No abstract

Intervention studies in animals suggest molecular changes underlying age-related disease and disability can be slowed or reversed. To speed translation of these so-called “geroprotective” therapies to prevent age-related disease and disability in humans, biomarkers are needed that can track changes in the rate of human aging over the course of intervention trials. Algorithm methods that measure biological processes of aging from combinations of DNA methylation marks or clinical biomarkers show promise. To identify next steps for establishing utility of these algorithm-based measures of biological aging for geroprotector trials, we considered the history a candidate biomarker of aging that has received substantial research attention, telomere length. Although telomere length possesses compelling biology to recommend it as a biomarker of aging, mixed research findings have impeded clinical and epidemiologic translation. Strengths of telomeres that should be established for algorithm biomarkers of aging are correlation with chronological age across the lifespan, prediction of disease, disability, and early death, and responsiveness to risk and protective exposures. Key challenges in telomere research that algorithm biomarkers of aging must address are measurement precision and reliability, establishing links between longitudinal rates of change across repeated measurements and aging outcomes, and clarity over whether the biomarker is a causal mechanism of aging. These strengths and challenges suggest a research agenda to advance translation of algorithm-based aging biomarkers: establish validity in young-adult and midlife individuals; test responsiveness to exposures that shorten or extend healthy lifespan; and conduct repeated-measures longitudinal studies to test differential rates of change.

Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter case, most work has relied on retrospective measures of early life stressors. The Dutch research (n ϭ 193) presented herein tested 3 hypotheses prospectively regarding effects of sensitive-insensitive parenting during the first 2.5 years on telomere length at age 6, when first measured, and change over the following 4 years. It was predicted that (1) less sensitive parenting would predict shorter telomeres and greater erosion and that such effects would be most pronounced in children (2) exposed to prenatal stress and/or (3) who were highly negatively emotional as infants. Results revealed, only, that prenatal stress amplified parenting effects on telomere change-in a differentialsusceptibility-related manner: Prenatally stressed children displayed more erosion when they experienced insensitive parenting and less erosion when they experienced sensitive parenting. Mechanisms that might initiate greater postnatal plasticity as a result of prenatal stress are highlighted and future work outlined.

Objective Exposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present pilot study outlines a novel experimental design to test how young adults' exposure to ELA influences neuroendocrine and inflammatory responses to acute stress. Materials and methods Participants were 12 males (mean age = 21.25), half of whom endorsed at least three significant adverse events up to age 18 years ('ELA group'), and half who confirmed zero ('controls'). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a nostress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of the glucocorticoid receptor (NR3C1), and plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) over a 4-hour window post-test. Results In this pilot study, the ELA group evinced higher cortisol response and blunted NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups.

New insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N = 273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models. Higher age-and sex- adjusted z-scored BMI was significantly correlated with household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r = 0.31, P < .0001), PhenoAge (r = 0.24, P < .0001), and DunedinPoAm (r = 0.38, P < .0001). In fully adjusted models, GrimAge (β = 0.07; P = .0009) and DunedinPoAm (β = 0.0017; P < .0001) remained significantly associated with higher age- and sex-adjusted z-scored BMI. Maltreatment-status was not associated with accelerated epigenetic aging. In a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk.

Biological processes of aging are thought to be modifiable causes of many chronic diseases. Measures of biological aging could provide sensitive endpoints for studies of risk factors hypothesized to shorten healthy lifespan and/or interventions that extend it. However, uncertainty remains about how to measure biological aging and if proposed measures assess the same thing. We tested four proposed measures of biological aging with available data from NHANES 1999-2002: Klemera-Doubal method (KDM) Biological Age, homeostatic dysregulation, Levine Method (LM) Biological Age, and leukocyte telomere length. All measures of biological aging were correlated with chronological age. KDM Biological Age, homeostatic dysregulation, and LM Biological Age were all significantly associated with each other, but were each not associated with telomere length. NHANES participants with older biological ages performed worse on tests of physical, cognitive, perceptual, and subjective functions known to decline with advancing chronological age and thought to mediate age-related disability. Further, NHANES participants with higher levels of exposure to life-course risk factors were measured as having older biological ages. In both sets of analyses, effect-sizes tended to be larger for KDM Biological Age, homeostatic dysregulation, and LM Biological Age as compared to telomere length. Composite measures combining cellular- and patient-level information tended to have the largest effect-sizes. The cellular-level aging biomarker telomere length may measure different aspects of the aging process relative to the patient-level physiological measures. Studies aiming to test if risk factors accelerate aging or if interventions may slow aging should not treat proposed measures of biological aging as interchangeable.

No abstract

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