright W.E. 2000. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol. Oct;1(1), pp.72-76.

Zhang D. et al., 2013. Homocysteine-related hTERT DNA demethylation contributes to shortened leukocyte telomere length in atherosclerosis. Atherosclerosis. Nov; 231(1), pp.173-179.

Zhang D.H., Wen X.M., Zhang L. & Cui W., 2014. DNA methylation of human telomerase reverse transcriptase associated with leukocyte telomere length shortening in hyperhomocysteinemia-type hypertension in humans and in a rat model. Circ J. 78(8), pp.1915-1923.

Wilcox D.C. et al., 2006. Caloric restriction and human longevity: what can we learn from the Okinawans? Biogerontology  7, pp.173–177.