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Sirtuins: Say "Yes SIR!" to Resveratrol

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By Tom Brock, Ph.D.

What's not to love about sirtuins? They lengthen life. They cure age-related diseases like diabetes, neurodegeneration, and cancer. And they are activated by resveratrol, a compound that occurs naturally in red grapes and is abundant in red wine. I would happily take a safe, natural compound that guarantees a longer healthier life, and I'd give it to my kids. No wonder GlaxoSmithKline recently paid $720 million for Sirtris, the company that's developing sirtuin activators.


The Proof of Increased Longevity

The evidence is clear: extra copies of the SIRT1 gene (or its homolog) increases longevity in yeast, nematodes and Drosophila. The only thing that increases life span in a comparable way is caloric restriction – a lifetime of eating 20-40% less than typical intake. Also, caloric restriction does not increase longevity in yeast or flies lacking the SIRT1 homolog. Perhaps most exciting of all, mice that were given a resveratrol analog with a high fat diet lived longer than mice receiving just the high fat diet.

Adding further interest, SIRT1 is activated by NAD+ (nicotinamide adenine dinucleotide), an important substrate in energy and oxidation reactions, so SIRT1 acts as an energy and redox sensor. Caloric restriction increases NAD+, which activates SIRT1. In addition, increased SIRT1 in mammalian cells allows some of the cells to survive stresses that would normally trigger programmed cell death. Since sirtuins are activated by NAD+, perhaps it's not surprising that sirtuin activators stimulate insulin secretion and glucose metabolism and are being developed to treat type II diabetes.


Technical Talk: How it Works

Of the seven human sirtuin proteins, five are deacetylases, while the other two function as ADP-ribosyl transferases. Acetylation of proteins, like phosphorylation, can activate, inactivate, or stabilize activity; deacetylation reverses the effect of acetylation. For example, acetylation of histones relaxes histone-DNA interactions and allows transcription, so histone deacetylases repress transcription. Sirtuins act on histones as well as many other proteins. Some sirtuins, like SIRT1, function in the cytoplasm and nucleus, while others, like SIRT4, act predominantly in the mitochondria.

Sirtuins are relatively ubiquitous, so they occur throughout the body. Neurologists may be familiar with the Wallerian mouse, which is resistant to neurodegeneration. It turns out that this mouse contains a duplicated piece of DNA which includes a gene for an enzyme that makes NAD+, so the extra NAD+ protects neurons by activating SIRT1. Also, resveratrol prevents nerve cells from dying in a murine model of Huntington's disease. In liver, muscle, and fat cells, SIRT1 acts as a sensor of changes in diet, using NAD+ as an indicator, to alter the activity of enzymes and genes that protect these cells from energy and redox stresses.

Two of the sirtuins, 4 and 6, are ADP-ribosyl transferases, transferring ADP-ribose from NAD+ onto proteins. This modification is known to be important in apoptosis and DNA repair. Cells lacking SIRT6 cannot perform DNA base excision repair. For this reason, SIRT6 knockout mice degenerate rapidly after birth and die within four weeks, suffering from weakened bones and a diminished immune system. While it might be exaggeration to call this 'premature aging', this suite of symptoms is unlike any known disease.


The Final Analysis

The proof is coming: a resveratrol analog, called SRT501, is in clinical trials for the treatment of type II diabetes. It has been shown to be safe and well-tolerated. More importantly, SRT501 was shown to lower glucose and improve insulin sensitivity in patients with type II diabetes. SRT501 is also being tested for the treatment of optic neuritis, multiple sclerosis, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome, as well as, more broadly, metabolic, neurological and cardiovascular diseases, and cancer.


References

1. Conforti, L., Fang, G., Bierowski, B., et al. Cell Death Differ. 14, 116-127 (2007).

2. Feng, Y., Paul, I.A., and LeBlanc, M.H. Brain Res. Bull. 69, 117-122 (2006).

3. Slomka, M., Zieminska, E., and Lazarewicz, J.W. Acta Neurobiol. 68, 1-9 (2008).

4. Gan, L., and Mucke, L. Neuron 58, 10-14 (2008).

5. Yamamoto, H., Schoonjans, K., and Auwerx, J. Molec. Endocrinol. 21, 1745-1755 (2007).

6. Schwer, B., and Verdin, E. Cell Metab. 7, 104-112 (2008).

7. Milne, J.C., and Denu, J.M. Curr. Opin. Chem. Biol. 12, 11-17 (2008).

 

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