Can limited alcohol consumption help stave off age related cognitive impairment?

Summary: A new paper raised the question, can limited alcohol consumption help stave off age related cognitive impairment?

Source: PLOS.

Wisdom and grace come with age, but so do mental slowing and increased risk for dementia. As the elderly population continues to grow, preserving brain health to maintain independence and quality of life into older age is a pressing concern. Researchers have identified some unsurprising factors that reduce one’s risk for cognitive decline, including education, exercise or a healthy diet. But a more controversial question that continues to perplex scientists is whether alcohol consumption might also stave off cognitive impairment with age.

The aging brain on alcohol

Image shows a glass of wine.

Anyone who’s experienced the fatigue and brain fog that follow a night of heavy drinking doesn’t need science to explain the dangers of excessive alcohol intake. These health risks may be especially impactful to the older brain, which is already particularly vulnerable to environmental stressors. However, in moderation, a glass of wine or beer may not only be harmless, but may in fact also confer resilience to the aging brain against cognitive decline. Numerous studies have reported that moderate drinking is associated with lower rates of dementia, better cognitive performance, and slower decline in memory and executive functions. Yet, not all studies support the notion that a nightcap can help keep the brain sharp into late life. These discrepant findings raise two obvious questions. First, why are some patterns of drinking neurobiologically healthy, while others are toxic? And second, how can we better identify drinking behaviors that promote the healthiest trajectories of cognitive aging?

Neuroprotective in moderation, neurotoxic in excess

In excess, alcohol works as a neurotoxin on many levels. Studies in animals have shown that binging on ethanol kills neurons and impairs neurogenesis–the birth of new neurons–in the hippocampus, a region critical to creating new memories. Furthermore, alcohol-induced dementia results from brain damage that occurs with prolonged alcohol abuse. The reasons for the observed benefits of alcohol are less clear. In contrast to binge drinking, moderate alcohol intake increases neurogenesis and may help counteract oxidative stress in neurons. It’s well documented that what’s good for the heart is good for the brain, and indeed, vascular dysfunction often co-exists with or precipitates many forms of dementia. A prevailing theory is that the neuroprotective properties of drinking stem largely from their positive effects on cerebrovascular health. Alcohol can reduce risk for stroke and heart disease, lower blood pressure and increase HDL (“good”) cholesterol. However, some evidence that wine is more strongly neuroprotective than other forms of alcohol suggests that resveratrol, a potent antioxidant found in red wine, may also play a role. Although resveratrol minimizes dementia pathology in animals, the extremely high doses required make it unlikely to be the primary source of neuroprotection from alcohol.

Unraveling healthy drinking patterns for the aging brain

For our aging population to reap the greatest benefit from alcohol, it will be essential to determine patterns of healthy drinking that are optimized for the individual. This will require, foremost, a comprehensive understanding of how alcohol distinctly affects you versus me based on our genetics, sex or lifestyle. For example, alcohol has been found to differentially influence brain structure and risk for dementia or cognitive impairment for those with and without the apolipoprotein E4 gene, a strong risk factor for Alzheimer’s disease. Furthermore, studies have inconsistently reported sex differences in how drinking influences cognitive decline, which may be explained by differences in how men and women metabolize alcohol.

Despite overwhelming evidence that moderate alcohol intake can be healthy for the aging brain, there are striking incongruences across findings–which may be due to differences in study design or confounding factors­–that muddle our understanding of alcohol’s benefits. ‘Survival bias,’ in which healthier individuals participate in studies for longer, is an unavoidable complication in longitudinal studies of aging. This could significantly skew results if unhealthy drinkers drop out early, leaving only “healthy” drinkers to be studied in very old age. Furthermore, most human studies on alcohol and brain aging rely on observed associations, which can be replete with confounding factors. For instance, it’s known that drinkers tend to live more healthy lifestyles (e.g., they may exercise more or follow a Mediterranean diet), or may drink more often simply because they’re more socially active, which alone is known to be brain-healthy. What’s more, effects of alcohol on cognitive aging may depend on the type of alcohol consumed, how alcohol intake is measured, or the definition of “non-drinkers.” Many studies group life-long abstainers together with quitters, who may avoid alcohol due to poor health or may have developed health problems from alcohol abuse. However, my postdoctoral adviser Linda McEvoy, who studies effects of alcohol on brain aging at UC San Diego, explains that “Randomized controlled trials offer a better alternative to more definitely answer the question of how moderate alcohol intake affects cognitive function. Such trials have demonstrated beneficial cardiometabolic effects in those randomized to drink moderate amounts of alcohol.”

A prescription for alcohol?

Despite some uncertainties in the research so far, it appears that regular moderate drinking is unlikely to be hazardous to cognitive function and may even support healthy brain aging. Until we have further clarification, McEvoy offers some advice to those hoping to preserve brain health into late life: “If a person consumes alcohol, I would advise drinking moderate amounts of alcohol (one or two drinks) with dinner. If the person does not drink, I would not advise starting. Some individuals have a hard time controlling the amount they drink, and heavy drinking has detrimental effects on brain health and cognitive function.”

Cancer rate dropping, higher rate in men with cancer due to smoking and alcohol

cancer rates.JPGFor 2017, the report estimated, there will be nearly 1.7 million new cancer diagnoses and more than 600,000 deaths. The most common causes are lung, colorectal and prostate malignancies in men, and lung, breast and colorectal cancers in women. These types account for almost half of all cancer deaths.

The report found that racial disparities in cancer death rates continue to decrease, although the cancer death rate remains 15 percent higher in blacks than in whites.

Lung, breast, prostate and colorectal cancers in women and men

How can we reduce these type of cancers?

Early detection, screening and prognostic biomarkers/genetic tests can help reduce these types of cancer. Smoking and alcohol cessation should also be the top priority in areas of public education and information.

Email to be added in future cancer risk detection using genetic test.

Anti-inflammatory herbs: panax notoginseng and others

panax.JPGPnS has an obvious anti-inflammatory effect and its mechanisms are related to the inhibition of the Neu-[Ca2+]i level and PLA2 activity, and reduction of Din content.

Herbal medicines have traditionally played a major role in the management of diabetes in Asian countries for centuries. Panax notoginseng (Burk) F. H. Chen (Araliaceae) known as Tiánqī or san qi is a well-known medicinal herb in Asia for its long history of use in Chinese medicine. Qualified as ‘the miracle root for the preservation of life’, it has been used in China for 600 years, for treatment of various diseases. Panax notoginseng saponins (PNS) are the key active components. PNS have been widely used in China for treatment of cardiovascular diseases. However, scientific studies have shown a wide range of other pharmacological applications including anti-cancer, neuroprotective and anti-inflammatory agents, immunologic adjuvant and prevention of diabetes complications. Recently, hypoglycemic and anti-obesity properties of PNS have also been demonstrated. The present review highlights the effects of PNS on glucose production and absorption, and on inflammatory processes that seem to play an important role in the development of diabetes.

Notoginseng Radix et Rhizoma (Sanqi), the underground part of Panax notoginseng (Burk.) F. H. Chen (Araliaceae) is commonly used in Chinese medicine for treatment of haemorrhage, haemostasis, swelling, etc. The aerial part including leaves, flowers and fruits are also applied for similar functions. Triterpenoid saponins are considered to be responsible for the biological activities of Sanqi. Up to date, more than 100 saponins have been isolated from theroots, rhizomes, leaves, flowers and fruits of P. notoginseng. The reported saponins can be classified into protopanaxadiol (PPD), protopanaxatriol (PPT), C17 side-chain varied and other types, according to the skeletons of the aglycons. The present review summarizes the saponins isolated from P. notoginseng and their distribution in different medicinal organs, as well as the pharmacological actions on cardiovascular system.

Rutin (Figure (Figure3B),3B), a glycoside of quercetin, is found in many foods such as red wine, apples and onions. Panchal et al[99] first proved that rutin can decrease adiposity, improve insulin sensitivity, and reduce cardiac remodeling and liver injury in HFD rats[100]. Consistently, in a successive study, rutin effectively inhibited palmitate-induced macrophage activation and reduced liver fat by suppressing transcription of SREBP-1c and CD36 in the liver[101]. Recently, troxerutin was also shown to reduce liver steatosis and improve metabolic syndrome-related pathology in mice fed a high-fat diet, by suppressing oxidative stress-mediated NAD depletion and stimulating fat oxidation[99]. Other flavonoids, including pueraria[102], baicalein[103], luteolin[104], hydroxysafflor yellow A[105], genistein[106,107], silybin[108], isorhamnetin[109], iridin[110], naringin[111], shikonin[112], apigenin[113], kaempferol[114], myricetin[115], and pinocembrin[116] (Figure (Figure3C-P),3C-P), also play significant roles in the treatment of NAFLD.

Curcumin (Figure (Figure3R),3R), responsible for the yellow colour of the plant Curcuma Longa L, is extracted from curry and spice. Its antioxidant properties are widely studied in liver metabolism[132]. Curcumin has also been studied for NASH and metabolic pathologies. Leclercq et al[133] showed that curcumin improves liver injury by inhibiting nuclear factor-kappa B (NF-κB) activation, which in turn inhibits the expression of NF-κB target genes, including intercellular cell adhesion molecule-1, cyclooxygenase-2, and monocyte chemotactic protein 1. Vizzutti et al[134] later extended that curcumin can reduce alpha-smooth muscle actin a level in the NASH mice and can reduce the production of reactive oxygen species and tissue inhibitor of metalloproteinases-1 secreting activated hepatic stellate cells. While some dietary supplements containing curcumin are commercially available, it should be emphasized that case-reports and case series provide insufficient clinical evidence to draw firm conclusions. Polyphenols including techin-3-gallate[135], salvianolic acid B[136], anthocyanidin[137], ellagic acid[138] and cyanidin-3-glucoside[139] (Figure (Figure3S-W)3S-W) also play significant roles in the treatment of NAFLD.

Curcumin alleviates the severity of hepatic inflammation in experimental steatohepatitis induced by the MCD diet, an effect likely to be mediated via inhibition of NF-kB activation and dependent pro-inflammatory genes. The NF-kappaB pathway is one among several possible signalling pathways by which inflammation is recruited in experimental steatohepatitis.

Saponins are glycoside aglycones of three terpenoids or spirostane compounds, mainly found in terrestrial plants[147]. The primary active ingredients in many Chinese traditional herbs, such as Panax ginseng (C. A. Mey.), Polygala tenuifolia (Willd.), Glycyrrhiza uralensis (Fisch), and Platycodon grandiflorus (Jacq.) A. DC., are saponins. Some saponins also have anti-bacterial, anti-pyretic, and anti-cancer activities[148,149].

Dioscin (Figure (Figure4E)4E) is a natural steroid saponin widely found in various herbs[150]. Previous studies have demonstrated that dioscin has anti-tumor[151], anti-hyperlipidemic[152], and anti-fungal activities[153]. Studies have shown that dioscin can gradually reduce the weight, but not suppress appetite or increase physical activity in obese mice. Oral administration of dioscin reduces blood lipid levels, improves fat accumulation in the liver, decreases liver cholesterol and FA and triglyceride deposition through inhibition of FAS, promotes FA beta oxidation, reduces oxidative stress and inflammation, and regulates the MAPK signaling pathway and autophagy[154]. Other saponins such as ginsenoside Rb1[155], ginsenoside Rg1[156] and trillin[157] (Figure (Figure4F-H)4F-H) also play significant roles in the treatment of NAFLD.

Alkaloids are a group of nitrogenous organic compounds present in nature. They are widely found in dicotyledons. They have many pharmacological activities, such as anti-bacterial, anti-inflammatory, analgesic, anti-tumor, and anti-fungal actions[158,159]. A large number of studies have indicated that alkaloids have significant effects on NAFLD.

Berberine (Figure (Figure4I)4I) is isolated from the herb Coptis chinensis Franch. and widely used to treat diarrhea and other inflammatory diseases in China[160]. Recent studies have proved a new therapeutic function of berberine in metabolic disorders, including obesity and diabetes[161,162]. Berberine can be used as a cholesterol lowering drug, through a unique mechanism distinct from statins[163]. These studies suggested a potential therapeutic activity of berberine for NAFLD. Liver gene expression profile analysis showed that high fat diet induced hepatic steatosis in rats led to global changes in gene expression, and treatment with berberine reversed this process. Several modules of berberine-regulated genes, including abundant long non-coding RNAs (lncRNAs), were identified by bioinformatics analysis.

Fetal alcohol syndrome

fasExposure of fetus to alcohol

Although most nutrients are affected by alcohol intake, specific nutrients noted from numerous studies are thiamin, riboflavin, vitamin B-12, vitamin E, selenium, vitamin A, vitamin C, folic acid, vitamin D, zinc, and a few trace minerals. Alcohol is metabolized within hepatocytes by 1 of the 3 following pathways:

  • Alcohol dehydrogenase pathway (ADH): The first pathway, known as ADH, occurs in the cytosol of the hepatocyte (Fig. 2). ADH metabolizes ethanol to acetaldehyde, which is subsequently converted into acetic acid in mitochondria (20). In the ADH pathway, ethanol competes with vitamin A, or retinol, for metabolism because both substrates are metabolized by the same pathway (this is discussed later). Ultimately, ethanol is oxidized, which leads to the production of acetaldehyde and large amounts of NADH.

Alcohol effects on vitamin A

Alcohol consumption during pregnancy depletes maternal vitamin A stores, which can interrupt normal cell growth of the fetus. The proposed mechanism for this is that when both retinol and alcohol are present, ADH involved in the rate-limiting step of retinol oxidation has a higher affinity to alcohol, therefore preferentially metabolizing alcohol instead of retinol. This results in a deficiency in retinoic acid synthesis (39, 40), which is required to signal and control the cells involved in fetal development, organogenesis, organ homeostasis, cell and neuronal growth and differentiation, development of the CNS, and limb morphogenesis (16, 40).


DHA is highly important during fetal development because it plays an essential role in cognitive and visual development, as well as the development of the CNS (53, 54). DHA is also a precursor of a potent neurotrophic factor (neuroprotectin D1), which protects the brain and retina against injury-induced oxidative stress and enhances cell survivals in these tissues. Thus, it is recognized as a conditionally essential nutrient for infants. There is no RDA for DHA, but the Adequate Intake (AI) for n–3 FAs for pregnancy is 1.4 g/d (55). DHA is esterified to membrane phospholipids to maintain optimal fluidity and cellular integrity. Among phospholipids, phosphatidylserine has been the most studied in association with CNS development (54, 56, 57). Optimal neuronal development of the fetus is dependent on maternal intake and dietary status of DHA. In humans, the accumulation and integration of DHA into phosphatidylserine and cell membranes occurs from 16 wk to term and continues into the early postnatal development period (53). It is specifically during the last trimester in which DHA is rapidly incorporated into phosphatidylserine synthesis and storage in the hippocampus, because it is during this period in which human brain growth rapidly occurs (57, 58).

Folate (folic acid)

Folic acid, a water-soluble vitamin, has been identified as an essential nutrient that may provide a protective effect against gestational ethanol exposure. For folic acid to become metabolically active, it must be reduced to tetrahydrofolic acid (FH4) as a carrier for single-carbon moieties. FH4 is involved in the biosynthesis of the DNA and RNA precursors thymidylate and purine bases (64). Therefore, adequate maternal folic acid status is integral for optimal fetal growth and development. During pregnancy, the demand for folic acid is increased because it is not only required to support the mother for increased RBC formation but also to support the rapid growth of the fetus, including neural tube formation (65). The RDA for folic acid during pregnancy is 600 μg/d (66), and dietary sources are found in green leafy vegetables, beef, liver, pulses, and foods produced from whole wheat.

Alcohol effects on zinc

Alcohol consumption on a chronic basis itself reduces the availability of zinc because there is decreased intake and absorption and increased urinary excretion. When acute zinc deficiency occurs as a result of ethanol exposure, metallothionein, a low-molecular-weight protein body, sequesters plasma zinc to the liver, resulting in a reduction in plasma zinc. This leads to decreased amounts available for placental transport, resulting in fetal zinc deficiency (81, 82).


Choline and its metabolites are invaluable in neurotransmission (acetylcholine), structural integrity of cell plasma membranes (phosphatidylcholine and sphingomyelin), and cell signaling and in folate-independent pathways as a methyl donor via its metabolite, betaine (42, 90). This nutrient is the most-studied nutrient related to brain development and memory function and has been classified as an essential nutrient by the Institute of Medicine and National Academy of Sciences in the United States (66).

Choline supplementation in animal models

A recent study looked at the effect of choline supplementation on specific neurons that are altered in FASD (94). Pregnant rat dams were fed an alcohol-containing liquid diet or a control diet during GDs 7 and 21 with or without choline (642 mg/L choline chloride). The results showed that gestational choline supplementation prevented the adverse effects of alcohol on the neurons (Table 1) (94). Previous research from Thomas and colleagues (9599) showed that perinatal choline supplementation can reduce the severity of FASD—specifically, hyperactivity and learning deficits in the rat model. The authors found that choline chloride supplementation (250 mg · kg−1 · d−1 choline chloride) prevented ethanol-induced alterations in tasks that require behavioral flexibility such as spontaneous alternation behavior and memory (Table 1) (98).


Antioxidants are compounds that are produced to scavenge free radicals and other compounds that threaten cellular oxidation. Cells can neutralize and scavenge reactive oxygen species through the enzymatic activity of SOD, glutathione peroxidase (GPx), and catalase. Nutrients such as folate, vitamin C (ascorbic acid), vitamin E (α-tocopherol), selenium, and zinc are important contributors to antioxidant activity.


Selenium is a micronutrient that serves as an important component for the generation of the enzyme GPx. GPx inhibits oxidation because it is involved in scavenging free radicals, specifically hydrogen peroxide, and converting them to harmless products such as water. Selenium-based GPx primarily is active within the cytosol or the mitochondria. The amount of selenium obtained from the diet is based on the amount in the soil or water where the food source was grown. Once consumed, it is predominantly stored in the liver, because alcohol metabolism in the liver produces various reactive oxygen species and free radicals. The RDA for selenium during pregnancy is 60 μg/d (105).

Alcohol effects on selenium.

Typically, selenium deposits and plasma concentratons are low in chronic alcoholics because of decreased dietary intake and increased production of free radicals resulting from alcohol metabolism (107). However, selenium concentrations in the plasma were reported to be increased and were significantly greater in women who drank heavily, defined as >140 g/wk, during their pregnancy in comparison to abstinent women and those who consumed alcohol moderately (108).

Clinical Trends in 2016

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How excess alcohol depresses immune function


Alcoholism suppresses the immune system, resulting in a high risk of serious, and even life-threatening infections. A new study shows that this effect stems largely from alcohol’s toxicity to immune system cells called dendritic cells. These cells play a critical role in immune function, responding to danger signals by searching for unfamiliar antigens within the body that would be coming from invading microbes, and presenting such antigens to T cells, thus activating them to seek and destroy cells containing these antigens. The research is published in the July 2011 issue of the journal Clinical and Vaccine Immunology.

Earlier studies in mice had shown that excessive drinking of impaired T cell function, and subsequently that this impairment could be reversed by exposure to dendritic (so named for their shape) from non-alcoholic mice, and that poor function in CD4 and CD8 T cells could be improved through exposure to cytokines produced by non-alcoholic dendritic cells. (Cytokines are immune regulatory cells.) In this study, Jack R. Wands and colleagues of Brown University, Providence, RI, compared dendritic cells produced by alcoholic and non-alcoholic mice, which they first removed from the mice.

The result: dendritic cells from the alcoholic mice had a poor ability to activate T cells, while the dendritic cells from mice on isocaloric diets containing no alcohol functioned normally. The researchers found further that the dendritic cells from alcohol-fed mice showed reduced antigen presentation compared to those from control mice, as well as less production of the regulatory cytokines. This research also confirmed earlier results showing that alcohol inhibits cytokine secretion by dendritic cells.

“This research helps us understand why alcoholics are predisposed to bacterial and viral infections, and why they do not respond well to vaccines,” says Wands. Understanding this, he says, will help in the development of ways to improve dendritic cell function in people with syndromes.

Explore further: Skin sentry cells promote distinct immune responses

More information: A. Eden, et al., 2011. Ethanol inhibits antigen presentation by dendritic cells. Clin. Vaccine Immunol. 18:1157-1166.)

Provided by: American Society for Microbiology