Mood for Life

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Archive of ‘evolution’ category

Whole grains for the whole brain (and other organs)



Certain wild cereals, or grasses, contain edible components in their grain, botanically a type of fruit.  Grains are small, hard, dry seeds, with or without attached hulls.

Some argue that from an evolutionary standpoint, grains are a relatively new addition to our diets and therefore should be excluded.

Undoubtedly grains have existed for many millennia, but the problem with harvesting had been that first of all these grains must be separated from the inedible grasses, requiring some winnowing process.  Secondly, the wild grains usually shatter when ripe, dispersing the seeds, making collection difficult.  Then the tiny hard grains would have to be further processed to avail digestion. Thus, patches of such grains in the wild may not have been favored by hominids until at least primitive hand tools were used and present near sites of grain-containing grasses.

Nevertheless, grains were apparently consumed well before animal domestication 10,000 years ago.

For example, a large amount of starch granules has been found on the surfaces of Middle Stone Age stone tools from Mozambique, showing that early Homo sapiens relied on grass seeds starting at least 105,000 years ago, including those of sorghum grasses[1]. That’s more than 5000 generations ago.

Of course if one has celiac disease, gluten intolerance, a food allergy or sensitivity to grains, grains should be avoided.

Grains for brains (as well as other organs)

Whole grain includes dark bread, whole-grain breakfast cereal, popcorn, oats, bran, brown rice, bran, and many other examples.

Whole-grain foods contain fiber, vitamins, magnesium and other minerals, phenolic compounds and other phytonutrients[2], which may have favorable effects on health by lowering serum lipids and blood pressure, improving glucose levels, insulin metabolism and endothelial function, as well as alleviating oxidative stress and inflammation.

A meta-analysis of 15 cohort studies with nearly a half million participants revealed that whole grain intake was associated with a reduced risk of vascular disease[3].

There is an association between dietary whole grain intake and mortality; two large prospective studies of more than one hundred thousand participants indicated a significant life extension independent of other dietary and lifestyle factors[4].

The effect was pronounced up to one-half serving per day after which there was a leveling off. This is shown in the figure below, taken from the Wu et al. aforementioned article, where the mortality risk is plotted against servings of whole grain.

Relative Mortality Risk v. Whole Grain Intake



[1] Mercader, J. (2009), Mozambican Grass Seed Consumption During the Middle Stone Age, Science, 326.

[2] Anderson, J. W. (2003). Whole grains protect against atherosclerotic cardiovascular disease. Proceedings of the Nutrition Society, 62(01), 135-142. doi:10.1079/pns2002222.

[3] Tang, G., Wang, D., Long, J., Yang, F., & Si, L. (2015). Meta-Analysis of the Association Between Whole Grain Intake and Coronary Heart Disease Risk. The American Journal of Cardiology, 115(5), 625-629.

[4] Wu, H., Flint, A. J., Qi, Q., Dam, R. M., Sampson, L. A., Rimm, E. B., . . . Sun, Q. (2015). Association Between Dietary Whole Grain Intake and Risk of Mortality.JAMA Internal Medicine JAMA Intern Med, 175(3), 373.

Nonbrowning GMO apple cleared for marketing



by Richard Aiken MD PhD @rcaiken

The US Department of Agriculture (USDA) on February 13, 2016, approved the first genetically modified (GM) apple developed to resist browning. They will go into production in the Midwest in the next few weeks (February, 2017).

Browning is caused by polyphenol oxidases (PPOs) naturally present in fruit and vegetables. When fruit is cut or bruised, these enzymes catalyze the oxidation of polyphenols to quinones, causing oxidative browning. The damage is superficial but can affect the taste and texture of the apple as well as its cosmetic qualities. In the Arctic varieties, the GM apples were genetically engineered with a transgene that produces specific RNAs to silence the expression of at least four browning PPO genes.

Is this a good idea?

polyphenol oxidase

The enzymes in the class polyphenol oxidase (PPO) appear to reside in the plastids of all land plants and are released when the plastid cell membrane is disrupted. PPO is thought to play an important role in the resistance of plants to microbial and viral infections and to adverse climatic conditions such as drought as although all land plants have PPO content, no PPO-like sequences have been reported in marine plants such as algae[1].

As stated above, in the presence of oxygen from air, the enzyme catalyzes the first steps in the biochemical conversion of phenolics to produce quinones, which undergo further polymerization to yield dark, insoluble polymers referred to as melanin. This is the same melanin that determines darkness of human skin and hair. In plants, melanin forms barriers and has antimicrobial properties that prevent the spread of infection in plant tissues.

Phenolic compounds are responsible for the color of many plants and impart taste and flavor, but more importantly, they are important phytonutrients and antioxidants.

Alteration of polyphenol oxidase

Given the activity of PPO in the adaptation of plants to, for example, plant dehydration, what are the implications of altered PPO activity on plant development, phenotype, and yield?  A clear effect of PPO silencing was observed, for example, in walnut plants which developed spontaneous necrotic lesions in the leaves suggesting increased susceptibility to oxidative stress[2].

A potential role for PPO in photosynthesis has been speculated[3].

Data suggest that PPO activity can confer both a productive advantage and be associated with an increased risk of oxidative damage. While PPO activity can be associated with non-enzymatic reactive oxygen species scavenging involving flavonoid and phenolic acid substrates[4], a role for PPO in plant function may also be associated with its pro-antioxidant activity through the generation of secondary reaction products[5].

So it is obvious that the role of PPO is extensive and not fully understood. It appears premature to genetically modify plants to remove this complex molecule.



[1] Tran LT, Taylor JS, Constabel CP. 2012. The polyphenol oxidase gene family in land plants: lineage-specific duplication and expansion. BMC Genomics 13, 395.

[2] Araji S, Grammer TA, Gertzen R, et al. 2014. Novel roles for the polyphenol oxidase enzyme in secondary metabolism and the regulation of cell death in walnut (Juglans regia). Plant Physiology 164, 1191–1203.


[3] Vaughn KC, Duke SO. 1984. Function of polyphenol oxidases in higher plants. Physiologia Plantarum 60, 106–112


[4] Parveen I, Threadgill MD, Moorby JM, Winters A. 2010. Oxidative phenols in forage crops containing polyphenol oxidase enzymes. Journal of Agricultural and Food Chemistry 58, 1371–1382.

[5] Thipyapong P, Joel DM, Steffens JC. 1997. Differential expression and turnover of the tomato polyphenol oxidase gene family during vegetative and reproductive development. Plant Physiology 113, 707–718.


All about vitamin D and mood


The fourth vitamin to be discovered, vitamin D, is technically not a vitamin as one’s body can produce it – it just requires sunlight.  No one is suggesting that sunlight is a vitamin per se.  And only a relatively short span of radiation from the sun is involved, the so-called UVB of the ultraviolet spectrum.  The intensity of UVB available depends on the weather, season, location on earth, and time of day; in the United States it maximizes between 10 am and 4 pm between April and October.

With moderate direct exposure to the summer sun (say 5 – 30 minutes twice a week), the body will make 10,000 to 20,000 IU. Sunscreen can effectively block UVB absorption; for an individual with frequent sun exposure (greater than twice per week), it might be prudent to place sunscreen after the first 10 – 15 minutes of sun exposure to avoid skin cancer but allow vitamin D production.  As our bodies can store vitamin D, it is thought that sufficient exposure during spring, summer, and early fall should be sufficient to provide needed vitamin D during the winter months.

So this is another recent modification in our evolution – to stay indoors a lot more than our ancestors, decreasing our vitamin D production.  The National Academies Institute of Medicine has no guidelines for vitamin D through sun exposure; they do have RDA but it is based on food intake.

The reaction of cholesterol (in the form of 7-dehydrocholesterol) in the skin with sunlight actually produces several fat-soluble related compounds, the most important being cholecalciferol, vitamin D3, and ergocalciferol, vitamin D2. The term “vitamin D” includes both of these compounds.

Very few foods in nature contain vitamin D, although some food products have vitamin D as an additive. To manufacture vitamin D industrially, 7-dehydrocholesterol,  a substance typically obtained from fish liver[1],or lanolin extracted from shorn sheep wool, is exposed to UVB light, producing vitamin D3. Vitamin D cannot be manufactured directly; it requires the photochemical process.

To become biologically active, vitamin D has to undergo two transformative reactions, one in the liver, then another in the kidney.

Vitamin D deficiency to the extent of causing rickets or osteomalacia is rare in the developed world but what we might call vitamin-D insufficiency, a lower than ideal biologically active form of vitamin D, appears to be quite common, particularly in the elderly.

Vitamin D toxicity is also rare.  There is a feedback loop associated with vitamin D production in the skin that lowers its production as adequate amounts are reached.  This natural regulatory  mechanism doesn’t apply to supplementation but for daily supplemental intake of 2,000 IU (about 50 micrograms) per day, there is very little risk of toxicity.[2]

As vitamin D is fat soluble, it requires the presence of fat for absorption; some supplements encapsulate cholecalciferol, vitamin D3, with fat; otherwise often it is recommended to take with a meal containing some degree of fat.

We have learned relatively recently that vitamin D has a lot larger effect on the body than just calcium absorption; for example, it has to do with modulation of cell growth, neuromuscular and immune function, and reduction of inflammation[3]. And mood states.

Vitamin D and psychiatric disorders

Vitamin D acts on receptors in a variety of regions in the brain such as the prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and substantia nigra and as such can influence neurochemistry[4] cognition, emotion, and behavior. Vitamin D deficiency in early life affects neuronal differentiation, and brain structure and function and appears to have some influence on disorders with a developmental basis, such as autistic spectrum disorder and schizophrenia ontogeny and brain structure and function[5].

The initial suggestion that vitamin D may be linked to clinical depression was based on the relation between low vitamin D and high prevalence of seasonal affective disorder (now considered to be a depressive disorder with seasonal pattern[6]) in winter at high latitudes[7].  One treatment modality for clinical depression with seasonal pattern is light therapy, although no ultra-violet light is used.  Vitamin D insufficiency is not considered to be directly causative for this disorder.

However, vitamin D concentrations have been shown to be low in many patients suffering from mood disorders and have been associated with poor cognitive function[8] [9]. For example, data from the third National Health and Nutrition Examination Survey were used to assess association between serum vitamin D and depression in 7,970 residents of the United States[10]. In that study, the likelihood of having depression in persons with vitamin D deficiency was found to be significantly higher compared to those with vitamin D sufficiency.

One thorough systematic review and meta-analysis of observational studies and randomized controlled trials was conducted and found that vitamin D insufficiency was strongly associated with clinical depression[11].  Another systematic review and meta-analysis showed a statistically significant improvement in depression with Vitamin D supplements[12].

Use of vitamin D as adjunctive therapy, i.e. together with an antidepressant medication in patients with vitamin D insufficiency has shown to be superior to an antidepressant alone[13]

What to do

This is another situation where recent changes in human lifestyle – here being indoors more than outdoors, can lead to a nutrient deficiency.  Because it is so common to have a vitamin D insufficiency and the health consequences, specifically mood states, I recommend more time in the outdoors, including some limited time (say 10 minutes a day) with face and arms without sunscreen.

If you do not spend regular time in the sun, I do recommend a vitamin D3 supplement to be taken before, during, or directly after a meal.  I think it wise to take these supplements during the winter months in any case.

Should you question whether or not you may be clinically depressed, professional assessment certainly is recommended as always; initial workup may include serum vitamin D levels (usually 25(OH)D is measured but various labs use different techniques resulting in varying “normal” level ranges).

A strict ethical vegan, however, faces a dilemma as the sources of vitamin D3 supplementation (and all “fortified products such as almond milk and tofu) are animal-based. Some literature supports vitamin D2 intake as sufficient, but good studies are too scarce to suggest this as the sole source for supplementation; vitamin D2 can be obtained from certain mushrooms set out in the sun for 10 minutes or so prior to consumption and there are supplements available from this source. It would appear that lifestyle emphasis on “fun in the sun” is indicated for vegans.


[1] Takeuchi A, Okano T, Sayamoto M, Sawamura S, Kobayashi T, Motosugi M, Yamakawa T; Okano; Sayamoto; Sawamura; Kobayashi; Motosugi; Yamakawa (1986). “Tissue distribution of 7-dehydrocholesterol, vitamin D3 and 25-hydroxyvitamin D3 in several species of fishes”. Journal of nutritional science and vitaminology32 (1): 13–22.

[2] Ross, A. C., Manson, J. E., Abrams, S. A., Aloia, J. F., Brannon, P. M., Clinton, S. K., . . . Shapses, S. A. (2011). The 2011 Dietary Reference Intakes for Calcium and Vitamin D: What Dietetics Practitioners Need to Know⁎⁎This article is a summary of the Institute of Medicine report entitled Dietary Reference Intakes for Calcium and Vitamin D (available at for dietetics practitioners; a similar summary for clinicians has also been published (Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. The 2011 report on Dietary Reference Intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab. 2011;96:53-58).Journal of the American Dietetic Association, 111(4), 524-527. doi:10.1016/j.jada.2011.01.004

[3] DRI – Dietary Reference Intakes – Calcium and Vitamin D20122 DRI – Dietary Reference Intakes – Calcium and Vitamin D . Institute of Medicine of the National Academies, , ISBN: 13‐978‐0‐309‐16394‐1. (2012). Nutrition & Food Science, 42(2), 131-131. doi:10.1108/nfs.2012.

[4] Yue, W., Xiang, L., Zhang, Y., Ji, Y., & Li, X. (2014). Association of Serum 25-Hydroxyvitamin D with Symptoms of Depression After 6 Months in Stroke Patients. Neurochem Res Neurochemical Research, 39(11), 2218-2224. doi:10.1007/s11064-014-1423-y

[5] Eyles, D. W., Burne, T. H., & Mcgrath, J. J. (2013). Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Frontiers in Neuroendocrinology, 34(1), 47-64. doi:10.1016/j.yfrne.2012.07.001

[6] Gabbard, Glen O. Treatment of Psychiatric Disorders2 (3rd ed.). Washington, DC: American Psychiatric Publishing. p. 1296.

[7] Stumpf WE, Privette TH: Light, vitamin D and psychiatry. Role of 1,25 dihydroxyvitamin D3 (soltriol) in etiology and therapy of seasonal affective disorder and other mental processes. Psychopharmacology (Berl) 1989, 97:285–294.

[8] Wilkins, C. H., Sheline, Y. I., Roe, C. M., Birge, S. J., & Morris, J. C. (2006). Vitamin D Deficiency Is Associated With Low Mood and Worse Cognitive Performance in Older Adults. The American Journal of Geriatric Psychiatry, 14(12), 1032-1040. doi:10.1097/01.jgp.0000240986.74642.7c

[9] Przybelski, R. J., & Binkley, N. C. (2007). Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Archives of Biochemistry and Biophysics, 460(2), 202-205. doi:10.1016/

[10] Ganji, V., Milone, C., Cody, M. M., Mccarty, F., & Wang, Y. T. (2010). Serum vitamin D concentrations are related to depression in young adult US population: The Third National Health and Nutrition Examination Survey. Int Arch Med International Archives of Medicine, 3(1), 29. doi:10.1186/1755-7682-3-29

[11] Anglin, R. E., Samaan, Z., Walter, S. D., & Mcdonald, S. D. (2013). Vitamin D deficiency and depression in adults: Systematic review and meta-analysis. The British Journal of Psychiatry, 202(2), 100-107. doi:10.1192/bjp.bp.111.106666

[12] Spedding, S. (2014). Vitamin D and Depression: A Systematic Review and Meta-Analysis Comparing Studies with and without Biological Flaws. Nutrients, 6(4), 1501-1518. doi:10.3390/nu6041501

[13] Khoraminya, N., Tehrani-Doost, M., Jazayeri, S., Hosseini, A., & Djazayery, A. (2012). Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Australian & New Zealand Journal of Psychiatry, 47(3), 271-275. doi:10.1177/0004867412465022

Aspirin from plants



Perhaps the first plant nutraceutic modified slightly to become a large commercial success was salicylic acid, found in particularly high amounts in the inner lining of white willow tree bark and central to defense mechanisms in plants against pathogen attack and environmental stress. It is the principal metabolite of the medication aspirin, which works through a completely different pathway in humans to affect an anti-inflammatory and antipyretic response.  However, dosing in isolated concentrated form resulted in severe gastrointestinal distress, so that a buffered form was developed – and patented – in 1900 as Aspirin (acetylsalicylic acid) by Bayer[1].  This approach to acquiring medicinal benefits from salicylic acid is still flawed by the fact that there is an increased risk of bleeding even for low-dose therapy.  About one in ten people on chronic low-dose aspirin develop stomach or intestinal ulcers, which can perforate the gut and cause life-threatening bleeding.[2]


There is a better way to take advantage of the healing properties of salicylic acid: eating plants.  All plants contain salicylic acid and vegetarians have as much in their blood as omnivores who take aspirin supplements – but without the risk[3].  Apparently this has been known empirically since the third millennium BC.


This is another recurring theme: plant-based diets can obviate the need for many supplements and prescribed medications.  Plant-based diets are anti-inflammatory not only because of salicylic acid but because of their many other anti-inflammatory phytonutrients that help prevent the body from overproducing inflammatory compounds.  Of course plant-based diets minimize one’s intake of inflammatory precursors present in meat and dairy products in the first place.  More on that later.


Just to review, this amazing substance, salicylic acid, the active metabolite of aspirin and a plant hormone, plays a central role in the immune system of plants by activating the production of pathogen-fighting proteins[4].  It can transmit the distress signal throughout the plant and even to neighboring plants[5].  But the amazing fact is its crossover and apparent inverse role that it has in humans: it reduces the immune response, i.e. serves as an anti-inflammatory.  This has an important role then in chronic inflammatory states such as cardio- and cerebrovascular disease, stroke, arthritis, even certain cancers.  Recently, mental disorders have been linked to chronic inflammatory states[6] and aspirin is finding a use for disorders ranging from mood disorders[7] to schizophrenia[8].


So this remarkable agent helps prevent disease in both plants and animals but by completely different mechanisms.


[1] Interestingly, Aspirin ® and Heroin ® were once trademarks belonging to Bayer. After Germany lost World War I, Bayer was forced to give up both trademarks as part of the Treaty of Versailles in 1919.

[2] Yeomans, N., Lanas, A., Talley, N., Thomson, A., Daneshjoo, R., Eriksson, B., . . . Hawkey, C. (2005). Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol Ther Alimentary Pharmacology and Therapeutics, 22(9), 795-801.

[3] Paterson, J., Baxter, G., Dreyer, J., Halket, J., Flynn, R., & Lawrence, J. (2008). Salicylic Acid sans Aspirin in Animals and Man: Persistence in Fasting and Biosynthesis from Benzoic Acid. Journal of Agricultural and Food Chemistry J. Agric. Food Chem., 56(24), 11648-11652.

[4] Pieterse, C., Van Der Does, C., Zamioudis, C., Leon-Reyes, A., & Van Wees, S. (2012). Hormonal modulation of plant immunity. Annu Rev Cell Dev Biol.

[5] Taiz, L., & Zeiger, E. (2002). Plant physiology (3rd ed., p. 306). New York: W.H. Freeman

[6] Berk, M., Dean, O., Drexhage, H., McNeil, J. J., Moylan, S., O’Neil, A., … Maes, M. (2013). Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Medicine, 11, 74. doi:10.1186/1741-7015-11-74

[7]Ayorech, Z., Tracy, D., Baumeister, D., & Giaroli, G. (2015). Taking the fuel out of the fire: Evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders. Journal of Affective Disorders, 174, 467-478.

[8] Keller, W., Kum, L., Wehring, H., Koola, M., Buchanan, R., & Kelly, D. (2012). A review of anti-inflammatory agents for symptoms of schizophrenia. Journal of Psychopharmacology (Oxford, England), 27(4), 337-342.

APOE ε4 predicts risk of future depression

The ApoE4 variant, apparently predominant in pre-modern hominids, is a known genetic risk factor for impaired lipid regulation leading to elevated cholesterol, triglycerides and poor modulation of inflammation and oxidative stress predisposing an individual to a range of abnormal conditions from vascular disease to Alzheimer’s disease. Now linked also to depression. More here; even more here.