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Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial.
Fitzgerald, KN, Hodges, R, Hanes, D, Stack, E, Cheishvili, D, Szyf, M, Henkel, J, Twedt, MW, Giannopoulou, D, Herdell, J, et al
Aging. 2021;(7):9419-9432
Abstract
Manipulations to slow biological aging and extend healthspan are of interest given the societal and healthcare costs of our aging population. Herein we report on a randomized controlled clinical trial conducted among 43 healthy adult males between the ages of 50-72. The 8-week treatment program included diet, sleep, exercise and relaxation guidance, and supplemental probiotics and phytonutrients. The control group received no intervention. Genome-wide DNA methylation analysis was conducted on saliva samples using the Illumina Methylation Epic Array and DNAmAge was calculated using the online Horvath DNAmAge clock (2013). The diet and lifestyle treatment was associated with a 3.23 years decrease in DNAmAge compared with controls (p=0.018). DNAmAge of those in the treatment group decreased by an average 1.96 years by the end of the program compared to the same individuals at the beginning with a strong trend towards significance (p=0.066). Changes in blood biomarkers were significant for mean serum 5-methyltetrahydrofolate (+15%, p=0.004) and mean triglycerides (-25%, p=0.009). To our knowledge, this is the first randomized controlled study to suggest that specific diet and lifestyle interventions may reverse Horvath DNAmAge (2013) epigenetic aging in healthy adult males. Larger-scale and longer duration clinical trials are needed to confirm these findings, as well as investigation in other human populations.
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DNA methylation-based biomarkers of aging were slowed down in a two-year diet and physical activity intervention trial: the DAMA study.
Fiorito, G, Caini, S, Palli, D, Bendinelli, B, Saieva, C, Ermini, I, Valentini, V, Assedi, M, Rizzolo, P, Ambrogetti, D, et al
Aging cell. 2021;(10):e13439
Abstract
Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed "next-generation clock" DNAmGrimAge outperforms "first-generation clocks" in predicting longevity and the onset of many age-related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm-based biomarker of healthy aging. A fundamental biological property of epigenetic, and in particular DNAm modifications, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the "Diet, Physical Activity, and Mammography" (DAMA) study: a 24-month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial. Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer-related pathways. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging-related epigenetic mechanisms.
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Evaluation of Measured Resting Metabolic Rate for Dietary Prescription in Ageing Adults with Overweight and Adiposity-Based Chronic Disease.
Cooney, C, Daly, E, McDonagh, M, Ryan, L
Nutrients. 2021;(4)
Abstract
The primary objective of this study was to compare weight changes in two groups of ageing Irish adults with overweight and adiposity-based chronic disease: participants who had dietary energy requirements prescribed on the base of measured RMR and participants whose RMR was estimated by a prediction equation. Fifty-four Caucasian adults (male n = 25; female n = 29, age 57.5 ± 6.3 years, weight 90.3 ± 15.1 kg, height 171.5 ± 9.5 cm, BMI 30.7 ± 4.6 kg/m2) were randomly assigned to a dietary intervention with energy prescription based on either measured RMR or estimated RMR. RMR was measured by indirect calorimetry after an overnight fast and predicted values were determined by the Mifflin et al. (1990) prediction equation. All participants received individual nutritional counselling, motivational interviewing and educational material. Anthropometric variables, blood pressure, blood glucose and blood lipid profile were assessed over 12 weeks. Body weight at week 12 was significantly lower (p < 0.05) for both groups following dietary interventions, mRMR: -4.2%; eRMR: -3.2% of initial body weight. There was no significant difference in weight loss between groups. Overall, 20.8% mRMR and 17.4% of eRMR participants experienced clinically meaningful (i.e., ≥5% of initial weight) weight reduction. Weight reduction in adults aged ≥50 years over the short term (12 weeks) favoured a reduction in blood pressure, triglycerides and glucose, thus reducing cardiovascular disease risk factors. This research indicates that employing a reduced-calorie diet using indirect calorimetry to determine energy needs when improving weight outcomes in adults (>50 years) with overweight and adiposity-based chronic disease is equal to employing a reduced-calorie diet based on the Mifflin et al. (1990) prediction equation. A reduced-energy diet based on mRMR or eRMR facilitates clinically meaningful weight reduction in adults (≥50 years) over the short term (12 weeks) and favours a reduction in blood pressure, triglycerides and glucose, thus reducing cardiovascular disease risk factors. Moreover, the addition of motivational interviewing and behaviour change techniques that support and encourage small behaviour changes is effective in short-term weight management.
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An Increase in Fat-Free Mass is Associated with Higher Appetite and Energy Intake in Older Adults: A Randomised Control Trial.
Johnson, KO, Holliday, A, Mistry, N, Cunniffe, A, Howard, K, Stanger, N, O'Mahoney, LL, Matu, J, Ispoglou, T
Nutrients. 2021;(1)
Abstract
Cross-sectional studies in younger adults have demonstrated a positive association between energy intake (EI) and fat-free mass (FFM), with this relationship seemingly mediated by resting metabolic rate (RMR). Establishing a causal effect longitudinally would be prudent in older adults suffering from loss of appetite. We investigated the effects of FFM on RMR, appetite and EI in 39 healthy older adults (age: 66 ± 4 years, BMI: 25.1 ± 3.5 kg∙m2) assigned to either 12-week resistance training + protein supplementation group (RT + PRO) or control group (CON). Body composition, subjective appetite, leptin, insulin, RMR and laboratory-measured ad libitum EI were measured at baseline, weeks 6 and 12 of the intervention, while daily EI at baseline and week 12. FFM (+1.2 kg; p = 0.002), postprandial subjective appetite (+8 mm; p = 0.027), ad libitum EI (+119 kcal; p = 0.012) and daily EI (+133 kcal; p = 0.010) increased from baseline to week 12 in the RT + PRO. RMR, fasted subjective appetite, leptin and insulin concentrations remained unchanged (all p > 0.05). The increases ad libitum EI correlated with increases in FFM (r = 0.527, p = 0.001), with 54% of the change in EI attributed to FFM changes. In conclusion, FFM increases were associated with an increased ad libitum EI and postprandial appetite in older adults.
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Lifestyle weight-loss intervention may attenuate methylation aging: the CENTRAL MRI randomized controlled trial.
Yaskolka Meir, A, Keller, M, Bernhart, SH, Rinott, E, Tsaban, G, Zelicha, H, Kaplan, A, Schwarzfuchs, D, Shelef, I, Gepner, Y, et al
Clinical epigenetics. 2021;(1):48
Abstract
BACKGROUND DNA methylation age (mAge), a methylation biomarker for the aging process, might serve as a more accurate predictor of morbidity and aging status than chronological age. We evaluated the role of multiple factors, including fat deposition, cardiometabolic risk factors and lifestyle weight-loss intervention, on the deviation of mAge from chronological age (mAge deviation) or 18-month change in mAge (∆mAge). In this sub-study of the CENTRAL magnetic resonance imaging weight-loss trial, we evaluated mAge by a validated 240-CpG-based prediction formula at baseline and after 18-month intervention of either low fat (LF) or mediterranean/low carbohydrate (MED/LC) diets. RESULTS Among 120 CENTRAL participants with abdominal obesity or dyslipidemia, mAge (mean ± SD: 60.3 ± 7.5 years) was higher than the chronological age (48.6 ± 9.3 years) but strongly correlated (r = 0.93; p = 3.1 × 10-53). Participants in the lowest tertile of mAge deviation from their chronological age had significantly lower waist-circumference, visceral adipose tissue, intrahepatic fat (IHF) content, fasting-glucose and HOMA-IR, as compared with participants in the highest sex-specific residual tertile (p < 0.05 for all). IHF% remained associated with greater mAge deviation after further adjustments (β = 0.23; p = 0.02). After 18-month weight-loss lifestyle intervention, mAge remained significantly correlated with chronological age (r = 0.94, p = 1.5 × 10-55). mAging occurred, with no difference between lifestyle intervention groups (∆ = 0.9 ± 1.9 years in MED/LC vs. ∆ = 1.3 ± 1.9 years in LF; p = 0.2); however, we observed a mAging attenuation in successful weight losers (> 5% weight loss) vs. weight-loss failures ( ∆ = 0.6 years vs. ∆ = 1.1 years; p = 0.04), and in participants who completed the trial with healthy liver fat content (< 5% IHF) vs. participants with fatty liver (∆ = 0.6 years vs. ∆ = 1.8 years; p = 0.003). Overall, 18 months of weight-loss lifestyle intervention attenuated the mAging of the men, mainly the older, by 7.1 months than the expected (p < 0.05). CONCLUSIONS Lifestyle weight-loss intervention may attenuate mAging. Deviation of mAge from chronological age might be related to body fat distribution and glycemic control and could indicate biological age, health status and the risk for premature cardiometabolic diseases. TRIAL REGISTRATION ClinicalTrials.gov NCT01530724. Registered 10 February 2012, https://clinicaltrials.gov/ct2/show/study/NCT01530724 .
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Community-Partnered Evaluation of the Aging Mastery Program in Los Angeles Area Senior Centers.
Guerrero, LR, Menkin, JA, Carrillo, CA, Reyes, CE, Trejo, L, Banks, C, Sarkisian, CA
Health education & behavior : the official publication of the Society for Public Health Education. 2020;(1):57-66
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Abstract
Background. The National Council on Aging's Aging Mastery Program (AMP) aims to help older adults implement health behavior and lifestyle changes to promote healthy aging and social engagement. The purpose of the present community-partnered evaluation was to test the effectiveness of AMP implementation in Los Angeles County to improve participants' quality of life, global physical and mental health, and patient activation. Method. A modified randomized wait-list controlled trial design was used to examine experimental, quasi-experimental, and dose-response evidence in five senior centers. Participants completed questionnaires at baseline and after the 10-week intervention, self-reporting their overall quality of life, physical health, mental health, and patient activation. Results. Experimental, intention-to-treat analyses found AMP assignment did not affect any measured outcomes (n = 71). Quasi-experimental, "as treated" analyses (n = 106) controlling for study site and sociodemographic characteristics indicated that participants who attended AMP reported more positive changes in global mental health than the control group. Attending AMP was not associated with changes in quality of life, physical health, or patient activation. Dose-response analyses among AMP participants who attended at least one class (n = 75) found that attending more classes was not significantly associated with greater improvements in mental health. Conclusions. Experimental, intention-to-treat analyses did not support effectiveness of AMP on quality of life, physical or mental health, or patient activation; quasi-experimental analyses found attending AMP was associated with improvements in mental health. Recruitment challenges and participants' nonadherence with condition assignment decreased our ability to detect effects. https://clinicaltrials.gov/ct2/show/NCT03342729?term=Aging+Mastery+Program&rank=1 .
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Resting state fMRI reveals differential effects of glucose administration on central appetite signalling in young and old adults.
Peters, R, White, DJ, Scholey, A
Journal of psychopharmacology (Oxford, England). 2020;(3):304-314
Abstract
BACKGROUND Healthy aging has been associated with reduced appetite and lower energy intake, which can lead to loss of bodyweight, undernutrition and related health problems. The causes for the decline in caloric intake are multifactorial, involving physiological and non-physiological processes. AIMS Here we examined the effect of glucose on brain function in healthy adults as well as age-related, physiological changes in brain responses associated with macronutrient intake. METHODS Using a randomized, double-blind, balanced cross-over design, younger (n = 16, aged 21-30) and older (n = 16, aged 55-78) adults received a drink containing glucose and a taste-matched placebo after an overnight fast. Blood glucose and hunger were assessed at baseline and 20 min post-ingestion, after which participants underwent resting state functional magnetic resonance imaging. RESULTS Frequency-dependent changes associated with glucose administration in slow-5 (0.01-0.027 Hz) and slow-4 (0.027-0.073 Hz) amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) of the blood oxygen level-dependent (BOLD) signal were investigated within the young healthy adults, and then extended to the older age group. Consistent with previous reports, glucose decreased amplitude in slow-5 fALFF within the left orbitofrontal cortex and insular cortex in the young adults. We observed a significant interaction in slow-5 ALFF and fALFF in the left insula, such that younger participants showed a decrease in BOLD amplitude, whereas older participants showed an increase, after glucose administration. We further observed an interaction in slow-4 ALFF in the occipital region and precuneus, with older participants showing an increase in magnitude of slow-4 ALFF and younger participants showing a decrease in the same measure. CONCLUSION These age-related, frequency-dependent changes in the magnitude of the BOLD signal in the insula, a key region related to energy homeostasis following feeding, may point to a change in satiety or homeostatic signalling contributing to behavioural changes in energy intake during senescence.
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Exercise Training Reduces Inflammation of Adipose Tissue in the Elderly: Cross-Sectional and Randomized Interventional Trial.
Čížková, T, Štěpán, M, Daďová, K, Ondrůjová, B, Sontáková, L, Krauzová, E, Matouš, M, Koc, M, Gojda, J, Kračmerová, J, et al
The Journal of clinical endocrinology and metabolism. 2020;(12)
Abstract
CONTEXT Metabolic disturbances and a pro-inflammatory state associated with aging and obesity may be mitigated by physical activity or nutrition interventions. OBJECTIVE The aim of this study is to assess whether physical fitness/exercise training (ET) alleviates inflammation in adipose tissue (AT), particularly in combination with omega-3 supplementation, and whether changes in AT induced by ET can contribute to an improvement of insulin sensitivity and metabolic health in the elderly. DESIGN, PARTICIPANTS, MAIN OUTCOME MEASURES The effect of physical fitness was determined in cross-sectional comparison of physically active/physically fit (trained) and sedentary/less physically fit (untrained) older women (71 ± 4 years, n = 48); and in double-blind randomized intervention by 4 months of ET with or without omega-3 (Calanus oil) supplementation (n = 55). Physical fitness was evaluated by spiroergometry (maximum graded exercise test) and senior fitness tests. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Samples of subcutaneous AT were used to analyze mRNA gene expression, cytokine secretion, and immune cell populations. RESULTS Trained women had lower mRNA levels of inflammation and oxidative stress markers, lower relative content of CD36+ macrophages, and higher relative content of γδT-cells in AT when compared with untrained women. Similar effects were recapitulated in response to a 4-month ET intervention. Content of CD36+ cells, γδT-cells, and mRNA expression of several inflammatory and oxidative stress markers correlated to insulin sensitivity and cardiorespiratory fitness. CONCLUSIONS In older women, physical fitness is associated with less inflammation in AT. This may contribute to beneficial metabolic outcomes achieved by ET. When combined with ET, omega-3 supplementation had no additional beneficial effects on AT inflammatory characteristics.
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Sensor-measured sedentariness and physical activity are differentially related to fluid and crystallized abilities in aging.
Burzynska, AZ, Voss, MW, Fanning, J, Salerno, EA, Gothe, NP, McAuley, E, Kramer, AF
Psychology and aging. 2020;(8):1154-1169
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Aerobic exercise and physical activity (PA) are known to benefit cognition in adulthood. However, a typical older adult spends most of the day sedentary or in light PA, behaviors that are typically poorly captured by questionnaires. To better understand the associations between time spent in different intensities of lifestyle PA and cognition, we measured average time spent daily in sedentariness, light, and moderate to vigorous PA using hip-worn sensors (ActiGraph accelerometers). We studied baseline data from 228 cognitively normal adults (Age 60-80) who took part in a clinical trial (clinical study identifier: NCT01472744). Fluid (processing speed, memory, and reasoning) and crystallized abilities (vocabulary knowledge) were assessed with the Virginia Cognitive Aging Battery. Adjusting for age, sex, and several modifiable socioeconomic, physical and functional health factors, time spent daily in moderate to vigorous PA was positively related with fluid abilities (perceptual speed and reasoning). Furthermore, we found that those spending more time sedentary performed better on vocabulary knowledge and reasoning tasks. In contrast, time spent in light PA was not related to either fluid or crystallized abilities. Our results add to the previous literature by providing the first sensor-based evidence that crystallized and fluid abilities in older age may be associated with engagement in different intensities of daily activity. Moreover, our findings suggest that the behavior of moderate to vigorous PA is at least as important in relation to cognition as the desirable long-term physiological effects of higher intensity PA and exercise. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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Increased Intestinal Permeability in Older Subjects Impacts the Beneficial Effects of Dietary Polyphenols by Modulating Their Bioavailability.
Hidalgo-Liberona, N, González-Domínguez, R, Vegas, E, Riso, P, Del Bo', C, Bernardi, S, Peron, G, Guglielmetti, S, Gargari, G, Kroon, PA, et al
Journal of agricultural and food chemistry. 2020;(44):12476-12484
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Abstract
Polyphenols have great potential in regulating intestinal health and ameliorating pathological conditions related to increased intestinal permeability (IP). However, the efficacy of dietary interventions with these phytochemicals may significantly be influenced by interindividual variability factors affecting their bioavailability and consequent biological activity. In the present study, urine samples collected from older subjects undergoing a crossover intervention trial with polyphenol-rich foods were subjected to metabolomics analysis for investigating the impact of increased IP on the bioavailability of polyphenols. Interestingly, urinary levels of phase II and microbiota-derived metabolites were significantly different between subjects with healthier intestinal barrier integrity and those with increased IP disruption. Our results support that this IP-dependent impaired bioavailability of polyphenols could be attributed to disturbances in the gut microbial metabolism and phase II methylation processes. Furthermore, we also observed that microbiota-derived metabolites could be largely responsible for the biological activity elicited by dietary polyphenols against age-related disrupted IP.