More On Caloric Restriction

Caloric restriction has benefits, but I would think that those few who are either underweight or close to underweight should be careful here.  The average American, however, who is overweight/obese, may derive some benefits, after consultation with their physician (obviously there are health conditions for which fasting/caloric restriction would not be advised).  Abstract:

PURPOSE OF REVIEW:

Obesity and obesity-related diseases, largely resulting from urbanization and behavioral changes, are now of global importance. Energy restriction, though, is associated with health improvements and increased longevity. We review some important mechanisms related to calorie limitation aimed at controlling of metabolic diseases, particularly diabetes.

RECENT FINDINGS:

Calorie restriction triggers a complex series of intricate events, including activation of cellular stress response elements, improved autophagy, modification of apoptosis, and alteration in hormonal balance. Intermittent fasting is not only more acceptable to patients, but it also prevents some of the adverse effects of chronic calorie restriction, especially malnutrition. There are many somatic and potentially psychologic benefits of fasting or intermittent calorie restriction. However, some behavioral modifications related to abstinence of binge eating following a fasting period are crucial in maintaining the desired favorable outcomes.

Intermittent Fasting Problem?

While there are a number of studies supporting benefits for of intermittent calorie restriction (ICR), a disturbing new study in mice suggests negative effects of ICR: an increase in cancer stem cells (CSCs) and enhancement of epithelial to mesenchymal transition, which promotes metastasis.  Keeping the mice in “continuous calorie restriction had no effect on tumor weight, metastasis, or the number of CSCs in tumors or blood” – not bad but not good either.  Speaking for myself, I eat three healthy meals per day (with approximately 12 hours between dinner and the subsequent breakfast), avoid overweight/obesity, and avoid any “fad diets.”  That’s what I’m doing, that is not necessarily a recommendation to anyone else.  Abstract:

The effect of intermittent calorie restriction (ICR) on cancer is controversial. In this study, we examined the effects of ICR and food content in syngeneic BALB/c mice injected with CT26 mouse colon cancer cells. Mice were subjected to 24-h fasting once a week for 4 weeks, and then provided with a control, high-calorie, or trans fatty acid-rich diet. While ICR resulted in increases in tumor weights, metastasis and in the number of cancer stem cells (CSCs) in the tumors or blood of mice fed the control and high-fat diets, it had no effect on body weight after 4 weeks. In particular, we detected increases in the numbers of CSCs in the tumor or blood on the day after starvation, when food overconsumption was detected. Conversely, continuous calorie restriction had no effect on tumor weight, metastasis, or the number of CSCs in tumors or blood. In the post-starvation period, energy metabolism in the tumor was altered from oxidative phosphorylation to glycolysis/lactate fermentation, with the acquisition of the epithelial-mesenchymal transition (EMT) phenotype. Hyperglycemia at the post-starvation period induced the expression of insulin-like growth factor-1, hypoxia-induced factor-1α and Nanog, as well as the phosphorylation of Stat3. Taken together, these findings suggest that ICR induces an increase in the number of CSCs and enhances EMT by promoting the Warburg/Crabtree effect following post-fasting food overconsumption.

Forever young versus the self-destruction of the body

The Daily Beast named 2015 "The Year We Decided to Live Forever". Why? Because the rich people (e.g., Peter Thiel, Sergey Brin, Mark Zuckerberg, etc.) would like to live if not forever, for a very, very long time, and therefore, are ready to fund research on extending human life with millions of dollars.

However, increasing the quality of the years, rather than the number of years, we live might be a better goal. For example, can we increase dramatically the quality of life beyond age of 50? To achieve this, we need to know exactly what causes aging and the associated conditions.


Artistic representation of human age
 
A 2015 study based upon 1554 individuals (including centenarians), established that among all physiological markers, the inflammation score was the best predictor of successful aging at extreme old age (Arai Y, et al. Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians. EBioMedicine. 2(10):1549-58; 2015.) This study confirmed the already established consensus that chronic inflammation is a defining feature of aging, and that inflammation is present in many, if not all age-associated diseases and conditions: Alzheimer’s disease, dementia, cardiovascular disease, multiple sclerosis, diabetes, etc. The increase in pro-inflammatory factors with age has been well documented. Plasma levels of the complement protein C1q were shown to increase with age and to promote age-related MuSC decline by activation of the Wnt signaling pathway (A. S. Brack et al., Science 317, 807–810 (2007) A. T. Naito et al., Cell 149, 1298–1313, 2012). Similarly, beta 2-microglobulin, a component of the major histocompatibility complex, was found to be elevated in the blood of aged mice and to contribute to the age-related decline of the organism (L. K. Smith et al., Nat. Med. 21, 932–937, 2015).

There are many hypotheses about the association between age and inflammation. However, scientists are still unsure whether inflammation causes aging, or vice versa, aging causes inflammation.

One of the best explanations (with most logic in it) is that inflammation does cause aging, and inflammation is the result of the immune response to the mutations that we accumulate with age. The more we live, the more mutations we accumulate. Some of these mutations could  contribute to cancer development, but some do not. However, all mutations that change our proteins sufficiently to induce immune response may contribute to the increasing levels of inflammation in the body. As a result, our own immune system starts attacking and damaging our own body.

To slow down, but not eliminate entirely, the accumulation of mutations (and therefore, the ensuing inflammation and aging) one needs to live a life free of mutagens (as a part of a healthy lifestyle). Of course, we cannot be entirely free of mutagens, but we can eliminate the most obvious ones (e.g., smoking, alcohol, processed meat, etc.).   

Another complimentary approach of evading fast aging is this of slowing down the division of the adult stem cells in our bodies. This is important, since most mutations accumulate during stem cell divisions (by the way, the attrition of telomeres also happens during cell division), and these stem cells can give rise to many other cells (stem cells, progenitor and differentiated cells of the body). 

Drosophila (fruit fly)

The only way that we might be able to slow down stem cell divisions in our body is through periodic fasting and calorie restriction. The more we eat, the faster the adult stem cells divide, and the faster we age. There is a direct evidence that well-fed state results in more stem cell divisions at least in studies of fruit flies.

More on intermittent fasting and reduced calorie intake

In October 2015, I posted on the ability of intermittent fasting (i.e., the regimen in which food intake is limited within six to eight hours for each 24 hours) to counteract cancer progression. The likely mechanism is the depletion of glucose, which is a primary source of energy for some (but not all) cancer cells. 

Intermittent fasting, however, has more benefits. Here is what I have found so far: 

• Intermittent fasting allows for a renewal of our immune system. It has been established that fasting promotes the regeneration of hematopoietic stem cells, which are responsible for the production of our immune cells. 

•  Reduced calorie intake decreases metabolism and attenuates telomere erosion; both effects may protect cells from DNA damage and therefore, from aging and cancer. I have previously written on the connection between telomere length and cancer risk. It remains to be seen, however, whether intermittent fasting without calorie restriction has the same benefits.

• Fasting counteracts inflammation, because it contributes to the generation of metabolites such as hydroxybutyrate (a ketone body) and lactic acid. It has been documented that these molecules bind receptors on macrophages, and suppress inflammation.

• Intermittent fasting can reduce acne by suppressing inflammation-associated signaling pathways (some of which are induced by our diet).

The bottom line is that the same way lean spending is good for your net worth, being lean on calorie intake boosts your health.