A number of interesting studies related to calorie restriction (CR) have shown up recently. I will discuss a few of these studies here, particularly ones relating CR to cancers. I will discuss additional studies relating CR to gene activation in a Part II post and speculate there on what I think these studies mean.
Calorie restriction involves systematic dietary restriction of calorie intake. It has long been known to work as an effective longevity-enhancing intervention. “CR when not associated with malnutrition, improves age related health and slows the aging process in some animals and fungi. CR is one of the few dietary interventions that has been documented to increase both the median and maximum lifespan in a variety of species, among them yeast, fish, rodents and dogs. There are currently ongoing studies on primates to show if CR works on primates, and even though they are showing positive indications it is still not certain that CR has a positive effect on longevity for primates and humans, due to the very lengthy time required for the completion of such lifespan studies(ref). “
The news this week in interesting since it describes effects of limiting glucose on the cellular level on both normal and precancerous cells. The online pre-publication is entitled Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. “We analyzed normal WI-38 and immortalized (precancerous) WI-38/S fetal lung fibroblasts and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells.” (Both sets of cells were exposed to either normal or reduced levels of glucose (sugar) while being grown in the laboratory.) “Moreover, in WI-38/S (precancerous) cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16INK4a. Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction.”
Said differently, reducing glucose decreased telomerase expression and increased apoptosis in precancerous cells leading them to die off, and produced the opposite effect in normal cells.
The observed effects were epigenetic. “The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as anti-aging approaches(ref).”
A 2008 report in Science Daily Calorie Restriction Limits — And Obesity Fuels — Development Of Epithelial Cancers further examines the CR-cancer connection. “A restricted-calorie diet inhibited the development of precancerous growths in a two-step model of skin cancer, reducing the activation of two signaling pathways known to contribute to cancer growth and development,–“ –“ This study employed four diets, two representing calorie reductions of 30 percent and 15 percent, a control diet including 10 percent kilocalories from fat, and an obesity-inducing diet consisting of 60 percent kilocalories from fat. Agents were then given to the mice to induce premalignant lesions called papillomas, which are precursors to cancer. — Those on the calorie restricted diets had statistically significant inhibition of papilloma formation compared with the other two diets. — In a separate experiment the development of carcinomas and the effect of dietary energy balance on conversion of papillomas to carcinomas was evaluated. This study demonstrated that dietary energy balance determines the number of carcinomas found through its effects on the number of premalignant lesions but does not affect the rate of malignant conversion.”
The molecular signaling pathways involved in the CR-cancer link appear to be ones discussed several times previously in this blog, namely IGF-1, Akt and mTOR(ref)(ref)(ref). “Epithelial cancers arise in the epithelium – the tissue that lines the surfaces and cavities of the body’s organs. They comprise 80 percent of all cancers. “Calorie restriction and obesity directly affect activation of the cell surface receptors epidermal growth factor (EGFR) and insulin-like growth factor (IGF-1R),” Moore said. “These receptors then affect signaling in downstream molecular pathways such as Akt and mTOR.” – “increased Akt and mTOR signaling are linked to the growth, proliferation and survival of many human cancers.” These findings provide the basis for future translational studies targeting Akt/mTOR pathways through combinations of lifestyle and pharmacologic approaches to prevent and control obesity-related epithelial cancers in humans,” DiGiovanni said(ref).”
It is interesting that CR inhibiting the Akt-mTOR pathways as mentioned in this study and glucose limitation inhibiting expression of hTERT and promoting P16 in cancer cells as mentioned in the other study seem on the surface to be independent effects. No doubt, on a deeper level these effects are linked.
Several other research reports highlight the association between CR and lower levels of cancer. One research study reported in 2008 “sheds light on the connection between obesity, calorie intake and pancreatic cancer by comparing a calorie restricted diet, an overweight diet and an obesity-inducing diet in a strain of mice that spontaneously develops pancreatic lesions that lead to cancer. – “Our findings indicate that calorie restriction hinders development of pancreatic cancer, which could have implications for prevention and treatment of pancreatic tumors caused by chronic inflammation and obesity.”– The group’s analysis points to a connection between calorie intake and a protein called Insulin-like Growth Factor (IGF) -1, with obesity increasing and calorie restriction decreasing levels of IGF-1. IGF-1 is an important growth factor known to stimulate the growth of many types of cancer cells. Inflammatory signaling proteins also were found to be reduced in the blood of the calorie-restricted mice.”
“Mice on the heavier diets had significantly more lesions and larger lesions than those on the restricted calorie diet, — These lesions develop into pancreatic cancer and virtually all of these mice die within six to eight months. The researchers fed the calorie restricted group a diet that was 30 percent lower in calories than that consumed by the overweight group and 50 percent lower than the obese group. Only 7.5 percent of mice on the calorie-restricted diet developed pancreatic lesions at the end of the experiment, and these lesions were so small that none exhibited symptoms of illness. For mice on the overweight diet, 45 percent developed lesions, as did 57.5 percent of those on the obesity-inducing diet. Lesions were also much larger in the overweight and obese mice than the calorie restricted mice. –. Pancreatic cancer is the fourth leading cause of cancer death and remains mostly intractable to existing treatments(ref).
Sex differences and hormonal factors may also impact on the results of CR. Regarding a 2008 study (ref) done by Spanish and Italian researchers, “Using lab rats as stand-ins for humans, the researchers found that the livers of both female rats and calorie-restricted rats produced different levels of 27 proteins than male rats or those on a normal diet. — The findings suggest that a previously unrecognized set of cellular pathways may be involved in the longevity boost from being female and eating a sparse diet, the study says, suggesting that these insights could lead to new ways of boosting human longevity(ref).”
I will continue this discussion in the follow-up post, Calorie restriction research roundup – Part II.