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.

Fasting And Stem Cell Function

In mice, a 24 hour fast improves the function of intestinal stem cells through effects on fatty acid oxidation (FAO).  Genetic knockout experiments emphasize the importance of FAO in the fasting effects and suggest possibilities for boosting intestinal stem cell regeneration.  Abstract:

Diet has a profound effect on tissue regeneration in diverse organisms, and low caloric states such as intermittent fasting have beneficial effects on organismal health and age-associated loss of tissue function. The role of adult stem and progenitor cells in responding to short-term fasting and whether such responses improve regeneration are not well studied. Here we show that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting. Acute genetic disruption of Cpt1a, the rate-limiting enzyme in FAO, abrogates ISC-enhancing effects of fasting, but long-term Cpt1a deletion decreases ISC numbers and function, implicating a role for FAO in ISC maintenance. These findings highlight a role for FAO in mediating pro-regenerative effects of fasting in intestinal biology, and they may represent a viable strategy for enhancing intestinal regeneration.

High Fat Diet And the Aging Mouse Brain

A high fat diet seems not to be very good for aging of the mouse brain.  Fasting and a low fat diet seemingly have different effects.  Abstract:

Fasting may be exploited as a possible strategy for prevention and treatment of several diseases such as diabetes, obesity, and aging. On the other hand, high-fat diet (HFD) represents a risk factor for several diseases and increased mortality. The aim of the present study was to evaluate the impact of fasting on mouse brain aging transcriptome and how HFD regulates such pathways. We used the NCBI Gene Expression Omnibus (GEO) database, in order to identify suitable microarray datasets comparing mouse brain transcriptome under fasting or HFD vs aged mouse brain transcriptome. Three microarray datasets were selected for this study, GSE24504, GSE6285, and GSE8150, and the principal molecular mechanisms involved in this process were evaluated. This analysis showed that, regardless of fasting duration, mouse brain significantly expressed 21 and 30 upregulated and downregulated genes, respectively. The involved biological processes were related to cell cycle arrest, cell death inhibition, and regulation of cellular metabolism. Comparing mouse brain transcriptome under fasting and aged conditions, we found out that the number of genes in common increased with the duration of fasting (222 genes), peaking at 72 h. In addition, mouse brain transcriptome under HFD resembles for the 30% the one of the aged mice. Furthermore, several molecular processes were found to be shared between HFD and aging. In conclusion, we suggest that fasting and HFD play an opposite role in brain transcriptome of aged mice. Therefore, an intermittent diet could represent a possible clinical strategy to counteract aging, loss of memory, and neuroinflammation. Furthermore, low-fat diet leads to the inactivation of brain degenerative processes triggered by aging.

One can speculate about the human situation.

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.

Mediterranean Diet, Hunger and Cancer

Evolutionary, our ancestors were able to survive on one daily meal, but sometimes went hungry for days.  Today, however, most Americans consume three meals a day with additional snacks. The notion that many small meals a day is healthy is being popularized; however, epidemiological studies have reported that a lesser number of eating episodes is associated with a reduced risk of colon cancer and other types of cancer.  Consistent with these results, rodent studies, controlled for caloric intake, have revealed that longer intervals between meals increase resistance to cancer.

Periods of strictly vegetarian diet and fasting are incorporated in many religious traditions.  For example, throughout the year, the Eastern Orthodox calendar includes 180 days of fasting, during which vegetarian days alternate with periods of complete abstinence from food. Thus, a strict Orthodox Christian observes the following weekly fasting rules: only one vegetarian meal on Wednesdays and no food on Fridays. In addition, there are prolonged periods of fasting during the year: the three main ones being the forty days before Christmas, Lent (40-48 days) and the Assumption (15 days).   According to the rules of these fasts, any meat and meat products, eggs, dairy products, fish, oil, and wine are excluded from the diet, although fish, wine, and oil are allowed on certain days of the week.  Interspersed within the long fasting periods are days or even weeks of complete abstinence from food (e.g., the week before Easter, Holy Week).  

Interestingly, this Orthodox Christian fasting regimen has been proposed as an alternative explanation for the health benefits of the Greek Mediterranean diet. Thus, the Mediterranean diet is not only rich in fiber (grains, vegetables and fruit) and olive oil, but it is accompanied by periods of fasting that might be beneficial by slowing down tumor cell growth and preventing cancer.  

The slowing of abnormal cell growth by fasting could be mediated by the changes in metabolism. What are these changes? Fasting forces the body to switch from one source of energy (carbohydrates, such as glucose), to another – fats.  According to metabolite studies, the glucose from the blood and its storage (glycogen, which is simply a chain of many glucose molecules) is utilized within the first 12 hours of complete fast. On day 2 of the fast, the body already relies on processing of fats (from the adipose tissues) to ketones as a source of energy. Does this major shift in metabolism explain the protective effect of fasting against cancer? Likely, yes. It has been long known that some cancer cells are addicted to sugar (glucose) as a source of energy; now we know that many human cancers exhibit this behavior.  

Such abnormal cells have an excess of glucose receptors on their surface, and therefore, “devour” more glucose from the blood than normal cells. Additional mechanisms also force cancer cells to rely mostly on glucose as their source of energy. Because of this dependence on glucose, the depletion of glucose (as in fasting) can result in the death of the tumor cells. Furthermore, in all cancer cells the depletion of glucose is likely to suppress all signaling pathways that support survival.

In 1921, Dr. Wilder proposed that the effects of fasting on the body could be mimicked by a diet, in which fat was the main component, the ketogenic diet. This diet consists mostly of fat; thus, the ratio of fat : protein : carbohydrate in this diet is close to 90 : 8 : 2. With this diet, the organism uses fat as its main source of energy and forms ketones the same way these compounds are produced during fasting. However, whereas in fasting the body uses its own fat storage to cope with the lack of other energy sources, during the ketogenic diet, exogenous (external) fat from the food is being processed. This difference between fasting and ketogenic diet results in very different levels of LDL cholesterol: fasting individuals compared to controls present with 12.5% lower end-total cholesterol (p < 0.001) and 15.9% lower end-LDL cholesterol (p< 0.001). Therefore, be aware that during ketogenic diet the levels of cholesterol skyrocket, and this is obviously not good for the long-term health outcomes.

Despite the ability of the fasting regimen and ketogenic diet to suppress tumor growth, the cancer therapeutic application of these approaches is limited in the U.S. These modalities are mostly applied as adjuvant (complimentary) modalities to mainstream cancer treatments. One reason to shy away from these approaches is that our medical doctors are not taught about them, and therefore, nor aware of them.

Here I did not discuss the benefits of fasting in reducing obesity and the obesity-related metabolic syndrome with its downstream consequences (e.g., cardiovascular diseases, type 2 diabetes, etc.). I also neglected to discuss the additional benefits of Mediterranean diet to human health. Hopefully, these will be subjects of future posts.

Actionables

It has been proposed that limiting the food and drink intake to 6-10 hours a day may have the same benefits as any longer-term fasting regimen. In practice, this means that one could fast  from early dinner till late breakfast next day, or skip breakfast or dinner. 

PS:
A later post also explores this topic.