On the mechanisms of ageing suppression by dietary restriction-is persistent glycolysis the problem?
The mechanism(s) by which dietary restriction (DR) suppresses ageing and onset of age-related pathologies are discussed in relation to frequency of glycolysis, and the reactivity of glycolytic intermediates. Most glycolytic intermediates are potentially toxic and readily modify (i.e. glycate) proteins and other macromolecules non-enzymically. Attention is drawn to the reactivity of methyglyoxal (MG) which is formed predominantly from the glycolytic intermediates dihydroxyacetone- and glyceraldehyde-3-phosphates. MG rapidly glycates proteins, damages mitochondria and induces a pro-oxidant state, similar to that observed in aged cells. It is suggested that because DR animals' energy metabolism is less glycolytic than in those fed ad libitum, intracellular MG levels are lowered by DR The decreased glycolysis during DR may delay senescence by lowering intracellular MG concentration compared to ad libitum-fed animals. Because of the reactivity MG and glycolytic intermediates, occasional glycolysis could be hormetic where glyoxalase, carnosine synthetase and ornithine decarboxylase are upregulated to control cellular MG concentration. It is suggested that in ad libitum-fed animals persistent glycolysis permanently raises MG levels which progressively overwhelm protective processes, particularly in non-mitotic tissues, to create the senescent state earlier than in DR animals. The possible impact of diet and intracellular glycating agents on age-related mitochondrial dysfunction is also discussed.
Hipkiss
Alan R
AR
Centre for Experimental Therapeutics, William Harvey Research Institute, John Vane Science Centre, Bart's and the London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. alanandjill@lineone.net
D000375:Aging / Q000502:physiology*; D000818:Animals; D005075:Biological Evolution; D031204:Caloric Restriction; D006019:Glycolysis / Q000502:physiology*; D006037:Glyoxal / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D013312:Stress, Physiological / Q000503:physiopathology
D006037:Glyoxal