Many researchers are betting that ageing and disease are two sides of the same coin. Here is the abstract of relevant work from Milne et al. in the Nov. 29 Nature, followed by a clip from a Nov. 28 Nature News Feature from Hayden.
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes1, 2. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
And, from Hayden's article:
The idea that growing old and growing ill are two sides of the same coin remains controversial. Backers of the concept include David Sinclair of Harvard Medical School who made headlines with findings that a chemical in red wine called resveratrol extends lifespan and might prevent diabetes-like symptoms in mice3 (see also page 712). “I don't see ageing as a disease, but as a collection of quite predictable diseases caused by the deterioration of the body,” Sinclair says.
But others don't see it that way. The University of Michigan's Richard Miller says that Sinclair's characterization is “missing the point in a subtle but important way”. Ageing is a major cause of many diseases, but not the only one, Miller argues. And, he adds, ageing has some effects that aren't considered disease states. “It's important to make a distinction between ageing and disease,” Miller says.
Still, those who differ agree that interfering with the ageing process could help patients who are suffering from age-related disease. Sinclair is already running a clinical trial using resveratrol to prevent diabetes in humans.
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