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Nature Genetics  37, 339 - 340 (2005)

Sirtuins for healthy neurons

David Sinclair is in the Department of Pathology, Harvard Medical School, Boston, Massachusetts, 02115 USA.

Sir2 deacetylases are believed to promote the survival and longevity of organisms during times of adversity. A new study shows that activation of Sir2 by small molecules called sirtuin-activating compounds increases neuronal survival in two different models of Huntington disease, possibly opening new avenues for treatment.

Scientists should avoid using words like 'miraculous'. But if ever there was a reason to make an exception, resveratrol is it. This small nontoxic molecule from Asian medicinal herbs and red wine is currently in human clinical trials to treat colon cancer and oral herpes; in rodents, it protects against inflammatory disorders, stroke, myocardial infarction, spinal cord injury and heart disease and is one of the most effective cancer chemopreventive agents known 1. No one really knows how resveratrol achieves such feats, but there is little doubt that this knowledge could open new avenues to develop truly revolutionary drugs. Now, on page 349 of this issue, Alex Parker and colleagues 2 show that resveratrol might be effective in treating hereditary polyglutamine (polyQ) disorders such as Huntington disease; moreover, they provide evidence for a mechanism.

STACs come of age

The foundation for understanding how resveratrol works came from a small group of researchers examining why yeast cells grow old and which genes, if any, control the process. They found that genomic instability of DNA repeats is a key cause of yeast aging3 and that overexpression of a gene called SIR2 suppresses genomic instability, leading to an increase in lifespan of 30% (ref. 4). Now we know that SIR2 genes are found in all eukaryotes (humans have seven, SIRT1-SIRT7) and that many of them encode NAD+-dependent deacetylases that direct the behavior of target proteins by removing acetyl groups from specific lysines. Overexpression of SIR2 homologs also extends the lifespans of organisms that age by mechanisms ostensibly unrelated to those in yeast, namely Caenorhabditis elegans5 and Drosophila melanogaster6.

A set of 18 small polyphenolic molecules including resveratrol was recently found to increase the affinity of the SIRT1 enzyme for certain protein targets, probably through an allosteric mechanism (Fig. 1). These molecules, known as sirtuin-activating compounds (STACs), extend the lifespan of yeast, worms and flies in a Sir2-dependent manner. Sir2 and STACs seem to work by increasing cell defenses against stress, through the same or similar pathways as caloric restriction, the strict diet that increases the life expectancy of mammals by delaying diseases of old age such as cancer, heart disease, diabetes and even neurodegeneration7.


Figure 1. Routes to increasing the activity of sirtuin deacetylases.



Increasing the abundance or activity of sirtuin (class III) deacetylases protects neurons from the toxic effects of mutant huntingtin. There are four known ways to increase the activity of sirtuins. STACs, which work by contacting the enzymes directly, fall into two classes: polyphenols produced by stressed plants, such as resveratrol and fisetin, lower the Km of sirtuins, possibly through an allosteric mechanism (1), and nicotinamide (NAM) analogs increase the Vmax by blocking inhibition by nicotinamide, a physiological regulator of sirtuin activity (2). Other routes include increasing the amount or activity of the NAD+ salvage pathway gene PNC1 or its functional equivalent in mammals, known as PBEF (visfatin) (3), or increasing the levels of NMNAT, as exemplified by the WldS mouse mutant that is resistant to axonal degeneration due to an NMNAT gene duplication (4). It is also feasible that sirtuin activity is stimulated by NAD+ precursors such as nicotinamide riboside or by secreted PBEF (visfatin).

Resveratrol versus Huntington

This brings us to the work of Parker and colleagues 2. There are four main polyQ disorders, one of which is Huntington disease, a progressive neurodegenerative disorder that typically presents around age 40 with uncontrolled movements and cognitive deterioration. PolyQ disorders are so named because they stem from mutations in DNA repeats of CAG, which encode the amino acid glutamine, resulting in a given protein (in this case, huntingtin) having many more sequential glutamines than normal. For reasons that are not known, mutant huntingtin is toxic to cells, leading to neuronal dysfunction and cell death.

Parker and colleagues2 investigated two models of Huntington disease. The first involved overexpressing a pathogenic version of huntingtin in C. elegans touch receptor neurons. In these worms, a subset of mechanosensory neurons accumulates huntingtin aggregates, and the worms often fail to twitch when prodded. The second model involved culturing neurons derived from transgenic mice engineered to overexpress mutant (109Q) huntingtin. In both model systems, resveratrol suppressed the deleterious effects of mutant huntingtin, as assessed by loss of the twitch response in the worms and cell death of the mouse neurons.

Resveratrol is commonly referred to as a 'dirty' molecule in the pharmaceutical industry, meaning that it seems to interact with many different proteins, including COX1/2, ribonucleotide reductase and SIRT1. What makes this new study important is that resveratrol is almost certainly working through Sir2 enzymes.

Overexpression of Sir2 in the worm suppresses cell toxicity, whereas worms lacking Sir2 are no longer protected by resveratrol. Similarly, in mouse neurons, the action of resveratrol is blocked by the Sir2 inhibitors sirtinol and nicotinamide. Although the authors did not test whether protection is provided by SIRT1 specifically, this seems a reasonable bet, given that SIRT1 has previously been linked to cell survival in a variety of cell types, including neurons8. Fisetin, a chemically distinct class of STAC, worked even better than resveratrol at protecting worm neurons, consistent with the finding that fisetin is a considerably more potent activator of C. elegans Sir2 than is resveratrol9.

The present study comes on the heels of a string of papers linking the effects of resveratrol in mammals to SIRT1 activation, including increased survival of neurons whose axons are cut8, mobilization of fatty acids in adipocytes10 and modulation of NF-B transactivation and TNF-induced apoptosis11.

To your health

Probably the most pressing question for many readers is whether a glass of red wine can provide enough resveratrol to activate SIRT1. Older literature indicates that it does not. Red wine results in serum levels of resveratrol that barely reach the micromolar concentrations thought to be required for SIRT1 activation; what's more, resveratrol is metabolized into sulfated and glucuronidated forms within 15 min of entering the bloodstream12. But Parker et al.2 show that we may need a concentration of only 500 nM of resveratrol to protect our neurons. We should also be aware that the metabolites of resveratrol, which circulate in serum for some 9 h (ref. 12), might also activate SIRT1.

One overarching question remains: why does a group of structurally related polyphenols produced by stressed plants protect cells, improve health and, in some cases, promote longer life in various organisms? STACs may resemble an as-yet-unidentified endogenous activator. Another explanation, known as the xenohormesis hypothesis13, holds that plants synthesize STACs during stressful times to activate their own Sir2-mediated defenses and that animals benefit from picking up on these chemical stress cues from the plant world because it allows them to mobilize defenses in anticipation of a deteriorating environment. Which of these theories is correct may not be known for many years, but whether STACs can effectively treat the major diseases of our time, including neurodegenerative disorders, may be known far sooner than that. Wouldn't that be a miracle?

REFERENCES
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Yeung, F. et al. EMBO J. 23, 2369-2380 (2004). | Article | PubMed  | ChemPort |
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