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.