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INTRODUCTION: The geroscience hypothesis proposes systemic biological aging is a root cause of cognitive decline. METHODS: We analyzed Framingham Heart Study Offspring Cohort data (n = 2296; 46% male; baseline age M = 62, SD = 9, range = 25–101 y). We measured cognitive decline across two decades of neuropsychological‐testing follow‐up. We measured pace of aging using the DunedinPACE epigenetic clock. Analysis tested if participants with faster DunedinPACE values experienced more rapid cognitive decline compared with those with slower DunedinPACE values. RESULTS: Participants with faster DunedinPACE had poorer cognitive functioning at baseline and experienced more rapid cognitive decline over follow‐up. Results were robust to confounders and consistent across population strata. Findings were similar for the PhenoAge and GrimAge epigenetic clocks. DISCUSSION: Faster pace of aging is a risk factor for preclinical cognitive decline. Metrics of biological aging may inform risk stratification in clinical trials and prognosis in patient care. Highlights: Faster DunedinPACE is associated with preclinical cognitive aging. Higher baseline cognition was protective of DunedinPACE‐associated cognitive decline. The DunedinPACE association with cognitive decline explained a fourth of dementia risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: The drivers of human life expectancy gains over the past 200 years are not well‐established, with a potential role for historical reductions in infectious disease. We investigate whether infectious exposures in infancy predict biological aging using DNA methylation‐based markers that forecast patterns of morbidity and mortality later in life. Methods: N = 1450 participants from the Cebu Longitudinal Health and Nutrition Survey—a prospective birth cohort initiated in 1983—provided complete data for the analyses. Mean chronological age was 20.9 years when venous whole blood samples were drawn for DNA extraction and methylation analysis, with subsequent calculation of three epigenetic age markers: Horvath, GrimAge, and DunedinPACE. Unadjusted and adjusted least squares regression models were evaluated to test the hypothesis that infectious exposures in infancy are associated with epigenetic age. Results: Birth in the dry season, a proxy measure for increased infectious exposure in the first year of life, as well as the number of symptomatic infections in the first year of infancy, predicted lower epigenetic age. Infectious exposures were associated with the distribution of white blood cells in adulthood, which were also associated with measures of epigenetic age. Conclusions: We document negative associations between measures of infectious exposure in infancy and DNA methylation‐based measures of aging. Additional research, across a wider range of epidemiological settings, is needed to clarify the role of infectious disease in shaping immunophenotypes and trajectories of biological aging and human life expectancy. [ABSTRACT FROM AUTHOR]

All humans age, but how we age—and how fast—differs considerably from person to person. This deviation between apparent age and chronological age is often referred to as "biological age" (BA) and until recently robust tools for studying BA have been scarce. "Epigenetic clocks" are starting to change this. Epigenetic clocks use predictable changes in the epigenome, usually DNA methylation, to estimate chronological age with unprecedented accuracy. More importantly, deviations between epigenetic age and chronological age predict a broad range of health outcomes and mortality risks better than chronological age alone. Thus, epigenetic clocks appear to capture fundamental molecular processes tied to BA and can serve as powerful tools for studying health, development, and aging across the lifespan. In this article, I review epigenetic clocks, especially as they relate to key theoretical and applied issues in human biology. I first provide an overview of how epigenetic clocks are constructed and what we know about them. I then discuss emerging applications of particular relevance to human biologists—those related to reproduction, life‐history, stress, and the environment. I conclude with an overview of the methods necessary for implementing epigenetic clocks, including considerations of study design, sample collection, and technical considerations for processing and interpreting epigenetic clocks. The goal of this review is to highlight some of the ways that epigenetic clocks can inform questions in human biology, and vice versa, and to provide human biologists with the foundational knowledge necessary to successfully incorporate epigenetic clocks into their research. [ABSTRACT FROM AUTHOR]

Objectives: Socioeconomic status (SES) is a powerful determinant of health, but the underlying biological mechanisms are poorly understood. This study investigates whether levels of DNA methylation at CpG sites across the genome are associated with SES in a cohort of young adults in the Philippines. Methods: DNA methylation was assayed with the Illumina HumanMethylation450 Bead Chip, in leukocytes from 489 participants in the Cebu Longitudinal Health and Nutrition Survey (mean age = 20.9 years). SES was measured in infancy/childhood and adulthood, and was based on composite measures of income, assets, and education. Genome‐wide analysis of variable probes identified CpG sites significantly associated with SES after adjustment for multiple comparisons. Functional enrichment analysis was used to identify biological pathways associated with these sites. Results: A total of 2,546 CpG sites, across 1,537 annotated genes, were differentially methylated in association with SES. In comparison with high SES, low SES was associated with increased methylation at 1,777 sites, and decreased methylation at 769 sites. Functional enrichment analysis identified over‐representation of biological pathways related to immune function, skeletal development, and development of the nervous system. Conclusions: Socioeconomic status predicts DNA methylation at a large number of CpG sites across the genome. The scope of these associations is commensurate with the wide range of biological systems and health outcomes that are shaped by SES, and these findings suggest that DNA methylation may play an important role. [ABSTRACT FROM AUTHOR]