Pregnancy is linked to faster epigenetic aging in young women.

A central prediction of evolutionary theory is that energy invested into reproduction comes at the expense of somatic maintenance and repair, accelerating biological aging. Supporting this prediction are findings that high fertility among women predicts shorter lifespan and poorer health later in life. However, biological aging is thought to begin before age-related health declines, limiting the applicability of morbidity and mortality for studying the aging process earlier in life. Here, we examine the relationship between reproductive history and biological aging in a sample of young (20 to 22yo) men and women from the Cebu Longitudinal Health and Nutrition Survey, located in the Philippines (n = 1,735). We quantify biological aging using six measures, collectively known as epigenetic clocks, reflecting various facets of cellular aging, health, and mortality risk. In a subset of women, we test whether longitudinal changes in gravidity between young and early-middle adulthood (25 to 31yo) are associated with changes in epigenetic aging during that time. Cross-sectionally, gravidity was associated with all six measures of accelerated epigenetic aging in women (n = 825). Furthermore, longitudinal increases in gravidity were linked to accelerated epigenetic aging in two epigenetic clocks (n = 331). In contrast, the number of pregnancies a man reported fathering was not associated with epigenetic aging among same-aged cohort men (n = 910). These effects were robust to socioecological, environmental, and immunological factors, consistent with the hypothesis that pregnancy accelerates biological aging and that these effects can be detected in young women in a high-fertility context.

Accelerated biological aging six decades after prenatal famine exposure.

To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944 to 1945, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life.

Diet, Pace of Biological Aging, and Risk of Dementia in the Framingham Heart Study.

OBJECTIVE: People who eat healthier diets are less likely to develop dementia, but the biological mechanism of this protection is not well understood. We tested the hypothesis that healthy diet protects against dementia because it slows the pace of biological aging. METHODS: We analyzed Framingham Offspring Cohort data. We included participants ≥60 years-old, free of dementia and having dietary, epigenetic, and follow-up data. We assessed healthy diet as long-term adherence to the Mediterranean-Dash Intervention for Neurodegenerative Delay diet (MIND, over 4 visits spanning 1991-2008). We measured the pace of aging from blood DNA methylation data collected in 2005-2008 using the DunedinPACE epigenetic clock. Incident dementia and mortality were defined using study records compiled from 2005 to 2008 visit through 2018. RESULTS: Of n = 1,644 included participants (mean age 69.6, 54% female), n = 140 developed dementia and n = 471 died over 14 years of follow-up. Greater MIND score was associated with slower DunedinPACE and reduced risks for dementia and mortality. Slower DunedinPACE was associated with reduced risks for dementia and mortality. In mediation analysis, slower DunedinPACE accounted for 27% of the diet-dementia association and 57% of the diet-mortality association. INTERPRETATION: Findings suggest that slower pace of aging mediates part of the relationship of healthy diet with reduced dementia risk. Monitoring pace of aging may inform dementia prevention. However, a large fraction of the diet-dementia association remains unexplained and may reflect direct connections between diet and brain aging that do not overlap other organ systems. Investigation of brain-specific mechanisms in well-designed mediation studies is warranted. ANN NEUROL 2024;95:1069-1079.

Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases.

BACKGROUND: Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type 2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to identify the metabolic changes that are associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and subsequently assess their link to disease. METHODS: NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases. RESULTS: Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2-0.3 SD, p < 3 × 10-3). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type 2 diabetes from the UK Biobank (r = 0.77, p = 3 × 10-27), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1 × 10-18). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 ≤ r ≤ 0.9, p < 3.2 × 10-4). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index. CONCLUSIONS: Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity.

Poverty and birth cohort effects of experiencing the 2007-2009 Great Recession during adolescence on major depressive episodes and mental health treatment of young adults in the United States.

PURPOSE: Household economic adversity during adolescence is hypothesized to be a risk factor for poor mental health later in life. To test this hypothesis, we conducted a quasi-experimental analysis of an economic shock, the Great Recession of 2007-2009. We tested if going through adolescence during the Great Recession was associated with increased risk of major depressive episodes (MDE) and mental health treatment in young adulthood with potential moderation by household poverty to explore differences by economic adversity. METHODS: We analyzed data on young adults age 18-29 years from the 2005-2019 National Survey on Drug Use and Health (N = 145,394). We compared participants who were adolescents during the recession to those followed-up prior to the recession. Regression analysis tested effect modification by household poverty status. RESULTS: Adolescent exposure to the Great Recession was associated with higher likelihood of MDE during young adulthood (aOR = 1.30, 95% CI = 1.23, 1.37); there was no relationship with mental health treatment. Effects on MDE were stronger among those in households with higher incomes compared to those living in poverty. CONCLUSION: Findings support the hypothesis that exposure to the Great Recession during adolescence may have increased risk for MDE, but raise questions about whether the mechanism of this association is economic distress.

Childhood Maltreatment and Biological Aging in Middle Adulthood: The Role of Psychiatric Symptoms.

Background: Childhood maltreatment and psychiatric morbidity have each been associated with accelerated biological aging primarily through cross-sectional studies. Using data from a prospective longitudinal study of individuals with histories of childhood maltreatment and control participants followed into midlife, we tested 2 hypotheses examining whether 1) psychiatric symptoms mediate the relationship between childhood maltreatment and biological aging and 2) psychiatric symptoms of anxiety, depression, or posttraumatic stress disorder (PTSD) act in conjunction with childhood maltreatment to exacerbate the association of child maltreatment to aging. Methods: Children (ages 0-11 years) with documented histories of maltreatment and demographically matched control children were followed into adulthood (N = 607) and interviewed over several waves of the study. Depression, anxiety, and PTSD symptoms were assessed at mean ages of 29 (interview 1) and 40 (interview 2) years. Biological age was measured from blood chemistries collected later (mean age = 41 years) using the Klemera-Doubal method. Hypotheses were tested using linear regressions and path analyses. Results: Adults with documented histories of childhood maltreatment showed more symptoms of depression, PTSD, and anxiety at both interviews and more advanced biological aging, compared with control participants. PTSD symptoms at both interviews and depression and anxiety symptoms only at interview 2 predicted accelerated biological aging. There was no evidence of mediation; however, anxiety and depression moderated the relationship between childhood maltreatment and biological aging. Conclusions: These new findings reveal the shorter- and longer-term longitudinal impact of PTSD on biological aging and the amplifying effect of anxiety and depression on the relationship between child maltreatment and biological aging.

Childhood maltreatment and psychiatric morbidity are associated with biological aging. We used data from a prospective longitudinal study of children with documented histories of maltreatment and demographically matched control participants followed and interviewed in adulthood. Depression, anxiety, and posttraumatic stress disorder (PTSD) were assessed at ages 29 and 40 years, and biological age was measured from blood chemistries collected later. Adults with histories of childhood maltreatment showed more symptoms of depression, PTSD, and anxiety and more advanced biological aging compared with control participants. PTSD symptoms predicted accelerated biological aging longitudinally. Anxiety and depression amplified the relationship between child maltreatment and biological aging.

More than nature and nurture, indirect genetic effects on children's academic achievement are consequences of dynastic social processes.

Families transmit genes and environments across generations. When parents' genetics affect their children's environments, these two modes of inheritance can produce an 'indirect genetic effect'. Such indirect genetic effects may account for up to half of the estimated genetic variance in educational attainment. Here we tested if indirect genetic effects reflect within-nuclear-family transmission ('genetic nurture') or instead a multi-generational process of social stratification ('dynastic effects'). We analysed indirect genetic effects on children's academic achievement in their fifth to ninth years of schooling in N = 37,117 parent-offspring trios in the Norwegian Mother, Father, and Child Cohort Study (MoBa). We used pairs of genetically related families (parents were siblings, children were cousins; N = 10,913) to distinguish within-nuclear-family genetic-nurture effects from dynastic effects shared by cousins in different nuclear families. We found that indirect genetic effects on children's academic achievement cannot be explained by processes that operate exclusively within the nuclear family.

Maternal Adverse Childhood Experiences and Biological Aging During Pregnancy and in Newborns.

Importance: Adverse childhood experiences (ACEs), potentially traumatic experiences occurring before the age of 18 years, are associated with epigenetic aging later in life and may be transmitted across generations. Objective: To test evidence of the transmission of biological embedding of life experience across generations by analyzing maternal ACEs and epigenetic clocks measured in mothers during pregnancy and in their children at birth. Design, Setting, and Participants: For this cross-sectional study, data from the Accessible Resource for Integrated Epigenomic Studies (ARIES) substudy of the Avon Longitudinal Study of Parents and Children (ALSPAC) were analyzed. The ALSPAC study recruited 14 541 women who gave birth in the Avon Health District in the UK between April 1, 1991, and December 31, 1992. The ARIES substudy comprised 1018 mother-offspring dyads based on the availability of DNA samples profiled in 2014. Epigenetic age was estimated using DNA methylation-based epigenetic clocks (including Horvath, Hannum, GrimAge, PhenoAge, and DunedinPACE) in mothers during pregnancy and the Knight and Bohlin cord blood epigenetic clocks in newborns. Analyses were performed between October 1, 2022, and November 30, 2023. Exposures: A composite measure of maternal ACEs was the primary exposure in both maternal and offspring models; as a secondary analysis, individual ACEs were measured separately. The Edinburgh Postnatal Depression Scale (EPDS) was used to investigate depression during pregnancy as an exposure. Main Outcomes and Measures: Changes in epigenetic age acceleration (EAA) were investigated as the primary outcome in maternal models during pregnancy. Changes in epigenetic gestational age acceleration (GAA) were the primary outcome in offspring analyses. Linear regression analyses were used to determine the association between maternal ACEs and both outcomes. Results: This study included 883 mother-child dyads. The mean (SD) maternal age at delivery was 29.8 (4.3) years. Pregnant women with higher ACE scores exhibited higher GrimAge EAA (ß, 0.22 [95% CI, 0.12 to 0.33] years; P < .001). Maternal ACEs were not associated with GAA in newborns using P < .05 as a cutoff to determine statistical significance. Depression was associated with higher GrimAge EAA (ß, 0.06 [95% CI, 0.02 to 0.10] years; P = .01) in mothers during pregnancy, but not in newborns, and did not mediate the association between ACEs and EAA. Conclusions and Relevance: The findings of this study suggest that maternal ACEs may be associated with epigenetic aging later in life, including during pregnancy, supporting a role for maternal ACEs in offspring development and health later in life.

Multi-discrimination exposure and biological aging: Results from the midlife in the United States study.

Discrimination is a social determinant of health and health disparities for which the biological mechanisms remain poorly understood. This study investigated the hypothesis that discrimination contributes to poor health outcomes by accelerating biological processes of aging. We analyzed survey and blood DNA methylation data from the Midlife in the United States (MIDUS) study (N = 1967). We used linear regression analysis to test associations of everyday, major, and workplace discrimination with biological aging measured by the DunedinPACE, PhenoAge, and GrimAge2 epigenetic clocks. MIDUS participants who reported more discrimination tended to exhibit a faster pace of aging and older biological age as compared to peers who reported less discrimination. Effect-sizes for associations tended to be larger for the DunedinPACE pace-of-aging clock (effect-size range r = 0.1-0.2) as compared with the PhenoAge and GrimAge2 biological-age clocks (effect-sizes r < 0.1) and for experiences of everyday and major discrimination as compared with workplace discrimination. Smoking status and body-mass index accounted for roughly half of observed association between discrimination and biological aging. Reports of discrimination were more strongly associated with accelerated biological aging among White as compared with Black participants, although Black participants reported more discrimination overall and tended to exhibit older biological age and faster biological aging. Findings support the hypothesis that experiences of interpersonal discrimination contribute to accelerated biological aging and suggest that structural and individual-level interventions to reduce discrimination and promote adaptive coping have potential to support healthy aging and build health equity.

Familial Loss of a Loved One and Biological Aging: NIMHD Social Epigenomics Program.

Importance: The link between familial loss of a loved one and long-term health decline is complex and not fully understood. Objective: To test associations of losing a parent, sibling, child, or partner or spouse with accelerated biological aging. Design, Setting, and Participants: Data from the National Longitudinal Study of Adolescent to Adult Health, a US population-based longitudinal cohort study, were analyzed. Participants were enrolled from 1994 to 1995 for wave 1, while in grades 7 to 12, and followed up through wave 5 in 2018. The study analyzed participant reports of loss collected at each wave from 1 to 5 over 24 years and used a banked wave 5 blood sample for subsequent DNA methylation testing and epigenetic clock calculation from 2018 to 2024. Data were analyzed from January 2022 to July 2024. Exposure: Loss of biological parents or parental figures, partners or spouses, siblings, or children at waves 1 to 3 or during childhood, adolescence (aged <18 years), or adulthood at wave 4 to wave 5 (aged 18-43 years). Main Outcomes and Measures: Biological aging assessed from blood DNA methylation using the Horvath, PhenoAge, GrimAge, and DunedinPACE epigenetic clocks at wave 5. Results: Data from 3963 participants were analyzed, with a weighted mean (range) age of 38.36 (36.78-39.78) years at wave 5; 2370 (50.3%) were male, 720 (15.97%) were Black, 400 (8.18%) were Hispanic, and 2642 (72.53%) were White. Nearly 40% of participants experienced loss by wave 5 when they were aged 33 to 43 years, and participants who were Black (379 participants [56.67%]), Hispanic (152 participants [41.38%]), and American Indian (18 participants [56.08%]) experienced a greater proportion of losses compared with White participants (884 participants [34.09%]). Those who experienced 2 or more losses tended to have older biological ages for several of the clocks (PhenoAge ß = 0.15; 95% CI, 0.02 to 0.28; GrimAge ß = 0.27; 95% CI, 0.09 to 0.45; DunedinPACE ß = 0.22; 95% CI, 0.10 to 0.34) compared with those with no losses. In contrast, there were no associations with 2 or more losses for the Horvath clock (ß = -0.08; 95% CI, -0.23 to 0.06). Conclusions and Relevance: This study reveals associations between various measures of loss experienced from childhood to adulthood and biological aging in a diverse sample of the US population. These findings underscore the potentially enduring impact of loss on biological aging even before middle age and may contribute to understanding racial and ethnic disparities in health and mortality.

Educational Mobility, Pace of Aging, and Lifespan Among Participants in the Framingham Heart Study.

Importance: People who complete more education live longer lives with better health. New evidence suggests that these benefits operate through a slowed pace of biological aging. If so, measurements of the pace of biological aging could offer intermediate end points for studies of how interventions to promote education will affect healthy longevity. Objective: To test the hypothesis that upward educational mobility is associated with a slower pace of biological aging and increased longevity. Design, Setting, and Participants: This prospective cohort study analyzed data from 3 generations of participants in the Framingham Heart Study: (1) the original cohort, enrolled beginning in 1948; (2) the Offspring cohort, enrolled beginning in 1971; and (3) the Gen3 cohort, enrolled beginning in 2002. A 3-generation database was constructed to quantify intergenerational educational mobility. Mobility data were linked with blood DNA-methylation data collected from the Offspring cohort in 2005 to 2008 (n = 1652) and the Gen3 cohort in 2009 to 2011 (n = 1449). Follow-up is ongoing. Data analysis was conducted from June 2022 to November 2023 using data obtained from the National Institutes of Health database of Genotypes and Phenotypes (dbGaP). Exposure: Educational mobility was measured by comparing participants' educational outcomes with those of their parents. Main Outcomes and Measures: The pace of biological aging was measured from whole-blood DNA-methylation data using the DunedinPACE epigenetic clock. For comparison purposes, the analysis was repeated using 4 other epigenetic clocks. Survival follow-up was conducted through 2019. Results: This study analyzed data from 3101 participants from the Framingham Heart Study; 1652 were in the Offspring cohort (mean [SD] age, 65.57 [9.22] years; 764 [46.2%] male) and 1449 were in the Gen3 cohort (mean [SD] age, 45.38 [7.83] years; 691 [47.7%] male). Participants who were upwardly mobile in educational terms tended to have slower pace of aging in later life (r = -0.18 [95% CI, -0.23 to -0.13]; P < .001). This pattern of association was similar across generations and held in within-family sibling comparisons. There were 402 Offspring cohort participants who died over the follow-up period. Upward educational mobility was associated with lower mortality risk (hazard ratio, 0.89 [95% CI, 0.81 to 0.98]; P = .01). Slower pace of aging accounted for approximately half of this association. Conclusions and Relevance: This cohort study's findings support the hypothesis that interventions to promote educational attainment may slow the pace of biological aging and promote longevity. Epigenetic clocks have potential as near-term outcome measures of intervention effects on healthy aging. Experimental evidence is needed to confirm findings.

Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort.

Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6-6.44 years biologically older compared to controls and 5-16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging.

Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases.

Background: Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type-2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to provide a deeper insight into the metabolic changes associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and explore their link to disease. Methods: NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases. Results: Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2-0.3 SD, p < 3x10-3). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type-2 diabetes (r = 0.77, p = 3x10-27), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1x10-18). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 ≤ r ≤ 0.9, p < 3.2x10-4). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index. Conclusions: Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity.

A blood biomarker of the pace of aging is associated with brain structure: replication across three cohorts.

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3380; total N individuals=2322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, greater burden of white matter microlesions, and thinner cortex. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.

Stressful life events, social support, and epigenetic aging in the Women's Health Initiative.

BACKGROUND: Elevated psychosocial stress has been linked with accelerated biological aging, including composite DNA methylation (DNAm) markers that predict aging-related outcomes ("epigenetic age"). However, no study has examined whether stressful life events (SLEs) are associated with epigenetic age acceleration in postmenopausal women, an aging population characterized by increased stress burden and disease risk. METHODS: We leveraged the Women's Health Initiative, a large muti-ancestry cohort of postmenopausal women with available psychosocial stress measures over the past year and epigenomic data. SLEs and social support were ascertained via self-report questionnaires. Whole blood DNAm array (450 K) data were used to calculate five DNAm-based predictors of chronological age, health span and life span, and telomere length (HorvathAge, HannumAge, PhenoAge, GrimAge, DNAmTL). RESULTS: After controlling for potential confounders, higher SLE burden was significantly associated with accelerated epigenetic aging, as measured by GrimAge (ß: 0.34, 95% CI: 0.08, 0.59) and DNAmTL (ß: -0.016, 95% CI: -0.028, -0.004). Exploratory analyses showed that SLEs-GrimAge associations were stronger in Black women as compared to other races/ethnicities and in those with lower social support levels. In women with lower social support, SLEs-DNAmTL associations showed opposite association in Hispanic women as compared to other race/ethnicity groups. CONCLUSIONS: Our findings suggest that elevated stress burden is associated with accelerated epigenetic aging in postmenopausal women. Lower social support and/or self-reported race/ethnicity may modify the association of stress with epigenetic age acceleration. These findings advance understanding of how stress may contribute to aging-related outcomes and have important implications for disease prevention and treatment in aging women.

Comparison of Infinium MethylationEPIC v2.0 to v1.0 for human population epigenetics: considerations for addressing EPIC version differences in DNA methylation-based tools.

Background: The recently launched DNA methylation profiling platform, Illumina MethylationEPIC BeadChip Infinium microarray v2.0 (EPICv2), is highly correlated with measurements obtained from its predecessor MethylationEPIC BeadChip Infinium microarray v1.0 (EPICv1). However, the concordance between the two versions in the context of DNA methylation-based tools, including cell type deconvolution algorithms, epigenetic clocks, and inflammation and lifestyle biomarkers has not yet been investigated. Findings: We profiled DNA methylation on both EPIC versions using matched venous blood samples from individuals spanning early to late adulthood across three cohorts. On combining the DNA methylomes of the cohorts, we observed that samples primarily clustered by the EPIC version they were measured on. Within each cohort, when we calculated cell type proportions, epigenetic age acceleration (EAA), rate of aging estimates, and biomarker scores for the matched samples on each version, we noted significant differences between EPICv1 and EPICv2 in the majority of these estimates. These differences were not significant, however, when estimates were adjusted for EPIC version or when EAAs were calculated separately for each EPIC version. Conclusions: Our findings indicate that EPIC version differences predominantly explain DNA methylation variation and influence estimates of DNA methylation-based tools, and therefore we recommend caution when combining cohorts run on different versions. We demonstrate the importance of calculating DNA methylation-based estimates separately for each EPIC version or accounting for EPIC version either as a covariate in statistical models or by using version correction algorithms.

Effect of long-term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis.

Caloric restriction (CR) modifies lifespan and aging biology in animal models. The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) 2 trial tested translation of these findings to humans. CALERIE™ randomized healthy, nonobese men and premenopausal women (age 21-50y; BMI 22.0-27.9 kg/m2), to 25% CR or ad-libitum (AL) control (2:1) for 2 years. Prior analyses of CALERIE™ participants' blood chemistries, immunology, and epigenetic data suggest the 2-year CR intervention slowed biological aging. Here, we extend these analyses to test effects of CR on telomere length (TL) attrition. TL was quantified in blood samples collected at baseline, 12-, and 24-months by quantitative PCR (absolute TL; aTL) and a published DNA-methylation algorithm (DNAmTL). Intent-to-treat analysis found no significant differences in TL attrition across the first year, although there were trends toward increased attrition in the CR group for both aTL and DNAmTL measurements. When accounting for adherence heterogeneity with an Effect-of-Treatment-on-the-Treated analysis, greater CR dose was associated with increased DNAmTL attrition during the baseline to 12-month weight-loss period. By contrast, both CR group status and increased CR were associated with reduced aTL attrition over the month 12 to month 24 weight maintenance period. No differences were observed when considering TL change across the study duration from baseline to 24-months, leaving it unclear whether CR-related effects reflect long-term detriments to telomere fidelity, a hormesis-like adaptation to decreased energy availability, or measurement error and insufficient statistical power. Unraveling these trends will be a focus of future CALERIE™ analyses and trials.

Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT.

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR.

"Hang Ups, Let Downs, Bad Breaks, Setbacks": Impact of Structural Socioeconomic Racism and Resilience on Cognitive Change Over Time for Persons Racialized as Black.

Introduction: Older adults racialized as Black experience higher rates of dementia than those racialized as White. Structural racism produces socioeconomic challenges, described by artist Marvin Gaye as "hang ups, let downs, bad breaks, setbacks" that likely contribute to dementia disparities. Robust dementia literature suggests socioeconomic factors may also be key resiliencies. Methods: We linked state-level data reflecting the racialized landscape of economic opportunity across the 20th Century from the U.S. Census (1930-2010) with individual-level data on cognitive outcomes from the U.S. Health and Retirement Study participants racialized as Black. A purposive sample of participants born after the Brown v. Board ruling (born 1954-59) were selected who completed the modified Telephone Interview for Cognitive Status between 2010 and 2020 (N=1381). We tested associations of exposure to structural racism and resilience before birth, and during childhood, young-adulthood, and midlife with cognitive trajectories in mid-late life using mixed-effects regression models. Results: Older adults born in places with higher state-level structural socioeconomic racism experienced a more rapid cognitive decline in later life compared to those with lower levels of exposure. In addition, participants born in places with higher levels of state-level structural socioeconomic resilience experienced slower cognitive change over time than their counterparts. Discussion: These findings reveal the impact of racist U.S. policies enacted in the past that influence cognitive health over time and dementia risk later in life.

Validation of biomarkers of aging.

The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.