Calorie Restriction, Glycolysis and Aging

The folk of the Calorie Restriction Society mailing lists recently pointed out a couple of papers proposing yet another way in which calorie restriction (known as dietary restriction in some scientific circles) may slow one of the root causes of age-related degeneration.

Glycolysis is a near-universal metabolic processing of glucose, a part of the normal day to day operations of your cells. However, like most metabolic processes, it generates intermediary and other products that can - and do - cause damage to cellular machinery. In essence, cells can get gunked up with sugars and sugar by-products. The first paper from earlier this year sets the stage:

Does Chronic Glycolysis Accelerate Aging? Could This Explain How Dietary Restriction Works?

The mechanisms by which dietary restriction (DR) suppresses aging are not understood. Suppression of glycolysis by DR could contribute to controlling senescence. Many glycolytic intermediates can glycate proteins and other macromolecules. Methyglyoxal (MG), formed from dihydroxyacetone- and glyceraldehyde-3-phosphates, rapidly glycates proteins, damages mitochondria, and induces a prooxidant state to create a senescent-like condition. Ad libitum-fed and DR animals differ in mitochondrial activity and glycolytic flux rates. Persistent glycolysis in the unrestricted condition would increase the intracellular load of glycating agents (e.g., MG) and increase [reactive oxygen species] generation by inactive mitochondria. Occasional glycolysis during DR would decrease MG and reactive oxygen species (ROS) production and could be hormetic, inducing synthesis of glyoxalase-1 and anti-glycating agents (carnosine and polyamines).

Which is the longer and more precise way of suggesting that (a) calorie restriction may lead to a more efficient metabolic process that produces less sugared-up (glycated) gunk to damage the cell, and (b) having just a little sugared-up gunk might actually be better for you than having none, a phenomenon known as hormesis. For a high level overview as to why having glycated junk floating around in your cells - or damaged, ROS-generating mitochondria - contributes to aging, you might want to try the science section of the Strategies for Engineered Negligible Senescence (SENS) website.

A second and more recent paper from the same researcher digs a little deeper into these mechanisms, using the comparison in results between constant calorie restriction and strategies such as alternate day fasting.

Dietary restriction, glycolysis, hormesis and ageing

The possibility is discussed that dietary restriction modulates ageing and onset of related pathologies by, in addition to upregulation of proteolysis, suppression of glycolysis which in turn decreases generation of methylglyoxal (MG), a highly toxic glycating agent which can provoke cellular senescence and many age-related pathologies. This proposal is supported by the observation that intermittent feeding can mimic dietary restriction's effects on mouse lifespan without any overall reduction in calorie intake. That MG-induced modification of the chaperone and anti-apoptotic protein (Hsp27) increases its protective functions suggests a possible hormetic response to transient MG production during transient periods of glycolysis in dietary restricted animals. It is suggested that in the ad libitum-fed state permanent glycolysis would suppress proteolysis and continuously generate MG which overwhelms the anti-MG defence systems. It is proposed that periods of fasting might be a more acceptable approach than permanent undernutrition in our attempts to slow human ageing, although timing of meals may prove important.

Proteolysis is the catch-all name for ways in which the cell gets rid of the proteins it doesn't want, such as harmful glycated proteins produced as a side-effect of glycolysis.

It is interesting to see biochemical arguments being marshalled on the side of intermittant fasting; the final answer as to the best way to use calorie intake to tune your metabolism will come with a more complete understanding of the processes involved. While there is no such thing as useless biochemistry in the long run, calorie restriction research - implicitly aimed at slowing the accumulation of some types of damage that causes aging - seems to me to be somewhat less important than finding ways to repair that damage. Slowing damage only gets you a little further down the road of longevity; repairing damage means the ability to go as far as you care to.

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