bims-longev Biomed News
on Longevity
Issue of 2023–05–28
sixteen papers selected by
Andreea Nitescu
  1. Exploring the Relationship between the Gut Microbiota and Ageing: A Possible Age Modulator.
  2. Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)-intervention study protocol.
  3. DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation.
  4. Follicular communication breakdown in aging ovaries.
  5. Accounting Gut Microbiota as the Mediator of Beneficial Effects of Dietary (Poly)phenols on Skeletal Muscle in Aging.
  6. Building the case for mitochondrial transplantation as an anti-aging cardiovascular therapy.
  7. Brown adipose tissue and aging: A potential role for exercise.
  8. Human Metabolome Reference Database in a Biracial Cohort across the Adult Lifespan.
  9. Biologia Futura: does the aging process contribute to the relativity of time?
  10. Unbiased evaluation of rapamycin's specificity as an mTOR inhibitor.
  11. Non-canonical telomere protection role of FOXO3a of human skeletal muscle cells regulated by the TRF2-redox axis.
  12. Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies.
  13. Association between perfluoroalkyl and polyfluoroalkyl internal exposure and serum α-Klotho levels in middle-old aged participants.
  14. Tick Tock, the Cartilage Clock.
  15. The Impact of Nutrition, Physical Activity, Beneficial Microbes, and Fecal Microbiota Transplant for Improving Health.
  16. Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.
  1. Int J Environ Res Public Health. 2023 May 17. pii: 5845. [Epub ahead of print]20(10):
    Exploring the Relationship between the Gut Microbiota and Ageing: A Possible Age Modulator.
    Juan Salazar, Pablo Durán, María P Díaz, Maricarmen Chacín, Raquel Santeliz, Edgardo Mengual, Emma Gutiérrez, Xavier León, Andrea Díaz, Marycarlota Bernal, Daniel Escalona, Luis Alberto Parra Hernández, Valmore Bermúdez.
      The gut microbiota (GM) has been the subject of intense research in recent years. Therefore, numerous factors affecting its composition have been thoroughly examined, and with them, their function and role in the individual's systems. The gut microbiota's taxonomical composition dramatically impacts older adults' health status. In this regard, it could either extend their life expectancy via the modulation of metabolic processes and the immune system or, in the case of dysbiosis, predispose them to age-related diseases, including bowel inflammatory and musculoskeletal diseases and metabolic and neurological disorders. In general, the microbiome of the elderly tends to present taxonomic and functional changes, which can function as a target to modulate the microbiota and improve the health of this population. The GM of centenarians is unique, with the faculty-promoting metabolic pathways capable of preventing and counteracting the different processes associated with age-related diseases. The molecular mechanisms by which the microbiota can exhibit anti-ageing properties are mainly based on anti-inflammatory and antioxidant actions. This review focuses on analysing the current knowledge of gut microbiota characteristics and modifiers, its relationship with ageing, and the GM-modulating approaches to increase life expectancy.
    Keywords:  ageing; centenarian; gut microbiota; immune system; longevity
    DOI:  https://doi.org/10.3390/ijerph20105845
  2. Geroscience. 2023 May 23.
    Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)-intervention study protocol.
    Elena Sandalova, Jorming Goh, Zi Xiang Lim, Zhi Meng Lim, Diogo Barardo, Rajkumar Dorajoo, Brian K Kennedy, Andrea B Maier.
      Targeting molecular processes of aging will enable people to live healthier and longer lives by preventing age-related diseases. Geroprotectors are compounds with the potential to increase healthspan and lifespan. Even though many of them have been tested in animal models, the translation to humans is limited. Alpha-Ketoglutarate (AKG) has been studied widely in model animals, but there are few studies testing its geroprotective properties in humans. ABLE is a double blinded placebo-controlled randomized trial (RCT) of 1 g sustained release Ca-AKG versus placebo for 6 months of intervention and 3 months follow up including 120 40-60-year-old healthy individuals with a higher DNA methylation age compared to their chronological age. The primary outcome is the decrease in DNA methylation age from baseline to the end of the intervention. A total of 120 participants will be randomized to receive either sustained release Ca-AKG or placebo. Secondary outcomes include changes in the inflammatory and metabolic parameters in blood, handgrip strength and leg extension strength, arterial stiffness, skin autofluorescence, and aerobic capacity from baseline to 3 months, 6 months, and 9 months. This study will recruit middle-aged participants with an older DNA methylation age compared to their chronological age, and test whether supplementation with Ca-AKG can reduce DNA methylation age. This study is unique in its inclusion of biologically older participants.
    Keywords:  Alpha-ketoglutarate; Biological age; DNA methylation age; Geroprotective intervention study; Geroscience
    DOI:  https://doi.org/10.1007/s11357-023-00813-6
  3. Geroscience. 2023 May 20.
    DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation.
    Matyas Jokai, Ferenc Torma, Kristen M McGreevy, Erika Koltai, Zoltan Bori, Gergely Babszki, Peter Bakonyi, Zoltan Gombos, Bernadett Gyorgy, Dora Aczel, Laszlo Toth, Peter Osvath, Marcell Fridvalszky, Timea Teglas, Aniko Posa, Sylwester Kujach, Robert Olek, Takuji Kawamura, Yasuhiro Seki, Katsuhiko Suzuki, Kumpei Tanisawa, Sataro Goto, Csaba Kerepesi, Istvan Boldogh, Xueqing Ba, Kelvin J A Davies, Steve Horvath, Zsolt Radak.
      DNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm)-based biomarkers that reflect the individual aging process. Here, we examine the relationship between physical fitness and DNAm-based biomarkers in adults aged 33-88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO2max (ρ = 0.2, p = 6.4E - 4, r = 0.19, p = 1.2E - 3), Jumpmax (p = 0.11, p = 5.5E - 2, r = 0.13, p = 2.8E - 2), Gripmax (ρ = 0.17, p = 3.5E - 3, r = 0.16, p = 5.6E - 3), and HDL levels (ρ = 0.18, p = 1.95E - 3, r = 0.19, p = 1.1E - 3) are associated with better verbal short-term memory. In addition, verbal short-term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration (ρ: - 0.18, p = 0.0017). DNAmFitAge can distinguish high-fitness individuals from low/medium-fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high-fit males and females (1.5 and 2.0 years younger, respectively). Our research shows that regular physical exercise contributes to observable physiological and methylation differences which are beneficial to the aging process. DNAmFitAge has now emerged as a new biological marker of quality of life.
    Keywords:  DNA methylation; DNAmFitAge; Regular exercise; Slower aging; Systemic adaptation
    DOI:  https://doi.org/10.1007/s11357-023-00826-1
  4. Nat Aging. 2023 May 25.
    Follicular communication breakdown in aging ovaries.
    Cecilia S Blengini, Karen Schindler.
      
    DOI:  https://doi.org/10.1038/s43587-023-00435-9
  5. Nutrients. 2023 May 18. pii: 2367. [Epub ahead of print]15(10):
    Accounting Gut Microbiota as the Mediator of Beneficial Effects of Dietary (Poly)phenols on Skeletal Muscle in Aging.
    Andrea Ticinesi, Antonio Nouvenne, Nicoletta Cerundolo, Alberto Parise, Tiziana Meschi.
      Sarcopenia, the age-related loss of muscle mass and function increasing the risk of disability and adverse outcomes in older people, is substantially influenced by dietary habits. Several studies from animal models of aging and muscle wasting indicate that the intake of specific polyphenol compounds can be associated with myoprotective effects, and improvements in muscle strength and performance. Such findings have also been confirmed in a smaller number of human studies. However, in the gut lumen, dietary polyphenols undergo extensive biotransformation by gut microbiota into a wide range of bioactive compounds, which substantially contribute to bioactivity on skeletal muscle. Thus, the beneficial effects of polyphenols may consistently vary across individuals, depending on the composition and metabolic functionality of gut bacterial communities. The understanding of such variability has recently been improved. For example, resveratrol and urolithin interaction with the microbiota can produce different biological effects according to the microbiota metabotype. In older individuals, the gut microbiota is frequently characterized by dysbiosis, overrepresentation of opportunistic pathogens, and increased inter-individual variability, which may contribute to increasing the variability of biological actions of phenolic compounds at the skeletal muscle level. These interactions should be taken into great consideration for designing effective nutritional strategies to counteract sarcopenia.
    Keywords:  anthocyanins; curcumin; flavonoids; isoflavones; physical frailty; sarcopenia
    DOI:  https://doi.org/10.3390/nu15102367
  6. Front Cardiovasc Med. 2023 ;10 1141124
    Building the case for mitochondrial transplantation as an anti-aging cardiovascular therapy.
    Colwyn A Headley, Philip S Tsao.
      Mitochondrial dysfunction is a common denominator in both biological aging and cardiovascular disease (CVD) pathology. Understanding the protagonist role of mitochondria in the respective and independent progressions of CVD and biological aging will unravel the synergistic relationship between biological aging and CVD. Moreover, the successful development and implementation of therapies that can simultaneously benefit mitochondria of multiple cell types, will be transformational in curtailing pathologies and mortality in the elderly, including CVD. Several works have compared the status of mitochondria in vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in CVD dependent context. However, fewer studies have cataloged the aging-associated changes in vascular mitochondria, independent of CVD. This mini review will focus on the present evidence related to mitochondrial dysfunction in vascular aging independent of CVD. Additionally, we discuss the feasibility of restoring mitochondrial function in the aged cardiovascular system through mitochondrial transfer.
    Keywords:  ROS; aging; cardiovascular system; endothelial cells; mitochondrial stress; oxidative stress; vascular smooth muscle cells
    DOI:  https://doi.org/10.3389/fcvm.2023.1141124
  7. Exp Gerontol. 2023 May 23. pii: S0531-5565(23)00139-0. [Epub ahead of print] 112218
    Brown adipose tissue and aging: A potential role for exercise.
    Shinsuke Nirengi, Kristin Stanford.
      Aging is one of the primary risk factors for the development of type 2 diabetes and cardiovascular disease, and regular physical activity can help to delay, prevent, or manage the onset and development of many chronic diseases present in older adults. Brown adipose tissue (BAT) is thermogenic tissue that protects against age-related disease, but BAT activity decreases with age. In this review, we discuss how aging contributes to impaired BAT function by inducing a 'whitening' of the BAT and altering beta 3 adrenergic receptor (β3AR) signaling, uncoupling protein 1 (UCP1) gene expression, and mitochondria respiration, and potential mechanisms for exercise to counteract the effects of aging on BAT.
    Keywords:  Aging; Brown adipose tissue; Exercise; Mitochondria; UCP1
    DOI:  https://doi.org/10.1016/j.exger.2023.112218
  8. Metabolites. 2023 Apr 25. pii: 591. [Epub ahead of print]13(5):
    Human Metabolome Reference Database in a Biracial Cohort across the Adult Lifespan.
    Qu Tian, M Gordian Adam, Enrique Ozcariz, Giovanna Fantoni, Nader M Shehadeh, Lisa M Turek, Victoria L Collingham, Mary Kaileh, Ruin Moaddel, Luigi Ferrucci.
      As one of the OMICS in systems biology, metabolomics defines the metabolome and simultaneously quantifies numerous metabolites that are final or intermediate products and effectors of upstream biological processes. Metabolomics provides accurate information that helps determine the physiological steady state and biochemical changes during the aging process. To date, reference values of metabolites across the adult lifespan, especially among ethnicity groups, are lacking. The "normal" reference values according to age, sex, and race allow the characterization of whether an individual or a group deviates metabolically from normal aging, encompass a fundamental element in any study aimed at understanding mechanisms at the interface between aging and diseases. In this study, we established a metabolomics reference database from 20-100 years of age from a biracial sample of community-dwelling healthy men and women and examined metabolite associations with age, sex, and race. Reference values from well-selected healthy individuals can contribute to clinical decision-making processes of metabolic or related diseases.
    Keywords:  aging; lifespan; reference database
    DOI:  https://doi.org/10.3390/metabo13050591
  9. Biol Futur. 2023 May 22.
    Biologia Futura: does the aging process contribute to the relativity of time?
    Vladimir Z Ajdžanović, Branka T Šošić-Jurjević, Jovan T Ranin, Branko R Filipović.
      In his Theory of relativity, Einstein determined that the time is relative to the reference frame of the observer. Under specific conditions, there is a difference in the elapsed time between two clocks, known as time dilation. A similar relativistic effect could be attributed to the brain operating at different frequencies, e.g., while it is slow and during the thought process. Time flow and the aging process are causally linked. Herein, we introduce physical relativity into the mind/thought context and elaborate changed perception of the time flow (the impression of the time acceleration) with aging. The phenomenology of time is observed in the context of physical and biological clock, as well as by introducing the category of 'mind time.' Mental processing impairment is crucial for the "aging-caused relativity of time," while adjusting of its' perception seems to be a matter of body/mind rest, mental hygiene and physical activity of the aging subject. We also provide a brief overview of the perception of time flow in some disease states that coincide with aging. Our main idea has a perspective for future development in the interdisciplinary synergy of philosophy, physical-mathematical elaboration, experimental biology and clinical investigations.
    Keywords:  Aging; Biological clock; Mind time; Physical clock; Time relativity
    DOI:  https://doi.org/10.1007/s42977-023-00167-2
  10. Aging Cell. 2023 May 24. e13888
    Unbiased evaluation of rapamycin's specificity as an mTOR inhibitor.
    Filippo Artoni, Nina Grützmacher, Constantinos Demetriades.
      Rapamycin is a macrolide antibiotic that functions as an immunosuppressive and anti-cancer agent, and displays robust anti-ageing effects in multiple organisms including humans. Importantly, rapamycin analogues (rapalogs) are of clinical importance against certain cancer types and neurodevelopmental diseases. Although rapamycin is widely perceived as an allosteric inhibitor of mTOR (mechanistic target of rapamycin), the master regulator of cellular and organismal physiology, its specificity has not been thoroughly evaluated so far. In fact, previous studies in cells and in mice hinted that rapamycin may be also acting independently from mTOR to influence various cellular processes. Here, we generated a gene-edited cell line that expresses a rapamycin-resistant mTOR mutant (mTORRR ) and assessed the effects of rapamycin treatment on the transcriptome and proteome of control or mTORRR -expressing cells. Our data reveal a striking specificity of rapamycin towards mTOR, demonstrated by virtually no changes in mRNA or protein levels in rapamycin-treated mTORRR cells, even following prolonged drug treatment. Overall, this study provides the first unbiased and conclusive assessment of rapamycin's specificity, with potential implications for ageing research and human therapeutics.
    Keywords:  ageing; mTORC1; proteomics; rapamycin; sirolimus
    DOI:  https://doi.org/10.1111/acel.13888
  11. Commun Biol. 2023 May 25. 6(1): 561
    Non-canonical telomere protection role of FOXO3a of human skeletal muscle cells regulated by the TRF2-redox axis.
    Maria Sol Jacome Burbano, Jérôme D Robin, Serge Bauwens, Marjorie Martin, Emma Donati, Lucia Martínez, Peipei Lin, Sabrina Sacconi, Frédérique Magdinier, Eric Gilson.
      Telomeric repeat binding factor 2 (TRF2) binds to telomeres and protects chromosome ends against the DNA damage response and senescence. Although the expression of TRF2 is downregulated upon cellular senescence and in various aging tissues, including skeletal muscle tissues, very little is known about the contribution of this decline to aging. We previously showed that TRF2 loss in myofibers does not trigger telomere deprotection but mitochondrial dysfunction leading to an increased level of reactive oxygen species. We show here that this oxidative stress triggers the binding of FOXO3a to telomeres where it protects against ATM activation, revealing a previously unrecognized telomere protective function of FOXO3a, to the best of our knowledge. We further showed in transformed fibroblasts and myotubes that the telomere properties of FOXO3a are dependent on the C-terminal segment of its CR2 domain (CR2C) but independent of its Forkhead DNA binding domain and of its CR3 transactivation domain. We propose that these non-canonical properties of FOXO3a at telomeres play a role downstream of the mitochondrial signaling induced by TRF2 downregulation to regulate skeletal muscle homeostasis and aging.
    DOI:  https://doi.org/10.1038/s42003-023-04903-1
  12. Aging Cell. 2023 May 26. e13874
    Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies.
    Boran Chen, Yushun Yan, Haoran Wang, Jianguo Xu.
      Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta-analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health-related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR-Egger, weighted median, MR-PRESSO, and multivariate MR. Meta-analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms (the strongest magnitude for osteosarcoma, GBM, glioma, thyroid cancer, and non-GBM glioma), six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Robust inverse association was observed for coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Meta-analyses of MR studies suggested that genetically determined LTL was associated with 12 neoplasms and 9 nonneoplasm outcomes. Evidence from published MR studies supports that LTL plays a causal role in various neoplastic and nonneoplastic diseases. Further research is required to elucidate the underlying mechanisms and to bring insight into the potential prediction, prevention, and therapeutic applications of telomere length.
    Keywords:  Mendelian randomization; health-related outcomes; leukocyte telomere length; meta-analysis; systematic review
    DOI:  https://doi.org/10.1111/acel.13874
  13. Front Public Health. 2023 ;11 1136454
    Association between perfluoroalkyl and polyfluoroalkyl internal exposure and serum α-Klotho levels in middle-old aged participants.
    Min Li, Yuanlin Ma, Wenli Cheng, Luyun Zhang, Cheng Zhou, Wenji Zhang, Wenjuan Zhang.
       Purpose: Exposure to perfluoroalkyl and polyfluoroalkyl substances causes oxidative stress, which is strongly associated with adverse health effects. Klotho protein plays an anti-aging role via antioxidation activity.
    Methods: We investigated the levels of serum α-Klotho and PFAS exposure in adults who participated in the National Health and Nutrition Examination Survey from 2013 to 2016. A nationally representative subsample of 1,499 adults aged 40-79 years was analyzed for the associations of serum α-Klotho levels with serum PFAS exposures by correlation analysis and multiple general linear models. Of note, the potential confounding factors including age and gender were adjusted. Quantile-based g-computation models were used to assess the effects of mixed PFAS exposure on serum α-Klotho levels.
    Results: The weighted geometric mean of serum α-Klotho was 791.38 pg/mL for the subjects during 2013-2016. After adjusting for potential confounders, serum Klotho levels showed a statistically significant downward trend with increasing quartiles of PFOA and PFNA. Multivariate adjusted general linear regression analysis showed that increased exposure to PFNA was substantially associated with lower serum levels of α-Klotho, and each 1-unit increase in PFNA concentration was accompanied by a 20.23 pg/mL decrease in α-Klotho level; while no significant association was observed between other PFAS exposures and serum α-Klotho levels. It was negatively correlated between α-Klotho and Q4 for PFNA relative to the lowest quartile (Q1) of exposure (P = 0.025). It was found that the strongest negative correlation between PFNA exposure and serum α-Klotho levels was in the middle-aged (40-59 years) female participants. Furthermore, the mixture of the four PFAS substances showed an overall inverse association with serum α-Klotho concentrations, with PFNA being the major contributor.
    Conclusions: Taken together, in a representative sample of the U.S. middle-aged and elderly populations, serum concentrations of PFAS, especially PFNA, have been negatively associated with serum levels of α-Klotho, which is strongly associated with cognition and aging. It was important to note that the majority of associations were limited to middle-aged women. It will be meaningful to clarify the causal relationship and the pathogenic mechanisms of PFAS exposure and α-Klotho levels, which is helpful to aging and aging-related diseases.
    Keywords:  NHANES; middle-aged women; perfluoroalkyl and polyfluoroalkyl substances (PFAS); perfluorononanoic acid (PFNA); α-Klotho
    DOI:  https://doi.org/10.3389/fpubh.2023.1136454
  14. Osteoarthritis Cartilage. 2023 May 23. pii: S1063-4584(23)00800-2. [Epub ahead of print]
    Tick Tock, the Cartilage Clock.
    Natalie Rogers, Qing-Jun Meng.
      Osteoarthritis (OA) is the most common age-related joint disease, affecting articular cartilage and other joint structures, causing severe pain and disability. Due to limited understanding of the underlying disease pathogenesis, there are currently no disease modifying drugs for OA. Circadian rhythms are generated by cell-intrinsic timekeeping mechanisms which are known to dampen during ageing, increasing disease risks. In this review, we focus on one emerging area of chondrocyte biology, the circadian clocks. We first provide a historical perspective of circadian clock discoveries and the molecular underpinnings. We will then focus on the expression and functions of circadian clocks in articular cartilage, including their rhythmic target genes and pathways, links to ageing, tissue degeneration and OA, as well as tissue niche-specific entrainment pathways. Further research into cartilage clocks and ageing may have broader implications in the understanding of OA pathogenesis, the standardization of biomarker detection and the development of novel therapeutic routes for the prevention and management of OA and other musculoskeletal diseases.
    Keywords:  Cartilage ECM; Chronotherapy; Circadian rhythm; Clock genes; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.joca.2023.05.010
  15. Life (Basel). 2023 May 02. pii: 1124. [Epub ahead of print]13(5):
    The Impact of Nutrition, Physical Activity, Beneficial Microbes, and Fecal Microbiota Transplant for Improving Health.
    Justine Keathley, Jessica White, Gregor Reid.
      The recognition that microbes are integral to human life has led to studies on how to manipulate them in favor of health outcomes. To date, there has been no conjoint recommendation for the intake of dietary compounds that can complement the ingested organisms in terms of promoting an improved health outcome. The aim of this review is to discuss how beneficial microbes in the form of probiotics, fermented foods, and donor feces are being used to manage health. In addition, we explore the rationale for selecting beneficial microbial strains and aligning diets to accommodate their propagation in the gut. A pilot clinical trial design is presented to examine the effects of probiotics and exercise in patients with phenylketonuria (PKU); it is the most common inborn error of amino acid metabolism, and it is a complication that requires lifelong dietary intervention. The example design is provided to illustrate the importance of using omics technology to see if the intervention elevates neuroactive biogenic amines in the plasma; increases the abundance of Eubacterium rectale, Coprococcus eutactus, Akkermansia muciniphila, or Butyricicoccus; and increases Escherichia/Shigella in the gut, all as markers of improved health. By emphasizing the combined importance of diet, microbial supplements, and the gut microbiome, we hope that future studies will better align these components, not only to improve outcomes, but also to enhance our understanding of the mechanisms.
    Keywords:  diet; fecal microbiota transplant; gut microbiota; health; probiotics
    DOI:  https://doi.org/10.3390/life13051124
  16. Epigenetics. 2023 Dec;18(1): 2211361
    Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.
    Amena Keshawarz, Roby Joehanes, Jiantao Ma, Gha Young Lee, Ricardo Costeira, Pei-Chien Tsai, Olatz M Masachs, Jordana T Bell, Rory Wilson, Barbara Thorand, Juliane Winkelmann, Annette Peters, Jakob Linseisen, Melanie Waldenberger, Terho Lehtimäki, Pashupati P Mishra, Mika Kähönen, Olli Raitakari, Mika Helminen, Carol A Wang, Phillip E Melton, Rae-Chi Huang, Craig E Pennell, Therese A O'Sullivan, Carolina Ochoa-Rosales, Trudy Voortman, Joyce B J van Meurs, Kristin L Young, Misa Graff, Yujie Wang, Douglas P Kiel, Caren E Smith, Paul F Jacques, Daniel Levy.
       BACKGROUND: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns.
    METHODS: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis.
    RESULTS: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated.
    CONCLUSIONS: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.
    Keywords:  Epigenetics; Vitamin C; Vitamin E; diet; epidemiology
    DOI:  https://doi.org/10.1080/15592294.2023.2211361
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