DNA methylation‐based biomarkers of aging were slowed down in a two‐year diet and physical activity intervention trial: the DAMA study

Fiorito, Giovanni; Caini, Saverio; Palli, Domenico; Bendinelli, Benedetta; Saieva, Calogero; Ermini, Ilaria; Valentini, Virginia; Assedi, Melania; Rizzolo, P.; Ambrogetti, Daniela; Ottini, Laura; Masala, Giovanna

doi:10.1111/acel.13439

Cited by 92 publications

(82 citation statements)

References 68 publications

(70 reference statements)

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“…In fact, childhood traumas have been associatedwith a high risk of alcoholism, smoking, physical inactivity, and severe obesity [30]. Several studies have demonstrated that adherence to a healthy lifestyle may slow phenotypic aging [31][32][33][34][35]. This confirms our hypothesis, childhood traumas → unhealthy lifestyle → accelerated phenotypic aging.…”

Section: Discussionsupporting

confidence: 85%

Unhealthy lifestyle mediates the adverse effect of childhood traumas on acceleration of aging: analysis of 110,596 UK Biobank participants

Yang

Cao

Zhang

et al. 2022

Preprint

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BackgroundAccelerated aging makes adults more vulnerable to chronic diseases and death. This study evaluates the association of childhood traumas with a phenotypic aging measure that captures mortality and morbidity risk, and the role of unhealthy lifestyle in mediating these associations.MethodsWe assembled data from 110,596 members of the UK Biobank aged 40-69 years who participated in the baseline survey (2006-2010) and online mental health questionnaire (2016). A phenotypic aging measure—Phenotypic Age Acceleration (PhenoAgeAccel) was calculated, with the higher value indicating the acceleration of aging. Body mass index, smoking status, alcohol consumption, physical activity, and diet were combined to construct an unhealthy lifestyle score (range: 0-5). Childhood traumas including physical neglect, emotional neglect, sexual abuse, physical abuse, and emotional abuse were assessed. General linear regression and formal mediation analysis were performed.ResultsEach individual childhood trauma and cumulative childhood traumas were significantly associated with PhenoAgeAccel. For instance, compared with participants who did not experience childhood traumas, those who experienced four (β=0.292, standard error [SE]: 0.091) or five childhood traumas had higher PhenoAgeAccel (β=0.669, SE: 0.169) in fully adjusted models. The formal mediation analysis revealed that unhealthy lifestyle partially mediated the associations of childhood traumas with PhenoAgeAccel (26.1%-42.6%).ConclusionsIn a large sample from UKB, childhood traumas were positively associated with acceleration of aging; and more importantly, unhealthy lifestyle partially mediated these associations. These findings reveal a novel pathway from childhood traumas to late-life health through lifestyle and underscore the potential of more psychological strategies beyond lifestyle interventions to promote healthy aging.

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Section: Discussionsupporting

confidence: 85%

Unhealthy lifestyle mediates the adverse effect of childhood traumas on acceleration of aging: analysis of 110,596 UK Biobank participants

Yang

Cao

Zhang

et al. 2022

Preprint

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“…Here, the intervention cohort showed a 3.23 year age reversal. These findings have been corroborated in a larger 2-year study on 219 women subjected to diet and exercise where the intervention group showed significant reduction in a marker of DNA methylation age (Fiorito et al, 2021). Clearly, these prospective trials show that epigenetic markers of aging can indeed be reversed.…”

Section: Exercisementioning

confidence: 67%

Clinical Trials Targeting Aging

2022

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The risk of morbidity and mortality increases exponentially with age. Chronic inflammation, accumulation of DNA damage, dysfunctional mitochondria, and increased senescent cell load are factors contributing to this. Mechanistic investigations have revealed specific pathways and processes which, proposedly, cause age-related phenotypes such as frailty, reduced physical resilience, and multi-morbidity. Among promising treatments alleviating the consequences of aging are caloric restriction and pharmacologically targeting longevity pathways such as the mechanistic target of rapamycin (mTOR), sirtuins, and anti-apoptotic pathways in senescent cells. Regulation of these pathways and processes has revealed significant health- and lifespan extending results in animal models. Nevertheless, it remains unclear if similar results translate to humans. A requirement of translation are the development of age- and morbidity associated biomarkers as longitudinal trials are difficult and not feasible, practical, nor ethical when human life span is the endpoint. Current biomarkers and the results of anti-aging intervention studies in humans will be covered within this paper. The future of clinical trials targeting aging may be phase 2 and 3 studies with larger populations if safety and tolerability of investigated medication continues not to be a hurdle for further investigations.

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“…In contrast to (poly-)genetic risk scores that are set at birth, the epigenetic clock changes throughout life. We and others have shown that these changes are potentially sensitive to interventions [47][48][49][50][51] and lifestyle factors [37]. Whether this is true for diabetes specific interventions needs to be examined in sufficiently sized longitudinal studies.…”

Section: Discussionmentioning

confidence: 97%

DNA Methylation Age Acceleration, Type 2 Diabetes, and its Complications: Cross-sectional and Longitudinal Data from the Berlin Aging Study II (BASE-II)

Vetter

Spieker

Sommerer

et al. 2022

Preprint

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Patients with diabetes mellitus are at risk for micro- and macrovascular complications that are responsible for a substantial part of the individual health burden and socio-economic costs. Therefore, implementable risk scores are needed to improve targeted prevention for patients that are particularly susceptible to complications. The "epigenetic clock" estimates an individual's biological age using DNA methylation profiles and was previously shown to be associated with morbidity and mortality. In this study, we examine older adults of the BASE-II study that were reexamined on average 7.4 years after baseline assessment as part of the GendAge study. For DNA methylation age (DNAmA) estimation we used the 7-CpG clock which was available for two timepoints (n=1,071 at follow-up). In addition, we determined epigenetic age using Horvath's clock, Hannum's clock, PhenoAge and GrimAge which were available at follow-up only (n=1,067). The deviation of DNAmA from chronological age, DNA methylation age acceleration (DNAmAA), was calculated as residuals of a leukocyte cell count adjusted linear regression analysis. Diabetes associated complications were assessed with the Diabetes Complications Severity Index (DCSI). Cross-sectionally, a statistically significant association between oral glucose tolerance test results and Hannum (beta=0.8, SE=0.3, p=0.02, n=762) and PhenoAge DNAmAA (beta=0.8, SE=0.3, p=0.003, n=762) was found. PhenoAge was also associated with fasting glucose (beta=0.3, SE=0.1, p=0.013, n=966). In contrast, we observed no cross-sectional association after covariate adjustment between DNAmAA and a diagnosis of diabetes mellitus with any of the five clocks employed. This was true for longitudinal analyses with the 7-CpG clock as well. However, longitudinal analyses showed that every year in the 7-CpG-based DNAmAA estimate at baseline increased the risk for developing of one or more additional complications or worsening of an already existing complication during the follow-up period by 11% in male participants with diabetes mellitus type 2. This association persisted after adjustment for DCSI at baseline, chronological age, smoking, alcohol, diabetes medication, and BMI (OR =1.11, p=0.045, n=56). No statistically significant association was found in the subgroup of women or when the whole dataset was analyzed (p>0.05). Although our findings still need to be independently validated, the 7-CpG clock appears to be a promising biomarker which is informative about the individual risk for diabetic complications independent of age, sex, lifestyle factors, or complications at baseline.

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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

Cited by 92 publications

References 68 publications

Unhealthy lifestyle mediates the adverse effect of childhood traumas on acceleration of aging: analysis of 110,596 UK Biobank participants

Unhealthy lifestyle mediates the adverse effect of childhood traumas on acceleration of aging: analysis of 110,596 UK Biobank participants

Clinical Trials Targeting Aging

DNA Methylation Age Acceleration, Type 2 Diabetes, and its Complications: Cross-sectional and Longitudinal Data from the Berlin Aging Study II (BASE-II)

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