Faculty Bibliography

Epigenetic aging biomarkers are used for evaluating morbidity and mortality, monitoring therapies, and direct-to-consumer testing. However, the influence of environmental exposures on epigenetic age acceleration (EAA), also known as epigenetic age deviation, has not been systematically evaluated. In this systematic review, we synthesized findings from human epidemiologic studies on chemical and climatic environmental exposures, particularly air pollution, chemicals, metals, climate, and cigarette smoke, and EAA. A total of 102 studies analyzing epigenetic data from over 180,000 subjects were evaluated. Overall, studies in each exposure category frequently included adult participants, used a variety of epigenetic clocks, analyzed whole blood samples, and had a low risk of bias. Exposure to air pollution (15/19 of studies; 79%), cigarette smoke (53/66; 80%), and synthetic and occupational chemicals (5/8; 63%) were notably associated with increased EAA. Results for essential and non-essential metal exposure were more equivocal: 7/13 studies (54%) reported increased EAA. One study reported increased EAA with greater temperature exposure. In summary, we identified environmental exposures, such as air pollution and cigarette smoke, that were strongly associated with increased EAA. Further research is needed with larger and more diverse samples and high-quality exposure assessment.

BACKGROUND:Epigenetic modifications linked to biological aging, like DNA methylation (DNAm), may serve as biomarkers for future cardiometabolic disease risk. However, existing studies have focused on older adults, overlooking the early-life origins of cardiometabolic health. METHODS:Among 378 participants from the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) study, we measured DNAm repeatedly from birth to age 18 years to calculate 4 epigenetic aging (EA) biomarkers: Horvath, Skin & Blood, Intrinsic epigenetic age, and DNAm Telomere Length (DNAmTL). We then developed a novel measure of cumulative EA spanning from birth to age 18 years. Using multinomial logistic and multivariable linear regression models, we examined associations between cumulative EA and several indicators of cardiometabolic health at 18 years. RESULTS:We observed an increased risk of obesity with an interquartile range increase in cumulative EA by Horvath (relative risk [RR], 2.61 [95% CI, 1.79-3.80]), Skin & Blood (RR, 2.76 [95% CI, 1.89-4.03]), and Intrinsic epigenetic age (RR, 1.61 [95% CI, 1.11-2.34]), whereas DNAm TL decreased obesity risk (RR, 0.32 [95% CI, 0.22 -0.45]). Similarly, cumulative EA was associated with higher body mass index, waist circumference, body fat percentage, systolic blood pressure, mean arterial pressure, and resting pulse/heart rate at age 18 years. CONCLUSIONS:Cumulative EA throughout childhood predicts young adult cardiometabolic health and may signal increased risk for later cardiometabolic disease, highlighting the value of life-course epigenetic clocks as biomarkers for early-life health interventions.

OBJECTIVE:Early childhood advanced primary care models are promising ways of addressing child and family needs, but there is limited evidence to support short-term sustainability within current Medicaid payment structures. We evaluate claims-based outcomes associated with 3-2-1 IMPACT (IMPACT), an early childhood advanced primary care model, compared with the standard of care. METHODS:Using New York State Medicaid claims, we identified and matched children aged 1 to 35 months receiving care at 3 IMPACT sites and 3 comparison sites within a large public hospital system. Regression models were used to analyze use, expenditure, enrollment, and quality outcomes between groups. RESULTS:There were 6045 children at the treatment sites and 4832 matched children from the comparison sites. IMPACT was associated with a significant increase in 6 or more well-child visits and a decrease in emergency department visit rates. There was also a significant increase in 6 more well-child visits specifically for Black and Hispanic children seeking care at IMPACT sites compared with comparison sites. There were no significant differences in expenditures, other use types, or Medicaid enrollment across groups. CONCLUSION/CONCLUSIONS:An early childhood advanced primary care model that incorporates multiple evidence-based programs can show short-term, positive effects on preventative and acute care use and quality within Medicaid. These results highlight short-term strategies for sustainability while awaiting the long-term, cross-sector benefits expected from models like IMPACT. Future studies addressing additive model component effects and longer-term outcomes across mother-child dyadic and social-emotional outcomes are warranted.

Reproductive aging, including timing of menarche and menopause, influences long-term morbidity and mortality in women, yet underlying biological mechanisms remain poorly understood. Using DNA methylation-based biomarkers, we assessed associations of age at menarche (N = 1,033) and menopause (N = 658) with epigenetic aging in a nationally representative sample of women ≥ 50 years. Later age at menopause was associated with lower GrimAge epigenetic age deviation (

Epigenetic clocks can serve as pivotal biomarkers linking environmental exposures with biological aging. However, research on the influence of environmental exposures on epigenetic aging has largely been limited to a small number of chemicals and specific populations. We harnessed data from the National Health and Nutrition Examination Survey 1999-2000 and 2001-2002 cycles to examine exposome-wide associations between environmental exposures and epigenetic aging. A total of 8 epigenetic aging biomarkers were obtained from whole blood in 2,346 participants ranging from 50-84 years of age. A total of 64 environmental exposures including phthalates, metals, pesticides, dioxins, and polychlorinated biphenyls (PCBs) were measured in blood and urine. Associations between log₂-transformed/standardized exposure measures and epigenetic age acceleration (EAA) were assessed using survey-weighted generalized linear regression. A 1 standard deviation (SD) increase in log₂ serum cadmium levels was associated with higher GrimAge acceleration (beta = 1.23 years, p = 3.63e-06), higher GrimAge2 acceleration (beta = 1.27 years, p = 1.62e-05), and higher DunedinPoAm (beta = 0.02, p = 2.34e-05). A 1 SD increase in log₂ serum cotinine levels was associated with higher GrimAge2 acceleration (beta = 1.40 years, p = 6.53e-04) and higher DunedinPoAm (beta = 0.03, p = 6.31e-04). Associations between cadmium and EAA across several clocks persisted in sensitivity models adjusted for serum cotinine levels, and other associations involving lead, dioxins, and PCBs were identified. Several environmental exposures are associated with epigenetic aging in a nationally representative US adult population, with particularly strong associations related to cadmium and cotinine across several epigenetic clocks.

BACKGROUND:One-carbon metabolism (OCM), a biochemical pathway dependent on micronutrients including B vitamins, plays an essential role in aging-related physiological processes. DNA methylation-based aging biomarkers may be influenced by OCM. OBJECTIVES/OBJECTIVE:This study investigated associations of OCM-related biomarkers with epigenetic aging biomarkers in the cross-sectional National Health and Nutrition Examination Survey (1999-2002). METHODS:Blood DNA methylation was measured in adults aged ≥50 y. The following epigenetic aging biomarkers were included: Horvath1, Horvath2, Hannum, PhenoAge, GrimAge2, Dunedin Pace-of-Aging (DunedinPoAm), and DNA methylation telomere length (DNAmTL). We tested for associations of serum folate, red blood cell folate, vitamin B12, homocysteine (Hcy), and methylmalonic acid (MMA) concentrations with epigenetic age deviation (EAD) among 2346 participants with epigenetic and nutritional status biomarkers using adjusted survey-weighted general linear regression models. RESULTS:A doubling of serum folate concentration was associated with -0.82 y (95% confidence interval: -1.40, -0.23) lower GrimAge2 EAD, -0.13 SDs (-0.22, -0.03) lower DunedinPoAm, and 0.02 kb (0.00, 0.04) greater DNAmTL EAD. Conversely, a doubling in Hcy concentration was associated with 1.05 y (0.06, 2.04) greater PhenoAge EAD, 1.93 y (1.16, 2.71) greater GrimAge2 EAD, and 0.26 SDs (0.10, 0.41) greater DunedinPoAm. Associations of serum folate with EAD were attenuated after adjusting for smoking status, alcohol intake, and estimated glomerular filtration rate. Furthermore, smoking modified the associations of Hcy with GrimAge2 EAD. Chronic kidney disease modified associations of B12 and MMA with Horvath1 and GrimAge2 EAD, respectively. CONCLUSIONS:In a nationally representative sample of United States adults, higher concentration of folate, a carbon donor, was associated with lower EAD, and higher concentration of Hcys, an indicator of OCM deficiencies, was associated with greater EAD; however, some associations were influenced by smoking and renal function. Future research should focus on high-risk populations. Long-term randomized controlled trials are also needed to establish causality and investigate the clinical relevance of changes in EAD.

Long-term exposure to ambient air pollution has been associated with epigenetic age acceleration (EAA) in adults, but its impact on children remains less understood. We analyzed data from 457 children (mean age: 7.9 years) in the Project Viva cohort (2007-2010, eastern Massachusetts, USA). We calculated the following EAAs from leukocytes: Horvath's epigenetic age acceleration (HorvathEAA), intrinsic epigenetic age acceleration (IEAA), and skin and blood epigenetic age acceleration (Skin&BloodEAA). We applied generalized additive models to evaluate associations of prior-365-day average and lifetime average exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3), as well as the distance to major roadways, with EAA. Results indicated that each IQR increase (1.9 μg m-3) in the prior-365-day average of PM2.5 was associated with 0.26 years (95% CI, -0.49 to -0.03) lower HorvathEAA, although it did not survive multiple testing adjustment. Similar patterns but with wider CIs were observed for IEAA (-0.22; 95% CI, -0.44 to 0.01) and Skin&BloodEAA (-0.04; 95% CI, -0.19 to 0.11). No associations were observed of exposure to lifetime average PM2.5, prior-365-day or lifetime average NO2 or O3, or distance to major roadways with EAA. These findings suggest higher prior-365-day average PM2.5 exposure may relate to lower HorvathEAA in children.

BACKGROUND/UNASSIGNED:The ketamine landscape in the USA is rapidly shifting, especially given recent increases in off-label prescribing of ketamine as a psychiatric treatment. Research is needed to determine the extent to which illicit ketamine is available, nonmedically used, and associated with morbidity and mortality in the USA. METHODS/UNASSIGNED:This observational study used eight unique annual repeated cross-sectional datasets to examine illicit ketamine availability (using seizure data as a proxy), use, and consequences of use, including self-reported nonmedical use among noninstitutionalized individuals aged ≥12 years (2006-2014, 2015-2019, and 2021-2023) and among 12th grade students (2000-2023). Further, it assessed reported ketamine-related poisonings (1991-2023) and mortalities (2020-2023), diversion of undispensed pharmaceutical ketamine (2008-2024), drug seizures testing positive for ketamine (2001-2024), and the number and total weight of ketamine seizures from two additional law enforcement agencies (2017-2024 and 2019-2024). Piecewise linear regression models were used to estimate annual trends. FINDINGS/UNASSIGNED:Nonmedical ketamine use among individuals aged ≥12 years increased between 2021 (0.19%) and 2023 (0.34%) (b [slope] = 0.08 [SE = 0.001], p = 0.0072). Regarding reported poisonings, there was initial increase from 1994 to 2000 (from 0.17 to 1.40 per 1,000,000 population; b = 0.20 [SE = 0.02], p < 0.0001), a decrease through 2003 (0.58 per 1,000,000 population; b = -0.34 [SE = 0.08, p = 0.0002) and an increase from 2017 through 2023 (from 0.76 to 1.54 per 1,000,000 population; b = 0.12 [SE = 0.03], p = 0.0002). The number of reported diversions increased from 2008 (n = 23) to 2017 (n = 202) (b = 18.72 [SE = 2.20], p < 0.0001) and again from 2021 (n = 183) to 2024 (n = 286) (b = 39.00 [SE = 12.04], p < 0.0001). Regarding seizures, there was an increase in ketamine reports to one agency from 2015 (n = 1448) through 2024 (n = 4008) (b = 201.41 [SE = 57.83], p = 0.0023). In another source, there was an increase in seizures from 2022 (n = 247) through 2024 (n = 502) (b = 127.50 [SE = 10.40], p = 0.0003). Rates of ketamine-involved deaths did not significantly shift between 2020 and 2023. Nonmedical use declined among 12th grade students, first from 2000 (2.49%) through 2005 (1.61%) (b = -0.19 [SE = 0.06], p = 0.0039] and then again from 2005 through 2023 (0.9%) (b = -0.04 [SE = 0.01], p = 0.0019). INTERPRETATION/UNASSIGNED:Ketamine poisonings, pharmaceutical diversion, and seizures have increased; trends in nonmedical ketamine use vary. Prevention and harm reduction are needed as use and morbidity are expected to continue to increase. FUNDING/UNASSIGNED:National Institute on Drug Abuse at the National Institutes of Health.

OBJECTIVE/UNASSIGNED:To compare the effectiveness of nurse led telephonic palliative care versus specialty outpatient palliative care on quality of life, symptom burden, loneliness, and healthcare use, after attending the emergency department. DESIGN/UNASSIGNED:Pragmatic, randomised clinical trial. SETTING/UNASSIGNED:Emergency Medicine Palliative Care Access (EMPallA) randomised controlled trial enrolling participants from 18 emergency departments in 15 geographically diverse healthcare systems in nine US states, from 1 April 2018 to 30 June 2022. PARTICIPANTS/UNASSIGNED:Of 39 254 eligible patients, 1283 adults who visited the emergency department, were aged ≥50 years, who spoke English or Spanish, and had advanced cancer or end stage organ failure, were randomised to receive nurse led telephonic palliative care (n=639) or specialty outpatient palliative care (n=644). INTERVENTIONS/UNASSIGNED:The nurse led telephonic palliative care arm consisted of weekly or biweekly calls over six months made by registered nurses certified in hospice and palliative care. For the specialty outpatient palliative care arm, patients had one visit each month for six months with a specialty trained hospice and palliative medicine provider. MAIN OUTCOME MEASURES/UNASSIGNED:The primary outcome was change in patient reported quality of life at six months, measured by the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. Secondary outcomes were change in symptom burden and patient reported loneliness after six months, and healthcare use, measured as the number of emergency department revisits, inpatient days, and hospice use, from enrolment to 12 months. RESULTS/UNASSIGNED:639 patients were assigned to nurse telephonic services and 434 (68%) engaged in care until death, or until they required hospice services or graduated from the programme. For specialty outpatient palliative care, 644 patients were assigned and 344 (53%) attended one or more visits, with an average of 2.7 visits. The mean change in FACT-G scores over six months for the nurse telephonic arm (n=418) was 3.7 (95% confidence interval (CI) 2.3 to 5.1) points compared with 3.1 (1.6 to 4.6) for those in the specialty outpatient care arm (n=409). In the model including all patients who survived to six months (n=1090), the estimated difference in average change in quality of life was 0.71 (95% CI -1.19 to 2.61) points higher in the nurse led telephonic palliative care arm. The analysis did not show any clinically meaningful differences in the change in quality of life between the treatment arms. Also, no important differences between groups were found for secondary outcomes or in subgroup analyses. CONCLUSIONS/UNASSIGNED:The results of the study provided no clear evidence that nurse led telephonic palliative care improved quality of life, or any secondary outcomes, relative to specialty outpatient palliative care. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov NCT03325985.

BACKGROUND/UNASSIGNED:Immigrant status and citizenship influence health and well-being, yet their associations with DNA methylation (DNAm)-based biomarkers of aging - key predictors of healthspan and lifespan, also known as epigenetic aging - remain underexplored. METHODS/UNASSIGNED:Using a representative sample of 2,336 United States (U.S.) adults from the 1999-2000 and 2001-2002 cycles of the National Health and Nutrition Examination Survey (NHANES), we analyzed cross-sectional associations of immigrant status and U.S. citizenship with seven epigenetic aging biomarkers: HannumAge, HorvathAge, SkinBloodAge, PhenoAge, GrimAge2, DNAm Telomere Length, and DunedinPoAm. RESULTS/UNASSIGNED: = 0.02) were attenuated after adjusting for other lifestyle/health variables. Immigrant status and citizenship were associated with estimated levels of several GrimAge2 DNAm component proteins, including adrenomedullin and C-reactive protein. CONCLUSION/UNASSIGNED:Our results support the paradigm of the immigrant mortality advantage and highlight the potential value of epigenetic age measures in studying socioeconomic and broader factors influencing citizen and immigrant health.