A Polyphenol-Rich Diet Affects Age-Related Brain Atrophy

The benefits were shown over other beneficial diets.



A preprint study originating from the DIRECT PLUS trial was recently released from the American Journal of Clinical Nutrition [1]. This study has been accepted into the journal but has not yet been peer reviewed.

Duckweed for health

This study focused on a plant called Mankai, a strain of the Wolffia globosa duckweed. Duckweed is an aquatic floating plant with different species distributed around the world [2,3].

In a prior study from this trial, individuals were fed a green Mankai shake for two weeks or a yogurt shake matched for carbohydrates, protein and calories. The green Mankai shake elicited a lower glucose response compared to yogurt [4]. In the researchers’ prior work, they also showed that Mankai protein is digested and absorbed similar to peas and soft cheese due to containing all nine essential amino acids [5]. The nutrient composition of the plant varies based on environment and cultivation conditions.

This 18-month study recruited 284 individuals with obesity and abnormal blood lipid levels. The participants were randomly assigned to one of three groups: healthy dietary guidelines, a regular Mediterranean diet, or the green-MED diet, which is a Mediterranean diet made higher in polyphenols with a shake containing 100 grams of frozen green Mankai. The green-MED diet was also lower in processed and red meat.


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All of the participants received physical activity guidance and had free access to a gym. To increase the study’s reliability, all lifestyle interventions were conducted in person at the workplace, which included 90-minute nutritional and physical activity sessions. These sessions included a multidisciplinary team of physicians, clinical dietitians, and fitness instructors.

The hippocampus, a structure in the brain, plays a major role in learning and memory [6]. The primary assessment the researchers used in this study, alongside other brain health markers, was a hippocampal-occupancy score (HOC) to estimate hippocampal volume loss. Prior research showed that the Mediterranean diet was associated with lower rates of atrophy and Alzheimer’s disease [7]. This study sought to examine the brain volume changes between the three diets.

Differences in brain volume

66% of all participants in this study experienced an average 1.7% decline in HOC during its 18-month course, which the authors attributed to aging. Participants who were at least 50 years old and on either Mediterranean diet had a significantly reduced decline in HOC and a smaller increase in lateral ventricle volume compared to the diet based solely on healthy dietary guidelines. Increased lateral ventricle volume is known to cause harm to the brain tissue around it.

Lateral ventricle volume among all age cohorts was significantly reduced in the green-MED group compared to the healthy dietary guidelines group. White matter tracts and executive function measurements were not differentially impacted between the interventions.

Effects on brain health

In this study, there was no significant interaction between APOE-e4 genotypes and brain volume parameters. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) takes into account fasting glucose and insulin to quantify insulin resistance. Participants who were at least 50 years old and had lower HOMA-IR, weight loss and triglyceride levels also had a lower decrease in HOC.


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In a different analysis, improved HOMA-IR was independently associated with a positive change in HOC. Waist circumference loss, weight loss, lower HOMA-IR, and blood pressure decline were associated with a positive change in lateral ventricle volume. When examining cholesterol, only low-density lipoprotein cholesterol (LDL) and total cholesterol decline were associated with benefits to the brain.

The green-MED group, the ones who consumed Mankai, enjoyed a better preserved HOC, as did people who consumed green tea. A reduction in red and processed meat, and an increase of urolithin A as measured in urine, were also associated with a reduced decline in HOC.


This study still needs to be peer reviewed, but the results are still exciting due to the importance of brain health for cognitive and bodily functions. This study did not use a placebo control group due to ethical reasons, and all groups had free gym memberships. The participants were 88% male, and this study was conducted at a workplace in Israel, where confidentiality concerns prevented the researchers from including parameters such as education status, baseline cognitive impairment, and depression in their analysis.

This study suggests that any Mediterranean diet may have a potentially neuroprotective effect against age-related neurodegeneration, thus promoting healthy brain aging. The most notable increase was the decrease in hippocampal atrophy in both Mediterranean diets, and prior research suggests that a decline in hippocampal volume is predictive of cognitive decline [8].

The authors discuss how the improvements shown in this study might be due to an increase in polyphenol consumption. Cell and animal research has demonstrated that polyphenols are able to cross the blood-brain barrier and reduce inflammation, promote neurogenesis in the adult hippocampus, and induce cell proliferation [9,10].

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[1] Kaplan, A., Zelicha, H., Meir, A. Y., Rinott, E., Tsaban, G., Levakov, G., Prager, O., Salti, M., Yovell, Y., Ofer, J., Huhn, S., Beyer, F., Witte, V., Villringer, A., Meiran, N., Emesh, T. B., Kovacs, P., von Bergen, M., Ceglarek, U., BlΓΌher, M., … Shai, I. (2022). The effect of a high-polyphenol Mediterranean diet (GREEN-MED) combined with physical activity on age-related brain atrophy: the DIRECT PLUS randomized controlled trial. The American journal of clinical nutrition, nqac001. Advance online publication. https://doi.org/10.1093/ajcn/nqac001

[2] Coughlan, N. E., Kelly, T. C., & Jansen, M. A. (2015). Mallard duck (Anas platyrhynchos)-mediated dispersal of Lemnaceae: a contributing factor in the spread of invasive Lemna minuta?. Plant biology (Stuttgart, Germany), 17 Suppl 1, 108–114. https://doi.org/10.1111/plb.12182

[3] Sree, K. S., Bog, M., and Appenroth, K-J. (2016). Taxonomy of duckweeds (Lemnaceae), potential new crop plants. Emir. J. Food Agric. 28, 291–302.

[4] Zelicha, H., Kaplan, A., Yaskolka Meir, A., Tsaban, G., Rinott, E., Shelef, I., Tirosh, A., Brikner, D., Pupkin, E., Qi, L., Thiery, J., Stumvoll, M., Kloting, N., von Bergen, M., Ceglarek, U., BlΓΌher, M., Stampfer, M. J., & Shai, I. (2019). The Effect of Wolffia globosa Mankai, a Green Aquatic Plant, on Postprandial Glycemic Response: A Randomized Crossover Controlled Trial. Diabetes care, 42(7), 1162–1169. https://doi.org/10.2337/dc18-2319

[5] Kaplan, A., Lapidot, M., Sela, I., & Shai, I. (2019). RE: Protein bioavailability of Wolffia globosa duckweed, a novel aquatic plant, a randomized controlled trial. Clinical nutrition (Edinburgh, Scotland), 38(5), 2464. https://doi.org/10.1016/j.clnu.2019.08.007

[6] Anand, K. S., & Dhikav, V. (2012). Hippocampus in health and disease: An overview. Annals of Indian Academy of Neurology, 15(4), 239–246. https://doi.org/10.4103/0972-2327.104323

[7] Gu, Y., Brickman, A. M., Stern, Y., Habeck, C. G., Razlighi, Q. R., Luchsinger, J. A., Manly, J. J., Schupf, N., Mayeux, R., & Scarmeas, N. (2015). Mediterranean diet and brain structure in a multiethnic elderly cohort. Neurology, 85(20), 1744–1751. https://doi.org/10.1212/WNL.0000000000002121

[8] Heister, D., Brewer, J. B., Magda, S., Blennow, K., McEvoy, L. K., & Alzheimer’s Disease Neuroimaging Initiative (2011). Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology, 77(17), 1619–1628. https://doi.org/10.1212/WNL.0b013e3182343314

[9] Figueira, I., Tavares, L., Jardim, C., Costa, I., Terrasso, A. P., Almeida, A. F., Govers, C., Mes, J. J., Gardner, R., Becker, J. D., McDougall, G. J., Stewart, D., Filipe, A., Kim, K. S., Brites, D., Brito, C., Brito, M. A., & Santos, C. N. (2019). Blood-brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro study. European journal of nutrition, 58(1), 113–130. https://doi.org/10.1007/s00394-017-1576-y

[10] Dias, G. P., Cavegn, N., Nix, A., do Nascimento Bevilaqua, M. C., Stangl, D., Zainuddin, M. S., Nardi, A. E., Gardino, P. F., & Thuret, S. (2012). The role of dietary polyphenols on adult hippocampal neurogenesis: molecular mechanisms and behavioural effects on depression and anxiety. Oxidative medicine and cellular longevity, 2012, 541971. https://doi.org/10.1155/2012/541971

About the author


Tovah has been a Registered Dietitian Nutritionist (RDN) for the past 11 years in clinical, research, teaching, community, and industry roles. Her dissertation work was focused on nutritional and behavioral neuroscience approaches for chronic disease prevention. She was a writer for Lifespan.io from 2021-22 and is still an active volunteer with the org.