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The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson’s disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD. Dysfunction of the gastrointestinal system, and to the autophagy lysososmal pathway (ALP) have been reported in Parkinson’s disease. Here the authors report epigenetic disruption of ALP related genes in the appendix of individuals with Parkinson’s disease.

Plasmapheresis is a medical procedure that separates plasma from blood cells, potentially removing pro-aging factors from circulation. Some studies suggest it may have rejuvenating effects by altering biomarkers of aging, but evidence on its impact on epigenetic aging in humans is limited. This study aimed to assess whether plasmapheresis without volume replacement with young plasma or albumin affects epigenetic age and other biomarkers in healthy adults. An automatic plasma collection system, the Haemonetics PCS2, was used for plasmapheresis. Healthy blood donors were divided into two groups using stratified randomization in a cross-over study with subjects undergoing either 8 plasmaphereses (8 pp) or 4 plasmaphereses (4 pp) for an 18-week period, with a minimum interval between plasmaphereses of 2 weeks (14 days). Samples were tested for biochemical, hematological analyses and epigenetic clocks. We documented the alteration in serum minerals, decreased serum lipids, mainly total cholesterol, non-HDL, triglycerides, apolipoprotein A levels, total proteins and albumin. Among hematologic parameters, we found an increase in Red Cell Distribution Width (RDW) and Mean Corpuscular Hemoglobin Concentration (MCHC). No significant epigenetic rejuvenation was observed based on epigenetic clock measurements. Instead, plasmapheresis was associated with increases in DNAmGrimAge, the Hannum clock, and the Dunedin Pace of Aging. Plasmapheresis can rapidly change the levels of pro-inflammatory and other pro-aging molecules in the circulation. However, the selected protocol has not provided conclusive data supporting benefits. Based on epigenetic clock parameters, it may accelerate epigenetic aging. More research into the long-term safety of this specific protocol is needed.

HIV infection accelerates biological aging, but the contribution of the host's age to this process is unknown. We investigated the influence of SIV infection in macaques (SIVmac) on the risk of comorbidities and aging in young and old rhesus macaques (RMs) by assessing pathogenesis markers, DNA methylation-based epigenetic age (EA), and EA acceleration (EAA) in blood and tissues. Initially, upon SIV infection, the young RMs showed greater resilience to CD4+ T cell depletion, better control of T cell activation, hypercoagulation, and excessive inflammation, yet this resilience was progressively lost in the advanced stages of infection. During the late stages of infection, the young RMs, but not the aged ones, showed an increase in EA in PBMCs; also, EAA in the cerebellum and heart of young RMs was higher compared with old RMs. SIV infection was more pathogenic in aged animals in early stages, leading to a more rapid disease progression; however, accelerated aging mostly affected young animals, so that the levels of multiple key pathogenesis markers in the young RMs converged toward those specific to aged ones in the late stages of infection. We conclude that SIV infection-driven age acceleration is tissue specific, and that host age influences the susceptibility of different tissues to enhanced aging.

Aging is the primary risk factor for sporadic Alzheimer's disease. Chronic low-grade inflammation associated with aging drives cognitive impairment through multiple mechanisms involving oxidative stress, insulin resistance, and dysregulation of metabolic, immunologic, and hematologic systems. In a 7-month, randomized, double-blind, placebo-controlled trial (NCT04669028), we investigated the safety and activity of bezisterim, a first-in-class, oral, blood-brain barrier-permeable, anti-inflammatory agent on cognitive, molecular, biochemical, physiological, and biological aging parameters in a subset of 50 mild-to-moderate probable Alzheimer's disease participants. These participants had source-document-verified clinical measures and samples, and they completed the protocol. This study focuses on epigenetic, metabolic, biomarker, and cognitive measures in the exploratory biomarker population that completed the protocol. Bezisterim was associated with non-significant directional improvements in multiple measures of cognitive and functional performance compared to placebo, with correlations to biological age (determined by DNA methylation \"clocks\") and to metabolism, inflammation, and dementia biomarkers. In addition, clinical measures correlated with the extent of DNA methylation of certain cytosine-phosphate-guanine (CpG) sites in genes associated with metabolic inflammation and neurodegeneration. The results suggest the possible use of bezisterim to target the multifactorial processes underlying dementia. https://clinicaltrials.gov/study/NCT04669028, Identifier: NCT04669028.

This study aims to evaluate differences between Infinium MethylationEPIC (EPICv1) and Infinium MethylationEPICv2 (EPICv2) arrays in estimating DNAm age with eleven DNAm clocks using buffy coat, peripheral blood mononuclear cell (PBMC), and saliva from 16 healthy middle-aged individuals. DNAm ages were estimated using six principal component-based (PC) clocks (PCHorvath1, PCHorvath2, PCHannum, PCPhenoAge, PCGrimAge, and PCDNAmTL) and five non-PC clocks (DunedinPACE, DNAmFit, YingCausAge, YingAdaptAge, and YingDamAge) across all biological samples. Agreement between arrays was assessed using Spearman correlation, Bland-Altman plots, and Wilcoxon Signed-Rank test. The 16 individuals with median age of 48 [43.5;53.8] years, were predominantly female, Chinese and non-smokers. High correlations (ρ > 0.8) were observed between EPICv1 and EPICv2 except for DunedinPACE, YingDamAge and YingAdaptAge. PC-based clocks showed lower systematic bias (MAPE:0.118-8.98%) compared to non-PC-based clocks (MAPE:5.31-21.2%). Saliva samples demonstrated greatest variability between arrays. EPICv2 introduces systematic biases especially in non-PC-based clocks and between different biological samples. Assessment of DNAm varies across platforms, especially in non-PC-based clocks and between buffy coat, peripheral blood mononuclear cell and saliva in 16 healthy middle-aged individuals.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder following Alzheimer’s disease, with a 1.5 times higher prevalence in males. Several lipid-related genetic risk factors for PD have been identified, and the brain lipid signature of PD patients is distinguishable from controls. To elucidate the molecular mechanisms underlying PD and its sex differences, we conducted a lipidomic analysis of postmortem brain samples from the primary motor cortex (Brodmann area 4) of 40 PD patients and 43 age- and sex-matched matched controls. Mass spectrometry based lipidomics analysis revealed notable differences in 95 lipid species, especially Triacylglycerols and Lysophosphatidylcholines. Notably, sex-stratified analysis suggested that mitochondrial dysfunction may explain the higher prevalence of PD in males. These findings highlight lipid dysregulation in PD and point to potential biomarkers for diagnosis, warranting further validation.

There are no approved treatments that slow Parkinson’s disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late stage PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of α-synuclein pathology in vitro. Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and reduced the accumulation of α-synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of TET2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.

5-hydroxymethylcytosine (5hmC) is the most prevalent intermediate on the oxidative DNA demethylation pathway and is implicated in regulation of embryogenesis, neurological processes, and cancerogenesis. Profiling of this relatively scarce genomic modification in clinical samples requires cost-effective high-resolution techniques that avoid harsh chemical treatment. Here, we present a bisulfite-free approach for 5hmC profiling at single-nucleotide resolution, named hmTOP-seq (5hmC-specific tethered oligonucleotide-primed sequencing), which is based on direct sequence readout primed at covalently labeled 5hmC sites from an in situ tethered DNA oligonucleotide. Examination of distinct conjugation chemistries suggested a structural model for the tether-directed nonhomologous polymerase priming enabling theoretical evaluation of suitable tethers at the design stage. The hmTOP-seq procedure was optimized and validated on a small model genome and mouse embryonic stem cells, which allowed construction of single-nucleotide 5hmC maps reflecting subtle differences in strand-specific CG hydroxymethylation. Collectively, hmTOP-seq provides a new valuable tool for cost-effective and precise identification of 5hmC in characterizing its biological role and epigenetic changes associated with human disease.

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, particularly among individuals under the age of 45. It is a complex, and heterogeneous disease with a multifaceted pathophysiology that remains to be elucidated. Metabolomics has the potential to identify metabolic pathways and unique biochemical profiles associated with TBI. Herein, we employed a longitudinal metabolomics approach to study TBI in a weight drop mouse model to reveal metabolic changes associated with TBI pathogenesis, severity, and secondary injury. Using proton nuclear magnetic resonance ( 1 H NMR) spectroscopy, we biochemically profiled post-mortem brain from mice that suffered mild TBI (N = 25; 13 male and 12 female), severe TBI (N = 24; 11 male and 13 female) and sham controls (N = 16; 11 male and 5 female) at baseline, day 1 and day 7 following the injury. 1 H NMR-based metabolomics, in combination with bioinformatic analyses, highlights a few significant metabolites associated with TBI severity and perturbed metabolism related to the injury. We report that the concentrations of taurine , creatinine , adenine , dimethylamine , histidine , N-Acetyl aspartate , and glucose 1-phosphate are all associated with TBI severity. Longitudinal metabolic observation of brain tissue revealed that mild TBI and severe TBI lead distinct metabolic profile changes. A multi-class model was able to classify the severity of injury as well as time after TBI with estimated 86% accuracy. Further, we identified a high degree of correlation between respective hemisphere metabolic profiles (r > 0.84, p < 0.05, Pearson correlation). This study highlights the metabolic changes associated with underlying TBI severity and secondary injury. While comprehensive, future studies should investigate whether: (a) the biochemical pathways highlighted here are recapitulated in the brain of TBI sufferers and (b) if the panel of biomarkers are also as effective in less invasively harvested biomatrices, for objective and rapid identification of TBI severity and prognosis.

ABSTRACT Knowledge of animal age is essential to wildlife managers for obtaining meaningful and accurate insights into demographic parameters. A common approach to aging wildlife, including bears (Ursus spp.), has been extracting a tooth during physical capture and counting the cementum annuli. Limitations to tooth‐based aging include questionable accuracy and differing results based on the observer and laboratory. DNA methylation‐based epigenetic aging clocks have been developed for many species but not yet for polar bears (Ursus maritimus). We generated DNA methylation data from whole blood samples (n = 109) obtained during live capture operations from polar bears of known age in the Chukchi Sea and southern Beaufort Sea subpopulations. We used these samples to calibrate a species‐specific epigenetic clock to estimate polar bear chronological age from DNA methylation (DNAm) age. The final polar bear clock was highly accurate (r = 0.97) with a median absolute error of approximately 9 months. We applied the polar bear clock to 74 blood samples from live‐captured polar bears with a cementum annuli‐estimated age. Predicted age estimates for these bears ranged from 1.43 to 18.63 years compared to the estimated tooth age range of 3.23–25.27. These epigenetic clocks can be used for polar bear research and management where accurate estimates of age are needed for estimating demographic parameters. We developed a DNA methylation‐based epigenetic aging clock for polar bears (Ursus maritimus) using whole blood samples from polar bears of known age. The final polar bear clock was highly accurate (r = 0.97) with a median absolute error of approximately 9 months.