To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and ...women, 22–93 years old, who were disease‐ and treatment‐free and had no physical and cognitive impairment. Using a p ≤ 3.83 × 10−5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 ± 0.001, p = 7.49 × 10−56). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort.
Epigenetic reprogramming underlies specification of immune cell lineages, but patterns that uniquely define immune cell types and the mechanisms by which they are established remain unclear. Here, we ...identified lineage-specific DNA methylation signatures of six immune cell types from human peripheral blood and determined their relationship to other epigenetic and transcriptomic patterns. Sites of lineage-specific hypomethylation were associated with distinct combinations of transcription factors in each cell type. By contrast, sites of lineage-specific hypermethylation were restricted mostly to adaptive immune cells. PU.1 binding sites were associated with lineage-specific hypo- and hypermethylation in different cell types, suggesting that it regulates DNA methylation in a context-dependent manner. These observations indicate that innate and adaptive immune lineages are specified by distinct epigenetic mechanisms via combinatorial and context-dependent use of key transcription factors. The cell-specific epigenomics and transcriptional patterns identified serve as a foundation for future studies on immune dysregulation in diseases and aging.
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•Identifies differential DNA methylation signatures of six human immune cell types•Combinations of transcription factor motifs associate with lineage-specific methylation•EBF1 binding coincides with DNA hypomethylated sites in human B cells•Adaptive and innate immune cells show distinct methylation and gene expression patterns
Epigenetic patterns that define immune cell lineages remain unclear. Roy et al. define DNA methylation signatures of six human immune cell types. Sites of cell-specific differential methylation are related to transcription factors, other epigenetic modifications, and gene expression. Their study reveals differences in the relationship of DNA methylation to tissue-selective gene expression in adaptive compared with innate immune cell types.
The association between blood‐based estimates of mitochondrial DNA parameters, mitochondrial DNA copy number (mtDNA‐CN) and heteroplasmy load, with skeletal muscle bioenergetic capacity was evaluated ...in 230 participants of the Baltimore Longitudinal Study of Aging (mean age:74.7 years, 53% women). Participants in the study sample had concurrent data on muscle oxidative capacity (τPCr) assessed by 31P magnetic resonance spectroscopy, and mitochondrial DNA parameters estimated from whole‐genome sequencing data. In multivariable linear regression models, adjusted for age, sex, extent of phosphocreatine (PCr) depletion, autosomal sequencing coverage, white blood cell total, and differential count, as well as platelet count, mtDNA‐CN and heteroplasmy load were not significantly associated with τPCr (both p > 0.05). However, in models evaluating whether the association between mtDNA‐CN and τPCr varied by heteroplasmy load, there was a significant interaction between mtDNA‐CN and heteroplasmy load (p = 0.037). In stratified analysis, higher mtDNA‐CN was significantly associated with lower τPCr among participants with high heteroplasmy load (n = 84, β (SE) = −0.236 (0.115), p‐value = 0.044), but not in those with low heteroplasmy load (n = 146, β (SE) = 0.046 (0.119), p‐value = 0.702). Taken together, mtDNA‐CN and heteroplasmy load provide information on muscle bioenergetics. Thus, mitochondrial DNA parameters may be considered proxy measures of mitochondrial function that can be used in large epidemiological studies, especially when comparing subgroups.
Mitochondrial DNA copy number and heteroplasmy load provide complementary information on mitochondrial oxidative capacity measured in skeletal muscle. The relationship between mitochondrial DNA copy number and muscle bioenergetics is different according to levels of heteroplasmy load. Assessing mitochondrial DNA copy number and heteroplasmy load may provide cost‐effective and accessible insight into muscle mitochondrial function in large epidemiological studies.
Age-related hearing loss (ARHL) is highly prevalent among older adults, but the potential mechanisms and predictive markers for ARHL are lacking. Epigenetic age acceleration has been shown to be ...predictive of many age-associated diseases and mortality. However, the association between epigenetic age acceleration and hearing remains unknown. Our study aims to investigate the relationship between epigenetic age acceleration and audiometric hearing in the Baltimore Longitudinal Study of Aging (BLSA).
Participants with both DNA methylation and audiometric hearing measurements were included. The main independent variables are epigenetic age acceleration measures, including intrinsic epigenetic age acceleration-"IEAA," Hannum age acceleration-"AgeAccelerationResidualHannum," PhenoAge acceleration-"AgeAccelPheno," GrimAge acceleration-"AgeAccelGrim," and methylation-based pace of aging estimation-"DunedinPoAm." The main dependent variable is speech-frequency pure tone average. Linear regression was used to assess the association between epigenetic age acceleration and hearing.
Among the 236 participants (52.5% female), after adjusting for age, sex, race, time difference between measurements, cardiovascular factors, and smoking history, the effect sizes were 0.11 995% CI: (-0.00, 0.23),
= 0.054 for Hannum's clock, 0.08 95% CI: (-0.03, 0.19),
= 0.143 for Horvath's clock, 0.10 95% CI: (-0.01, 0.21),
= 0.089 for PhenoAge, 0.20 95% CI: (0.06, 0.33),
= 0.004 for GrimAge, and 0.21 95% CI: (0.09, 0.33),
= 0.001 for DunedinPoAm.
The present study suggests that some epigenetic age acceleration measurements are associated with hearing. Future research is needed to study the potential subclinical cardiovascular causes of hearing and to investigate the longitudinal relationship between DNA methylation and hearing.
The study of age‐related biomarkers from different biofluids and tissues within the same individual might provide a more comprehensive understanding of age‐related changes within and between ...compartments as these changes are likely highly interconnected. Understanding age‐related differences by compartments may shed light on the mechanism of their reciprocal interactions, which may contribute to the phenotypic manifestations of aging. To study such possible interactions, we carried out a targeted metabolomic analysis of plasma, skeletal muscle, and urine collected from healthy participants, age 22–92 years, and identified 92, 34, and 35 age‐associated metabolites, respectively. The metabolic pathways that were identified across compartments included inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function.
A targeted metabolomic analysis of plasma, skeletal muscle, and urine from healthy participants was carried out to compare and contrast metabolite changes with aging across and within compartments. The metabolic pathways that were identified included inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function.
Epigenetic marks such as DNA methylation have generated great interest in the study of human disease. However, studies of DNA methylation have not established population-epigenetics principles to ...guide design, efficient statistics, or interpretation. Here, we show that the clustering of correlated DNA methylation at CpGs was similar to that of linkage-disequilibrium (LD) correlation in genetic SNP variation but for much shorter distances. Some clustering of methylated CpGs appeared to be genetically driven. Further, a set of correlated methylated CpGs related to a single SNP-based LD block was not always physically contiguous—segments of uncorrelated methylation as long as 300 kb could be interspersed in the cluster. Thus, we denoted these sets of correlated CpGs as GeMes, defined as potentially noncontiguous methylation clusters under the control of one or more methylation quantitative trait loci. This type of correlated methylation structure has implications for both biological functions of DNA methylation and for the design, analysis, and interpretation of epigenome-wide association studies.
There is evidence that the association of protein intake and frailty may depend on the source of dietary protein. The mechanism underlying this association is not clear. In this study, we explore ...circulating metabolites as mediators of the relationship between dietary protein and of frailty in participants of the Baltimore Longitudinal Study of Aging (BLSA). Cross-sectional analyses in 735 BLSA participants of associations between plant and animal protein intake and frailty. Usual protein intake from plant and animal sources were estimated with a Food Frequency Questionnaire (FFQ) and frailty was assessed with a 44-item Frailty Index (FI). Compared with the lowest quartile, higher quartiles of plant, but not animal, protein were associated with lower FI. Twenty-five plasma metabolites were associated with plant protein intake; of these, fifteen, including phosphatidylcholines, cholesterol esters, sphingomyelins, and indole metabolites, mediated the association between plant protein intake and FI. The protective association between plant protein consumption and FI is mediated by lower abundance of lipid metabolites and higher abundance of tryptophan-related metabolites.
Human aging is associated with a decline of physical and cognitive function and high susceptibility to chronic diseases, which is influenced by genetics, epigenetics, environmental, and ...socio-economic status. In order to identify the factors that modulate the aging process, established measures of aging mechanisms are required, that are both robust and feasible in humans. It is also necessary to connect these measures to the phenotypes of aging and their functional consequences. In this review, we focus on how this has been addressed from an epidemiologic perspective using proteomics. The key aspects of epidemiological models of aging can be incorporated into proteomics and other omics which can provide critical detailed information on the molecular and biological processes that change with age, thus unveiling underlying mechanisms that drive multiple chronic conditions and frailty, and ideally facilitating the identification of new effective approaches for prevention and treatment.
Mitochondrial DNA copy number (mtDNAcn) in tissues and blood can be altered in conditions like diabetes and major depression and may play a role in aging and longevity. However, little is known about ...the association between mtDNAcn and personality traits linked to emotional states, metabolic health, and longevity. This study tests the hypothesis that blood mtDNAcn is related to personality traits and mediates the association between personality and mortality.
We assessed the big five personality domains and facets using the Revised NEO Personality Inventory (NEO-PI-R), assessed depressive symptoms with the Center for Epidemiologic Studies Depression Scale (CES-D), estimated mtDNAcn levels from whole-genome sequencing, and tracked mortality in participants from the Baltimore Longitudinal Study of Aging. Results were replicated in the SardiNIA Project.
We found that mtDNAcn was negatively associated with the Neuroticism domain and its facets and positively associated with facets from the other four domains. The direction and size of the effects were replicated in the SardiNIA cohort and were robust to adjustment for potential confounders in both samples. Consistent with the Neuroticism finding, higher depressive symptoms were associated with lower mtDNAcn. Finally, mtDNAcn mediated the association between personality and mortality risk.
To our knowledge, this is the first study to show a replicable association between mtDNAcn and personality. Furthermore, the results support our hypothesis that mtDNAcn is a biomarker of the biological process that explains part of the association between personality and mortality.
Support for this work was provided by the Intramural Research Program of the National Institute on Aging (Z01-AG000693, Z01-AG000970, and Z01-AG000949) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. AT was also supported by the National Institute on Aging of the National Institutes of Health Grant R01AG068093.
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.
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