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Institute of Medicine (US) Committee on Nutrition, Trauma, and the Brain; Erdman J, Oria M, Pillsbury L, editors. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington (DC): National Academies Press (US); 2011.

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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel.

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14Polyphenols

Polyphenols are a diverse group of naturally occurring compounds widely distributed in many plant-based foods and plant-derived beverages. More than 8,000 have been identified in various plant species, and commonly consumed phytonutrient-rich foods include cocoa, tea, soy products, apples, onions, and Ginkgo biloba. Polyphenols arise from the common intermediate phenylalanine, or a precursor, shikimic acid. The main classes of polyphenols, based on their structure, are phenolic acids, flavonoids, stilbenes, and lignans. In food, these compounds are usually found complexed to sugar groups that must be removed by intestinal or colonic microfloral enzymatic hydrolysis. This process makes the identification of all the metabolites and evaluation of biological activity difficult, but the increase in antioxidant capacity of the plasma after consumption of polyphenol-rich foods provides evidence of absorption through the gut barrier (Pandey and Rizvi, 2009) (see Doré in Appendix C). There is interest in this group of compounds because of human and animal studies suggesting that long-term consumption is associated with protection against many chronic diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. It is important to note, however, that although studies on plasma levels and dietary intakes can be used to initiate hypotheses about nutrient status and health outcomes, their findings often vary, making it difficult to reach conclusions. It is obvious that these bioactive compounds are a heterogeneous group, with different structures and pharmacological properties.

Although few studies have been conducted to test their effects in traumatic brain injury (TBI), their mechanism of action in protecting against cardiovascular and neurodegenerative diseases suggests that they warrant attention as neuroprotectants against this disease. Flavonoids, for example, are able to interact with neuronal signaling pathways critical in controlling neuronal survival (see Doré in Appendix C). The committee selected flavonoids, specifically the flavonoid curcumin, and a stilbene, resveratrol, for review because their health effects have been studied most extensively. A list of human studies evaluating the effectiveness of these compounds in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in the acute phase is presented in Tables 14-1 (flavonoids) and 14-2 (resveratrol), which also include supporting evidence from animal models of TBI. All studies included in these tables are from 1990 and after. The occurrence or absence of adverse effects in humans is included if reported by the authors.

TABLE 14-1. Relevant Data Identified for Flavonoids.

TABLE 14-1

Relevant Data Identified for Flavonoids.

TABLE 14-2. Relevant Data Identified for Resveratrol.

TABLE 14-2

Relevant Data Identified for Resveratrol.

FLAVONOIDS

Flavonoids are the group of polyphenols most studied. Their structure consists of two aromatic rings bound together by three carbons that form an oxygenated heterocycle. More than 4,000 flavonoids have been identified and categorized into seven subclasses, based on their structure: flavonols (e.g., quercetin), flavones (e.g., apigenin), flavanones (e.g., hesperetin), flavan-3-ols (e.g., epicatechin), anthocyanins (e.g., cyanidin), polymers (e.g., proanthocyanidins), and isoflavones (e.g., genistein). In addition to their antioxidant capacity, flavonoids can also alleviate neuroinflammation and regulate mitochondrial function and neuronal cell signaling cascades (Ramassamy, 2006; Spencer, 2008; Vafeiadou et al., 2007). Because of these properties and their ability to pass through the blood-brain barrier (BBB) (Dreiseitel et al., 2009; Youdim et al., 2004), flavonoids have been suggested as potential neuroprotective agents. Below is an overview of selected human trials that summarizes the evidence on flavonoid use for the prevention of cardiovascular diseases, a group of diseases that share some common pathways (e.g., oxidative stress and inflammation) with TBI (see Table 14-1 for both human and animal studies from 1990 and later). The results from animal studies on flavonoids and TBI are also presented. The committee highlights curcumin as one flavonoid for which there is substantial evidence of neuroprotectant effects in animal models of TBI.

In light of the work of Miller and colleagues (2005), any trials undertaken should ensure that dose levels of flavonoids do not approach levels that might cause adverse events, such as higher risk of mortality.

Evidence Indicating Effects on Resilience

Human Studies

Hollman and colleagues reviewed six prospective observational studies (n = 111,067) addressing the effects of dietary intake of flavonol on stroke risk (Hollman et al., 2010). In this review, the pooled RR of stroke, for the highest versus the lowest intake of flavonol, was 0.80. In a sample of 9,208 Finnish men and women, apple consumption was significantly associated with a reduced risk of developing thrombotic stroke during a 28-year follow-up period (Knekt et al., 2000). However, the authors failed to find any significant association between quercetin and stroke (Knekt et al., 2000). Consumption of tea, as well as catechin, was not associated with significantly lower risks of stroke in the Zutphen Elderly study (806 men aged 65–84 years at baseline) in the Netherlands (Arts et al., 2001), or the College Alumni Health Study in Japan (17,228 participants with a mean age of 59.5 years at baseline) (Sesso et al., 2003b). The Women’s Health study, a large, randomized, clinical control trial that looked at vitamin E and cardiovascular disease, examined the association of food intakes of flavonols and flavones and primary food sources of flavonoids with cardiovascular disease (Sesso et al., 2003a). The study found no clear association with stroke. The authors observed nonsignificant inverse associations of the consumption of broccoli, apples, and tea with important vascular events. It is, however, noteworthy that estimation of total flavonoid intake in this study was based on an obsolete food composition table, which included only two flavonoid subclasses (flavonols and flavones). The potential neuroprotective effects of several other important flavonoids, such as flavan-3-ols, isoflavone, and anthocyanins, could therefore not be evaluated.

Despite these disappointing results, other human studies have found better cerebrovascular disease outcomes from the consumption of flavonoids. In a large Japanese cohort (n=40,462), greater intake of soy and isoflavone was significantly associated with lower risk of cerebral infarctions in women (adjusted RRs ranged from 0.35 to 0.64, comparing two extreme intake categories), though not in men (adjusted RR ranged from 0.95 to 1.21, comparing two extreme intake categories) (Kokubo et al., 2007). Another large prospective population-based study found an inverse association between high intakes of flavonoid subclasses and stroke, suggesting that high intakes of certain flavonoids could be neuroprotective (Mursu et al., 2008). This was supported by an earlier, smaller study that also tested the association between flavonoids and incidence of stroke (Keli et al., 1996). In a 2009 review, Macready and colleagues summarized 15 human dietary intervention studies that examined associations between administration of flavonoid pure supplements or a flavonoid-rich herbal extract (e.g., Ginkgo biloba) and cognitive function. The results are encouraging: nine studies reported that flavonoid supplementation provided greater neuroprotection than placebo. However, due to the great variations in exposure and outcome assessments across studies, results based on this review should be interpreted with caution.

Evidence Indicating Effects on Treatment

Human Studies

The committee found no clinical trials that tested the potential benefits of flavonoids in TBI, but did find evidence for other diseases or conditions included in the review of the literature (subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy). Included here are the results from two clinical trials and two meta-analyses that may be relevant to the hypothesis that flavonoids are beneficial for TBI. In a randomized, double-blind, placebo-controlled trial including 102 individuals with acute ischemic stroke, there was significant inverse association between isoflavone supplementation and impairment of brachial flow-mediated dilatation and serum C-reactive protein concentrations (Chan et al., 2008). A double-blind trial conducted among 309 dementia patients also found that after 26 weeks of treatment with Ginkgo biloba extract, participants had significantly better cognitive performance, as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog), than controls (Le Bars et al., 2000). In contrast, a meta-analysis failed to show significant protective effects of puerarin, an isoflavone found mainly in Pueraria, on acute ischemic stroke (only one trial was included) (Tan et al., 2008). Another meta-analysis including nine studies found that treatment with dengzhanhua, an herb widely used in China, produced “marked neurological improvement” in acute cerebral infarction patients, but the overall quality of the included studies was low (i.e., there was a “high risk of bias”) (Cao et al., 2008). Thus, no firm conclusion on the use of flavonoids could be reached.

CURCUMIN

Curcumin is a flavonoid derived from the spice turmeric, which has been used as a therapeutic agent in China and India (Sun et al., 2008). Many studies have demonstrated its antioxidant and anti-inflammatory properties, but more recent studies have also pointed to a potential ability to bind amyloid and prevent fibril and oligomer formation.

Curcumin and the Brain

Although neurodegenerative diseases are not included in this review, it is noteworthy that curcumin is being studied for potential benefits for Parkinson’s disease and Alzheimer’s disease (AD). Curcumin was shown to protect against oxidative damage and synaptophysin loss, and to lower the level of oxidized proteins and cytokines in animal models of AD. Neuroprotective effects against Parkinson’s disease were hypothesized to result from a protection of the BBB (Sun et al., 2008). The mechanism of action of curcumin is not fully elucidated, but the array of molecular targets found for curcumin (e.g., transcription factors, growth factors, antioxidant enzymes, cell-surviving kinases and signaling molecules) suggests the multifaceted mode of action of this flavonoid. Recently, several animal studies have investigated the potential effects of curcumin on TBI and on diseases with mechanistic similarities to TBI. The committee did not identify any human studies on this topic.

Uses and Safety

In a review that examined published papers included in the database MEDLINE that addressed the safety of curcumin, the investigators found no safety concerns reported in six human trials. One human trial with 25 subjects used up to 8,000 mg/day of curcumin for three months, and the other five human trials used 1,125–2,500 mg/day of curcumin (Chainani-Wu, 2003). It is, however, worth noting that curcumin may slow down blood clotting, especially when administered with anticoagulant drugs or dietary supplements having a similar effect.1

Humans and rodents metabolize curcumin differently (i.e., curcumin hydrolyzes in the gastrointestinal tract in humans but not in rodents), so investigators should ensure that they use a form of curcumin that is physiologically stable and absorbable by humans.

Evidence Indicating Effect on Resilience

Human Studies

There have been no human trials or observational studies conducted to study curcumin’s potential to impart resilience against TBI. Likewise, there are no human studies to assess the effect of curcumin on subarachnoid or intracranial hemorrhage, intracranial aneurysm, ischemia, stroke, or epilepsy.

Animal Studies

A small number of studies employing animal epilepsy models (e.g., Sharma et al., 2010), using a pentylenetetrazol-induced oxidative stress model, and Gupta et al. (2009) using a kainic acid–induced model, have consistently shown that curcumin is anticonvulsant. This finding may have relevance in TBI, because epilepsy is an effect seen in both its acute and long-term phases.

Studies also have assessed the neuroprotective effects of curcumin, using moderate or mild fluid percussion as a model of TBI. In an animal study of TBI using male CD-1 mice (8–10 weeks old; n = 8–12 per group), pretreatment with intraperitoneal injection of curcumin (75 or 150 mg/kg) resulted in significantly lower brain water content and neuroin-flammation as well as better neurological function, as assessed by the open field activity test and a two-trial novel object recognition task, than controls treated by the vehicle [dimethyl sulfoxide (DMSO)] only (Laird et al., 2010). In another animal study, however, giving adult male Sprague-Dawley rats DMSO alone conferred neuroprotective effects against neuron death due to TBI that were similar to the curcumin treatment group. In other words, there was no difference between the two treatment groups (Di Giorgio et al., 2008). Oral administration of curcumin prior to injury also has been shown to improve neurobehavioral and cognitive performance, promote membrane homeostasis, regulate energy homeostasis, reduce infarct area, and reduce lipid peroxidation in other animal studies of TBI or ischemic stroke (Sharma et al., 2009; Shukla et al., 2008; Wu et al., 2006).

Evidence Indicating Effect on Treatment

Human Studies

There have been no studies conducted with TBI patients. Likewise, there have been no human studies conducted to assess the effect of curcumin on subarachnoid or intracranial hemorrhage, intracranial aneurysm, ischemia, stroke, or epilepsy.

Animal Studies

Various animal studies conducted to test outcomes that are mechanistically similar to the pathology of TBI have shown that curcumin holds promise to lessen the effects of TBI. For example, curcumin given after injury in models of cerebral ischemia and reperfusion resulted in decreases in oxidative stress as measured by levels of malondialdehyde, cytochrome c, and cleaved caspase 3 and mitochondrial Bcl-2 expression (Zhao et al., 2010). In addition to lowering indicators of stress using similar models (Wang et al., 2005), studies have shown improved behavioral outcomes (Yang et al., 2009), attenuated neurological deficits and reactive oxygen species (Dohare et al., 2008; Jiang et al., 2007), and reduction in infarct and edema volume (Jiang et al., 2007; Thiyagarajan and Sharma, 2004).

The animal study by Laird and colleagues (2010) also included experiments with animals treated with curcumin intraperitoneally after the injury. As with preinjury administration, curcumin was found to be neuroprotective against deteriorative events caused by TBI, such as lipid peroxidation, inflammation, and cognitive impairment. Similar findings were reported in an earlier study by Shukla and colleagues (2008), where curcumin was given both pre- and postinjury. The authors of this study could make no conclusions about whether the effects of curcumin were due to its administration before the injury, or after (Shukla et al., 2008).

RESVERATROL

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) belongs to a class of polyphenolic compounds called stilbenes. Resveratrol and other stilbenes are produced by some types of plants in response to stress and injury (for example, when under attack by bacteria or fungi), presumably to aid in recovery. Resveratrol was first isolated from the roots of white hellebore in 1940, but it began to attract more interest in 1992, when its potential protective effects on the cardiovascular system were hypothesized. Resveratrol is now the subject of numerous animal and human studies on its anti-inflammatory and anticarcinogenic effects as well as its potential to confer protection from heart disease, aging, and the effects of brain damage after a stroke (Baur and Sinclair, 2006).

Resveratrol and the Brain

Resveratrol has been shown to exert anti-inflammatory and anti-aging effects in vitro and in animal models. Resveratrol inhibits the activity of several inflammatory enzymes in vitro, including cyclooxygenase and lipoxygenase, resulting in a suppressive effect upon inflammatory and oxidative stress (Ghanim et al., 2010). Resveratrol also may inhibit proinflammatory transcription factors, such as NFκB or AP-1. Other mechanisms by which resveratrol may improve brain injury effects are restoration of cerebral blood flow, repair of neural loss, and scavenging of free radicals.

Recent evidence suggests that SIRT12 inhibitors may be neuroprotective; however, resveratrol does not appear to act directly as a SIRT1 inhibitor (Tang, 2010), because it does not activate SIRT1 during the acute phase of neuronal cell demise. Resveratrol may indirectly increase SIRT1 activity in recovering or spared cells via elevation by 5′ AMP-activated protein kinase (AMPK) of NAD+ levels, which then translates into an overall beneficial outcome (activation of AMPK, another enzyme with a key role in cellular energy homeostasis, may be neuroprotective). Table 14-2 lists studies (from 1990 and after) evaluating the effectiveness of resveratrol in providing resilience or treating TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, epilepsy) in the acute phases.

Uses and Safety

An expanding body of preclinical evidence suggests resveratrol may be beneficial in treating a variety of human diseases. For this reason, resveratrol is being sold as a dietary supplement, despite the absence of definitive information about resveratrol’s effects in humans, and while research into the potential health benefits of resveratrol is continuing. As with other food components, it appears that the health benefits of resveratrol are dose-dependent. Low doses of resveratrol have been found to lead to beneficial health outcomes, while high doses of resveratrol can be detrimental to health (Mukherjee et al., 2010). High doses of resveratrol may, however, be required for treatment of pathological conditions, such as destruction of cancer cells (Mukherjee et al., 2010).

A 2011 review describes the available clinical data on safety and potential mechanisms of action following multiple dosing with resveratrol (Patel et al., 2011). The review acknowledged that a complete picture of the safety of resveratrol could not be asserted, because out of 16 clinical trials, only 5 included information on adverse effects, and only 1 of these studies included a placebo control group. Still, the authors found resveratrol to be safe and reasonably well tolerated at doses of up to 5 g/day. The review found some mild to moderate side effects, such as gastrointestinal disturbances, if used at doses higher than 1 g/day.

Evidence Indicating Effect on Resilience

Human Studies

There have been no human trials or observational studies conducted to study resveratrol’s potential to impart resilience against TBI. Likewise, there are no human studies to assess the effect of resveratrol on subarachnoid or intracranial hemorrhage, intracranial aneurysm, ischemia, stroke, or epilepsy.

Animal Studies

Numerous studies using rat models of ischemia reperfusion have demonstrated the ability of resveratrol, administered either intravenously or orally, to improve ischemia outcomes. The outcomes evaluated include cerebral blood flow, infarct volume, indicators of oxidative stress and inflammation, apoptotic cell death, and mitochondrial function. Studies have looked at the effects of intake of resveratrol as early as 21 days before the injury (Sinha et al., 2002), but even oral intake 3 days before the injury showed positive effects. For example, in an ischemia model in rats, infarct volume decreased when resveratrol was given orally once daily for three days before the injury, but there was no decrease when it was given one hour prior to injury (Inoue et al., 2003). Likewise, when administered intraperitoneally immediately after occlusion and at the time of reperfusion, oxyresveratrol (an analogue of resveratrol) at 10 and 20 mg/kg reduced the infarct volume and, in the range of 10–30 mg/ kg, improved neurological outcomes. It also reduced apoptotic cell death and damage to the mitochondria. Similar results in infarct volume reduction were reported by Gao and colleagues (2006) when resveratrol was given seven days before the injury at 50 mg/kg, and by Li and colleagues (2010) when rats were injected with 30 mg/kg of resveratrol intraperitoneally for 6 days before the injury. Li and colleagues (2010) also showed a reduction in neurological deficit scores when evaluated with a neuromotor test two hours after reperfusion. When the release of neurotransmitters was measured, rats that received resveratrol showed lower levels of glutamine and aspartate and higher levels of gamma-aminobutyric acid, glycine, and taurine than control ischemic rats. The excitotoxicity index, measured as excitation versus inhibition (i.e., glutamate × glycine/gamma-aminobutyric acid), was also lower in resveratrol-treated animals than in the injured controls. Resveratrol’s effects on resilience were also observed in younger animals. When administered before injury, resveratrol showed dose-dependent protection (but not at ≤ 0.002 mg/kg) against caspase-3 activation and also decreased the number of necrotic cells and reduced tissue loss in a neonatal model of ischemia (West et al., 2007).

Resveratrol also was beneficial in increasing the latency of pentylenetetrazol-induced epilepsy, as well as decreasing convulsions at doses ranging from 20 to 80 mg/kg. This enhanced protection also was observed when resveratrol was administered in combination with other known anticonvulsants (Gupta et al., 2002).

Evidence Indicating Effect on Treatment

Human Studies

There have been no studies conducted with TBI patients. Likewise, there have been no human studies conducted to assess the effect of resveratrol on subarachnoid or intracranial hemorrhage, intracranial aneurysm, ischemia, stroke, or epilepsy.

Animal Studies

One of the earliest investigations of the effect of resveratrol in brain injury used a model of ischemic injury in Mongolian gerbils that were given resveratrol immediately after injury and again 24 hours after injury (Wang et al., 2002). The decrease in neuronal cell death and decreased activation of astrocytes and glial cells led the authors to propose this polyphenol as a protective agent against ischemic injury. This study also demonstrated that resveratrol can cross the BBB, and has often been subsequently mentioned as a pivotal investigation. Given these positive findings, many studies have investigated the benefits of resveratrol, typically using ischemia reperfusion models in rodents. Improved measures of oxidative stress, brain damage, and blood flow indicate that the use of resveratrol is beneficial to ischemia outcomes. For example, resveratrol was found to reduce infarct volume when administered before or after injury at very low intravenous doses (10−9 and 10−10 mg/kg) (Huang et al., 2001). A single dose of resveratrol significantly increased the level of nitric oxide and decreased the hydroxyl radical level (Kwok et al., 2006) in a cerebral ischemia model in rats. Subsequent research in humans not suffering from brain damage demonstrated that oral administration resulted in dose-dependent increases in cerebral blood flow (Kennedy et al., 2010). In an effort to more precisely determine the time window of resveratrol’s efficacy after ischemia, and considering that patients will not have access to care immediately after injury, a 2010 study of mice given resveratrol three hours after ischemia showed it to be effective in suppressing indicators of inflammation, microglial activation, and reactive oxidation species (Shin et al., 2010). Yousuf and colleagues (2009) conducted a very thorough study measuring functional and histopathological indicators after a rat model of ischemia. All indicators, including mitochondrial function, energy metabolism, oxidation, apoptosis, cell death, neurological behavior, reduced DNA fragmentation, and brain damage, suggested that resveratrol was beneficial in preserving anatomy and function of the brain after injury.

Animal models of TBI also have demonstrated the benefits of resveratrol. In a fluid percussion model of TBI for rat pups, those rats treated with 100 mg/kg resveratrol immediately after trauma showed that posttraumatic memory decline (evaluated using the novel object recognition test) was restored to 66 percent of the uninjured control (Sönmez et al., 2007). In the same experiment, locomotor activity was normalized in the rats treated with resveratrol. In a weight-drop animal model of TBI, immediate treatment with a single dose of 100 mg/kg of resveratrol reduced lesion volume and brought the levels of oxidative stress indicators (malondialdehyde, nitric oxide, xanthine oxidase, and glutathione) back to preinjury levels (Ates et al., 2007). Reinforcing these positive results are the results found by Singleton and colleagues (2010) in a trial with a TBI rat model, a controlled cortical impact model. In this case, resveratrol was given intraperitoneally at 10 or 100 mg/kg three times after injury (i.e., 5 minutes, 1 day, and 2 days after injury). Motor control and coordination of the animals were tested on days 1–5 after injury, and a cognitive test (the Morris water maze) was given on days 14–20 after the injury. The 100 mg/kg dose demonstrated benefits in all measures. Contusion volume was less and hippocampal preservation increased. Cognitive test results and motor skills were improved in animals treated with the highest level of resveratrol. Animals given the 10 mg/kg dose did not see the same behavior improvements when compared to the injured controls.

CONCLUSIONS AND RECOMMENDATIONS

Given the oxidative and inflammatory processes associated with TBI, the committee supports efforts to provide a high-quality diet that supplies a mix of polyphenols. This would concur with the Dietary Guidelines for Americans, 2010, which recommends consuming a greater amount and variety of fruits and vegetables.3

The evidence presented of potential benefits of polyphenols on TBI suggests several conclusions. This review suggests that polyphenols fall into a category of compounds that exert their effects via not only their antioxidant properties, but also through modulation of enzymes important for the progression of the disease. This characteristic distinguishes this class of compounds from other antioxidants and gives them an advantage in protecting against a disease process as complex as TBI. Because there are many biological activities attributed to the flavonoids, some of which could be either beneficial or detrimental depending on specific circumstances, further studies in both the laboratory and with patient populations are warranted.

Curcumin has not been tested in humans who have experienced a TBI event. However, in animal models of TBI, curcumin administration has consistently resulted in positive outcomes such as improved neurological function and neurobehavioral performance, as well as reduced neuroinflammation and lipid oxidation. Although resveratrol has not been tested in a human TBI trial, the positive findings from studies using animal models of ischemia and TBI described above likewise support the notion that resveratrol may also be beneficial for resilience or treatment of TBI in humans.

Although caution must be exerted because the mechanisms of action of curcumin and resveratrol have not been completely elucidated, there have been no adverse effects reported from the studies reviewed. The committee concluded there is enough evidence to concur that further research needs to be conducted to confirm the results seen so far in small-animal studies and duplicate them in humans.

RECOMMENDATION 14-1. Based on positive outcomes with curcumin and resveratrol in small-animal models of TBI, DoD should consider conducting human trials. In addition, other flavonoids (e.g., isoflavones, flavanols, epicatechin, theanine) should be evaluated in animal models of TBI.

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Footnotes

1

Available online: http://www​.nlm.nih.gov​/medlineplus/druginfo/natural/662.html (accessed March 1, 2011).

2

The NAD-dependent deacetylase sirtuin-1 (SIRT1) is an enzyme that deacetylates proteins contributing to cellular regulation, including reaction to stressors.

3

Available online: http://www​.cnpp.usda​.gov/DGAs2010-PolicyDocument.htm (accessed March 1, 2011).

Copyright 2011 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK209315
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