Biomarker Of Biological Aging Research Articles

Telomere-telomerase system status in patients with acute myocardial infarction with ST-segment elevation - relationship with oxidative stress.

Telomeres are protective chromosomal ends. Short telomeres are a proven biomarker of biological aging. We aimed to find an association of telomere length and telomerase activity in circulating leukocytes and thromboaspirates of patients with acute myocardial infarction. Furthermore, association of the telomere-telomerase system with oxidative stress markers (as common risk factors for coronary artery disease (CAD)) was tested. Patients were selected from the patients admitted to the intensive care unit with acute myocardial infarction with ST-segment elevation (STEMI), with the following inclusion criteria - STEMI patients between 18 and 80 years old of both genders and candidates for primary percutaneous coronary intervention, with infarction pain present for a maximum of 12 h. In all the patients leukocyte telomere length, telomerase activity and scores related to oxidative-stress status (Protective, Damage and OXY) were evaluated. Patients were divided into different groups: with stable angina pectoris (AP) (n = 22), acute myocardial infarction with: STEMI (n = 93), non-obstructive coronary arteries (MINOCA) (n = 7), blood vessel rupture (n = 6) at three time points, and compared to the group of 84 healthy subjects. Telomerase activity was significantly higher in all CAD sub-groups compared to the control group (AP = 0.373 (0.355-0.386), STEMI = 0.375 (0.349-0.395), MINOCA = 0.391 (0.366-0.401), blood vessel rupture = 0.360 (0.352-0.385) vs. CG = 0.069 (0.061-0.081), p < 0.001), while telomeres were significantly shorter in STEMI, MINOCA and blood vessel rupture groups compared to the control group (STEMI = 1.179 (0.931-1.376), MINOCA = 1.026 (0.951-1.070), blood vessel rupture = 1.089 (0.842-1.173) vs. CG = 1.329 (1.096-1.624), p = 0.030]. Values of OXY score were significantly higher in STEMI and MINOCA patients compared to the control group and AP patients (5.83 (4.55-7.54) and 10.28 (9.19-10.72) vs. 4.94 (3.29-6.18) and 4.18 (2.58-4.86), p < 0.001). Longer telomeres and higher telomerase activity were found in thromboaspirates, compared to the peripheral blood leukocytes in the same patients (1.25 (1.01-1.84) vs. 1.18 (0.909-1.516), p = 0.036; and 0.366 (0.367-0.379) vs. 0.366 (0.367-0.379), p < 0.001, respectively). In addition, telomere length and telomerase activity had good diagnostic ability to separate STEMI patients from healthy persons. Leukocyte telomere length and telomerase activity can differentiate CAD patients from healthy persons, and relate CAD to oxidative stress.

The 12-lead electrocardiogram as a biomarker of biological age.

We have demonstrated that a neural network is able to predict a person's age from the electrocardiogram (ECG) [artificial intelligence (AI) ECG age]. However, some discrepancies were observed between ECG-derived and chronological ages. We assessed whether the difference between AI ECG and chronological age (Age-Gap) represents biological ageing and predicts long-term outcomes. We previously developed a convolutional neural network to predict chronological age from ECGs. In this study, we used the network to analyse standard digital 12-lead ECGs in a cohort of 25144 subjects ≥30 years who had primary care outpatient visits from 1997 to 2003. Subjects with coronary artery disease, stroke, and atrial fibrillation were excluded. We tested whether Age-Gap was correlated with total and cardiovascular mortality. Of 25144 subjects tested (54% females, 95% Caucasian) followed for 12.4 ± 5.3 years, the mean chronological age was 53.7 ± 11.6 years and ECG-derived age was 54.6 ± 11 years (R 2 = 0.79, P < 0.0001). The mean Age-Gap was small at 0.88 ± 7.4 years. Compared to those whose ECG-derived age was within 1 standard deviation (SD) of their chronological age, patients with Age-Gap ≥1 SD had higher all-cause and cardiovascular disease (CVD) mortality. Conversely, subjects whose Age-Gap was ≤1 SD had lower all-cause and CVD mortality. Results were unchanged after adjusting for CVD risk factors and other survival influencing factors. The difference between AI ECG and chronological age is an independent predictor of all-cause and cardiovascular mortality. Discrepancies between these possibly reflect disease independent biological ageing.

Longitudinal course of GDF15 levels before acute hospitalization and death in the general population.

Growth differentiation 15 (GDF15) is a potential novel biomarker of biological aging. To separate the effects of chronological age and birth cohort from biological age, longitudinal studies investigating the associations of GDF15 levels with adverse health outcomes are needed. We investigated changes in GDF15 levels over 10 years in an age-stratified sample of the general population and their relation to the risk of acute hospitalization and death. Serum levels of GDF15 were measured three times in 5-year intervals in 2176 participants aged 30, 40, 50, or 60 years from the Danish population-based DAN-MONICA cohort. We assessed the association of single and repeated GDF15 measurements with the risk of non-traumatic acute hospitalizations. We tested whether changes in GDF15 levels over 10 years differed according to the frequency of hospitalizations within 2 years or survival within 20 years, after the last GDF15 measurement. The change in GDF15 levels over time was dependent on age and sex. Higher GDF15 levels and a greater increase in GDF15 levels were associated with an increased risk of acute hospitalization in adjusted Cox regression analyses. Participants with more frequent admissions within 2 years, and those who died within 20 years, after the last GDF15 measurement already had elevated GDF15 levels at baseline and experienced greater increases in GDF15 levels during the study. The change in GDF15 levels was associated with changes in C-reactive protein and biomarkers of kidney, liver, and cardiac function. Monitoring of GDF15 starting in middle-aged could be valuable for the prediction of adverse health outcomes.

Characterization of the effects of age and childhood maltreatment on ELOVL2 DNA methylation.

DNA methylation of the elongation of very long chain fatty acids protein 2 (ELOVL2) was suggested as a biomarker of biological aging, while childhood maltreatment (CM) has been associated with accelerated biological aging. We investigated the association of age and CM experiences with ELOVL2 methylation in peripheral blood mononuclear cells (PBMC). Furthermore, we investigated ELOVL2 methylation in the umbilical cord blood mononuclear cells (UBMC) of newborns of mothers with and without CM. PBMC and UBMC were isolated from 113 mother-newborn dyads and genomic DNA was extracted. Mothers with and without CM experiences were recruited directly postpartum. Mass array spectrometry and pyrosequencing were used for methylation analyses of ELOVL2 intron 1, and exon 1 and 5' end, respectively. ELOVL2 5' end and intron 1 methylation increased with higher age but were not associated with CM experiences. On the contrary, overall ELOVL2 exon 1 methylation increased with higher CM, but these changes were minimal and did not increase with age. Maternal CM experiences and neonatal methylation of ELOVL2 intron 1 or exon 1 were not significantly correlated. Our study suggests region-specific effects of chronological age and experienced CM on ELOVL2 methylation and shows that the epigenetic biomarker for age within the ELOVL2 gene does not show accelerated biological aging years after CM exposure.

Estimation of the effect of surrogate multi-omic biomarkers.

Multiple technologies which measure the same omics data set but are based on different aspects of the molecules exist. In practice, studies use different technologies and have therefore different biomarkers. An example is the glycan age index, which is constructed by three different ultra-performance liquid chromatography (UPLC) IgG glycans, and is a biomarker for biological age. A second technology is liquid chromatography- mass spectrometry (LCMS). To estimate the effect of a biomarker on an outcome variable, two issues need to be addressed. Firstly, a measurement error is needed to map one technology to the other one using a calibration study. Here, we consider two approaches, namely one based on the chemical properties of the two technologies and one based on the estimation of this relationship using O2PLS. Secondly, the use of an approximation of the biomarker in the main study needs to be taken into account by use of a regression calibration method. The performance of the two approaches is studied via simulations. The methods are used to estimate the relationship between glycan age and menopause. We have data from two cohorts, namely Korcula and Vis. In conclusion, (1) both measurement error models give similar results and suggest that there is an association between the glycan age index and the menopause status, (2) the chemical mapping approach outperforms O2PLS in the low measurement error variance, while on the larger measurement error variance, O2PLS works better, (3) statistical efficiency is lost due to increased noise level by adding irrelevant information.

Advanced Glycation End Products for Preoperative Frailty Screening in Elderly Cardiac Surgery Patients

Background: Advanced glycation end products (AGEs) are a potential biomarker of biological age. Skin Auto Fluorescence (SAF) can assess AGEs non-invasively. We evaluated the association of SAF levels with frailty and its predictive ability for adverse outcomes in elderly cardiac surgery patients. Methods & Results: We measured SAF level in cardiac surgery patients aged ≥70 and analyzed the correlation with frailty diagnosed with geriatric assessment. A decision algorithm for frailty screening was developed using Conditional Interference Tree analysis and compared with the Frailty Phenotype (FP), a validated frailty assessment tool. We evaluated the association of SAF level with severe postoperative complications and a composite endpoint of one-year disability (defined by WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) questionnaire) and mortality with Poisson regression analyses. Among 555 enrolled patients, 122 (22%) were classified as frail. Of all frailty characteristics, SAF level was most strongly associated with dependent living status (aRR 2.61 (95% CI 1.23-5.53) and handgrip strength (aRR 1.72 (95% CI 1.28-2.32). A decision algorithm including SAF level, sex, prescription drugs, preoperative hemoglobin and EuroSCORE II resulted in a C-statistic of 0.72 (95% CI 0.67-0.77) vs 0.66 (95% CI 0.61-0.71) for the FP. SAF level was also associated with disability/death after one year (aRR 1.18 (95% CI 1.06-1.30). The RR for severe complications was 1.32 (95% CI 0.99-1.75). Conclusion: Higher SAF level is associated with frailty in elderly cardiac surgery patients, as well as an increased risk of death and disability. This biomarker could potentially optimize preoperative screening for cardiac surgery.

Greater Perceived Physical Fatigability Is Associated with Lower Cognition: The Long Life Family Study

Greater perceived physical fatigability is associated with physical functional decline, but few studies have examined its relation with cognition. Adults ≥60 (mean±SD age 73.7±10.5, 54.7% female, 99.6% white) from the Long Life Family Study (n=2355) completed the Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater fatigability) and a neurocognitive examination. Generalized estimating equations were used to account for family structure. Covariates included age, sex, field center, depressive symptoms (Center for Epidemiological Studies-Depression), education, and self-reported health. Each 1-point greater PFS was associated with lower: (1) global cognition (Mini-Mental Status Exam; β=-0.36,p<.0001), (2) verbal fluency (phonemic: β=-0.09,p=.029 and semantic: β=-0.14,p<.0001), (3) memory (Hopkins Verbal Learning Test-Revised: β=-0.06,p=.037), and (4) psychomotor speed (Digit Symbol Substitution Test: β=-0.10,p<.0001), after covariate adjustment. Greater perceived physical fatigability was significantly associated with lower memory and cognitive function in older adults, and may represent a promising new biomarker of biological aging reflecting declining brain reserve, resilience, and neurodegeneration.

Abstract PO-158: Social-demographics, health behaviors, and p16INK4a mRNA expression in White and Black breast cancer patients

Abstract It has been assumed that minority populations have accelerated aging through the “wear and tear” on their bodies that result from chronic exposure to social adversity and unhealthy behaviors. Consistent with this assumption, research shows that Black women who have shorter telomere length (an indicator of more rapid cellular aging), are more likely to have earlier onset of breast cancer, more aggressive forms of breast tumors, and a shorter survival compared with Whites. In addition to telomere length, studies in the past decades have discovered multiple other molecular mechanisms contributing to accelerated biological aging, including cellular senescence. Cellular senescence is a stress response mechanism that will lead to replication arrest and complex changes in morphology, chromatin organization, and expression of typical protein biomarkers. p16INK4a mRNA serves as a potent biomarker of biological aging and physiologic reserve that may play a causal role in aging by promoting cellular senescence. In this study, we examined cross-sectional associations among social-demographics, lifestyle behaviors, tumor characteristics, and p16INK4a mRNA expression in peripheral blood leukocytes, among a cohort of 828 breast cancer patients aged 20 to 80 years (including 601 Whites and 227 Blacks), who were diagnosed with primary stage I to III breast cancer at M.D. Anderson Cancer Center from 2013 to 2018. p16INK4a mRNA expression levels were inversely correlated with age (ρ=-0.15, ρ&amp;lt;0.001). In the multivariate analysis, p16INK4a mRNA expression levels were significantly higher among Blacks than Whites (P&amp;lt;0.001). Then, we assessed the associations between p16INK4a mRNA expression levels with social-demographics and healthy behaviors at baseline. p16INK4a mRNA expression levels were higher among breast cancer cases currently smoking cigarettes (P=0.021), being physical inactive (P=0.014), having no college level of education (P=0.014), and having &amp;lt; $20,000 annual income (P=0.027), compared to their counterparts. The significant associations between p16INK4a mRNA expression with education and income were more evident among Blacks than Whites. Finally, we assessed the associations between p16INK4a mRNA expression levels with breast tumor characteristics at baseline, including estrogen receptor (ER) status, and tumor stage, grade, and size, as well as age of disease onset. Overall, no significant association was observed. However, when stratified by race, significant associations were observed for ER status and tumor grade among Blacks. Higher levels of p16INK4a mRNA expression were associated with increased odds of having ER negative (ER-) and poorly differentiated breast tumors (ER-: Odds Ratio (OR): 1.39, 95% Confidence Interval (CI): 1.12, 1.70; poorly differentiated: 1.23, 95%CI: 1.02, 1.48) among Blacks. In summary, our results support the notion that p16INK4a mRNA is a biological mechanism by which social demographics and health behaviors “get under the skin” to affect health. Citation Format: Jie Shen, Renduo Song, Bernard Fuemmeler, Wong-Ho Chow, Hua Zhao. Social-demographics, health behaviors, and p16INK4a mRNA expression in White and Black breast cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-158.

Associations between alcohol use and accelerated biological ageing

Abstract Background Harmful alcohol use is a leading cause of premature death, and is associated with age-related disease. Ageing is highly variable between individuals, and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (based on DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates. Methods First, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (AUDIT scores), and accelerated brain and epigenetic ageing in 20,258 and 8,051 individuals, respectively. Second, we used Mendelian randomization to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing. Results Alcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β=0.053, p=3.16×10−13; AUDIT-P: β=0.052, p=1.6×10−13; total AUDIT score: β=0.062, p=5.52×10−16; units/week: β=0.078, p=2.20×10−16), and DNA methylation GrimAge (Units/week: β=0.053, p=1.48×10− 7) and PhenoAge (Units/week: β=0.077, p=2.18×10−10). Mendelian randomization analyses revealed some evidence for a causal effect of AUD on accelerated brain ageing (β=0.272, p=0.044), and no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing. Conclusions We provide consistent phenotypic evidence linking alcohol use with accelerated biological ageing. There is possible evidence for a causal effect of AUD on brain age, but not for any other alcohol-related trait on brain or epigenetic age acceleration. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.

Association between telomere length, frailty and death in older adults.

Frailty is considered a clinical marker of functional ageing. Telomere length (TL) has been proposed as a biomarker of biological age but its role in human ageing is controversial. The main aim of the study was to evaluate the longitudinal association of TL with incident frailty and mortality in two cohorts of Spanish community-dwelling older adults. TL was determined at baseline in blood samples from older adults included in Toledo Study for Healthy Aging and ENRICA cohorts while frailty was determined by frailty phenotype (FP) at baseline and at follow-up (3.5years). Deaths occurring during follow-up were also recorded. Associations of TL with frailty and mortality were analysed by logistic regression with progressive adjustment. Data were separately analysed in the two cohorts and in all subjects by performing a meta-analysis. TL was not different between frail and non-frail subjects. Longer telomeres were not associated with lower risk of prevalent frailty. Similarly, TL at baseline failed to predict incident frailty (OR: 1.04 [0.88-1.23]) or even the development of a new FP criterion (OR: 0.97 [0.90-1.05]) at follow-up. Lack of association was also observed when analysing the development of specific FP criteria. Finally, while frailty at baseline was significantly associated with higher risk of death at follow-up (OR: 4.08 [1.97-8.43], p < 0.001), TL did not significantly change the mortality risk (OR: 1.05 [0.94-1.16]). Results show that TL does not predict incident frailty or mortality in older adults. This suggests that TL is not a reliable biomarker of functional age.

Land Use Mix and Leukocyte Telomere Length in Mexican Americans

It has been well-known that built environment features influence the risk of chronic diseases. However, the existing data of its relationship with telomere length, a biomarker of biological aging, is still limited, with no study available for Mexican Americans. This study investigates the relationship between several factors of the built environment with leukocyte telomere length among 5,508 Mexican American adults enrolled in Mano-A-Mano, the Mexican American Cohort Study (MACS). Based on the quartile levels of telomere length, the study population was categorized into four groups, from the lowest (1st quartile) to the highest telomere length group (4th quartile). For individual built environment factors, their levels did not differ significantly across four groups. However, in the multinominal logistic regression analysis, increased Rundle’s land use mixture (LUM) and Frank’s LUM were found statistically significantly associated with increased odds of having high levels of telomere length (Rundle’s LUM: 2nd quartile: Odds ratio (OR)=1.26, 95% Confidence interval (CI): 1.07, 1.48; 3rd quartile: OR=1.25, 95% CI: 1.06, 1.46; 4th quartile: OR=1.19, 95% CI: 1.01, 1.41; Frank’s LUM: 2nd quartile: OR=1.34, 95% CI: 1.02, 2.63; 3rd quartile: OR=1.55, 95% CI: 1.04, 2.91; 4th quartile: OR=1.36, 95% CI: 1.05, 2.72, respectively). The associations for Rundle’s LUM remained significant after further adjusting other non-redundant built environment factors. Finally, in stratified analysis, we found the association between Rundle’s LUM and telomere length was more evident among younger individuals (<38 years old), women, and those with obesity, born in Mexico, having low levels of physical activity, and having low levels of acculturation than their relative counterparts. In summary, our results indicate that land use mixture may impact telomere length in leukocytes in Mexican Americans. Funding Statement: The Mano a Mano Cohort Study receives funds collected pursuant to the Comprehensive Tobacco Settlement of 1998 and appropriated by the 76th legislature to The University of Texas MD Anderson Cancer Center, as well as funds from the Caroline W. Law Fund for Cancer Prevention and the Duncan Family Institute for Risk Assessment and Cancer Prevention. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study was approved by the Institutional Review Board of MD Anderson Cancer Center. All methods were performed in accordance with the relevant guidelines and regulations. Written consent has been obtained from all participants.

Telomere length in newborns is associated with exposure to low levels of air pollution during pregnancy

Telomere length (TL) is a biomarker of biological aging that may be affected by prenatal exposure to air pollution. The aim of this study was to assess the association between prenatal exposure to air pollution and TL in maternal blood cells (leukocytes), placenta and umbilical cord blood cells, sampled immediately after birth in 296 Danish mother-child pairs from a birth cohort. Exposure data was obtained using the high-resolution and spatial–temporal air pollution modeling system DEHM-UBM-AirGIS for PM2.5, PM10, SO2, NH4+, black carbon (BC), organic carbon (OC), CO, O3, NO2, and NOx at residential and occupational addresses of the participating women for the full duration of the pregnancy. The association between prenatal exposure to air pollutants and TL was investigated using distributed lag models. There were significant and positive associations between TL in umbilical cord blood cells and prenatal exposure to BC, OC, NO2, NOx, CO, and O3 during the second trimester. TL in umbilical cord blood was significantly and inversely associated with prenatal exposure to PM2.5, BC, OC, SO2, NH4+, CO and NO2 during the third trimester. There were similar inverse associations between TL from umbilical cord blood cells and air pollution exposure at the residential and occupational addresses. There were weaker or no associations between air pollution exposure and TL in placenta tissue and maternal blood cells. In conclusion, both the second and third trimesters of pregnancy are shown to be sensitive windows of exposure to air pollution affecting fetal TL.

Environmental exposures and health behavior in association with mental health: a study design

BackgroundAir pollution, green space and smoking are known to affect human health. However, less is known about their underlying biological mechanisms. One of these mechanisms could be biological aging. In this study, we explore the mediation of biomarkers of exposure and biological aging to explain the associations between environmental exposures, health behavior and mental health.MethodsThe study population of this cross-sectional study (n = 1168) is a subsample of the Belgian 2018 Health Interview Survey (BHIS). Mental health indicators including psychological and severe psychological distress, life satisfaction, vitality, eating disorders, suicidal ideation, subjective health and depressive and anxiety disorders, demographics and health behavior such as smoking are derived from the BHIS. Urine and blood samples are collected to measure respectively the biomarkers of exposure (urinary black carbon (BC) and (hydroxy)cotinine) and the biomarkers of biological aging (mitochondrial DNA content (mtDNAc) and telomere length (TL)). Recent and chronic exposure (μg/m3) to nitrogen dioxide (NO2), particulate matter ≤2.5 μm (PM2.5) and ≤ 10 μm (PM10) and BC at the participants’ residence are modelled using a high resolution spatial temporal interpolation model. Residential green space is defined in buffers of different size (50 m – 5000 m) using land cover data in ArcGIS 10 software. For the statistical analysis multivariate linear and logistic regressions as well as mediation analyses are used taking into account a priori selected covariates and confounders.ResultsAs this study combined data of BHIS and laboratory analyses, not all data is available for all participants. Therefore, data analyses will be conducted on different subsets. Data on air pollution and green space exposure is available for all BHIS participants. Questions on smoking and mental health were answered by respectively 7829 and 7213 BHIS participants. For biomarker assessment, (hydroxy) cotinine, urinary BC and the biomarkers of biological aging are measured for respectively 1130, 1120 and 985 participants.ConclusionBy use of personal markers of air pollution and smoking, as well as biological aging, we will gain knowledge about the association between environmental exposures, health behavior, and the mental health status. The results of the study can provide insights on the health of the Belgian population, making it a nationwide interesting study.

Coronavirus (COVID-19): the potential contamination among dentistry professionals in Brazil

The coronavirus (COVID-19) is considered a global pandemic with several respiratory syndrome caused by coronavirus 2 (SARS-CoV-2). The main symptoms of COVID-19 are fever, cough, and fatigue, while other symptoms include sputum production, diarrhea and alterations on the gastrointestinal system. The COVID-19 was recently identified in the saliva of infected patients and the transmission through of droplets and aerosols generated during clinical dental care is possible among dentists, oral health assistants and/or oral health technicians and others around the social cycle of the friendship of these health professionals, such as families and colleagues. Thus, there is very necessary to improve the several types of prevention to healthcare professionals that realize the liberation of aerosol during oral assistance. It’s important to mention that these precautions are important to prevent human-to-human transmission and protect the global system of health. In addition, this care is essential to decrease the spread of COVID-19 in this moment. Descriptors: Coronavirus Infections; Dentistry; Occupational Diseases.ReferencesLi LY, Wu W, Chen S, Gu JW, Li XL, Song HJ et al. Digestive system involvement of novel coronavirus infection: Prevention and control infection from a gastroenterology perspective. J Dig Dis. 2020;21(4):199-204. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.Pan L, Mu M, Yang P, Sun Y, Wang R, Yan J et al. Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study. Am J Gastroenterol. 2020;115(5):766-73.Gabutti G, d'Anchera E, Sandri F, Savio M, Stefanati A. Coronavirus: update related to the current outbreak of COVID-19. Infect Dis Ther. 2020;9(2):1-13.Liu L, Wei Q, Alvarez X, Wang H, Du Y, Zhu H et al. Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques. J Virol. 2011;85(8):4025-30.To KK, Tsang OT, Yip CC, Chan KH, Wu TC, Chan JMC et al. Consistent Detection of 2019 Novel Coronavirus in Saliva. Clin Infect Dis. 2020;71(15):841-43.Sabino-Silva R, Jardim ACG, Siqueira WL. Coronavirus COVID-19 impacts to dentistry and potential salivary diagnosis. Clin Oral Investig. 2020;24(4):1619-21.Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-69.Brazilian Ministry of Health. https://saude.gov.br/Brazilian Institute of Geography and Statistic. https://www.ibge.gov.br/Lauc G, Sinclair D. Biomarkers of biological age as predictors of COVID-19 disease severity. Aging (Albany NY). 2020;12(8):6490-91.Federal Council of Dentistry from Brazil. http://website.cfo.org.br/dados-estatisticos-de-profissionais-e-entidades-ativas-por-ano/Regional Dentistry Council of the State of São Paulo. http://www.crosp.org.br/intranet/estatisticas/estMunicipios.phpThompson RN. Novel Coronavirus Outbreak in Wuhan, China, 2020: Intense Surveillance Is Vital for Preventing Sustained Transmission in New Locations. J Clin Med. 2020;9(2):498.

Psychological aging, depression, and well-being.

Aging is a multifactorial process, which affects the human body on every level and results in both biological and psychological changes. Multiple studies have demonstrated that a lower subjective age is associated with better mental and physical health, cognitive functions, well-being and satisfaction with life. In this work we propose a list of non-modifiable and modifiable factors that may possibly be influenced by subjective age and its changes across an individual’s lifespan. These factors can be used for a future development of individual psychological aging clocks, which may be utilized as a sensitive measure for health status and overall life satisfaction. Furthermore, recent progress in artificial intelligence and biomarkers of biological aging have enabled scientists to discover and evaluate the efficacy of potential aging- and disease-modifying drugs and interventions. We propose that biomarkers of psychological age, which are just as important as those for biological age, may likewise be used for these purposes. Indeed, these two types of markers complement one another. We foresee the development of a broad range of parametric and deep psychological and biopsychological aging clocks, which may have implications for drug development and therapeutic interventions, and thus healthcare and other industries.

Abstract 2332: Correlation of lifestyle factors with epigenetic aging unveiled in the practice of a DNA methylation-based age test

Abstract Background: DNA methylation clocks have been developed recently to estimate epigenetic age which is associated with chronological age in mouse and human. Changes in epigenetic age were reported in patients with health conditions including cancer. Different from genetic variations, epigenetic properties can be modified by environmental factors. Epigenetic age tests using blood samples have been offered directly to customers recently. We sought to analyze relationships between epigenetic aging and lifestyle factors, medication and aging interventions in the hope of assisting healthier living. Methods: Epigenetic age, called DNAge, is estimated using linear regression of DNA methylation levels at 206 loci containing 1344 CpGs and chronological age. Delta age is defined as the difference of epigenetic age minus chronological age. Correlations between lifestyle factors or medication and delta age of hundreds of whole blood samples were evaluated using biweight midcorrelation. Statistical significance is set at 0.05. Results: Our results showed positive correlations between accelerated epigenetic aging and BMI (bicor=0.148, p=0.009, n=311), current smoker (bicor=0.143, p=0.011, n=315), or stress (bicor=0.088, p=0.128, n=302). Factors with positive correlation but not reaching statistical significance included total cholesterol, alcohol consumption and Keto diet. Factors with negative correlation but not statistically significant included exercise, balanced diet, mostly meat, mostly vegetables, and education. Conclusions: The epigenetic age analysis of real customer data confirmed beneficial and adversarial health effects of certain lifestyle factors. The DNAge test offered proves to be useful as a biomarker for biological age and as a practical tool for monitoring and evaluation of health status which may be used in cancer epidemiology study and help cancer prevention. Citation Format: Wei Guo, Yap Ching Chew, Xiaojing Yang, Michiko Suwoto, Taikun Yamada, Xi Yu Jia. Correlation of lifestyle factors with epigenetic aging unveiled in the practice of a DNA methylation-based age test [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2332.

The Importance of Telomere Shortening for Atherosclerosis and Mortality.

Telomeres are the protective end caps of chromosomes and shorten with every cell division. Short telomeres are associated with older age and adverse lifestyle factors. Leucocyte telomere length (LTL) has been proposed as a biomarker of biological age. The shortening of LTL with age is the result of the end-replication problem, environmental, and lifestyle-related factors. Epidemiologic studies have shown that LTL predicts cardiovascular disease, all-cause mortality, and death from vascular causes. Age appears to be an important co-variate that explains a substantial fraction of this effect. Although it has been proposed that short telomeres promote atherosclerosis and impair the repair of vascular lesions, existing results are inconsistent. Oxidative stress and chronic inflammation can both accelerate telomere shortening. Multiple factors, including homocysteine (HCY), vitamin B6, and vitamin B12 modulate oxidative stress and inflammation through direct and indirect mechanisms. This review provides a compact overview of telomere physiology and the utility of LTL measurements in atherosclerosis and cardiovascular disease. In addition, it summarizes existing knowledge regarding the impact of oxidative stress, inflammation, HCY, and B-vitamins on telomere function.

U-Shaped Relationship of Leukocyte Telomere Length With All-Cause and Cancer-Related Mortality in Older Men.

Telomeres are essential DNA-protein complexes whose attrition results in cellular dysfunction and senescence. Leukocyte telomere length (LTL) correlates with tissue telomere length, representing a biomarker for biological age. However, its predictive value for mortality risk, and for cardiovascular versus cancer deaths, in older adults remains uncertain. We studied 3608 community-dwelling men aged 77.0 ± 3.6 years. Leukocyte telomere length was measured using multiplex quantitative PCR, expressed as amount of telomeric DNA relative to single-copy control gene (T/S ratio). Deaths from any cause, cardiovascular disease (CVD), and cancer were ascertained using data linkage. Curve fitting used restricted cubic splines and Cox regression analyses adjusted for age, cardiometabolic risk factors, and prevalent disease. There was a U-shaped association of LTL with all-cause mortality. Men with T/S ratio in the middle quartiles had lower mortality (quartiles, Q2 vs Q1, hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.77-0.97, p = .012; Q3 vs Q1 HR = 0.88, CI 0.79-0.99, p = .032). There was no association of LTL with CVD mortality. There was a U-shaped association of LTL with cancer mortality. Men with LTL in the middle quartiles had lower risk of cancer death (Q2 vs Q1, HR = 0.73, CI 0.59-0.90, p = .004; Q3 vs Q1, HR = 0.75, CI 0.61-0.92, p = .007). In older men, both shorter and longer LTL are associated with all-cause mortality. A similar U-shaped association was seen with cancer deaths, with no association found for cardiovascular deaths. Further research is warranted to explore the prognostic utility of LTL in ageing.

Association between Nrf2 and CDKN2A expression in patients with end-stage renal disease: a pilot study.

Patients with end-stage renal disease (ESRD) display phenotypic features of premature biological aging, characterized by disproportionately high morbidity and mortality at a younger age. Nuclear factor erythroid 2-related factor 2 (Nrf2) activity, a master regulator of antioxidative responses, declines with age and is implicated in the pathogenesis of age-related disorders; however, little is known about the association between Nrf2 and premature biological aging in ESRD patients. In a cross-sectional pilot cohort of 34 ESRD patients receiving maintenance hemodialysis, we measured the expression of Nrf2 and cyclin-dependent kinase inhibitor 2A (CDKN2A, or p16INK4a, a biomarker of biological aging) genes in whole blood and examined the association of Nrf2 with CDKN2A expression, using Spearman’s rank correlation and multivariable linear regression models with adjustment for potential confounders. There was a significant negative correlation between Nrf2 and CDKN2A expression (rho=-0.51, P=0.002); while no significant correlation was found between Nrf2 expression and chronological age (rho=-0.02, P=0.91). After multivariable adjustment, Nrf2 expression remained significantly and negatively associated with CDKN2A expression (β coefficient=-1.51, P=0.01), independent of chronological age, gender, race, and diabetes status. These findings suggest a potential contribution of Nrf2 dysfunction to the development of premature biological aging and its related morbidities in ESRD patients.

Shortened Relative Leukocyte Telomere Length Is Associated With Prevalent and Incident Cardiovascular Complications in Type 2 Diabetes: Analysis From the Hong Kong Diabetes Register.

Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes. Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code. Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P < 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than did subjects without CVD (4.6 ± 1.2 ΔΔCt) (P < 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 ± 1.2 ΔΔCt) (P < 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195-1.311], P < 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084-1.200], P < 0.001). rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.