The Mediterranean diet and biological ageing: what the DIRECT PLUS trial showed
Most discussions of diet and cancer focus on what you eat and what you avoid. Fewer ask a more fundamental question: can what you eat slow the biological ageing processes that underlie cancer in the first place?
That is precisely what the DIRECT PLUS trial set out to investigate — and its findings are among the most striking in recent nutritional science.
What the DIRECT PLUS trial was
The DIRECT PLUS trial was an 18-month randomised controlled trial involving 294 participants. It compared three dietary interventions: a standard healthy diet based on conventional guidelines, a Mediterranean diet, and a “Green Mediterranean” diet — an enhanced version that added three specific components: 28 grams of walnuts per day, three to four cups of green tea per day, and a daily 100-gram frozen Wolffia globosa (duckweed) plant-based protein shake rich in polyphenols.
Published in BMC Medicine in 2023, the trial measured multiple metabolic outcomes. But its most striking finding was epigenetic: participants were assessed using established biological age clocks — mathematical models that use DNA methylation patterns to estimate the biological age of cells. These clocks measure not how old you are chronologically, but how old your cells appear to be based on their epigenetic state.
The Green Mediterranean diet group showed an average attenuation of biological age of approximately 8.9 months over the 18-month trial period, compared to the standard healthy diet group. The standard Mediterranean diet group showed an intermediate effect.
To be clear about what this means: participants in the Green Mediterranean group did not simply slow their biological ageing — their epigenetic clocks moved in a younger direction relative to the control group over the course of the trial. An 8.9-month attenuation over 18 months represents a meaningful effect size for a dietary intervention.
Why biological age matters for cancer
Biological ageing and cancer are deeply connected. Epigenetic age acceleration — the state in which your biological age runs ahead of your chronological age — is associated with increased cancer incidence across multiple tumour types. A 2017 prospective study published in the International Journal of Cancer (Dugué et al.) found that epigenetic age acceleration was associated with significantly increased cancer risk in a large population cohort. A 2021 study (Chung et al., Epigenetics) found similar associations, with accelerated biological age predicting elevated cancer risk independent of conventional risk factors.
The logic is mechanistic: as cells age biologically, their DNA methylation patterns drift, gene expression regulation becomes less precise, damaged cells accumulate, and the surveillance mechanisms that identify and eliminate pre-cancerous cells become less efficient. A dietary pattern that measurably slows or partially reverses this process is, in principle, reducing the biological substrate on which cancer develops.
The DIRECT PLUS trial is one of the first randomised trials to demonstrate that a dietary intervention can measurably shift epigenetic age in a favourable direction in humans. That is a significant finding, even at the scale of one trial.
What the Green Mediterranean diet contains — and why it may work
The Green Mediterranean diet is not a radical departure from the standard Mediterranean pattern. It shares the same foundation: abundant olive oil, vegetables, legumes, whole grains, nuts, fish, and limited red meat. What distinguishes it is the addition of three specific, polyphenol-rich elements.
Walnuts are one of the richest plant sources of alpha-linolenic acid (a plant-based omega-3) and ellagitannins, which are metabolised by gut bacteria into urolithin A — a compound with emerging evidence for effects on mitochondrial function and cellular senescence. The DIRECT PLUS trial used 28 grams daily, equivalent to a small handful.
Green tea is exceptionally rich in epigallocatechin-3-gallate (EGCG), the most studied tea polyphenol. EGCG has well-characterised effects on DNA methylation enzyme activity in cell studies, though human trial evidence for direct epigenetic effects remains early-stage. The trial used three to four cups per day.
Wolffia globosa (duckweed) is less familiar but nutritionally remarkable: it contains a complete amino acid profile, significant polyphenol content, and was chosen specifically as a high-polyphenol plant protein source. It is not yet widely available in the UK as a food product, but the principle it represents — high-quality plant protein with polyphenol content — can be approximated with other whole-food protein sources such as tempeh, edamame, and hemp seeds.
The underlying mechanism across all three additions is likely the combination of polyphenol load, omega-3 fatty acids, and plant protein — all of which influence gut microbiome composition, reduce systemic inflammation, and potentially influence one-carbon metabolism, the biochemical pathway central to DNA methylation.
What the Experimental Gerontology review adds
A 2023 review published in Experimental Gerontology, examining the Mediterranean diet’s effects on obesity and chronic disease across multiple study populations, provides important context for the DIRECT PLUS findings. The review confirms consistent associations between Mediterranean dietary adherence and lower inflammatory markers, better insulin sensitivity, and reduced risk of the metabolic conditions — obesity, type 2 diabetes, cardiovascular disease — that share mechanistic pathways with cancer.
Crucially, the review underscores that the Mediterranean pattern’s benefits are dose-dependent: higher adherence scores are associated with larger effect sizes. This is consistent with what DIRECT PLUS found — the enhanced Green Mediterranean diet, which achieves higher polyphenol density than the standard Mediterranean pattern, produced larger epigenetic effects than the standard Mediterranean diet alone.
What this means in practice
Build from the Mediterranean foundation. The evidence base for the standard Mediterranean dietary pattern — abundant vegetables, legumes, whole grains, olive oil, fish, nuts, and limited red and processed meat — is among the deepest in nutritional science. This is where to start. It does not require eliminating all animal foods, adhering to rigid rules, or spending significantly more on food.
Add polyphenol density deliberately. The Green Mediterranean enhancements target polyphenol intake specifically. Practical equivalents accessible in the UK include: a small daily handful of walnuts, regular green tea consumption (three cups per day is achievable), dark berries, dark chocolate (85%+), extra virgin olive oil as the primary cooking fat, and a wide variety of colourful vegetables.
Prioritise plant protein sources. The DIRECT PLUS duckweed shake was chosen as a high-polyphenol plant protein. Accessible equivalents include edamame, tempeh, hemp seeds, and lentils — all of which combine meaningful protein content with polyphenol or phytochemical activity.
Adherence over time matters more than perfection. The DIRECT PLUS trial ran for 18 months, and the epigenetic benefit accumulated over that period. One-off dietary changes do not produce epigenetic shifts — sustained patterns do. The Mediterranean diet’s advantage partly comes from its flexibility and palatability, which make long-term adherence more realistic than more restrictive dietary approaches.
What the evidence does not show
The DIRECT PLUS trial involved 294 participants over 18 months. Replication in larger and more diverse populations is needed before these findings can be considered established. The trial was conducted in Israel, in a population that differs from a UK perimenopausal cohort in multiple relevant ways.
The epigenetic age attenuation observed does not directly translate into a quantified reduction in cancer risk. The association between biological age acceleration and cancer incidence is well supported; the magnitude of cancer risk reduction from an 8.9-month biological age attenuation in midlife women specifically has not been established.
And the Wolffia globosa component is not readily available in the UK. The trial’s findings reflect the overall dietary pattern, not any single ingredient — which means the principle is transferable even where the exact components are not.
The bottom line
The DIRECT PLUS trial is one of the first randomised controlled trials to demonstrate that an enhanced Mediterranean dietary pattern can measurably shift biological age in a favourable direction — by approximately 8.9 months over 18 months in participants following the Green Mediterranean diet. Given the well-established link between epigenetic age acceleration and cancer risk, a diet that measurably slows this process represents a meaningful preventive strategy. The practical implementation is not radical: a Mediterranean foundation, deliberately enriched with polyphenol-dense foods, plant protein sources, and green tea. Sustained over years, not days.
Scientific references
- Yaskolka Meir A, et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. BMC Medicine. 2023;21(1):99. DOI: 10.1186/s12916-023-03067-3
- Álvarez-Álvarez I, et al. Mediterranean diet, obesity and metabolic syndrome. Experimental Gerontology. 2023. DOI: 10.1016/j.exger.2023.112121
- Dugué PA, et al. Epigenetic clock and cancer risk: a prospective study. International Journal of Cancer. 2017. DOI: 10.1002/ijc.31189
- Chung W, et al. Epigenetic age acceleration and risk of cancer. Epigenetics. 2021. DOI: 10.1080/15592294.2020.1861401
- Fitzgerald KN, et al. Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomised clinical trial. Aging. 2021. DOI: 10.18632/aging.202913
This article is written for educational and informational purposes only. It is not intended as medical advice and should not be used to diagnose, treat, prevent, or cure any medical condition, including cancer. If you have a cancer diagnosis or are undergoing treatment, please discuss any lifestyle or dietary changes with your oncologist or medical team before making them. The studies cited reflect current research at the time of writing; the field is evolving rapidly and findings may be updated or superseded. Chloe Archard is a nutritional health coach, not a medical doctor.
