Why SIRT1 in your brain may keep you smart
August 10, 2010 by David Despain
Picture a scene in the ancient wild: a time when drought and famine have taken the land, food is scant and predators are near, and staying alive depends on being active, alert, and quick-witted — and asking, “Where did I find those nuts last year, and where was that water hole?“
A protein called SIRT1 in our brains may explain how our ancestors lived through such nutritionally scarce situations by protecting neurons and keeping the brain smart in extreme situations of survival.
Additionally, recent research in animals suggests that through calorie restriction, periodic fasting, taking compounds such as resveratrol, and drug therapies of the future, humans today could increase production of SIRT1 to sharpen their own thinking and memory, and guard against the onset of diseases such as Alzheimer’s.
This hypothesis, that SIRT1 sustains learning and memory, received a major boost in July when five connected studies evaluated mice bred to have lower or increased levels of the SIRT1 protein in their neurons. The studies showed that the protein is critical for learning and memory, protects against memory loss, and keeps mice alert, physically active, and burning calories efficiently.
Sidebar: 10 Steps to Enhance Brain Power
The human brain evolved primarily to increase our chances of survival. So the trick to boosting brain power and creativity – and sharpening thinking and memory — depends on tapping into the brain’s neural mechanisms that allow you to adapt to situations, solve problems, and live to see another day of passing on genes.
Unfortunately, modern life does little for brain power. Because SIRT1 is a crucial protein keeping the brain healthy, active and smart, it’s important to adopt habits that potentially increase levels of SIRT1 in the brain for learning and memory. In parallel, there are other major changes we can make that also improve the brain.
- Eat like a wild, ancient human. Consuming fewer calories and fasting periodically as our ancestors would have in an environment where food was occasionally scarce can be healthier for the brain, apart from eating a diet of natural foods rich in nutrients. Lowering calories and fasting leads to losing weight, which is critical for brain health and reducing risk of dementia, Alzheimer’s disease, and other chronic diseases. In addition, studies in animals also show that calorie restriction and fasting can increase production of SIRT1 in the brain. While it’s still unclear if lowering caloric intake increases SIRT in humans, epidemiological studies suggest that’s the case.
- Supplement with resveratrol. The natural plant compound, found in many foods including red grapes and red wine, is a known SIRT1 activator. However, at least one randomized, clinical trial in humans has found that doses of 250 and 500 milligrams—more than 100 and 200 times the amount found in a glass of pinot noir—taken twice daily is enough resveratrol to boost blood flow in the brain. As little as 40 milligrams of resveratrol daily in humans was also recently shown to suppress oxidative stress and inflammation.
- Exercise like a wild, ancient human. Our brains evolved once our ancestors were bipedal, and research now shows that aerobic exercise—even the simple act of going for walks a couple of times weekly—is enough to improve brain function, learning and memory, by boosting blood flow and increasing circulation in the brain.
- Get enough of the “sunshine vitamin.” Vitamin D—made naturally in your skin when it’s exposed to the sun’s UV-B rays—is not really a vitamin at all, but a hormone, with receptors throughout the body, including the brain’s cortex and hippocampus, and responsible for cognitive performance. The hormone is now known to be involved in protection and growth of neurons, and new research shows that vitamin D may be associated with protecting against neurological diseases. Additionally, low levels of vitamin D are associated with poor learning and memory. Recent research suggests most people have low levels of vitamin D and that greater intake daily in ranges of 1,000-2,000 international units daily are needed to guard against insufficiency.
- Eat fish or supplement with fish oil. Your brain is about 60 percent fat, and most of that fat is a type of long-chain omega-3 fatty acid found in rich amounts in fish, called docosahexaenoic acid, or DHA. The last decade of research has revealed a strong association between declining amount of DHA in the brain and memory loss. In fact, one study showed older adults who ate fish at least once a week had 60 percent less risk of Alzheimer’s disease.
- Eat blueberries. These berries are rich in antioxidants called anthocyanins, which have been found to protect animals from neuronal damage and even improve learning memory. Earlier this year, a randomized, double-blind clinical trial also showed that drinking 2 or more cups of wild blueberry juice daily improves learning and memory in older adults. Additional research suggests that the blueberries are even more preventive the earlier they’re adopted in the diet.
- Limit alcohol. Excessive alcohol consumption can destroy brain cells and research in rhesus monkeys shows chronic consumption can even harm mental executive function and memory. One drink a day for women, two drinks a day for men—that’s the generally accepted rule.
- Drink coffee and tea (preferably green tea). Both of these drinks contain caffeine, our favorite drug, which has been associated recently with restoring and improving brain function, preventing damage in the brain, and reducing production of beta-amyloid plaques (implicated in Alzheimer’s). Green tea also adds antioxidant catechins that have shown effects in reducing oxidative stress in the brain.
- Never stop learning. The phrase, “use it or lose it” applies to the brain. A higher level of education is, in fact, associated with lower risk of Alzheimer’s disease. Brain exercises such as reading, writing, playing chess and playing music all improve brain power by strengthening connections between synapses. Socializing is particularly powerful, as even as little as 10 minutes daily has been found to improve learning and memory.
- Sleep. Because sleeping is the time when the brain repairs neuronal damage, lack of sleep saps learning and memory. The human brain also requires a good night’s rest to consolidate what it has learned during the day. In fact, studies show that sleeping within a few hours after learning consistently enhances memory, specifically the recall of information learned earlier.
Losing weight to avoid becoming prey
First to appear, on July 7, was a study in Cell Metabolism showing that SIRT1 in neurons of the hypothalamus in mice prevents excess weight gain, which, according to lead author Roberto Coppari of University of Texas Southwestern Medical Center, was necessary to survive in the wild.
At first glimpse, blocking fat storage appears counterintuitive during famine or drought, as one might guess there’s an evolutionary advantage for storing fat, not shedding it. But Coppari disagrees, telling me that there’s an advantage to avoiding obesity in the wild, because obesity was likely to increase chances of becoming easy prey.
The second and third studies to appear in July both discovered that SIRT1 in the brain is critical for maintaining synaptic plasticity, which is in turn critical for learning and memory.
On July 11 in Nature, Jun Gao and colleagues of MIT’s Picower Institute for Learning and Memory showed that mice lacking SIRT1 had diminished ability to recognize what should have been familiar objects. Then, on July 27 in Journal of Neuroscience, Valter Longo of University of Southern California and collaborators from NIH Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health (NIH) Gerontology Research Center explained that SIRT1 was “indispensable” to proper function of the mind, noting that mice lacking brain SIRT1 exhibited “impaired cognitive abilities, including immediate memory, classical conditioning, and spatial learning.”
Evolutionary biologist David Sinclair of Harvard Medical School, a co-author of the July 27 study, told me that SIRT1 may actually enhance memory. However, Longo thinks it’s too early to tell, writing to me, “I think that what we know thus far is that SIRT1 is important for normal memory.”
Shielding against memory loss
The fourth study, published July 23 in Cell, received the most media attention because it showed “clearly” that higher levels of brain SIRT1 reduced memory loss in mice bred to be prone to Alzheimer’s disease. Leonard Guarente and fellow MIT researchers showed that SIRT1 gave the brain a double dose of brain protection: SIRT1 guards the brain against memory loss by reducing production of beta-amyloid, a “junk” protein implicated with producing plaques. SIRT1 also activates the “notch pathway,“ a mechanism that boosts repair of neuronal damage.
In a commentary about Guarente’s paper in the same issue of Cell, Michael Wolfe and Dennis Selkoe of Harvard Medical School described SIRT1′s “one-two” punch on Alzheimer’s disease as having major potential, offering hope to millions of elderly who suffer from memory loss.
Making you more alert and active
Lastly, the fifth study, published July 28 in Journal of Neuroscience, clarifies how SIRT1 in the brain controls alertness and activity of the body in response to eating fewer food calories.
Shin-Ichiro Imai and colleagues at Washington University School of Medicine observed that mice genetically engineered to have higher levels of SIRT1 in their brains showed enhanced behavior (increased activity and alertness) for seeking and expecting food under conditions of two-day fasting and calorie restriction.
What Imai points out is that SIRT1′s major effects take place in the hypothalamus—a small region of the brain that controls hunger, metabolism and body temperature.
Enhancing the mind
To summarize, each of the five studies add to a growing weight of evidence that SIRT1 in the brain acts as a key regulator for staying alert, active and keeping up brain power—while also controlling fat metabolism and slowing aging.
The research basically says: to enhance your brain, you should adjust your lifestyle, diet, and use of compounds or drugs to increase levels of SIRT1 in the brain. The target: an enhanced mind — as alert as those of our ancestors — that thinks more clearly, stays smart, and learns longer.
SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 2010;12:78-87.
SIRT1 Is Essential for Normal Cognitive Function and Synaptic Plasticity. J Neurosci 2010;30:9695-707.
SIRT1 Suppresses beta-Amyloid Production by Activating the alpha-Secretase Gene ADAM10. Cell 2010;142:320-32.
Giving Alzheimer’s the old one-two. Cell 2010;142:194-6.