Biological Age Acceleration Research Articles

Genetic and phenotypic analysis of the causal relationship between aging and COVID-19

BackgroundEpidemiological studies revealed that the elderly and those with comorbidities are most affected by COVID-19, but it is important to investigate shared genetic mechanisms between COVID-19 risk and aging.MethodsWe conducted a multi-instrument Mendelian Randomization analysis of multiple lifespan-related traits and COVID-19. Aging clock models were applied to the subjects with different COVID-19 conditions in the UK-Biobank cohort. We performed a bivariate genomic scan for age-related COVID-19 and Mendelian Randomization analysis of 389 immune cell traits to investigate their effect on lifespan and COVID-19 risk.ResultsWe show that the genetic variation that supports longer life is significantly associated with the lower risk of COVID-19 infection and hospitalization. The odds ratio is 0.31 (P = 9.7 × 10−6) and 0.46 (P = 3.3 × 10−4), respectively, per additional 10 years of life. We detect an association between biological age acceleration and future incidence and severity of COVID-19 infection. Genetic profiling of age-related COVID-19 infection indicates key contributions of Notch signaling and immune system development. We reveal a negative correlation between the effects of immune cell traits on lifespan and COVID-19 risk. We find that lower B-cell CD19 levels are indicative of an increased risk of COVID-19 and decreased life expectancy, which is further validated by COVID-19 clinical data.ConclusionsOur analysis suggests that the factors that accelerate aging lead to an increased COVID-19 risk and point to the importance of Notch signaling and B cells in both. Interventions that target these factors to reduce biological age may reduce the risk of COVID-19.

Association between housing type and accelerated biological aging in different sexes: moderating effects of health behaviors.

Introduction: Despite associated with multiple geriatric disorders, whether housing type, an indicator of socioeconomic status (SES) and environmental factors, is associated with accelerated biological aging is unknown. Furthermore, although individuals with low-SES have higher body mass index (BMI) and are more likely to smoke, whether BMI and smoking status moderate the association between SES and biological aging is unclear. We examined these questions in urbanized low-SES older community-dwelling adults.Methods: First, we analyzed complete blood count data using the cox proportional hazards model and derived measures for biological age (BA) and biological age acceleration (BAA, the higher the more accelerated aging) (N = 376). Subsequently, BAA was regressed on housing type, controlling for covariates, including four other SES indicators. Interaction terms between housing type and BMI/smoking status were separately added to examine their moderating effects. Total sample and sex-stratified analyses were performed.Results: There were significant differences between men and women in housing type and BAA. Compared to residents in ≥3 room public or private housing, older adults resided in 1–2 room public housing had a higher BAA. Furthermore, BMI attenuated the association between housing type and BAA. In sex-stratified analyses, the main and interaction effects were only significant in women. In men, smoking status instead aggravated the association between housing type and BAA.Conclusion: Controlling for other SES indicators, housing type is an independent socio-environmental determinant of BA and BAA in a low-SES urbanized population. There were also sex differences in the moderating effects of health behaviors on biological aging.

Air pollution, Telomere length and Mortality- A systemic review

BACKGROUND AND AIM: Adverse effects of air pollution on cardiovascular morbidity, mortality, and all-cause mortality have been demonstrated over the last few decades. Acceleration of biological aging by air pollution could be a plausible underlying mechanism. Telomeres are tandem repetitive DNA complexes, considered as one of the critical markers of aging. This study sought to review the existing literature on the association between air pollution and telomere length (TL) as well as the association between TL and mortality to elucidate the underlying mechanism between air pollution and mortality. METHODS: We have searched on electronic databases including PUBMED, SCOPUS, and WEB OF SCIENCE using keywords “air pollution,” “telomere length,” and “all-cause mortality” from 2003-2017. RESULTS:A total of 20 articles remained for final review with 10,488 subjects to explore the association between air pollution and telomere length. Most of the observational studies were cross-sectional (12), remaining studies were cohort (5) and case-control (3). Eighteen (90%) assessed leukocyte telomere length (LTL), of which 15 found associations between air pollution and shorter TL, 2 with longer TL, and 1 had no association. Only two studies found shorter TL from saliva was associated with household air pollutants. Particulate matter was investigated in 70% of articles (14), and the remainder assessed black carbon (BC), Ozone, benzene, and NO2. We have found 21 published articles to explore the association between TL and all-cause mortality. Of which 11 studies found an association between shorter TL and all-cause mortality. The remainder found no association. However, we could not perform a quantitative meta-analysis due to discordance in the reporting formats. CONCLUSIONS:Most of the studies support the association of air pollution with shorter TL as well as mortality with shorter TL- that suggested a possible explanation of how environmental stress may promote earlier onset of age-related diseases and mortality if the observed associations are causal. KEYWORDS: Air pollution, Telomere length, All-cause mortality

Molecular markers of aging, exercise capacity, & physical activity in COPD

BackgroundExercise capacity (EC) and physical activity (PA) are independent, potentially modifiable predictors of clinical outcomes in COPD. Molecular measures of biological age may help characterize variability in EC and PA observed among COPD patients. MethodsVeterans with COPD (FEV1/FVC<0.7 or emphysema on chest computed tomography) enrolled in 2 cohorts at VA Boston completed questionnaires, a 6-min walk distance (6MWD) for EC, and blood collection at enrollment. PA data (average daily step count) was collected using an HJ-720 ITC pedometer over ≥5 days. A subset of subjects returned for repeat assessment after 12 weeks. DNA methylation data was generated using the HumanMethylationEPIC platform; epigenetic estimates of biological age and age acceleration were generated using established algorithms. Multivariable models examined the associations between biological age, 6MWD, PA and future acute exacerbations (AEs), adjusting for chronological age, sex, race, smoking status, pack-years, body mass index, cohort, and estimated cell counts. ResultsSubjects (n = 269) were predominantly male (98.5%), white (92.9%), and elderly (70.6 ± 8.5 years) with average FEV1% of 57.7 ± 21.1, 6MWD of 374.3 ± 93.5 m, and daily steps of 3043.4 ± 2374 at baseline. In adjusted models, multiple measures of baseline epigenetic age and age acceleration were inversely associated with 6MWD; only GrimAge was inversely associated with PA. Longitudinal change in Hannum-Age was inversely associated with change in EC at 12 weeks (n = 94). No measures of biological age were significantly associated with prospective AEs over 1.3 ± 0.3 years. ConclusionsEpigenetic measures of biological age are independent predictors of EC and PA, but not AEs, among individuals with COPD.

Acceleration of Biological Aging and Underestimation of Subjective Age Are Risk Factors for Severe COVID-19.

In an epidemic, it is important to have methods for reliable and rapid assessment of risk groups for severe forms of the disease for their priority vaccination and for the application of preventive lockdown measures. The aim of this study was to investigate risk factors for severe forms of COVID-19 in adults using indicators of biological and subjective aging. Longitudinal studies evaluated the severity of the disease and the number of cases. Respondents (447) were divided into “working group” and “risk group” (retirees with chronic diseases). During the lockdown period (in mid-2020), accelerated aging was observed in the group of workers (by 3.9–8 years for men and an increase at the tendency level for women). However, the respondents began to feel subjectively younger (by 3.3–7.2 years). In the risk group, there were no deviations from the expected biopsychological aging. The number of cases at the end of 2020 was 31% in workers and 0% in the risk group. Reasonably, the risk group followed the quarantine rules more strictly by 1.5 times. In working men, indicators of relative biological and relative subjective aging (measured in both 2019 and mid-2020) significantly influenced the incidence at the end of 2020. In women, only the indicators obtained in mid-2020 had a significant impact. The relative biological aging of an individual tested in the middle of 2020 had a direct impact on the risk of infection (p < 0.05) and on the probability of death (p < 0.0001). On the contrary, an increase in the relative subjective (psychological) aging index reduced the risk of infection (at the tendency level, p = 0.06) and the risk of death (p < 0.0001). Both the risk of infection and the risk of death increased with calendar age at the tendency level. Conclusions: Indicators of individual relative biological and subjective aging affect the probability of getting COVID-19 and its severity. The combination of high indicators of biological aging and underestimated indicators of subjective aging is associated with increased chances of developing severe forms of the disease.

Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors.

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).

Reductions in Gray Matter Linked to Epigenetic HIV-Associated Accelerated Aging.

A growing literature suggests a relationship between HIV-infection and a molecular profile of age acceleration. However, despite the widely known high prevalence of HIV-related brain atrophy and HIV-associated neurocognitive disorder (HAND), epigenetic age acceleration has not been linked to HIV-related changes in structural MRI. We applied morphological MRI methods to study the brain structure of 110 virally suppressed participants with HIV infection and 122 uninfected controls age 22-72. All participants were assessed for cognitive impairment, and blood samples were collected from a subset of 86 participants with HIV and 83 controls to estimate epigenetic age. We examined the group-level interactive effects of HIV and chronological age and then used individual estimations of epigenetic age to understand the relationship between age acceleration and brain structure. Finally, we studied the effects of HAND. HIV-infection was related to gray matter reductions, independent of age. However, using epigenetic age as a biomarker for age acceleration, individual HIV-related age acceleration was associated with reductions in total gray matter. HAND was associated with decreases in thalamic and hippocampal gray matter. In conclusion, despite viral suppression, accentuated gray matter loss is evident with HIV-infection, and greater biological age acceleration specifically relates to such gray matter loss.

Deep longitudinal phenotyping of wearable sensor data reveals independent markers of longevity, stress, and resilience.

Biological age acceleration (BAA) models based on blood tests or DNA methylation emerge as a de facto standard for quantitative characterizations of the aging process. We demonstrate that deep neural networks trained to predict morbidity risk from wearable sensor data can provide a high-quality and cheap alternative for BAA determination. The GeroSense BAA model was trained and validated using steps per minute recordings from 103,830 one-week long and 2,599 of up to 2 years-long longitudinal samples and exhibited a superior association with life-expectancy over the average number of steps per day in, e.g., groups stratified by professional occupations. The association between the BAA and effects of lifestyles, the prevalence of future incidence of diseases was comparable to that of BAA from models based on blood test results. Wearable sensors let sampling of BAA fluctuations at time scales corresponding to days and weeks and revealed the divergence of organism state recovery time (resilience) as a function of chronological age. The number of individuals suffering from the lack of resilience increased exponentially with age at a rate compatible with Gompertz mortality law. We speculate that due to the stochastic character of BAA fluctuations, its mean and auto-correlation properties together comprise the minimum set of biomarkers of aging in humans.

Epigenetic Clock Analysis in Children With Fetal Alcohol Spectrum Disorder.

Fetal alcohol spectrum disorder (FASD) is characterized by severe clinical impairment, considerable social burden, and high mortality and morbidity, which are due to various malformations, sepsis, and cancer. As >50% of deaths from FASD occur during the first year of life, we hypothesized that there is the acceleration of biological aging in FASD. Several recent studies have established genome-wide DNA methylation (DNAm) profiles as "epigenetic clocks" that can estimate biological aging, and FASD has been associated with differential DNAm patterns. Therefore, we tested this hypothesis using epigenetic clocks. We investigated 5 DNAm-based measures of epigenetic age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and telomere length (DNAmTL) using 4 independent publicly available DNAm datasets; 2 datasets were derived from buccal epithelium, and the other 2 datasets were derived from peripheral blood. Compared with controls, children with FASD exhibited an acceleration of GrimAge in 1 buccal and 2 blood datasets. No significant difference was found in other DNAm ages and DNAmTL. Meta-analyses showed a significant acceleration of GrimAge in the blood samples but not in the buccal samples. This study provides novel evidence regarding accelerated epigenetic aging in children with FASD.

Personal characteristics affecting the biological age of the individual

The aim of the research is to study the influence of personality traits and the life path on the rate of biological aging of adults, depending on their gender and age. Methods: diagnostic (questioning the life path, self-esteem of personality, determination of biological age) and statistical (automatic neural networks). Subjects: 987 people (including 575 women) aged 35-70 years from various regions of the Russian Federation. Continuous target variable: relative biological aging of the organism (Biological Age – Proper Biological Age). Continuous input variables: indicators of life path and personality self-esteem. Results: the general factors influencing the rate of biological aging were identified: negative factors that enhance aging - addictions and overwork; and positive factors that slow down aging are having children and professionalization. Personal indicators that changed their sign after a person retired were also found. Women changed their sign from negative to positive for indicators “work at the present time” and “study at the present time”, for men – “a positive attitude to pension reform” and professional activities of the types “Human-Technology”, “Human-Sign”. The negative strategies of organizing the life path leading to the acceleration of biological aging are highlighted: “forming the addictions and striving for excesses” and “multiplication of the load”. Positive strategies are also highlighted: “positive activity strategy” (for women and men of retirement age) and “family strategy” (for men of pre-retirement age).

Parity predicts biological age acceleration in post-menopausal, but not pre-menopausal, women

Understanding factors contributing to variation in ‘biological age’ is essential to understanding variation in susceptibility to disease and functional decline. One factor that could accelerate biological aging in women is reproduction. Pregnancy is characterized by extensive, energetically-costly changes across numerous physiological systems. These ‘costs of reproduction’ may accumulate with each pregnancy, accelerating biological aging. Despite evidence for costs of reproduction using molecular and demographic measures, it is unknown whether parity is linked to commonly-used clinical measures of biological aging. We use data collected between 1999 and 2010 from the National Health and Nutrition Examination Survey (n = 4418) to test whether parity (number of live births) predicted four previously-validated composite measures of biological age and system integrity: Levine Method, homeostatic dysregulation, Klemera–Doubal method biological age, and allostatic load. Parity exhibited a U-shaped relationship with accelerated biological aging when controlling for chronological age, lifestyle, health-related, and demographic factors in post-menopausal, but not pre-menopausal, women, with biological age acceleration being lowest among post-menopausal women reporting between three and four live births. Our findings suggest a link between reproductive function and physiological dysregulation, and allude to possible compensatory mechanisms that buffer the effects of reproductive function on physiological dysregulation during a woman’s reproductive lifespan. Future work should continue to investigate links between parity, menopausal status, and biological age using targeted physiological measures and longitudinal studies.

Association of Epigenetic Metrics of Biological Age With Cortical Thickness

Magnetic resonance imaging (MRI) studies of aging adults have shown substantial intersubject variability across various brain metrics, and some of this variability is likely attributable to chronological age being an imprecise measure of age-related change. Accurately quantifying one's biological age could allow better quantification of healthy and pathological changes in the aging brain. To investigate the association of DNA methylation (DNAm)-based biological age with cortical thickness and to assess whether biological age acceleration compared with chronological age captures unique variance in cortical thinning. This cross-sectional study used high-resolution structural brain MRI data collected from a sample of healthy aging adults who were participating in a larger ongoing neuroimaging study that began in May 2014. This population-based study accrued participants from the greater Omaha, Nebraska, metropolitan area. One hundred sixty healthy adults were contacted for the MRI component, 82 of whom participated in both DNAm and MRI study components. Data analysis was performed from March to June 2019. Vertexwise cortical thickness, DNAm-based biological age, and biological age acceleration compared with chronological age were measured. A pair of multivariable regression models were computed in which cortical thickness was regressed on DNAm-based biological age, controlling for sex in the first model and also controlling for chronological age in the second model. Seventy-nine adult participants (38 women; mean [SD] age, 43.82 [14.50] years; age range, 22-72 years) were included in all final analyses. Advancing biological age was correlated with cortical thinning across frontal, superior temporal, inferior parietal, and medial occipital regions. In addition, biological age acceleration relative to chronological age was associated with cortical thinning in orbitofrontal, superior and inferior temporal, somatosensory, parahippocampal, and fusiform regions. Specifically, for every 1 year of biological age acceleration, cortical thickness would be expected to decrease by 0.024 mm (95% CI, -0.04 to -0.01 mm) in the left orbitofrontal cortex (partial r, -0.34; P = .002), 0.014 mm (95% CI, -0.02 to -0.01 mm) in the left superior temporal gyrus (partial r, -0.36; P = .001), 0.015 mm (95% CI, -0.02 to -0.01 mm) in the left fusiform gyrus (partial r, -0.38; P = .001), 0.015 mm (95% CI, -0.02 to -0.01 mm) in the right fusiform gyrus (partial r, -0.43; P < .001), 0.019 mm (95% CI, -0.03 to -0.01 mm) in the right inferior temporal sulcus (partial r, -0.34; P = .002), and 0.011 mm (95% CI, -0.02 to -0.01 mm) in the right primary somatosensory cortex (partial r, -0.37; P = .001). To our knowledge, this is the first study to investigate vertexwise cortical thickness in relation to DNAm-based biological age, and the findings suggest that this metric of biological age may yield additional insight on healthy and pathological cortical aging compared with standard measures of chronological age alone.

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

BackgroundSevere obesity is a growing, worldwide burden and conventional therapies including radical change of diet and/or increased physical activity have limited results. Bariatric surgery has been proposed as an alternative therapy showing promising results. It leads to substantial weight loss and improvement of comorbidities such as type 2 diabetes. Increased adiposity is associated with changes in epigenetic profile, including DNA methylation. We investigated the effect of bariatric surgery on clinical profile, DNA methylation, and biological age estimated using Horvath’s epigenetic clock.ResultsTo determine the impact of bariatric surgery and subsequent weight loss on clinical traits, a cohort of 40 severely obese individuals (BMI = 30–73 kg/m2) was examined at the time of surgery and at three follow-up visits, i.e., 3, 6, and 12 months after surgery. The majority of the individuals were women (65%) and the mean age at surgery was 45.1 ± 8.1 years. We observed a significant decrease over time in BMI, fasting glucose, HbA1c, HOMA-IR, insulin, total cholesterol, triglycerides, LDL and free fatty acids levels, and a significant small increase in HDL levels (all p values < 0.05). Epigenome-wide association analysis revealed 4857 differentially methylated CpG sites 12 months after surgery (at Bonferroni-corrected p value < 1.09 × 10−7). Including BMI change in the model decreased the number of significantly differentially methylated CpG sites by 51%. Gene set enrichment analysis identified overrepresentation of multiple processes including regulation of transcription, RNA metabolic, and biosynthetic processes in the cell. Bariatric surgery in severely obese patients resulted in a decrease in both biological age and epigenetic age acceleration (EAA) (mean = − 0.92, p value = 0.039).ConclusionsOur study shows that bariatric surgery leads to substantial BMI decrease and improvement of clinical outcomes observed 12 months after surgery. These changes explained part of the association between bariatric surgery and DNA methylation. We also observed a small, but significant improvement of biological age. These epigenetic changes may be modifiable by environmental lifestyle factors and could be used as potential biomarkers for obesity and in the future for obesity related comorbidities.

Индивидуально-личностные факторы пенсионного стресса у представителей профессий интеллектуального типа, проживающих в России и иммигрировавших в страны Евросоюза

The article introduces data from the study of the severity of social anxiety caused by the expectation of retirement and subsequent retirement; highlights signs of retirement stress: acceleration of biological aging, the discrepancy of psychological and biological age. It also regards individual-personal factors of biopsychological aging. The article presents the results of an empirical study of the biopsychological age of people – Russians by origin – pursuing intel-lectual professions and living in the European Union and in Russia. All the participants were continuing their research activity and were aged from 32 to 70 years, both living in Russia (n=101, women, 62), and having migrated to the European Union countries (n=101, women 56). Methods of assessing biological age with regard on health indicators, subjective psychological age, as well as the questionnaire of life path were applied. The results showed that in Russian sample the signs of retirement stress are more pronounced: the subjects have an acceleration of biological aging at the age of 51–65 years. The personal strategies for preventing retirement stress and maintaining relative juvenility, typical for the intellectual occupation professionals, were singled out: for men — democratic working conditions, positive attitude, collaborative non-ambitious non-aggressive behaviour; and for women — wellbeing, respectful partnership in the couple, friendly working conditions; multiple changes of place of residence. However, the difference in relative juvenility strategy for residents in Russian and EU was also observed.

Novel age-associated DNA methylation changes and epigenetic age acceleration in middle-aged African Americans and whites

BackgroundAfrican Americans (AAs) experience premature chronic health outcomes and longevity disparities consistent with an accelerated aging phenotype. DNA methylation (DNAm) levels at specific CpG positions are hallmarks of aging evidenced by the presence of age-associated differentially methylated CpG positions (aDMPs) that are the basis for the epigenetic clock for measuring biological age acceleration. Since DNAm has not been widely studied among non-European populations, we examined the association between DNAm and chronological age in AAs and whites, and the association between race, poverty, sex, and epigenetic age acceleration.ResultsWe measured genome-wide DNA methylation (866,836 CpGs) using the Illumina MethylationEPIC BeadChip in blood DNA extracted from 487 middle-aged AA (N = 244) and white (N = 243), men (N = 248), and women (N = 239). The mean (sd) age was 48.4 (8.8) in AA and 49.0 (8.7) in whites (p = 0.48). We identified 4930 significantly associated aDMPs in AAs and 469 in whites. Of these, 75.6% and 53.1% were novel, largely driven by the increased number of measured CpGs in the EPIC array, in AA and whites, respectively. AAs had more age-associated DNAm changes than whites in genes implicated in age-related diseases and cellular pathways involved in growth and development. We assessed three epigenetic age acceleration measures (universal, intrinsic, and extrinsic). AAs had a significantly slower extrinsic aging compared to whites. Furthermore, compared to AA women, both AA and white men had faster aging in the universal age acceleration measure (+ 2.04 and + 1.24 years, respectively, p < 0.05).ConclusionsAAs have more wide-spread methylation changes than whites. Race and sex interact to underlie biological age acceleration suggesting altered DNA methylation patterns may be important in age-associated health disparities.

Methylation-Based Biological Age and Breast Cancer Risk.

Age is one of the strongest predictors of cancer, chronic disease, and mortality, but biological responses to aging differ among people. Epigenetic DNA modifications have been used to estimate "biological age," which may be a useful predictor of disease risk. We tested this hypothesis for breast cancer. Using a case-cohort approach, we measured baseline blood DNA methylation of 2764 women enrolled in the Sister Study, 1566 of whom subsequently developed breast cancer after an average of 6 years. Using three previously established methylation-based "clocks" (Hannum, Horvath, and Levine), we defined biological age acceleration for each woman by comparing her estimated biological age with her chronological age. Hazard ratios and 95% confidence intervals for breast cancer risk were estimated using Cox regression models. All statistical tests were two-sided. Each of the three clocks showed that biological age acceleration was statistically significantly associated with increased risk of developing breast cancer (5-year age acceleration, Hannum's clock: hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.00 to 1.21, P = .04; Horvath's clock: HR = 1.08, 95% CI = 1.00 to 1.17, P = .04; Levine's clock: HR = 1.15, 95% CI = 1.07 to 1.23, P < .001). For Levine's clock, each 5-year acceleration in biological age corresponded with a 15% increase in breast cancer risk. Although biological age may accelerate with menopausal transition, age acceleration in premenopausal women independently predicted breast cancer. Case-only analysis suggested that, among women who develop breast cancer, increased age acceleration is associated with invasive cancer (odds ratio for invasive = 1.09, 95% CI = 0.98 to 1.22, P = .10). DNA methylation-based measures of biological age may be important predictors of breast cancer risk.

Blood Biochemistry Analysis to Detect Smoking Status and Quantify Accelerated Aging in Smokers

There is an association between smoking and cancer, cardiovascular disease and all-cause mortality. However, currently, there are no affordable and informative tests for assessing the effects of smoking on the rate of biological aging. In this study we demonstrate for the first time that smoking status can be predicted using blood biochemistry and cell count results andthe recent advances in artificial intelligence (AI). By employing age-prediction models developed using supervised deep learning techniques, we found that smokers exhibited higher aging rates than nonsmokers, regardless of their cholesterol ratios and fasting glucose levels. We further used those models to quantify the acceleration of biological aging due to tobacco use. Female smokers were predicted to be twice as old as their chronological age compared to nonsmokers, whereas male smokers were predicted to be one and a half times as old as their chronological age compared to nonsmokers. Our findings suggest that deep learning analysis of routine blood tests could complement or even replace the current error-prone method of self-reporting of smoking status and could be expanded to assess the effect of other lifestyle and environmental factors on aging.

Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.

The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8,823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria, we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally, we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt-signaling pathways in the aging of human liver.

M16 - Epigenetic Age Acceleration Assessed In White-Matter Integrity: Towards A Biomarker of Successfully Brain Aging

Background Biological age acceleration as measured by aggregate epigenetic markers has been associated with a number of phenotypes including Parkinson’s, obesity and physical fitness in the elderly. Additionally, epigenetic indices of age acceleration are touted as molecular biomarkers of brain aging, based on findings linking epigenetic age of prefrontal cortex tissue with Alzheimer’s-related phenotypes. Yet, in order to develop a clinically useful brain age acceleration biomarker, peripheral tissue, rather than neural tissue, is preferable. Likewise, in vivo neuroimaging measures are desirable. To that end, we examined the relationship between blood-derived epigenetic measures of age acceleration and white matter integrity, as indexed with diffusion weighted imaging (DWI), in a large randomly ascertained family cohort. Our goal was to investigate processes that underlie inter-individual variability in age-related changes in the white matter tracts. DWI measures of white mater integrity are among the most sensitive imaging measures of aging with demonstrated heritabilities. Methods Using blood DNA methylation data taken from a Mexican-American extended pedigree sample (n=634; mean age=49.16y, range 28.11y-97.52y), epigenetic age was estimated using the method developed by S. Horvath (2013). Epigenetic age acceleration was calculated as epigenetic age regressed upon age, sex, age x sex, age2, age2 x sex, and blood cell count estimates. 379 of these individuals had available DWI scans collected on a Siemens 3T Trio MRI located at the Research Imaging Institute, UTHSCSA. An average fractional anisotropy (FA) map was derived for each subject and skeletonized using the TBSS algorithm, providing FA measures for each of 16 white matter tracts and a global index. Variance decomposition methods were then used to investigate the interrelationship between epigenetic age acceleration and white matter integrity and identify genetic influences on these two phenotypes. Results Consistent with previous reports, both epigenetic age acceleration and white matter integrity measures are heritable in this sample. We observe significant (FDR Discussion Here we demonstrate that age acceleration, as measured via methylation profiles from peripheral blood, is significantly correlated with white matter integrity in a number of tracts within the brain. We also demonstrate evidence of shared genetic influences acting on both age acceleration and white matter integrity. These findings provide an interesting window into the neurobiology of aging processes within the brain and a potential new biomarker of normal and pathological brain aging.

WRNMutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.