The effect of polyphenols on DNA methylation-assessed biological age attenuation: the DIRECT PLUS randomized controlled trial.

Anat Yaskolka Meir, Maria Keller, Anne Hoffmann, Ehud Rinott, Gal Tsaban, Alon Kaplan, Hila Zelicha, Tobias Hagemann, Uta Ceglarek, Berend Isermann, Ilan Shelef, Matthias Blüher, Michael Stumvoll, Jun Li, Sven-Bastian Haange, Beatrice Engelmann, Ulrike Rolle-Kampczyk, Martin von Bergen, Frank B Hu, Meir J Stampfer, Peter Kovacs, Liming Liang, Iris Shai

Journal: BMC medicine 2023;21(1):364

PMID: 37743489

Free Full Text on BioMed Central View on PubMed

Plain Language Summary

Biological age differs from chronological age and is determined by assessing our DNA, this is known as mAge. A healthy lifestyle and weight loss have been shown to be of benefit to mAge. The Mediterranean (MED) diet includes ingredients such as vitamins and naturally occurring chemicals, known as polyphenols, which may alter biological age. This randomised control trial of 256 aimed to determine the effects of a MED diet richer in green vegetables and lower in meat (Green-MED) compared to the MED diet and recommendations for healthy eating. The results showed that after 18 months of healthy eating and weight loss, none of the diets was able to lower the biological age, however the Green-MED diet and in particular the intake of green tea and the vegetable Mankai were associated with slower biological ageing compared to the other two diets. The polyphenol tyrosol was also associated with slower biological ageing. It was concluded that the diets were unable to reverse biological ageing, but a GreenMed diet rich in polyphenols, may be able to slow it. This study could be used by healthcare professionals to understand that as higher biological age is associated with poorer health outcomes, a diet rich in polyphenols may have additional benefits beyond just weight loss.

Abstract

BACKGROUND

Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined.

METHODS

We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3-4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight).

RESULTS

Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e - 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = - 0.41, p = 0.004 and beta = - 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = - 1.8; p = 0.061) and green tea (beta = - 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02).

CONCLUSIONS

This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging.

TRIAL REGISTRATION

ClinicalTrials.gov, NCT03020186.

Address: The Health & Nutrition Innovative International Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, 8410501, Be'er Sheva, Israel.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA.; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, 04103, Leipzig, Germany.; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, University of Leipzig, Liebigstrasse 21, 04103, Leipzig, Germany.; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, 04103, Leipzig, Germany.; The Health & Nutrition Innovative International Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, 8410501, Be'er Sheva, Israel.; The Health & Nutrition Innovative International Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, 8410501, Be'er Sheva, Israel.; Soroka University Medical Center, 84101, Be'er Sheva, Israel.; Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University of Leipzig Medical Center, 04103, Leipzig, Germany.; Soroka University Medical Center, 84101, Be'er Sheva, Israel.; Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and, Harvard Medical School, Boston, MA, 02115, USA.; Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research GmbH, 04318, Leipzig, Germany.; Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research GmbH, 04318, Leipzig, Germany.; Institute of Biochemistry, Faculty of Life Sciences, University of Leipzig, 04103, Leipzig, Germany.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA.; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, University of Leipzig, Liebigstrasse 21, 04103, Leipzig, Germany. [email protected].; Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA. [email protected].; The Health & Nutrition Innovative International Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, 8410501, Be'er Sheva, Israel. [email protected].; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, 04103, Leipzig, Germany. [email protected].; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. [email protected].; Faculty of Medicine, Leipzig University, Leipzig, 04103, Germany. [email protected].

DOI: 10.1186/s12916-023-03067-3