Small molecules that regulate lifespan: evidence for xenohormesis.
Barring genetic manipulation, the diet known as calorie restriction (CR) is currently the only way to slow down ageing in mammals. The fact that CR works on most species, even microorganisms, implies a conserved underlying mechanism. Recent findings in the yeast Saccharomyces cerevisiae indicate that CR extends lifespan because it is a mild biological stressor that activates Sir2, a key component of yeast longevity and the founding member of the sirtuin family of deacetylases. The sirtuin family appears to have first arisen in primordial eukaryotes, possibly to help them cope with adverse conditions. Today they are found in plants, yeast, and animals and may underlie the remarkable health benefits of CR. Interestingly, a class of polyphenolic molecules produced by plants in response to stress can activate the sirtuins from yeast and metazoans. At least in the case of yeast, these molecules greatly extend lifespan by mimicking CR. One explanation for this surprising observation is the 'xenohormesis hypothesis', the idea that organisms have evolved to respond to stress signalling molecules produced by other species in their environment. In this way, organisms can prepare in advance for a deteriorating environment and/or loss of food supply.
Harvard Medical School, Department of Pathology, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Dudley W
DW
Lamming
Jason G
JG
Wood
David A
DA
Sinclair
D000818:Animals; D031204:Caloric Restriction; D005419:Flavonoids / Q000494:pharmacology*; D015966:Gene Expression Regulation, Fungal; D018869:Heat-Shock Response; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology*; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D056565:Sirtuin 2; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases