Age-related atrophy of the human hippocampus and the enthorinal cortex starts accelerating at around age 60. Due to the contributions of these regions to many cognitive functions seamlessly used in everyday life, this can heavily impact the lives of elderly people. The hippocampus is not a unitary structure and mechanisms of its age-related decline appear to differentially affect its subfields. Human and animal studies have suggested that altered sleep is associated with hippocampal atrophy. Yet, we know little about subfield specific effects of altered sleep in healthy aging and their effect on cognition. Here, in a sample of 118 older adults (M = 63.25 years), we examined the association between highly reliable hippocampal subfield volumetry, sleep measures derived from multi-night recordings of portable electroencephalography and episodic memory. Objective sleep efficiency, but not self-report measures of sleep, was associated with entorhinal cortex volume when controlling for age. Age related differences in subfield volumes were associated with objective sleep efficiency, but not with self-report measures of sleep. Moreover, older adults characterized by a common multivariate pattern of subfield volumes that contributed to positive sleep-subfield volume associations, showed lower rates of forgetting. Our results showcase the benefit of objective sleep measures in identifying potential contributors of age-related differences in brain-behavior couplings. | Make paid
The 40-50 RNA modifications of the epitranscriptome regulate posttranscriptional gene expression. Here we show that flaviviruses hijack the host tRNA epitranscriptome to promote expression of pro-viral proteins, with tRNA-modifying ALKBH1 acting as a host restriction factor in dengue virus infection. Early in the infection of human Huh-7 cells, ALKBH1 and its tRNA products 5-formylcytidine (f5C) and 2'-O-methyl-5-formylcytidine (f5Cm) were reduced. ALKBH1 knockdown mimicked viral infection, but caused increased viral NS3 protein levels during infection, while ALKBH1 overexpression reduced NS3 levels and viral replication, and increased f5C and f5Cm. Viral NS5, but not host FTSJ1, increased f5Cm levels late in infection. Consistent with reports of impaired decoding of leucine UUA codon by f5Cm-modified tRNALeu(CAA), ALKBH1 knockdown induced translation of UUA-deficient transcripts, most having pro-viral functions. Our findings support a dynamic ALKBH1/f5Cm axis during dengue infection, with virally-induced remodeling of the proteome by tRNA reprogramming and codon-biased translation. | Make paid
A causal relationship exists among the aging process, organ decay and dis-function, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed EklfK74R/K74R or Eklf(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/ EKLF has been generated that possesses extended lifespan and healthy characteristics including cancer resistance. We show that the healthy longevity characteristics of the Eklf(K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age- and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Eklf(K74R) mice could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild type NK cells. Targeted/global gene expression profiling analysis has identified changes of the expression of specific proteins, including the immune checkpoint factors PD-1 and PD-L1, and cellular pathways in the leukocytes of the Eklf(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/ blood system for long-term anti-cancer and, potentially, for anti-aging. | Make paid
While accumulated publications support the existence of neurogenesis in the adult human hippocampus, the homeostasis and developmental potentials of neural stem cells (NSCs) under different contexts remain unclear. Based on our generated single-nucleus atlas of the human hippocampus across neonatal, adult, aging and injury, we dissected the molecular heterogeneity and transcriptional dynamics of human hippocampal NSCs under different contexts. We further identified new specific neurogenic lineage markers that overcome the lack of specificity found in some well-known markers. Based on developmental trajectory and molecular signatures, we found that a subset of NSCs exhibit quiescent properties after birth, and most NSCs become deep quiescence during aging. Furthermore, certain deep quiescent NSCs are re-activated following stroke injury. Together, our findings provide valuable insights into the development, aging, and re-activation of the human hippocampal NSCs, and help to explain why adult hippocampal neurogenesis is infrequently observed in humans. | Make paid
In the preclinical model of peripheral arterial disease (PAD), M2-like anti-inflammatory macrophage polarization and angiogenesis are required for revascularization. The regulation of cell metabolism and inflammation in macrophages is tightly linked to mitochondrial dynamics. Drp1, a mitochondrial fission protein, has shown context-dependent macrophage phenotypes with both pro- and anti-inflammatory characteristics. However, the role of macrophage Drp1 in reparative neovascularization remains unexplored. Here we show that Drp1 expression was significantly increased in F4/80+ macrophages within ischemic muscle at day 3 following hindlimb ischemia (HLI), an animal model of PAD. Myeloid-specific Drp1-/- mice exhibited reduced limb perfusion recovery, angiogenesis and muscle regeneration after HLI. These effects were concomitant with enhancement of pro-inflammatory M1-like macrophages, p-NFkB, and TNF levels, while showing reduction in anti-inflammatory M2-like macrophages and p-AMPK in ischemic muscle of myeloid Drp1-/- mice. In vitro, Drp1-/- macrophages under hypoxia serum starvation (HSS), an in vitro PAD model, demonstrated enhanced glycolysis via reducing p-AMPK as well as mitochondrial dysfunction and excessive mitochondrial ROS, resulting in increased M1-gene and reduced M2-gene expression. Conditioned media from HSS-treated Drp1-/- macrophages exhibited increased secretion of pro-inflammatory cytokines and suppressed angiogenic responses in cultured endothelial cells. Thus, Drp1 deficiency in macrophages under ischemia drives inflammatory metabolic reprogramming and macrophage polarization, thereby limiting revascularization in experimental PAD. | Make paid
Autophagy is an essential component of proteostasis and a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy and mTOR/upstream pathways were determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400m walking speed, and leg power), and thigh muscle volume were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy and pexophagy (PPARGC1A, PPARA, EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion and fission related genes (NIPSNAP2, DNM1L, OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1) and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence. | Make paid
With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calcium-dependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (Chrna1, Chrnd, Chrne), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervation-responsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age. | Make paid
Background and aims: Inhibitors of apolipoprotein C-III (apoC3) are currently approved for the reduction of triglyceride levels in patients with Familial Chylomicronemia Syndrome. We used drug target Mendelian randomization (MR) to assess the effect of genetically predicted decrease in APOC3 blood protein levels on cardiometabolic traits and diseases. Methods: We quantified lifelong reductions in APOC3 blood levels by selecting all genome wide significant and independent (r2<0.1) single nucleotide polymorphisms (SNPs) in the APOC3 gene region +/-1Mb, from three genome-wide association studies (GWAS) of apoC3 blood protein levels (deCODE, n = 35,378, Fenland, n = 10,708 and ARIC, n = 7,213). We included the largest GWASes on 18 cardiometabolica traits and 9 cardiometabolic diseases as study outcomes. Results: A one standard deviation lowering in apoC3 blood protein levels was associated with lower triglycerides, apolipoprotein B, density lipoprotein cholesterol, alanine aminotransferase, and glomerular filtration rate as well as higher high-density lipoprotein cholesterol levels. APOC3 lowering was also associated with lower risk of acute pancreatitis (odds ratio [OR] = 0.91 95% CI=0.82 to 1.00), aortic stenosis (OR = 0.82 95% CI=0.73 to 0.93), and coronary artery disease (OR = 0.86 95% CI=0.80 to 0.93), and was associated with increased parental lifespan (0.06 95% CI=0.03 to 0.09 years). These results were concordant across robust MR methods, the three protein datasets and upon adjustment for APOA1, APOA4 and APOA5 using a multivariable MR framework. Conclusions: These results provide evidence that apoC3 lowering could result in widespread benefits for cardiometabolic health and encourage the launch of trials on apoC3 inhibition for coronary artery disease prevention. | Make paid
Importance: People who complete more education live longer lives with better health. New evidence suggests that these benefits operate through a slowed pace of biological aging. If so, measurements of the pace biological aging could offer intermediate endpoints for studies of how interventions to promote education will impact healthy longevity. Objective: To test the hypothesis that upward educational mobility contributes to a slower pace of biological aging and increased longevity. Design: Prospective cohort study. Setting: We analyzed data from three generations of participants in the Framingham Heart Study: the Original cohort, enrolled beginning in 1948, the Offspring cohort, enrolled beginning in 1971, and the Gen3 cohort, enrolled beginning in 2002. Follow-up is on-going. Data analysis was conducted during 2022-2023 using data obtained from dbGaP (phs000007.v33). Participants: We constructed a three-generation database to quantify intergenerational educational mobility. We linked mobility data with blood DNA methylation data collected from the Offspring cohort in (2005-2008) (n=1,652) and the Gen3 cohort in 2009-2011 (n=1,449). These n=3,101 participants formed our analysis sample. Exposure: We measured educational mobility by comparing participants' educational outcomes with those of their parents. Outcomes: We measured the pace of biological aging from whole-blood DNA-methylation data using the DunedinPACE epigenetic clock. For comparison purposes, we repeated analysis using four other epigenetic clocks. Survival follow-up was conducted through 2019. Results: Participants who were upwardly mobile in educational terms tended to have slower DunedinPACE in later life (r=-0.18, 95% CI [-0.23,-0.13], p<0.001). This pattern of association was similar across generations and held in within-family sibling comparisons. 402 Offspring-cohort participants died over the follow-up period. Upward educational mobility was associated with lower mortality risk (HR=0.89, 95% CI [0.81,0.98] p=0.014). Slower DunedinPACE accounted for roughly half of this association. Conclusions and Relevance: Our findings support the hypothesis that interventions to promote educational attainment will slow the pace of biological aging and promote longevity. Epigenetic clocks, like DunedinPACE, have potential as near-term outcome measures of intervention effects on healthy aging. Experimental evidence is needed to confirm findings. | Make paid
Patients with mitochondrial disorders present with clinically diverse symptoms, largely driven by heterogeneous mutations in mitochondrial-encoded and nuclear-encoded mitochondrial genes. These mutations ultimately lead to complex biochemical disorders with a myriad of clinical manifestations, often accumulating during childhood on into adulthood, contributing to life-altering and sometimes fatal events. It is therefore important to diagnose and characterize the associated disorders for each mitochondrial mutation as early as possible since medical management might be able to improve the quality and longevity of life in mitochondrial disease patients. Here we identify a novel mitochondrial variant in a mitochondrial transfer RNA for histidine (mt-tRNA-his) [m.12148T>C], that is associated with the development of ocular, aural, neurological, renal, and muscular dysfunctions. We provide a detailed account of a family harboring this mutation, as well as the molecular underpinnings contributing to cellular and mitochondrial dysfunction. In conclusion, this investigation provides clinical, biochemical, and morphological evidence of the pathogenicity of m.12148T>C. We highlight the importance of multiple tissue testing and in vitro disease modeling in diagnosing mitochondrial disease. | Make paid
Increased protein ubiquitination was observed in fracture callus and particularly in aged mice. Treatment of proteasome inhibitor enhanced fracture repair in young and mice by increasing the number of mesenchymal progenitor cells (MPCs). However, the protein targets of proteasome inhibitor are still not known. Ub-proteomics identifies the top ub-proteins in MPCs and osteoblasts. Among them, PDGFR{beta} plays important roles both in osteogenesis and angiogenesis, which were reduced in callus of aged mice. We examine the dramatic decrease of PDGFR{beta} protein level, increased Ub-PDGFR{beta}, but mild decrease of mRNA in callus of aged mice, suggesting dys-regulated protein modification is the major cause of decreased PDGFR{beta} level. Decreased PDGFR{beta} results in the failure of PDGF-BB enhanced MPCs proliferation and fracture repair in aged mice. Co-treatment with proteasome inhibitor rescues the ability of PDGF-BB on MPC proliferation and fracture repair. Our findings not only discover the protein target of proteasome inhibitor in MPCs, but importantly connect the compromised effect of PDGF treatment on diseases with PDGFR{beta} proteasomal degradation. We open a new avenue for the treatment of fracture repair in elderly with the combination of PDGF-BB and proteasome inhibitor. | Make paid
Disruption of the circadian clock as well as reduced NAD+ levels are both hallmarks of aging. While circadian rhythms and NAD+ metabolism have been linked in heart disease, their relationship during cardiac aging is less clear. Here, we show that aging leads to disruption of diurnal gene expression in the heart. Long-term supplementation with the NAD+ precursor nicotinamide riboside (NR) boosts NAD+ levels, reprograms the diurnal transcriptome and reverses naturally occurring cardiac enlargement in aged female mice. In addition, complete abolishment of NAD+ levels in CMs impairs PER2::luc oscillations, which is rescued by NR supplementation. These findings reveal an essential role for NAD+ in regulation of the cardiac circadian clock upon aging, which opens up new avenues to counteract age-related cardiac disorders. | Make paid
Neurogenic competence is actively repressed in mature mammalian Muller glial cells, and previous studies have predicted that this is in part mediated by active Notch signaling. To determine whether global loss of Notch signaling could induce reprogramming of, we selectively deleted the common Notch transcriptional mediator Rbpj in adult mouse Muller glia while simultaneously tracing the fate of Muller glia-derived cells. We observed that Rbpj-deficient Muller glia directly transdifferentiate into bipolar and amacrine cells in the absence of injury, but also observed that this effect was significantly enhanced by NMDA-dependent excitotoxic injury. We found that Muller glia-specific loss of function of Notch1 and Notch2 phenocopied this injury-induced induction of neurogenic competence. Integrated multiomic and Cut&Tag analysis revealed that Rbpj directly activates Notch effectors and mature Muller glial-specific genes, and indirectly represses expression of neurogenic bHLH factors. Moreover, we find that combined loss of function of Rbpj and Nfia/b/x leads to a near-complete conversion of Muller glia to neurons in the absence of proliferation, leading to a severe disruption of retinal structure as the result of Muller glia depletion. Finally, however, we show that induction of Muller glial proliferation by AAV-mediated overexpression of dominant-active Yap both preserves retinal structure and supports efficient levels of Muller glia-derived neurogenesis in both Rbpj- and Nfia/b/x/Rbpj-deficient Muller glia. These findings demonstrate that, like in zebrafish, Notch signaling actively represses neurogenic competence in mammalian Muller glia, and imply that inhibition of Notch signaling in combination with Nfia/b/x loss of function and overexpression of activated Yap, could be an effective component of regenerative therapies for degenerative retinal diseases. | Make paid
Aging is associated with a wide range of physiological and behavioral changes in many species. Like humans, zebrafish exhibit gradual senescence, and thus may be a useful model organism for identifying evolutionarily conserved mechanisms related to aging. Here, we compared behavior in the novel tank test of young (6-month-old) and middle aged (12-month-old) zebrafish from two strains (TL and TU) and both sexes. We find that this modest age difference results in a reduction in locomotor activity and strain dependent changes in predator avoidance behaviors related to anxiety. Older TL fish have an elevation in bottom dwelling whereas older TU fish have a decrease in thigmotaxis. We found no consistent effects of age on either short-term (within session) or long-term (1 day later) habituation to the novel tank. Our findings support the use of zebrafish for the study of how age affects locomotion and how genetics interacts with age to alter the regulation of emotional behaviors in response to novelty. | Make paid
It has been demonstrated that short-term stress can enhance cellular responses and promote longevity, whereas long-term stress shortens lifespan. Understanding the relationship between short-term and long-term stress could offer new insights into comprehending and modulating age-related diseases. In this study, we investigate this relationship using transcriptomic and metabolomic analyses in the yeast model system (Saccharomyces cerevisiae). We employed three metabolic treatments: firstly, treating yeast cells with threshold levels of benzoic acid for 24 hours (Short-term [ST] Stressed Cells); secondly, treating yeast cells with threshold levels of benzoic acid for 500 hours, with sub-culturing every 24 hours (Long-term [LT] Stressed Cells); and thirdly, allowing the long-term stressed cells to grow for 16 hours without any benzoic acid (Recovered Cells). Here, we propose that aging is an evolutionarily conserved cellular adaptation mechanism in response to long-term stress exposure. Under short-term stressed conditions, prominent lifespan-extending metabolites such as trehalose and metabolites linked to tumor suppression in humans, such as 5-methylthioadenosine, were overexpressed. In contrast, LT Stressed Cells activated genes such as those responsible for epigenetic regulatory enzymes that govern the aging process, and secondary stress response genes, such as heat shock proteins (HSPs) which are associated with adaptation to cell damage but also often associated with aged cells. Chronological lifespan experiments showed that LT stressed cells lived a shorter lifespan compared to ST Stressed Cells. This suggests that the markers of aging (eg. HSPs, certain epigenetic regulators) are expressed in response to long-term stress to enable cell survival but have the long-term effect of reducing lifespan. In support of this hypothesis, we also show that genes exclusively activated in ST Stressed Cells are conserved solely in eukaryotes, while those significantly expressed in LT Stressed Cells (aging related) exhibit high conservation across all domains of life, with a majority having originated from bacteria hinting at the potential evolutionary benefit of aging. | Make paid
We establish the mathematical foundation that links the rate of change in any molecular biomarker to species lifespan. Specifically, we propose a robust approach that identifies the strong inverse relationship for certain biomarkers using two comprehensive methylation datasets. After examining 54 chromatin states, we found the rates of change of CpG sites in bivalent chromatin states are negatively associated to the lifespans of 90 dog breeds in the first dataset, and the discoveries are further strengthened with 125 mammalian species in the second dataset. Our research leads to three key findings: First, a reciprocal relationship exists between the average rate of methylation change (AROCM) in bivalent promoter regions and maximum lifespan: AROCM ~ 1/MaxLifespan. Second, the correlation between age and average methylation bears no relation to maximum lifespan, Cor(Methly,Age) independent of MaxLifespan. Third, the rate of methylation change in young animals is related to that in old animals: Young animals' AROCM ~ Old AROCM. These findings hinge on the chromatin context, as different results emerge when defining AROCM using different chromatin states. Our analytical framework is versatile and readily extendable to a broad range of other molecular assessments. Overall, our study demonstrates that epigenetic aging rates in specific chromatin states exhibit an inverse relationship with maximum lifespan in mammals. | Make paid
Extracellular matrix (ECM) interacts with cancer cells to regulate carcinogenesis. DDR2 is a collagen receptor that is dysregulated in cancer cells, but its precise role in carcinogenesis remains unclear. In this study, we perform RNA-seq to determine how DDR2 and the biomechanical environment regulate cancer cell behaviors. We show that DDR2 knockdown in SH-SY5Y neuroblastoma cells inhibits proliferation and promotes senescence by regulating relevant genes. Moreover, increasing substrate stiffness reduces proliferation and enhances cell contractility, but does not change senescence or transcriptome. Additionally, DDR2 knockdown modulates cellular responses to substrate stiffness changes, unraveling a crosstalk between DDR2 and mechanosensing. These findings indicate DDR2, and ECM biomechanics regulate cancer cell behavior through distinct mechanisms, providing new mechanistic insights of cancer progression. | Make paid
INTRODUCTION: Plasma phosphorylated tau181 (p-tau181) associations with global cognition and memory are clear, but the link between p-tau181 with other cognitive domains and subjective cognitive decline (SCD) across the clinical spectrum of Alzheimer's disease (AD) and how this association changes based on genetic and demographic factors is poorly understood. METHODS: Participants were drawn from the Alzheimer's Disease Neuroimaging Initiative and included 1185 adults aged >55 years with plasma p-tau181 and neuropsychological test data. Linear regression models related plasma p-tau181 to neuropsychological composite and SCD scores with follow-up models examining plasma p-tau181 interactions with cognitive diagnosis, APOE-{epsilon}4 carrier status, age, and sex on cognitive outcomes. RESULTS: Higher plasma p-tau181 was associated with worse memory, executive functioning, and language abilities, and greater informant-reported SCD. Visuospatial abilities and self-report SCD were not associated with plasma p-tau181. Associations were generally stronger in MCI or dementia, APOE-{epsilon}4 carriers, women, and younger participants. DISCUSSION: Higher levels of plasma p-tau181 are associated with worse neuropsychological test performance across multiple cognitive domains; however, these associations vary based on disease stage, genetic risk status, age, and sex. | Make paid
Deep learning can be used effectively to predict participants' age from brain magnetic resonance imaging (MRI) data, and a growing body of evidence suggests that the difference between predicted and chronological age--referred to as brain-predicted age difference (brain-PAD)--is related to various neurological and neuropsychiatric disease states. A crucial aspect of the applicability of brain-PAD as a biomarker of individual brain health is whether and how brain-predicted age is affected by MR image artifacts commonly encountered in clinical settings. To investigate this issue, we trained and validated two different 3D convolutional neural network architectures (CNNs) from scratch and tested the models on a separate dataset consisting of motion-free and motion-corrupted T1-weighted MRI scans from the same participants, the quality of which were rated by neuroradiologists from a clinical diagnostic point of view. Our results revealed a systematic increase in brain-PAD with worsening image quality for both models. This effect was also observed for images that were deemed usable from a clinical perspective, with brains appearing older in medium than in good quality images. These findings were also supported by significant associations found between the brain-PAD and standard image quality metrics indicating larger brain-PAD for lower-quality images. Our results demonstrate a spurious effect of advanced brain aging as a result of head motion and underline the importance of controlling for image quality when using brain-predicted age based on structural neuroimaging data as a proxy measure for brain health. | Make paid
Background: Subjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimers disease (AD) biomarkers in non-demented older adults. Method: Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=156, 72{+/-}6 years, 37% mild cognitive impairment, 33% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test-III Reading subtest to assess reading level at baseline as a a proxy for educational quality. Cerebrospinal fluid (CSF) biomarkers for AD ({beta}-amyloid42 (A{beta}42), A{beta}42/40 ratio, phosphorylated tau (p-tau), tau, and neurofilament light (NfL)) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers and follow-up models assessed SCD x sex, SCD x reading level, and SCD x education interactions on AD biomarkers. Result: In main effect models, higher SCD was associated with lower A{beta}42 and A{beta}42/40 ratio (p-values<0.004). SCD was not associated with tau, p-tau, or NfL levels (p-values>0.38). SCD score interacted with sex on A{beta}42/40 ratio (p=0.03) but no other biomarkers (p-values>0.10). In stratified models, higher SCD was associated with lower A{beta}42/40 ratio in men (p=0.0003) but not in women (p=0.48). SCD score interacted with education on A{beta}42 (p=0.005) and A{beta}42/40 ratio (p=0.001) such that higher education was associated with a stronger negative association between SCD and amyloid levels. No SCD score x reading level interaction was found (p-values>0.51) though significant associations between SCD and amyloid markers were seen in the higher reading level group (p-values<0.004) but not the lower reading level group (p-values>0.12) when stratified by a median split in reading level. Conclusion: Among community-dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes in men and individuals with higher quantity and quality of education. SCD was not associated with CSF markers of tau pathology or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults. | Make paid
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 1944-5, 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. | Make paid
Importance Earlier identification of high coronary artery disease (CAD) risk individuals may enable more effective prevention strategies. However, existing 10-year risk frameworks are ineffective at earlier identification. Understanding the variable importance of genomic and clinical factors across life stages may significantly improve lifelong CAD event prediction. Objective To assess the time-varying significance of genomic and clinical risk factors in CAD risk estimation across various age groups. Design, Setting, and Participants A longitudinal study was performed using data from two cohort studies: the Framingham Offspring Study (FOS) with 3,588 participants aged 19-57 years and the UK Biobank (UKB) with 327,837 participants aged 40-70 years. A total of 134,765 and 3,831,734 person-time years were observed in FOS and UKB, respectively. Main Outcomes and Measures Hazard ratios (HR) for CAD were calculated for polygenic risk scores (PRS) and clinical risk factors at each age of enrollment. The relative importance of PRS and Pooled Cohort Equations (PCE) in predicting CAD events was also evaluated by age groups. Results The importance of CAD PRS diminished over the life course, with an HR of 3.58 (95% CI 1.39-9.19) at age 19 in FOS and an HR of 1.51 (95% CI 1.48-1.54) by age 70 in UKB. Clinical risk factors exhibited similar age-dependent trends. PRS significantly outperformed PCE in identifying subsequent CAD events in the 40-45-year age group, with 3.2-fold more appropriately identified events. The mean age of CAD events occurred 1.8 years earlier for those at high genomic risk but 9.6 years later for those at high clinical risk (p<0.001). Overall, adding PRS improved the area under the receiving operating curve of the PCE by an average of +5.1% (95% CI 4.9-5.2%) across all age groups; among individuals <55 years, PRS augmented the AUC-ROC of the PCE by 6.5% (95% CI 5.5-7.5%, p<0.001). Conclusions and Relevance Genomic and clinical risk factors for CAD display time-varying importance across the lifespan. The study underscores the added value of CAD PRS, particularly among individuals younger than 55 years, for enhancing early risk prediction and prevention strategies. | Make paid
Cellular reprogramming of mammalian glia to an induced neuronal fate holds potential for restoring diseased brain circuits. While the proneural factor Ascl1 is widely used for neuronal reprogramming, in the early postnatal mouse cortex Ascl1 fails to induce glia-to-neuron conversion, instead promoting proliferation of oligodendrocyte progenitor cells (OPC). Since Ascl1 activity is post-translationally regulated, here we investigated the consequences of mutating six serine phospho-acceptor sites to alanine (Ascl1SA6) on lineage reprogramming in vivo. Ascl1SA6 exhibited increased neurogenic activity in glia of the early postnatal mouse cortex, an effect enhanced by co-expression of Bcl2. Genetic fate-mapping revealed that most induced neurons originated from astrocytes while only a few derived from OPCs. Intriguingly, many Ascl1SA6/Bcl2-induced neurons expressed parvalbumin and were capable of high-frequency action potential firing. Our study demonstrates authentic conversion of astroglia into neurons featuring subclass hallmarks of cortical interneurons, advancing our scope of engineering neuronal fates in the brain. | Make paid
Senescent cells accumulate in multiple tissues with aging. Depletion of senescent cells benefits the aging related disease, such as aging bone fracture. However, the molecular mechanisms by which senescent cells regulate their neighboring bone cells are still not well-known. We reported that proteasome inhibitor enhanced fracture repair in aged mice. Senescent cells are major source of chronic inflammatory cytokines, which in turn induce protein ubiquitination. We reported that PDGFRbeta was one of the highly ubiquitinated proteins in mesenchymal progenitors (MPCs) and TGFbeta was the most increased SASP. In the current study, we found TGFbeta induced PDGFRbeta ubiquitination and proteasomal degradation through its E3 ligases. TGFbeta neutralizing antibody blocked the inhibited callus derived MPC growth and increased Ub-PDGFRbeta by senescent cells, which could be further prevented PDGFRbeta inhibitor. These findings suggested senescent cells derived TGFbeta impaired fracture repair in aged mice through elevating ubiquitination of PDGFRbeta. The discovery of TGFbeta-PDGFRbeta pathway triggered by senescent cells opens avenues for optimizing treatment strategies for aging related disease by combination with the ligand of PDGFRbeta. | Make paid
Objectives: Buprenorphine is an effective evidence-based medication for opioid use disorder (OUD). Yet premature discontinuation undermines treatment effectiveness, increasing risk of mortality and overdose. We developed and evaluated a machine learning (ML) framework for predicting buprenorphine care discontinuity within 1-year following treatment initiation. Methods: This retrospective study used United States 2018-2021 MarketScan commercial claims data of insured individuals aged 18-64 who initiated buprenorphine between July 2018 and December 2020 with no buprenorphine prescriptions in the previous six months. We measured buprenorphine prescription discontinuation gaps of [≥]30 days within the first year of initiating treatment. We developed predictive models employing logistic regression, decision tree classifier, random forest, XGBoost, aboost, and random forest-XGBoost ensemble. We applied recursive feature elimination with cross-validation to reduce dimensionality and identify the most predictive features while maintaining model robustness. We focused on two distinct treatment stages: at the time of treatment initiation and one and three months after treatment initiation. We employed SHapley Additive exPlanations (SHAP) analysis that helped us explain the contributions of different features in predicting buprenorphine discontinuation. We stratified patients into risk subgroups based on their predicted likelihood of treatment discontinuation, dividing them into decile subgroups. Additionally, we used a calibration plot to analyze the reliability of the models. Results: A total of 30,373 patients initiated buprenorphine and 14.98% (4,551) discontinued treatment. C-statistic varied between 0.56 and 0.76 for the first-stage models including patient-level demographic and clinical variables. Inclusion of proportion of days covered (PDC) measured at one-month and three-month following treatment initiation significantly increased the models discriminative power (C-statistics: 0.60 to 0.82). Random forest (C-statistics: 0.76, 0.79 and 0.82 with baseline predictors, one-month PDC and three-month PDC, respectively) outperformed other ML models in discriminative performance in all stages (C-statistics: 0.56 to 0.77). Most influential risk factors of discontinuation included early stage medication adherence, age, and initial days of supply. | Make paid
Background Social health markers, including marital status, contact frequency, network size, and social support, have shown associations with cognition. However, the underlying mechanisms remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. Methods In the English Longitudinal Study of Ageing (ELSA; n=7,136; aged 50+), we used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein (CRP) and fibrinogen (assessed at an intermediate time point) mediated associations between social health and subsequent standardised cognition (verbal fluency, delayed and immediate recall) including cognitive change, with slopes derived from multilevel models (ELSA: 12-year slope). We examined whether findings replicated in the Swedish National Study of Aging and Care in Kungsholmen (SNAC-K; n=2,846; aged 60+; 6-year slope). Findings We found indirect effects via depressive symptoms of network size, positive support and less negative support on subsequent verbal fluency, and positive support on subsequent immediate recall (pure indirect effect (PIE)=0.002 [0.000-0.003]). The positive support-verbal fluency mediation finding replicated in SNAC-K. Depressive symptoms partially mediated associations between less negative support and slower immediate (PIE=0.001 [0.000-0.002]) and delayed recall decline (PIE=0.001 [0.000-0.002]), and between positive support and slower immediate recall decline (PIE=0.001, [0.000-0.001]), which replicated in SNAC-K. We did not observe mediation by inflammatory biomarkers. Interpretation Findings provide new insights into mechanisms linking social health with cognition, suggesting that associations between cognition and interactional aspects of social health in particular, such as social support, are partly underpinned by depressive symptoms. | Make paid
This article describes a stem cell line derived by reprogramming of native human islet cells that consistently generates pure populations of endocrine pancreatic clusters following a simple differentiation protocol. Surprisingly, the population of stem cell derived pancreatic endocrine clusters that was most consistently capable of regulating blood glucose in rodent models of diabetes lacked robust expression of the key beta cell maturation-associated factor NKX6-1 but did manifest high expression of other key drivers of endocrine cell specification and maturation, ISL1 and MAFA. These data support the hypothesis that multiple pancreatic profiles can be identified in stem cell derived cultures and that these have disparate in vivo potency. The population with low NKX6-1 and high in vivo potency was further characterized by transcriptome profiling as an endocrine-committed population progressively maturing in vitro to a state proximal to the native islet. | Make paid
Cytokines mediate cell-to-cell communication across the immune system and therefore are critical to immunosurveillance in cancer and other diseases. Several cytokines show dysregulated abundance or signaling responses in breast cancer, associated with the disease and differences in survival and progression. Cytokines operate in a coordinated manner to affect immune surveillance and regulate one another, necessitating a systems approach for a complete picture of this dysregulation. Here, we profiled cytokine signaling responses of peripheral immune cells from breast cancer patients as compared to healthy controls in a multidimensional manner across ligands, cell populations, and responsive pathways. We find alterations in cytokine responsiveness across pathways and cell types that are best defined by integrated signatures across dimensions. Alterations in the abundance of a cytokine's cognate receptor do not explain differences in responsiveness. Rather, alterations in baseline signaling and receptor abundance suggesting immune cell reprogramming are associated with altered responses. These integrated features suggest a global reprogramming of immune cell communication in breast cancer. | Make paid
Objective: Our objective was to study kinetics and associations between inflammation related proteins in circulation after pediatric allogenic hematopoietic stem cell transplantation (HSCT) to reveal proteomic signatures or individual soluble proteins associated with specific complications post HSCT. Methods: We used a proteomics method called Proximity Extension Assay to repeatedly measure 180 different proteins together with clinical variables, cellular immune reconstitution, and blood viral copy numbers in 27 children aged 1-18 years during a two-year follow up after allogenic HSCT. Protein profile analysis was done using unsupervised hierarchical clustering and a regression-based method, while Bonferroni-corrected Mann-Whitney U test was used for time point specific comparison of individual proteins against outcome. Results: At 6 months after allogenic HSCT, we could identify a protein profile pattern that was associated with occurrence of the complications chronic graft-versus-host disease, viral infections, relapse, and death. When protein markers were analyzed separately, the plasma concentration of the inhibitory and cytotoxic T cell surface protein FCRL6 (Fc receptor-like 6) was higher in patients with CMV viremia (log2-fold change 1.5 (p=9.9 x 10-4), 2.5 (p=3.5 x 10- 4) and 2.2 (p=0.045) at time points 6, 12 and 24 months). Flow cytometry confirmed that FCRL6 expression was higher in innate-like T cells, indicating that these cells have a role in controlling CMV reactivation in HSCT recipients. Conclusions: The potentially druggable FCRL6 receptor on cytotoxic T cells appears to have role in controlling CMV viremia post-HSCT. Our results suggests that system level analysis is a useful addition to the studying of single biomarkers in allogeneic HSCT. | Make paid
Background: Mental disorders and discrimination share common risk factors. The association between having a mental disorder and experiencing discrimination is well-known, but the extent to which familial factors, such as genetic and shared environmental factors, might confound this association, including gender differences in familial confounding, remains unexplored. Aims: We investigated potential unmeasured familial confounding in the relationship between mental disorders and discrimination. Method: We examined 2,044 same-sex twin pairs aged 16-25 years from the German population-based study 'TwinLife'. We used a matched design and random-effects regression applied to within-individual and within-and-between pair models for the association between mental disorder and discrimination, and used likelihood ratio tests (LRTs) to compare these models. Multivariable models were adjusted for body-mass-index, educational attainment, and global life satisfaction. Results: Mental disorder and discrimination were associated in the adjusted within-individual model (adjusted odds ratio=2.19, 95% Confidence Interval:1.42-3.39, P<0.001). However, the within-and-between pair model showed that this association was explained by the within-pair mean (aOR=4.24, 95%CI:2.17-8.29, P<0.001) and not the within-pair difference (aOR=1.26, 95%CI:0.70-2.28, P=0.4) of mental disorder. Therefore, this association was mostly explained by familial confounding, which is also supported by the LRTs for the unadjusted and adjusted models (P<0.001 and P=0.03, respectively). This familial confounding was more prominent for males than females. Conclusions: Our findings show that the association between mental disorder and discrimination is almost fully explained by unmeasured familial factors. Incorporating family members in interventions targeted at ameliorating mental ill-health and experiences of discrimination among adolescents may improve efficacy. | Make paid