For release: Monday, April 30, 2012
Two studies suggest that the sirtuin-1 (Sirt1) gene, known for its possible role in longevity, may be a therapeutic target for Huntington's disease. The studies found that boosting the levels of Sirt1 reduced the loss of brain tissue in mouse models of Huntington’s disease.
"The role of sirtuins in aging and disease has been the focus of intense research. Together, these studies provide some of the strongest evidence to date that sirtuins may have a protective role in neurodegenerative disease," said Margaret Sutherland, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. The studies were funded by NINDS and published in Nature Medicine.
Sirtuins were first linked to longevity in 1999, when researchers at the Massachusetts Institute of Technology found that yeast cells lived longer with increased levels, or over-expression, of a sirtuin gene. Similar results were found with roundworms and fruit flies. In another milestone, sirtuins were linked to calorie restriction. Restricting calorie intake increases lifespan and produces healthy metabolic changes in laboratory animals; there is evidence that sirtuins are needed for at least some of these effects.
Sirt1 over-expression protects against brain atrophy in the mouse model of Huntington's disease (HD). In these MRI scans, the white lines represent the normal contours of the mouse brain. Left: an HD mouse. Right: an HD mouse over-expressing Sirt1. From Jiang et al., Nature Medicine 2011.
Recent data, however, suggest that those early studies may have over-estimated the effects of sirtuins on lifespan. One theory is that sirtuins may influence the susceptibility to age-related diseases, not the aging process itself.
Research into how sirtuins affect Huntington’s disease has its own ambiguities. Sirtuins seem to counteract Huntington's pathology in worms, but aggravate it in fruit flies. The two recent studies are the first to show that sirtuins can protect against Huntington's disease in mice.
Huntington’s disease is a genetic disorder that attacks parts of the brain involved in movement and thinking. Symptoms usually appear in middle age and include involuntary movements, personality changes and mental decline. The disease worsens over time, and is usually fatal within 20 years of onset. It is caused by mutations in a gene called huntingtin.
The recent studies utilized mice carrying these huntingtin mutations to investigate whether Sirt1 over-expression could protect against the disease. One study was led by Dimitri Krainc, M.D., Ph.D., who is an investigator at Massachusetts General Hospital and a professor of neurology at Harvard Medical School in Boston.* The other was led by Wenzhen Duan, M.D., Ph.D., a professor of neurobiology at The Johns Hopkins University in Baltimore, with Dr. Krainc as a co-author.**
Both studies found that Sirt1 helped prevent atrophy (shrinkage) of a brain region called the striatum, which is a common feature of Huntington’s disease. Other results of the two studies diverge but still point to a protective effect. For example, Sirt1 over-expression improved survival of the mice only in Dr. Krainc’s study, and it slowed motor impairment only in Dr. Duan’s study.
The researchers say some of their unique findings are likely due to differences in the overall genetic makeup of the mouse lines used and in the way that Sirt1 gene expression was controlled. In Dr. Duan’s study, the extra Sirt1 was targeted to the brain; in Dr. Krainc’s study, the gene was over-expressed in other tissues, too.
“In all of the mice we examined, Sirt1 protected against brain atrophy. On that issue – which is essential in any therapeutic approach to Huntington’s disease – our studies are in complete agreement. But the differences are interesting and they should be explored,” Dr. Krainc said.
Like prior research on sirtuins, Dr. Duan’s study hints at a link between sirtuins and calorie restriction. In normal mice, calorie restriction reduces the incidence of hyperglycemia (high levels of glucose in the blood) and diabetes. Some Huntington’s mice are prone to hyperglycemia. Dr. Duan found that this could be corrected either by calorie restriction or by over-expression of Sirt1.
Other questions for future research include how much Sirt1 is needed, and where, for optimal protection against Huntington’s disease.
"The dosage of sirtuins may be a critical factor, and could be responsible for some of the controversy in prior studies," said Dr. Duan. She is also interested in knowing which cell types must express Sirt1 in order to see its protective effects.
The researchers have begun to look at the cellular changes that Sirt1 triggers to counteract Huntington’s disease. Sirt1 is an enzyme that regulates other proteins, but many of its targets are unknown. Dr. Krainc’s group found that Sirt1 can activate a gene-regulatory protein called TORC1, which in turn activates pro-survival genes. Working together, the two groups found that the mutant huntingtin protein inhibits Sirt1's enzymatic activity.
Assuming that these data are confirmed in human studies, the ultimate question is whether Sirt1 and its effects against Huntington’s can be kick-started with a drug treatment. Some research has found that resveratrol, a chemical found in trace amounts in red wine, can activate sirtuins, possibly mimicking the effects of calorie restriction. As research continues to try to define these effects, pharmaceutical companies are developing sirtuin activators as potential treatments for age-related diseases.
Drs. Duan and Krainc agree that for now, efforts to test such compounds against Huntington’s disease would be premature.
"We are still trying to understand the role of Sirt1 in the normal brain versus its role in disease. We want to lay that groundwork before we begin evaluating therapeutic compounds," said Dr. Krainc. He also noted that currently available Sirt1 activators have non-specific effects on other proteins and do not efficiently penetrate the brain.
"The development of Sirt1 activators and other novel therapeutics for Huntington's disease will require a collaborative effort involving NIH, academia, industry and foundations," Dr. Sutherland said. She noted that NINDS has partnered with the Huntington's research nonprofit CHDI, Inc. to encourage projects that will zero in on the most robust therapeutic targets.
In addition to NINDS, the research received support from CHDI, Inc., and the Hereditary Disease Foundation. Dr. Krainc’s study was also supported by the Paul F. Glenn Foundation and NIH’s National Institute of Mental Health and National Center for Research Resources. Dr. Duan’s study received additional NIH support from the National Institute on Aging intramural program, the National Institute of Biomedical Imaging and Bioengineering, and the National Institute for Environmental Health Sciences.
- By Daniel Stimson, Ph.D.
*Jeong H et al. "Sirt1 mediates neuroprotection from mutant huntingtin by activation of TORC1 and CREB transcriptional pathway." Nature Medicine, published online December 12, 2011.
**Jiang M et al. "Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets." Nature Medicine, published online December 12, 2011.
Last Modified May 1, 2012