In an article published on September 14, 2017 in Nature Communications, Temple University researchers reveal an explanation for the life extending effect of calorie restriction. Jean-Pierre J. Isaa, MD, and colleagues discovered that restricting the amount of calories consumed slows the ageing-related rate of change of the epigenome, which consists of proteins and other compounds that can attach to DNA and control its action. The team is also the first to demonstrate that the rate of epigenomic change is associated with lifespan."Our study shows that epigenetic drift, which is characterised by gains and losses in DNA methylation in the genome over time, occurs more rapidly in mice than in monkeys and more rapidly in monkeys than in humans," explained Dr Issa, of the Fels Institute for Cancer Research at Temple’s Lewis Katz School of Medicine. "Our next question was whether epigenetic drift could be altered to increase lifespan.”After studying age-related DNA methylation, Dr Issa and colleagues compared the age-related epigenetic drift of 22 to 30-year-old rhesus monkeys that received calorie restricted diets beginning at 7 to 14 years of age to a group of monkeys that were fed non-restricted diets. They found that the calorie restricted animals’ blood methylation age was 7 years less than their chronologic age. Similar effects were observed in older mice that were fed restricted diets."The impacts of calorie restriction on lifespan have been known for decades, but thanks to modern quantitative techniques, we are able to show for the first time a striking slowing down of epigenetic drift as lifespan increases," Dr Issa stated. "Our lab was the first to propose the idea of modifying epigenetic drift as a way of modifying disease risk. But why epigenetic drift occurs faster in some people and slower in others is still unclear."
Calorie restriction promotes longevity through effects on the mitochondrial network
Research reported on October 26, 2017 in Cell Metabolism helps explain the effects of calorie restriction and activation of AMP-activated protein kinase (AMPK, an energy-sensing protein) on longevity. Harvard researchers have determined that AMPK and calorie restriction promote homeostasis and plasticity of networks formed by the cells’ power plants known as mitochondria.Mitochondria networks change shape according to energy demand, however, this ability declines with age. “Dynamic remodeling of mitochondrial networks by fusion and fission promotes maintenance of cellular homeostasis,” explain Heather J. Weir and colleagues at the Harvard T. H. Chan School of Public Health. “Dysregulation of mitochondrial dynamics and aberrant mitochondrial morphology are hallmarks of ageing and are thought to contribute to the pathology of numerous age-related pathologies including Alzheimer’s and Parkinson’s disease.”By restricting calories in the diet of round worms or using a strain of roundworm in which an AMPK sub-unit is activated, the researchers found that the roundworms maintained a youthful fused mitochondrial network shape with age. The youthful networks lengthen life by communicating with peroxisomes within the cells to alter fat metabolism."Low-energy conditions such as dietary restriction and intermittent fasting have previously been shown to promote healthy ageing,” Dr Weir commented. “Understanding why this is the case is a crucial step towards being able to harness the benefits therapeutically. Our findings open up new avenues in the search for therapeutic strategies that will reduce our likelihood of developing age-related diseases as we get older.""Although previous work has shown how intermittent fasting can slow ageing, we are only beginning to understand the underlying biology," added senior author William Mair. "Our work shows how crucial the plasticity of mitochondria networks is for the benefits of fasting. If we lock mitochondria in one state, we completely block the effects of fasting or dietary restriction on longevity."
A calorie restricted diet rejuvenates the biologic clock
The August 10, 2017 issue of Cell reported an ability for calorie restriction to prevent the impact of ageing on circadian rhythms. “The process of ageing and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to ageing remains unknown,” the authors write in their introductory remarks.For the current investigation, researchers at the University of California, Irvine fed calorie restricted or unrestricted diets to young and old mice. At 6 and 18 months, liver tissue samples were analysed. Although calorie restriction did not affect the 24-hour cycle of the older group’s circadian-controlled metabolic system, older cells showed signs of inefficient energy processing. "This mechanism works great in a young animal, but it basically shuts off in an old mouse," explained lead researcher Paolo Sassone-Corsi.In older animals given calorie restricted diets, cellular energy processing was improved. "In fact, caloric restriction works by rejuvenating the biological clock in a most powerful way," Dr Sassone-Corsi observed.A companion study reported in the same issue of Cell evaluated circadian rhythms in skin stem cells from the young and old mice. The researchers also found a benefit for a calorie restricted diet. "The low-calorie diet greatly contributes to preventing the effects of physiological ageing," commented coauthor Salvador Aznar Benitah. "Keeping the rhythm of stem cells 'young' is important because in the end these cells serve to renew and preserve very pronounced day-night cycles in tissue. Eating less appears to prevent tissue ageing and, therefore, prevent stem cells from reprogramming their circadian activities.""These studies also present something like a molecular holy grail, revealing the cellular pathway through which ageing is controlled," Dr Sassone-Corsi stated. "The findings provide a clear introduction on how to go about controlling these elements of ageing in a pharmacological perspective."
Is calorie restriction a diabetes cure?
Research reported at the European Association for the Study of Diabetes (EASD 2017) annual meeting, held September 11-15, 2017, adds evidence to the hypothesis that type 2 diabetes is caused by excess fat in the pancreas and liver, which can be eliminated by consuming a low calorie diet. Professor Roy Taylor presented an overview of decades of research that led to his Twin Cycle Hypothesis. He asserts that fatty liver caused by the intake of excess calories results in poor response of the organ to insulin and increased glucose production. Excess liver fat increases the export of fat to all tissues, including the pancreas, where it negatively impacts insulin-producing cells. By consuming fewer calories, fat loss occurs in the pancreas, which can normalise insulin production and reverse type 2 diabetes. A study published in Diabetologia documented a reduction in liver fat and normalisation of insulin sensitivity in the livers of diabetics a week after the initiation of a low calorie diet. After 8 weeks, pancreatic fat content subsequently declined and first phase insulin secretion became normalised. "I think the real importance of this work is for the patients themselves," Professor Taylor remarked. "Many have described to me how embarking on the low calorie diet has been the only option to prevent what they thought - or had been told - was an inevitable decline into further medication and further ill health because of their diabetes. By studying the underlying mechanisms, we have been able to demonstrate the simplicity of type 2 diabetes." "The good news for people with type 2 diabetes is that our work shows that even if you have had the condition for 10 years, you are likely to be able to reverse it by moving that all important tiny amount of fat out of the pancreas,” he added.
Higher Resveratrol dose linked to lower glucose levels in type 2 diabetics
The results of a meta-analysis that were published on September 22, 2017 in Nutrition & Metabolism add evidence to an association between supplementing with resveratrol and improved management of type 2 diabetes.
“As a potent antioxidant, resveratrol is a plant-derived polyphenolic compound that possesses anti-inflammatory, antiplatelet aggregation, anti-carcinogenic, cartilage-protective, and anti-ageing properties,” Ling Li of Southeast University in Nanjing, China and colleagues write. “Some studies have revealed that resveratrol administration improves insulin sensitivity in diabetic rats and patients with type 2 diabetes mellitus.” For their analysis, Dr Li and associates selected nine randomised, controlled trials involving a total of 283 type 2 diabetics that compared levels of glucose, insulin and other factors among participants who received resveratrol to those who received a placebo or a control group of diabetics. Resveratrol doses ranged from 8 milligrams (mg) to 3,000 mg per day, administered during a period of 4 weeks to one year. The analysis concluded that resveratrol supplementation was associated with significantly reduced insulin levels and insulin resistance. Fasting plasma glucose was reduced by an average of 5.2 milligrams per deciliter (mg/dL) among those who received resveratrol compared to placebo or control groups. Further analysis determined that only 100 mg or higher doses of resveratrol were associated with lower glucose levels. Blood pressure mildly improved among those treated with resveratrol. “Resveratrol supplementation may improve fasting plasma glucose, HOMA-IR (a measure of insulin resistance), and insulin in diabetic patients,” the authors conclude. “The dose and/or duration of treatment with resveratrol might also influence the effect of resveratrol on glucose homeostasis. Therefore, studies with durations longer than three months should be designed to confirm the efficacy of resveratrol and determine the appropriate dosage regimen in managing type 2 diabetes mellitus.”
Resveratrol supplementation improves arterial stiffness in type 2 diabetics
A randomised, double-blind study reported on August 3, 2017 in the International Heart journal found improvements in arterial stiffness and oxidative stress among type 2 diabetics who were supplemented with resveratrol. The trial included 50 diabetic men and women who received 100 milligrams resveratrol or a placebo daily for 12 weeks. Cardio-ankle vascular index (CAVI, a novel diagnostic measure of arterial stiffness that is a marker of atherosclerosis) and blood pressure were assessed at the beginning and end of the study, in addition to blood assessments of oxidative stress and other factors.At the end of the study, subjects who received resveratrol had significantly lower blood pressure, less oxidative stress and decreased arterial stiffness in comparison with values obtained at the beginning of the study. Participants who received a placebo experienced no significant changes in these areas.“The primary finding in the present study was that oral supplementation of resveratrol for 12 weeks decreased CAVI in patients with type 2 diabetes mellitus,” authors Haruki Imamura, MD, and colleagues at Toho University Sakura Medical Center in Japan write. “Many previous studies have demonstrated increased CAVI in atherosclerotic diseases such as acute coronary syndrome and stroke, and these reports indicate that CAVI reflects organic atherosclerosis.”They suggest that a reduction in oxidative stress may be one mechanism involved in the improvement in arterial stiffness observed in this study among participants who received resveratrol. Improved endothelial function via increased nitric oxide production may be another mechanism.“Resveratrol may be beneficial in preventing the development of atherosclerosis induced by diabetes,” the authors conclude. “However, a large-scale cohort study is required to validate the present findings.”