Nearly two decades ago, Guarente was the first to discoverthat sirtuins prolong lifespan in yeast; since then, they have been shown tohave similar effects in worms, mice and other animals. By deleting the SIRT1gene from organs such as brain and liver to pinpoint its effects moreprecisely, Guarente and his colleagues have shown that SIRT1 protects againstthe neurodegeneration seen in Alzheimer's, Huntington's and Parkinson'sdiseases. More recently, as reported in ddnin 2011, Guarente's lab published further work on SIRT1 showing that italso plays a role in the psychological response to dietary restriction and itscorrelation to anxiety and panic disorder.
"These findings brought us to the question we'd beenworrying about for a long time: What happens to SIRT1, either in the diseasestate, or in aging? We suspected that somehow, either disease or aging leads toa decline in activity, but we'd never been able to wrap our arms around aspecific mechanism until this paper," he says.
In the paper, published Aug. 8 in the journal Cell Metabolism, Guarante investigated whathappens when the SIRT1 protein is missing from adipose cells, which make upbody fat. Adipose tissue plays an important role in storing excess nutrientsand preventing ectopic lipid accumulation in other organs. Obesity leads toexcess lipid storage in adipocytes, resulting in the generation of stresssignals and the derangement of metabolic functions. SIRT1 is an importantregulatory sensor of nutrient availability in many metabolic tissues.
Guarente reports that SIRT1 functions in adipose tissue toprotect from inflammation and obesity under normal feeding conditions, and to forestallthe progression to metabolic dysfunction under dietary stress and aging.Genetic ablation of SIRT1 in adipose tissue leads to gene expression changesthat highly overlap with changes induced by high-fat diet in wild-type mice. Thisfinding prompted Guarente to test the hypothesis that stress signals generatedin obesity might inhibit SIRT1 activity in white adipose tissue.
"We show that a high-fat diet induces the cleavage of SIRT1protein in adipose tissue by the inflammation-activated caspase-1, providing alink between dietary stress and predisposition to metabolic dysfunction," saysGuarente.
It's already known that high-fat diets can provokeinflammation, though it's unclear exactly how that happens, Guarente says.
"What our study says is that once you induce theinflammatory response, the consequence in the fat cells is that SIRT1 will becleaved," he says.
The researchers also found that as normal mice aged, theywere more susceptible to the effects of a high-fat diet than younger mice, suggestingthat they lose the protective effects of SIRT1 as they age. Aging is known toincrease inflammation, so Guarente's lab is now studying whether age-relatedinflammation also provokes SIRT1 loss.
The findings "suggest new strategies to look for drugs forinflammatory and metabolic disorders," says Guarente.
"Imagine if you had a drug that could bind to SIRT1 or thecaspase-1 protease and block the cleavage of SIRT1," he suggests.
Guarente is on the scientific advisory board of Sirtris Pharmaceuticals,a division of GlaxoSmithKline PLC, and he notes that the company is "heavily investedin looking at many ways to activate SIRT1."
"Twenty years later, SIRT1 is still a very attractive targetfor ameliorating the diseases of aging. This includes inflammatory andmetabolic diseases, but also a lot of neurodegenerative diseases which likelyhave a component of inflammation involved," he says.
The study, "High-Fat Diet Triggers Inflammation-InducedCleavage of SIRT1 in Adipose Tissue To Promote Metabolic Dysfunction," wasfunded by the U.S. National Institutes of Health, the Glenn Medical Foundationand the American Heart Association.
