Potential reversal of epigenetic age using a diet and lifestyle

 

IMAGE: INTERVENTION GROUP AGE CHANGE. PARTICIPANTS SCORED AN AVERAGE OF 1.96 YEARS YOUNGER THAN BASELINE (P=0.066). OF 18 PARTICIPANTS INCLUDED IN THE FINAL ANALYSIS, 8 SCORED AGE REDUCTION, 9 WERE UNCHANGED,... view more 

CREDIT: CORRESPONDENCE TO: KARA N. FITZGERALD EMAIL: KF@DRKARAFITZGERALD.COM

A groundbreaking clinical trial shows we can reduce biological age (as measured by the Horvath 2013 DNAmAge clock) by more than three years in only eight weeks with diet and lifestyle through balancing DNA methylation.

A first-of-its-kind, peer-reviewed study provides scientific evidence that lifestyle and diet changes can deliver immediate and rapid reduction of our biological age. Since aging is the primary driver of chronic disease, this reduction has the power to help us live better, longer.

The study, released on April 12, utilized 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, resulting in a statistically significant reduction of biological age--over three years younger, compared to controls.

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.

The dietary recommendations employed as part of the treatment protocol for this study were based largely on biochemistry and generalized measures of health, because few dietary associations with the DNAmAge clock have yet been established. A modest, but significant, reduction in DNAmAge in individuals consuming a non-specific lean meat, fish and plant-based diet (as measured by blood carotenoids) has been observed [12]. It is possible that changes of a greater magnitude require a more targeted approach. The dietary intervention used here was also plant-centered, but including a high intake of nutrients that are substrates or cofactors in methylation biosynthetic pathways (e.g. containing folate, betaine), ten-eleven translocation (TET) demethylase cofactors and modulators (e.g. alpha ketoglutarate, vitamin C and vitamin A) [13] and polyphenolic modulators of DNA methyl transferases (DNMT) (e.g. curcumin, epigallocatechin gallate (EGCG), rosmarinic acid, quercetin, luteolin) [14]. It also included limited nutrient-dense animal proteins (e.g. liver, egg). The diet restricted carbohydrates and included mild intermittent fasting, both designed to lower glycemic cycling. The diet was supplemented daily with a fruit and vegetable powder, also rich in polyphenolic modulators of DNMT activity, and a probiotic providing 40 million CFU of Lactobacillus plantarum 299v. L. plantarum has been shown to be a folate producer in the presence of para aminobenzoic acid (PABA) [15]; it also has been demonstrated to alter gene expression [16].

Lifestyle guidance in this study included a minimum of 30 minutes of exercise per day, at least 5 days per week at an intensity of 60-80 percent of maximum perceived exertion. Exercise is well-known to be broadly beneficial for almost every aspect of health and has been shown to extend mean lifespan in animal models. Exploration of the effect of exercise on the methylome has recently begun. For example, regular tai chi practice was associated with slowing of age-related DNA methylation losses in 500 women [17]. In another study of 647 women, a lifelong history of exercise was associated with a similar endpoint [18]. These results were not reported in terms of the Horvath clock, because it had not yet been developed. One systematic review of human studies found that regular, daily physical activity was associated with lower blood levels of homocysteine, which when elevated, suggests an insufficiency of methylation capacity [19]. Excessive exercise may accelerate methylation aging, but this danger has only been observed in elite, competitive athletes [20].

Twice-daily breathing exercises that elicit the Relaxation Response were prescribed for stress reduction. It was recently demonstrated that 60 days of relaxation practice designed to elicit the Relaxation Response, 20 minutes twice per day, could significantly reduce DNAmAge as measured by the Zbieć-Piekarska clock in their group of healthy participants (though not in their ‘patient’ group) [21]. Almost a quarter of the DNAmAge CpG sites (85/353) are located in glucocorticoid response elements, pointing to a likely relationship between stress and accelerated aging. Cumulative lifetime stress has been shown to be associated with accelerated aging of the methylome [22]. Zannas et al. also reported that dexamethasone, a glucocorticoid agonist, can advance the DNAmAge clock and induce associated transcriptional changes. Dexamethasone-regulated genes showed enriched association of aging-related diseases, including coronary artery disease, arteriosclerosis and leukemias. Other findings include that PTSD contributes to accelerated methylation age [23]; and that greater infant distress (lack of caregiver contact) is associated with an underdeveloped, younger epigenetic age [24].

This study aimed to optimize sleep, with a recommendation for at least seven hours nightly. Seven hours is generally considered to be healthy [25], but the limited data on accelerated aging only relates to extremes of sleep deprivation. A (presumably transient) effect of sleep deprivation on genome-wide methylation patterns in blood has been demonstrated [26]. Acceleration of the DNAmAge clock has been associated with insomnia in a sample of 2078 women [27]. Carskadon et al [28] found an association between poor quality / fewer hours of sleep with age acceleration in a small sample of 12 female college students.