Fasting may boost metabolic activity, slow ageing

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DietFasting may help people lose weight, but a small new Japanese study suggests going without food may also boost human metabolic activity, generate antioxidants, and help reverse some effects of ageing. Scientists at the Okinawa Institute of Science and Technology Graduate University (OIST) and Kyoto University identified 30 previously-unreported substances whose quantity increases during fasting and indicate a variety of health benefits.

“We have been researching aging and metabolism for many years and decided to search for unknown health effects in human fasting,” said Dr Takayuki Teruya, first author of the paper and a technician in the OIST G0 Cell Unit, led by Professor Mitsuhiro Yanagida. “Contrary to the original expectation, it turned out that fasting induced metabolic activation rather actively.”

The study presents an analysis of whole human blood, plasma, and red blood cells drawn from four fasting individuals. The researchers monitored changing levels of metabolites – substances formed during the chemical processes that grant organisms energy and allow them to grow. The results revealed 44 metabolites, including 30 that were previously unrecognised, that increased universally among subjects between 1.5- to 60-fold within just 58 hours of fasting.

In previous research, the G0 Cell Unit identified various metabolites whose quantities decline with age, including three known as leucine, isoleucine, and ophthalmic acid. In fasting individuals, these metabolites increase in level, suggesting a mechanism by which fasting could help increase longevity. “These are very important metabolites for maintenance of muscle and antioxidant activity, respectively,” said Teruya. “This result suggests the possibility of a rejuvenating effect by fasting, which was not known until now.”

The human body tends to utilise carbohydrates for quick energy – when they’re available. When starved of carbs, the body begins looting its alternate energy stores. The act of “energy substitution” leaves a trail of evidence, namely metabolites known as butyrates, carnitines, and branched-chain amino acids. These well-known markers of energy substitution have been shown to accumulate during fasting.

But fasting appears to elicit effects far beyond energy substitution. In their comprehensive analysis of human blood, the researchers noted both established fasting markers and many more. For example, they found a global increase in substances produced by the citric acid cycle, a process by which organisms release energy stored in the chemical bonds of carbohydrates, proteins and lipids. The marked increase suggests that, during fasting, the tiny powerhouses running every cell are thrown into overdrive.
Fasting also appeared to enhance the metabolism of purine and pyrimidine, chemical substances which play key roles in gene expression and protein synthesis. The finding suggests fasting may reprogram which proteins cells build at what time, thus altering their function. The change may promote homeostasis in cells, or serve to edit their gene expression in response to environmental influences.

When metabolised, purine and pyrimidine also boost the body’s production of antioxidants. Several antioxidants, such as ergothioneine and carnosine, were found to increase significantly over the 58-hour study period. Antioxidants serve to protect cells from free radicals produced during metabolism. Products of a metabolic pathway called the “pentose phosphate pathway” also stay the harmful effects of oxidation, and were similarly seen to increase during fasting, but only in plasma.

The authors suggest that these antioxidative effects may stand as the body’s principal response to fasting, as starvation can foster a dangerously oxidative internal environment. Their exploratory study provides the first evidence of antioxidants as a fasting marker. In addition, the study introduces the novel notion that fasting might boost production of several age-related metabolites, abundant in young people, but depleted in old.

“Recent ageing studies have shown that caloric restriction and fasting have a prolonging effect on lifespan in model animals…but the detailed mechanism has remained a mystery,” said Teruya. “It might be possible to verify the anti-aging effect from various viewpoints by developing exercise programs or drugs capable of causing the metabolic reaction similar to fasting.”

The findings expand on established ideas of what fasting could do for human health. The next step would be to replicate these results in a larger study, or investigate how the metabolic changes might be triggered by other means.

“People are interested in whether human beings can enjoy the effects of prevention of metabolic diseases and prolonging life span by fasting or caloric restriction, as with model animals,” said Teruya. “Understanding the metabolic changes caused by fasting
is expected to give us wisdom for maintaining health.”

Abstract
During human fasting, metabolic markers, including butyrates, carnitines, and branched-chain amino acids, are upregulated for energy substitution through gluconeogenesis and use of stored lipids. We performed non-targeted, accurate semiquantitative metabolomic analysis of human whole blood, plasma, and red blood cells during 34–58 hr fasting of four volunteers. During this period, 44 of ~130 metabolites increased 1.5~60-fold. Consistently fourteen were previously reported. However, we identified another 30 elevated metabolites, implicating hitherto unrecognized metabolic mechanisms induced by fasting. Metabolites in pentose phosphate pathway are abundant, probably due to demand for antioxidants, NADPH, gluconeogenesis and anabolic metabolism. Global increases of TCA cycle-related compounds reflect enhanced mitochondrial activity in tissues during fasting. Enhanced purine/pyrimidine metabolites support RNA/protein synthesis and transcriptional reprogramming, which is promoted also by some fasting-related metabolites, possibly via epigenetic modulations. Thus diverse, pronounced metabolite increases result from greatly activated catabolism and anabolism stimulated by fasting. Anti-oxidation may be a principal response to fasting.

Authors
Takayuki Teruya, Romanas Chaleckis, Junko Takada, Mitsuhiro Yanagida, Hiroshi Kondoh

Okinawa Institute of Science and Technology (OIST) Graduate University material
Scientific Reports abstract


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