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MITís latest SIRT1 research links dietary stress and predisposition to metabolic dysfunction
CAMBRIDGE, Mass.óAs he marks a trailblazing 20-year career exploring the potential for a set of proteins called sirtuins to treat inflammatory, metabolic and neurologic disorders, Massachusetts Institute of Technology (MIT) biology professor Leonard Guarente is making headlines again, this time for a study showing that SIRT1, which has been shown to slow aging in mice and other animals, also protects against the effects of a high-fat dietóincluding diabetes, a disease impacting patients worldwide by the millions.
Nearly two decades ago, Guarente was the first to discover that sirtuins prolong lifespan in yeast; since then, they have been shown to have similar effects in worms, mice and other animals. By deleting the SIRT1 gene from organs such as brain and liver to pinpoint its effects more precisely, Guarente and his colleagues have shown that SIRT1 protects against the neurodegeneration seen in Alzheimer's, Huntington's and Parkinson's diseases. More recently, as reported in ddn in 2011, Guarente's lab published further work on SIRT1 showing that it also plays a role in the psychological response to dietary restriction and its correlation to anxiety and panic disorder.
"These findings brought us to the question we'd been worrying about for a long time: What happens to SIRT1, either in the disease state, or in aging? We suspected that somehow, either disease or aging leads to a decline in activity, but we'd never been able to wrap our arms around a specific mechanism until this paper," he says.
In the paper, published Aug. 8 in the journal Cell Metabolism, Guarante investigated what happens when the SIRT1 protein is missing from adipose cells, which make up body fat. Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues.
Guarente reports that SIRT1 functions in adipose tissue to protect from inflammation and obesity under normal feeding conditions, and to forestall the progression to metabolic dysfunction under dietary stress and aging. Genetic ablation of SIRT1 in adipose tissue leads to gene expression changes that highly overlap with changes induced by high-fat diet in wild-type mice. This finding prompted Guarente to test the hypothesis that stress signals generated in obesity might inhibit SIRT1 activity in white adipose tissue.
"We show that a high-fat diet induces the cleavage of SIRT1 protein in adipose tissue by the inflammation-activated caspase- 1, providing a link between dietary stress and predisposition to metabolic dysfunction," says Guarente.
It's already known that high-fat diets can provoke inflammation, though it's unclear exactly how that happens, Guarente says.
"What our study says is that once you induce the inflammatory response, the consequence in the fat cells is that SIRT1 will be cleaved," he says.
The researchers also found that as normal mice aged, they were more susceptible to the effects of a high-fat diet than younger mice, suggesting that they lose the protective effects of SIRT1 as they age. Aging is known to increase inflammation, so Guarente's lab is now studying whether age-related inflammation also provokes SIRT1 loss.
The findings "suggest new strategies to look for drugs for inflammatory and metabolic disorders," says Guarente.
"Imagine if you had a drug that could bind to SIRT1 or the caspase-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 invested in looking at many ways to activate SIRT1."
"Twenty years later, SIRT1 is still a very attractive target for ameliorating the diseases of aging. This includes inflammatory and metabolic diseases, but also a lot of neurodegenerative diseases which likely have a component of inflammation involved," he says.