Search

To define metrics of phenotypic aging, it is essential to identify biological and environmental factors that influence the pace of aging. Previous attempts to develop aging metrics were hampered by cross-sectional designs and/or focused on younger populations. In the Baltimore Longitudinal Study of Aging (BLSA), we collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration/neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging and demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity and shorter survival. These associations are more robust compared with the use of phenotypic and epigenetic measurements at a single time point. Estimation of these metrics required repeated measures of multiple phenotypes over time but may uniquely facilitate the identification of mechanisms driving phenotypic aging and subsequent age-related functional decline., Competing Interests: Competing interests M.E.L. holds licenses for epigenetic clocks that she has developed. All other authors declare no conflict of interest.

Stress, social isolation, and changes in health behaviors during the COVID-19 pandemic period may have a lasting influence on health. Here, the correlation between current or prior demographic, social and health related characteristics, including psychosocial factors with perceived impact of the COVID-19 pandemic assessed by questionnaire during the early pandemic period is evaluated among 770 participants of the Baltimore Longitudinal Study of Aging. In multinomial logistic regression models participants with higher pre-pandemic personal mastery, a construct related to self-efficacy, were more likely to report "both positive and negative" impact of the pandemic than a solely "negative" impact (OR: 2.17, 95% CI: 1.29-3.65). Higher perceived stress and frequent contact with family prior to the pandemic were also associated with pandemic impact. These observations highlight the relevance of psychosocial factors in the COVID-19 pandemic experience and identify characteristics that may inform interventions in future public health crises., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

The g-ratio, defined as the inner-to-outer diameter of a myelinated axon, is associated with the speed of nerve impulse conduction, and represents an index of axonal myelination and integrity. It has been shown to be a sensitive and specific biomarker of neurodevelopment and neurodegeneration. However, there have been very few magnetic resonance imaging studies of the g-ratio in the context of normative aging; characterizing regional and time-dependent cerebral changes in g-ratio in cognitively normal subjects will be a crucial step in differentiating normal from abnormal microstructural alterations. In the current study, we investigated age-related differences in aggregate g-ratio, that is, g-ratio averaged over all fibers within regions of interest, in several white matter regions in a cohort of 52 cognitively unimpaired participants ranging in age from 21 to 84 years. We found a quadratic, U-shaped, relationship between aggregate g-ratio and age in most cerebral regions investigated, suggesting myelin maturation until middle age followed by a decrease at older ages. As expected, we observed that these age-related differences vary across different brain regions, with the frontal lobes and parietal lobes exhibiting slightly earlier ages of minimum aggregate g-ratio as compared to more posterior structures such as the occipital lobes and temporal lobes; this agrees with the retrogenesis paradigm. Our results provide evidence for a nonlinear association between age and aggregate g-ratio in a sample of adults from a highly controlled population. Finally, sex differences in aggregate g-ratio were observed in several cerebral regions, with women exhibiting overall lower values as compared to men; this likely reflects the greater myelin content in women's brain, in agreement with recent investigations., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

In mice, cellular senescence and senescence-associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof-of-concept study, we investigated the expressions of p16, p21, and other senescence-associated biomarkers during human wound healing in 24 healthy subjects using a double-biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex-matched younger (30.2 ± 1.3 years) and 12 sex-matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase-4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence-associated β-galactosidase (SA-β-gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects., (© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Age-associated changes in gene expression in skeletal muscle of healthy individuals reflect accumulation of damage and compensatory adaptations to preserve tissue integrity. To characterize these changes, RNA was extracted and sequenced from muscle biopsies collected from 53 healthy individuals (22-83 years old) of the GESTALT study of the National Institute on Aging-NIH. Expression levels of 57,205 protein-coding and non-coding RNAs were studied as a function of aging by linear and negative binomial regression models. From both models, 1134 RNAs changed significantly with age. The most differentially abundant mRNAs encoded proteins implicated in several age-related processes, including cellular senescence, insulin signaling, and myogenesis. Specific mRNA isoforms that changed significantly with age in skeletal muscle were enriched for proteins involved in oxidative phosphorylation and adipogenesis. Our study establishes a detailed framework of the global transcriptome and mRNA isoforms that govern muscle damage and homeostasis with age.

We describe a data repository on heritable disorders of connective tissue (HDCT) assembled by the National Institutes of Health's National Institute on Aging (NIA) Intramural Research Program between 2001 and 2013. Participants included affected persons with a wide range of heritable connective tissue phenotypes, and unaffected family members. Elements include comprehensive history and physical examination, standardized laboratory data, physiologic measures and imaging, standardized patient-reported outcome measures, and an extensive linked biorepository. The NIA made a commitment to make the repository available to extramural investigators and deposited samples at Coriell Tissue Repository (N = 126) and GenTAC registry (N = 132). The clinical dataset was transferred to Penn State University College of Medicine Clinical and Translational Science Institute in 2016, and data elements inventoried. The consented cohort of 1,009 participants averaged 39 ± 18 years (mean ± SD, range 2-95) at consent; gender distribution is 71% F and 83% self-report Caucasian ethnicity. Diagnostic categories include Ehlers-Danlos syndrome (classical N = 50, hypermobile N = 99, vascular N = 101, rare types and unclassified N = 178), Marfan syndrome (N = 33), Stickler syndrome (N = 60), fibromuscular dysplasia (N = 135), Other HDCT (N = 72). Unaffected family members (N = 218) contributed DNA for the molecular archive only. We aim to develop further discrete data from unstructured elements, analyze multisymptom HDCT manifestations, encourage data use by other researchers and thereby better understand the complexity of these high-morbidity conditions and their multifaceted effects on affected persons., (© 2019 Wiley Periodicals, Inc.)

Introduction: We investigated brain demyelination in aging, mild cognitive impairment (MCI), and dementia using a direct magnetic resonance imaging marker of myelin., Methods: Brains of young and old controls, and old subjects with MCI, Alzheimer's disease, or vascular dementia were scanned using our recently developed myelin water fraction (MWF) mapping technique, which provides greatly improved accuracy over previous comparable methods. Maps of MWF, a direct and specific myelin measure, and relaxation times and magnetization transfer ratio, indirect and nonspecific measures, were constructed., Results: MCI subjects showed decreased MWF compared with old controls. Demyelination was greater in Alzheimer's disease or vascular dementia. As expected, decreased MWF was accompanied by decreased magnetization transfer ratio and increased relaxation times. The young subjects showed greater myelin content than the old subjects., Discussion: We believe this to be the first demonstration of myelin loss in MCI, Alzheimer's disease, and vascular dementia using a method that provides a quantitative magnetic resonance imaging-based measure of myelin. Our findings add to the emerging evidence that myelination may represent an important biomarker for the pathology of MCI and dementia. This study supports the investigation of the role of myelination in MCI and dementia through use of this quantitative magnetic resonance imaging approach in clinical studies of disease progression, and relationship of functional status to myelination status. Furthermore, mapping MWF may permit myelin to serve as a therapeutic target in clinical trials., (Published by Elsevier Inc.)

Purpose: We applied our recently introduced Bayesian analytic method to achieve clinically-feasible in-vivo mapping of the proteoglycan water fraction (PgWF) of human knee cartilage with improved spatial resolution and stability as compared to existing methods., Materials and Methods: Multicomponent driven equilibrium single-pulse observation of T 1 and T 2 (mcDESPOT) datasets were acquired from the knees of two healthy young subjects and one older subject with previous knee injury. Each dataset was processed using Bayesian Monte Carlo (BMC) analysis incorporating a two-component tissue model. We assessed the performance and reproducibility of BMC and of the conventional analysis of stochastic region contraction (SRC) in the estimation of PgWF. Stability of the BMC analysis of PgWF was tested by comparing independent high-resolution (HR) datasets from each of the two young subjects., Results: Unlike SRC, the BMC-derived maps from the two HR datasets were essentially identical. Furthermore, SRC maps showed substantial random variation in estimated PgWF, and mean values that differed from those obtained using BMC. In addition, PgWF maps derived from conventional low-resolution (LR) datasets exhibited partial volume and magnetic susceptibility effects. These artifacts were absent in HR PgWF images. Finally, our analysis showed regional variation in PgWF estimates, and substantially higher values in the younger subjects as compared to the older subject., Conclusions: BMC-mcDESPOT permits HR in-vivo mapping of PgWF in human knee cartilage in a clinically-feasible acquisition time. HR mapping reduces the impact of partial volume and magnetic susceptibility artifacts compared to LR mapping. Finally, BMC-mcDESPOT demonstrated excellent reproducibility in the determination of PgWF., (Published by Elsevier Inc.)