Biological aging (BA) is a universal process that involves the deterioration of vital functions. One of the root causes of BA is epigenetic DNA hypermethylation. The latter defines epigenetic age (EA), being the most important risk factor for chronic non-communicable diseases, so its modulation is an exciting emerging field of science. Although there are numerous investigations on the mechanisms of aging, today there are few studies that measure EA in humans after an intervention. The objective of this research was to evaluate the EA and the body composition after the consumption of wine enriched with Resveratrol. The results showed a decrease in EA after three and a half months of the study intervention (p < 0.01). We also demonstrated significant improvements in body composition with a 1.6 kg decrease in fat mass, (p < 0.0004); and an increase in muscle mass of 300 g (p < 0.019). To our knowledge, it is the first time that a highly significant reduction of EA has been demonstrated in consumers of wine enriched with Resveratrol combined with a healthy remodeling of body composition. These findings could be relevant to maintaining health, increasing life expectancy, and preventing the damages caused by aging.
Research Article
Reversal of epigenetic age and improvement of body composition in consumers of wine enriched with Resveratrol.
https://doi.org/10.21203/rs.3.rs-3149712/v1
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epigenetic age
biological aging
body composition
muscle mass
fat mass
wine enriched
Resveratrol
wine and health
antiaging wine
As the population ages, the need to maintain healthy longevity increases. According to epidemiological studies, the number of people older than 60 years is currently 11% and is expected to increase to 22% by 2050 [1]. The increase in longevity is directly related to the increase in the prevalence of chronic diseases [2]. The latter leads to impaired health in the elderly and places a huge burden on carers and society. Therefore, aging has become a growing problem throughout the world and this field of research becomes particularly important, where the accurate measurement of aging, the prediction and identification of risks, and the development of effective interventions are essential [1, 3]. The aging process involves significant changes at the cellular, subcellular, and nuclear levels, including the misfolding of the proteins, genomic instability, telomere shortening, epigenetic changes, loss of proteostasis, dysregulation of nutrient sensors, mitochondrial dysfunction, stem cell depletion and altered intercellular communication [4, 5]. These processes are somehow interconnected, and there is growing interest in understanding the underlying mechanisms. Many theories of why humans age have been proposed, including programmatic and based damage theories, with the former being the most widely accepted and studied [4, 6–9]. In recent years, the development of epigenetic clocks has shown that hypermethylation or hypomethylation of specific methylation sites can predict human chronological age with a high degree of accuracy [10–13].
Epigenetics determines which genes are expressed and which are silenced, these modifications in the reading of the genome promote profound changes in phenotypic responses. It is worth clarifying that epigenetic alterations do not imply permanent changes in the DNA sequence [14]. Typically, the alterations involve changes in DNA methylation, histone acetylation, phosphorylation, and ubiquitination [15, 16]. These biochemical processes are associated to redox regulation of intracellular homeostasis involving proteins, molecular sensors (glutathione and hydrogen peroxide) and messengers (oxidants, reactive oxygen species (ROS) and transcription factors), signaling the expression of genes and synthesis of antioxidant enzymes [17]. Aging cells acquire cumulative epigenetic alterations in both intrinsic and extrinsic processes. The intrinsic ones consist of stochastic and genetic influences. The decline in vital functions and the onset of chronic diseases have been shown to correlate with impaired metabolism and upstream with hypermethylation of active sectors of DNA, or euchromatin. Epigenetic information is lost, something that severely affects the rest of the phases of metabolism. Therefore, we need to consider an epigenetic perspective of aging to achieve healthy longevity. Today we know that epigenetics is a key parameter to assess human health and monitor aging. Maintaining a healthy epigenetic will be the first condition for the metabolism to develop a healthy cellular life and it is essential to maintain phenotypic health, which immediate secondary effect is the prevention of diseases. The concept of information in biology has a long history [18], and biological systems can be seen as very complex information systems. The idea that aging could be related to the deterioration or loss of information has been proposed, particularly in the context of the information theory of aging [19]. According to this theory, the loss of genetic [20] or epigenetic [19, 21] information with age, driven by DNA damage, is the main cause of aging. One hypothesis is that errors accumulate in the DNA, corrupting the information in the genome and, ultimately, disrupting tissue homeostasis causing aging [22, 23]. Mitochondrial DNA rearrangement mutations have been found in patients suffering from age-related diseases, including chronic coronary artery disease [24] and Alzheimer's disease [25]. As a result, mutation and damage to chromosomal and mitochondrial DNA can cause aging. In cultured cells, DNA damage accumulates over time, accelerating the aging process. Cells and organisms have endogenous systems for DNA repair and ROS removal; however, these systems do not work effectively in aged cells.
The moderate and regular consumption of wine is an ancient habit that has been related to good health since its origins. Since the publication of the French Paradox in 1992 [26], resveratrol (a polyphenol presents in Vitis vinifera grapes and wine) has been linked to several effects i.e., anti-inflammatory [27], direct and induced antioxidants, chemopreventive, improvement of fat metabolism, skeletal muscle, [28], endothelial function [29] and prevention of myocardial ferroptosis [30,31].
Sarcopenia is a skeletal muscle disorder characterized by a progressive and generalized decline in strength (dynapenia), muscle mass, and performance that is associated with an increased likelihood of adverse outcomes, such as falls, fractures, physical disability, and mortality. Sarcopenia is defined by impaired muscle strength, muscle quantity/quality, and physical performance as indicators of severity. Beyond the age of 50, loss of muscle mass (1–2% per year) and strength (1.5–5% per year) in the legs have been reported [32]. The administration of resveratrol impacts on skeletal muscle by increasing mitochondrial biogenesis, promoting the migration of satellite stem cells of the muscle fiber and activating myocyte differentiation [33]. Furthermore, in adipose tissue, resveratrol promotes lipolysis, inhibits stem cell differentiation into adipocytes, and inhibits adipogenesis. The hypothesis of this research is to consider that the regular consumption of wine enriched with Resveratrol decreases the biological age and improves the body composition in people with cardiovascular risk factors.
2.1 Volunteers: Between January and June 2022, there was an open call to participate in clinical trial #26122021 approved by the Ethics Committee of the Hospital de Clínicas, of the University of Buenos Aires. Thirty volunteers who met the inclusion criteria were selected. We defined cardiovascular risk factors (CVF) as the diagnosis of hyperglycemia or diabetes, arterial hypertension, low HDL Cholesterol, high triglycerides, central obesity, and sedentarism.
2.2. Study design: The study design was prospective, longitudinal, interventional, and voluntary against itself. This design was selected to avoid the interindividual differences in the bioavailability of the active ingredients, determined by the intestinal microbiome and intestinal barrier permeability [49,50]. The study design was based on comparing the volunteer's own biomarkers before and after the intervention and then comparing the statistical significance of the median using a student's t-test for paired data. With this design we minimize the potential impact on the results of the biological, environmental, and social variables that determine a health phenotype, what we now know as an exposome [51].
2.3. DNAm PhenoAge: DNAm PhenoAge, a new composite biomarker developed to calculate the epigenetic age using peripheral blood clinical biochemistry variables was measured in this research. It was developed with the use of a proportional hazard penalized regression model to narrow from 42 to 9 biomarkers and chronological age. This epigenetic clock measures the speed of aging through the estimation of DNA methylation considering ten variables (albumin, creatinine, glucose, ultrasensitive C-reactive protein, percentage of lymphocytes, mean cell volume, red cell distribution width (RDW), alkaline phosphatase, white blood cell count, and chronological age). The DNAm PhenoAge is developed using a novel two-step method and is highly predictive of nearly every morbidity and mortality outcome tested. The biomarker is based on epigenetic predictors of phenotypic age, which led to substantial improvement in mortality/healthspan predictions over the first generation of DNAm based biomarkers of chronological age from Hannum and Horvath [52]. DNAm PhenoAge tracks chronological age and relates to disease risk in samples other than whole blood. The biomarker is associated with activation of pro-inflammatory, interferon, DNAm damage repair, transcriptional/translational signaling, and various markers of immuno-senescence. In addition, it predicts differences in morbidity and mortality associated with epigenetic age in individuals with the same chronological age (Figure 1) [37,53].
2.4. Medical follow-up: During the first visit, we performed a medical examination, analyzed the inclusion criteria, and obtained the informed consent of the participants. The inclusion criteria were being a wine consumer, avoiding any dietary supplement with antioxidant effects two weeks before start taking the investigation’s wine and throughout the period of the study, and not modifying the usual diet or existing medical treatments. After the second week, we carried out a baseline blood sample and measurement of the body composition (fat and muscle mass). Then the participants began the intervention of the trial, consisting in taking 250 cc or 150 cc of a wine enriched with Resveratrol with meals (for men and women respectively). After 3 months, the participants repeated the body composition measurement and blood analysis.
2.5. Diet control: A nutritional survey was carried out. To validate the information self-reported, we performed a non-invasive transdermal scan using a NIRS Biozoom ® near-infrared spectrometer to measure carotenoids (an indirect measurement of the consumption of fruit and vegetables) [35, 36].
2.6. Blood chemistry and Body Composition assessment: Blood tests were performed twice, at the beginning and at the end of the treatment. The variables that were measured in plasma were: Albumin, Creatinine, Glycemia, US-CRP, Lymphocytes, Mean Corpuscular Volume, Red cell distribution width (RDW), Alkaline Phosphatase, White Blood Cells, HDL Cholesterol, Triglycerides, Total Cholesterol, Ferritin. Biochemical measurements were obtained using a diagnostic kit from Roche Laboratories, measured with Hitach Covas C311. Hematological measurements were made using LABIX reactive kits measured with SEAC HECO.
The anthropometric measurements of height, weight, body mass index, and abdominal circumference were taken. The body composition was quantified as skeletal muscle mass (lean mass) and fat mass in absolutes values and percentages. The latter was obtained three times for each volunteer, using a non-invasive bioimpedance analysis (Inbody 120).
2.7. Wine Enriched with Resveratrol: The production of wine enriched with Resveratrol 150 mg/L was approved by the National Institute of Viticulture and carried out by https://vinospiner.com.ar/ Tiempo Ganado SRL. We use 100% pure Malbec wine from Mendoza, Argentine, 2022 harvest. In a previous investigation, we demonstrated that wine enriched with resveratrol does not have significant differences in physical and organoleptic characteristics compared to conventional wine [47].
2.8. Resveratrol: Veri-te ® Resveratrol of Swiss origin, produced by EVOLVA AG, was used to enrich the wine.
2.9. Statistical analysis: The statistical analysis was performed using the Student t-test for paired samples (Prism 7.0, GraphPad, San Diego, CA, USA). The Student t-test was selected to evaluate a single biomarker at a time in eight series of paired data (D0 vs. D90 for chronological and DNAm PhenoAge, muscle mass and fat mass) for each patient before and after the intervention. Results with p < 0.05 were considered significant.
Thirty volunteers were included in the investigation. At the initial evaluation, a medical history was recorded, 12/30 (40%) participants had hyperglycemia or diabetes, 19/30 (63%) had arterial hypertension, 18/30 (60%) had low HDL Cholesterol, 6/30 (20%) had high triglycerides, 24/30 (80%) had central obesity and 21/30 (70%) sedentary lifestyle. The median ± DS age was 66.63 ± 10,14 years old. The majority gender was male (22/30, 73%). The main characteristics of the population are listed in Table 1.
Table 1. Main characteristics of the study population.
According to the main characteristics of the population of volunteers in this study, it was observed that they were mostly men and that in order of prevalence of the cardiovascular risk factors the most important were central obesity, arterial hypertension, low plasma HDL cholesterol levels, hyperglycemia or diabetes, high plasma triglyceride levels and sedentarism. The co-occurrence of cardiovascular risk factors is listed in Table 2.
Table 2. Co-occurrence of cardiovascular risk factors (CVF), defined as hyperglycemia or diabetes, arterial hypertension, low HDL Cholesterol, high triglycerides, central obesity and sedentarism, in each volunteer.
|
Cardiovascular Risk Factor |
Volunteers (N=30) (%) |
|
|
1 |
5 |
17 |
|
2 |
8 |
27 |
|
3 |
13 |
43 |
|
4 |
3 |
10 |
|
5 6 |
1 21 |
3 70 |
Following the enrolment in the trial, the thirty volunteers were instructed to stop taking any dietary supplement for two weeks. After that period, blood samples were obtained, and they started drinking the wine enriched with resveratrol with the main meals (125 mL for women and 250 mL for men); the difference in the volume of the wine was determine according to the gender recommendations of daily alcohol intake [34]. The volunteers were followed throughout the intervention period. After a median of 105 ± 12.4 days of treatment, 3.5 months, the thirty participants completed the final visit where another blood samples were collected. Diet consumption, epigenetic age and body composition were evaluated, the following observations were found:
3.1. Diet control: The nutritional survey showed no significant differences during the period of the intervention. The Biozoom ® near-infrared scanner results did not reveal significant differences between the baseline and 3-month analyses (5.24 vs 5.22 reflectance units respectively). Those two results confirmed that the diet of the studied population did not vary in the consumption of fruit and vegetables [35,36].
3.2. Epigenetic age (EA): The comparison between the chronological age (CA) and EA at the beginning of the study showed a difference of 3.08 years, in favor of a lower EA. Data were analyzed with a paired t-test, chronological age median ± DS (66.63 ± 10.14 ) compared to baseline EA (63.55 ± 12.27 years) showed two-tailed p value= 0.0192 (considered very significant) with correlation coefficient (r): 0.6495. When CA 3.5 months (66.95 ± 10.30 years) was compared to post-treatment EA (60.31 ± 10.55 years), differences were two-tailed p value < 6 x 10 -10, correlation coefficient (r): 0.8079. It is very important to point out that the change between CA and EA post-treatment proved to be beneficial for EA, with a decrease highly significant two-tailed p-value and correlation coefficient. Regarding the comparison between ages at the end of the intervention, it was observed that it presented a difference of 6.64 years, also in favor of a lower EA, adding 3.56 years more, representing an additional benefit of 116%, taking into account the changes respect to chronological age before and post-treatment. We found that this reversal in epigenetic age basal vs 3.5 months was statistically significant, with p < 0.01 (Figure 1, Table 3).
Table 3. Chronological age (CA) and epigenetic age (EA) median ± standard error, initial and final analysis. Delta (Δ) represents the difference between CE and EA.
|
Analysis |
Chronological Age, (median ± SE) |
Epigenetic Age,
(median ± SE) |
Δ |
p-value |
|
Initial |
66.63 ± 1,85 |
63.55 ± 2,24 |
-3,08 |
0.0192 |
|
Final |
66.95 ± 1,88 |
60.31 ± 1,92 |
-6,64 |
6 x 10 -10 |
|
p-value |
NS |
< 0.01 |
|
|
Participants had all cardiovascular risk factors appropriately treated and a free diet, including regular wine consumption with meals. The latter and the lifestyle of each participant may have been part of the good result obtained in the baseline DNAm PhenoAge, in accordance with a study that demonstrated a decrease in biological age with a lifestyle and healthy diet [10]. It is necessary to distinguish between chronological age and biological age. Thus, people of different races and genders can be unified within a chronological age. However, the aging status may vary widely among individuals of similar chronological age, likely due to differences in health conditions, lifestyles and genetic determinants. The epigenetic age calculated by the DNAm PhenoAge biomarker reflects an individual's physiological and functional state [37]. Biological age can be older or younger than chronological age, reflecting aging and health status [38]. Epigenetic alterations such as histone modification, chromatin remodeling, and DNA methylation occur progressively in cells of aging individuals [39] and are associated with aging different phenotypes and the development of age-related diseases. Therefore, multiple damages to DNA or the repair system lead to an accumulation of DNA damage, resulting in epigenetic alterations that cause premature aging [40]. Since epigenetic alterations can be reset to a younger configuration, epigenetic age reversal is a potential therapeutical target to delay cell aging [41]. For each year of increase in DNAm PhenoAge, the risk of mortality from different causes increases [37]. Taking the percentages indicated in Table 4 (Column 1) as a reference, we hypothesize that the decrease in the epigenetic age after our intervention could decrease the risk of mortality for all causes and specific diseases, according to the number of years reversed between the initial and final analysis (Table 4, column 3).
Table 4. Prediction of the increased risk of mortality from all causes and specific causes related to the increase of 1 year of epigenetic age greater than the chronological age and the percentage of reduction associated with the results of EA found at the initial and final analysis in the studied population.
|
Mortality |
% of increase by 1 year + EA |
% of decrease related with initial EA (- 3.08) |
% of decrease related with the final EA (- 6.64) |
|
All-causes |
9 |
-27.72 |
-59.76 |
|
Aging-Related |
9 |
-27.72 |
-59.76 |
|
Cardiovascular diseases |
10 |
-30.80 |
-66.40 |
|
Cancer |
10 |
-30.80 |
-66.40 |
|
Diabetes |
20 |
-61.60 |
-132.80 |
|
Chronic lower respiratory diseases |
9 |
-27.72 |
-59.76 |
According to these results, the regular consumption of red wine enriched with Resveratrol decreased the epigenetic age in people with cardiovascular risk factors, so we also hypothesized that it would decrease the risk of mortality from chronic diseases.
3.3. Body Composition
3.3.1. Muscle mass: the measurement of the muscle mass using bioimpedance showed that the intervention produced a median increase of 300 g (Figure 2).
Results indicate that the median baseline muscle mass (kg) ± standard error was 32.70 ± 1.16 kg and 33.0 ± 1.23 kg after treatment, considered significant with t-test for paired data (two-tailed p value= 0.0189 and r= 0.9907). According to the literature, the natural evolution of aging is towards a decline in strength (dynapenia) and muscle mass (sarcopenia) from the age of 27 years old [42]. Beyond the age of 50, the loss of muscle mass has been calculated with a rate of decline of 1-2% per year [31]. Our research showed an average increase of 1% in muscle mass, which represents a statistically significant result with a p 0.019 (Table 5).
Table 5. Results of the initial and final non-invasive bioimpedance analysis (In Body 120) of the muscle and fat mass.
3.3.2. Fat Mass: the measurement of the fat mass showed a decrease of median of 1.6 kg after the intervention period (p<0.0004), highly significant, representing 5.8 % (Figure 3; Table 5).
Results in Figure 3 indicate that the median ± standard error baseline fat mass was 29.30 ± 2.01 and 27.70 ± 1.96 kg after treatment, considered extremely significant with t paired t-test (two-tailed p value= 0.0004 and r= 0.9863). Among the mechanisms investigated, resveratrol can affect the metabolism of lipids by directly inhibiting the peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor expressed in adipose tissue, or indirectly through Sirtuin 1 (SIRT1), leading to decreased adipogenesis and an increased in lipolysis [43]. SIRT1 is also known to repress Nuclear Factor kappa-B (NF-κB) activity and thus reduce inflammation. Resveratrol modulates inflammation by directly interacting with cyclooxygenases (COX), which catalyze the formation of prostaglandins, bioactive lipids with hormone-like effects [44].
Sarcopenia in combination with excess body fat, known as sarcopenic obesity, is increasingly recognized as a major health problem in the aging population due to its association with an increased risk of cardiometabolic abnormalities [45-48].
Aging is inherent to all human beings, but why we age is still a highly controversial issue. Most mechanistic explanations postulate that aging is caused by the accumulation of various forms of molecular damage. Indeed, aging is characterized by several changes at the cellular, subcellular, and nuclear levels, one of which is epigenetic aging. Although resveratrol has a strong impact on metabolism [54], some of its benefits are a consequence of epigenetic modifications. In fact, resveratrol can induce epigenetic modifications in the DNA sequence. Epigenetic modifications include DNA methylation, histone modifications, and nucleosome positioning. These modifications can interact with each other to influence gene expression [55]. This research aimed to evaluate the phenotypic expression of epigenetic aging using the PhenoAge mDNA composite biomarker and body composition (muscle mass/fat mass) using non-invasive bioimpedance analysis in a population of people with cardiovascular risk factors. The call for volunteers was public and our objective was to evaluate the consumption of wine enriched with Resveratrol in the general population with cardiovascular risk factors. In this work we demonstrate that the consumption of wine enriched with resveratrol reverses the epigenetic age in 3.56 years, which represents a decrease of 116% compared to the difference between the chronological and epigenetic age of the individuals at the beginning of the study. Based on the results from DNAm PhenoAge, we hypothesize that this finding represents a highly significant reduction in all-cause and disease-specific mortality. Body composition also improves with the administration of the wine enriched with Resveratrol, showing an increase in muscle mass of 300 g and a decrease in fat mass of 1.6 kg. To the best of our knowledge, it is the first time that a human health clinical trial has been conducted with wine enriched with Resveratrol to assess epigenetic aging and body composition. These findings could be relevant for an improvement in quality of life together with a focus on the prevention of chronic diseases.
Tiempo Ganado SRL is the sole owner of a provisional patent application of which RFP is the inventor.
Author Contributions: Conceptualization, R.F.P., Z.M.C., E.P. and IP; methodology, R.F.P. and E.P.; software, I.P. and I.C.; validation, M.G.R. and A.L.; formal analysis, M.G.R., C.S.M., C.A.B., and F.L.; investigation, R.F.P., Z.M.C., E.P. and I.P.; resources, R.F.P. and Z.M.C, data curation, I.P., E.P. and M.M.S; writing—original draft preparation, R.F.P.; writing—review and editing, Z.M.C., M.G.R. and I.P.; visualization, L.I., A.C. and J.A.; supervision, R.H.I., A.R., C.T., C.C., C.S.M, CAB and J.A.; project administration, Z.M.C.; funding acquisition, R.F.P. and Z.M.C.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Hospital de Clínicas Universidad de Buenos Aires protocol code and #26122021 date of approval for studies involving humans.
Data Availability Statement: The data will be made available from the corridor upon reasonable request.
Acknowledgments: The authors acknowledge to Instituto Nacional de Vitivinicultura, Universidad of Buenos Aires and Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET).
Conflicts of Interest: RFP is scientific advisor ofTiempo Ganado SRLhttps://vinospiner.com.ar/The other authors declare no competing interests.
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