Alzheimer's disease (AD) is driven by genetic and epigenetic factors. A knowledge gap remains in applying DNA methylation (DNAm) to capture AD-specific signatures. We developed the AD DNA Methylation Index (AD-DMI), a brain-derived risk index constructed from 100 CpG sites identified by elastic-net logistic regression of methylation data from postmortem dorsolateral prefrontal cortex tissue. AD-DMI was evaluated in 722 older adults, including individuals with normal cognition (NC), mild cognitive impairment (MCI), and AD. AD-relevant associations were tested using generalized linear models, logistic regression, and path analyses, with applicable covariate adjustments. Higher AD-DMI scores were associated with lower global cognitive function, greater global AD neuropathologic burden, and increased odds of subjective memory complaints. AD-DMI predicted clinical diagnosis across the continuum, independent of cognition and pathology. Compared to the Cortical clock, AD-DMI showed stronger and more specific associations with both cognitive and pathological outcomes. Genes mapped to AD-DMI CpGs overlapped with eight genetic loci identified in AD genome-wide association studies, including RELN, LRP1B, and PDE9A. AD-DMI was significantly associated with increased methylation at CpGs in APOE, HOXA3, and ANK1. AD-DMI provides a biologically grounded framework for linking disease-relevant methylation changes with cognitive and pathological outcomes in AD.

Numerous studies document age-related declines in memory using laboratory-based measures, yet little research exists on what older people might have to say about their memory in daily life. The present research examined how age-related memory changes are perceived, managed, remediated, and feared among 50 very old adults. Participants answered nine open-ended questions that tapped four complementary dimensions: memory self-efficacy, memory management, memory remediation, and fears about memory aging. Their oral responses were recorded and transcribed verbatim. Qualitative analyses were carried out on their narrative responses. Results yielded 4 core themes: (1) memory self-efficacy perceptions favored prospective remembering, (2) memory management strategies included frequent use of external memory aids, (3) affective consequences of forgetting concerned violated social conventions with improvement desired for remembering people's names, and (4) neurocognitive decline and loss of independence were salient memory-related fears. Implications of these data for promoting cognitive vitality in later life are discussed.

Alzheimer’s disease (AD) remains the leading cause of dementia. While existing biomarkers provide insights into AD pathology, they often fall short in early detection and tracking cognitive decline. This study examines the longitudinal relationship between the Alzheimer’s Disease Methylation Index (AD-DMI), a novel, disease-specific epigenetic biomarker, and cognitive trajectories preceding AD diagnosis. Data from 541 ROSMAP participants (mean age = 88 years; 308 AD cases, 233 controls) with up to 16 years of cognitive assessments were analyzed. AD-DMI was developed using dorsolateral prefrontal cortex DNA methylation via elastic-net logistic regression, which selected 100 CpGs that best distinguished AD cases from controls (AUC = 0.79). AD-DMI scores were computed as the average methylation across these CpGs. Multivariable linear mixed-effects models assessed AD-DMI’s association with episodic memory, semantic memory, perceptual speed, visuospatial ability, working memory, and global cognition, adjusting for covariates. Higher AD-DMI scores were significantly associated with steeper decline across all domains (β range: -0.15 to -0.37, q < 0.001). Functional enrichment analysis of AD-DMI CpG-mapped genes identified biological processes related to AD, synaptic function, and autophagy. Eight of these genes overlapped with AD-associated genes previously identified in GWAS. Additionally, AD-DMI scores were significantly associated with increasing methylation at CpGs mapped to APOE, ANK1, and HOXA3 (β range: 0.56 to 2.13, q < 0.01), previously reported as hypermethylated in AD in EWAS. AD-DMI tracks epigenetic signatures linked to AD, supporting its potential for disease monitoring. Future studies should validate AD-DMI in diverse cohorts and assess its non-invasive potential.

Aging increases the risk for Alzheimer’s disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in the prefrontal cortex (PFC). We present the first subcellular-resolution spatial transcriptome atlas of the human prefrontal cortex (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages and six age-matched male controls. Our analyses revealed distinct transcriptional alterations across PFC layers, highlighted disruptions in laminar structure, and exposed AD-related shifts in layer-to-layer and cell-cell interactions. Notably, we identified genes highly upregulated in stressed neurons and nearby glial cells, where AD diminished stress-response interactions that promote Aβ clearance. Further, cell-type-specific co-expression analysis highlighted three neuronal modules linked to neuroprotection, protein dephosphorylation, and Aβ regulation, with all modules downregulated as AD progresses. We identified ZNF460 as a transcription factor regulating these modules, offering a potential therapeutic target. In summary, this spatial transcriptome atlas provides valuable insight into AD’s molecular mechanisms. Aging increases the risk for Alzheimer’s disease (AD). Here, the authors present a spatial transcriptome atlas of the human prefrontal cortex in AD, revealing distinct transcriptional alterations.

Aging significantly elevates the risk for Alzheimer’s disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aβ clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aβ plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.

The hallmarks of aging have contributed immensely to the systematization of research on aging and have influenced the emergence of geroscience. The developments that led to the concepts of the hallmarks and geroscience were first marked by the proliferation of 'theories' of aging, mostly based on the experimental predilections of practitioners of aging research. Deeper consideration of the concepts of hallmarks of aging and geroscience leads to the quandary of whether a biological aging process exists beyond disease itself. To address this difficulty, a metric of biological age as opposed to calendar age is necessary. Several examples of biological age measured using similar assumptions, but different methods, exist. One of these, the frailty index was the first to successfully characterize aging in terms of loss of integrated function, and it is simpler than and superior to other constructs for measuring biological age. Though relatively simple in construction, the frailty index is rich conceptually, however, pointing to a network model of the aging organism. This network functions as a nonlinear complex system that is governed by stochastic thermodynamics, in which loss of integration leads to increasing entropy. Its structure transcends all levels of biological organization, such that its parts form hierarchies that are self-similar (fractal). The hallmarks of aging are simply nodes in the aging network, which can be found repetitively in various locations of the network. Stochastic thermodynamics implies that the aging system with higher entropy can exist in a multitude of possible microstates that are tantamount to high disorder with a high probability to assume a certain state. This explains the observed variability among aging individuals.

BACKGROUND:The role of Th17 cells in prostate cancer is not fully understood. The transcription factor BATF controls the differentiation of Th17 cells. Mice deficient in Batf do not produce Th17 cells. METHODS:In this study, we aimed to characterize the role of Batf-dependent Th17 cells in prostate cancer by crossbreeding Batf knockout mice with mice conditionally mutant for Pten. RESULTS:We found that Batf knockout mice had changes in the morphology of prostate epithelial cells compared with normal mice, and Batf knockout mice deficient in Pten (called Batf-) had smaller prostate size and developed fewer invasive prostate adenocarcinomas than Pten-deficient mice with Batf expression (called Batf+). The prostate tumors in Batf- mice showed reduced proliferation, increased apoptosis, decreased angiogenesis and inflammatory cell infiltration, and activation of nuclear factor-κB signaling. Moreover, Batf- mice showed significantly reduced interleukin 23 (IL-23)-IL-23R signaling. In the prostate stroma of Batf- mice, IL-23R-positive cells were decreased considerably compared with Batf+ mice. Splenocytes and prostate tissues from Batf- mice cultured under Th17 differentiation conditions expressed reduced IL-23/IL-23R than cultured cells from Batf+ mice. Anti-IL-23p19 antibody treatment of Pten-deficient mice reduced prostate tumors and angiogenesis compared with control immunoglobulin G-treated mice. In human prostate tumors, BATF messenger RNA level was positively correlated with IL-23A and IL-23R but not RORC. CONCLUSION:Our novel findings underscore the crucial role of IL-23-IL-23R signaling in mediating the function of Batf-dependent Th17 cells, thereby promoting prostate cancer initiation and progression. This finding highlights the BATF-IL-23R axis as a promising target for the development of innovative strategies for prostate cancer prevention and treatment.

Aging significantly elevates the risk for Alzheimer's disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, STOmics® SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the human PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aβ clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aβ plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.

Risk factors contributing to dementia are multifactorial. Accumulating evidence suggests a role for pathogens as risk factors, but data is largely correlative with few causal relationships. Here, we demonstrate that intermittent murine cytomegalovirus (MCMV) infection of mice, alters blood brain barrier (BBB) permeability and metabolic pathways. Increased basal mitochondrial function is observed in brain microvessels cells (BMV) exposed to intermittent MCMV infection and is accompanied by elevated levels of superoxide. Further, mice score lower in cognitive assays compared to age-matched controls who were never administered MCMV. Our data show that repeated systemic infection with MCMV, increases markers of neuroinflammation, alters mitochondrial function, increases markers of oxidative stress and impacts cognition. Together, this suggests that viral burden may be a risk factor for dementia. These observations provide possible mechanistic insights through which pathogens may contribute to the progression or exacerbation of dementia.

Supplementary Methods, Figures 1-3, Table 1 from Suppression of Glucosylceramide Synthase Restores p53-Dependent Apoptosis in Mutant p53 Cancer Cells

Various risk factors of Alzheimer’s disease (AD) are known, such as advanced age, possession of certain genetic variants, accumulation of toxic amyloid-β (Aβ) peptides, and unhealthy lifestyle. An estimate of heritability of AD ranges from 0.13 to 0.25, indicating that its phenotypic variation is accounted for mostly by non-genetic factors. DNA methylation is regarded as an epigenetic mechanism that interfaces the genome with non-genetic factors. The Tg2576 mouse model has been insightful in AD research. These transgenic mice express a mutant form of human amyloid precursor protein linked to familial AD. At 9–13 months of age, these mice show elevated levels of Aβ peptides and cognitive impairment. The current literature lacks integrative multiomics of the animal model. We applied transcriptomics and DNA methylomics to the same brain samples from ~ 11-month-old transgenic mice. We found that genes involved in extracellular matrix structures and functions are transcriptionally upregulated, and genes involved in extracellular protein secretion and localization are differentially methylated in the transgenic mice. Integrative analysis found enrichment of GO terms related to memory and synaptic functionability. Our results indicate a possibility of transcriptional modulation by DNA methylation underlying AD neuropathology.

Cancer is a disease of aging, but most studies on cancer are in young but not aged animal models, and cancer clinical trials are rarely performed in older adults. Recognition of the connections between aging and cancer and improvement of treatment for elderly cancer patients has become one of the most critical medical issues with the global increase in the elderly population. Mouse models are essential experimental tools for understanding the molecular mechanisms of complex processes and related gene pathways of biological aging. However, few mouse models can be used to understand the role of aging in cancer development and the underlying mechanisms. One of the hallmarks of aging is chronic inflammation, often called inflammaging. This is our rationale for examining the role of aging-related inflammation in prostate cancer, a major aging malignancy. We have now developed a novel method to generate age-related cancer models in mice to better understand how age impacts cancer initiation and progression in the natural aging process. We discuss its application to elucidate some of the contributing mechanisms.

Biological age captures some of the variance in life expectancy for which chronological age is not accountable, and it quantifies the heterogeneity in the presentation of the aging phenotype in various individuals. Among the many quantitative measures of biological age, the mathematically uncomplicated frailty/deficit index is simply the proportion of the total health deficits in various health items surveyed in different individuals. We used 3 different statistical methods that are popular in machine learning to select 17-28 health items that together are highly predictive of survival/mortality, from independent study cohorts. From the selected sets, we calculated frailty indexes and Klemera-Doubal's biological age estimates, and then compared their mortality prediction performance using Cox proportional hazards regression models. Our results indicate that the frailty index outperforms age and Klemera-Doubal's biological age estimates, especially among the oldest old who are most prone to biological aging-caused mortality. We also showed that a DNA methylation index, which was generated by applying the frailty/deficit index calculation method to 38 CpG sites that were selected using the same machine learning algorithms, can predict mortality even better than the best performing frailty index constructed from health, function, and blood chemistry.

A reliable model of biological age is instrumental in the field of geriatrics and gerontology. This model should account for the heterogeneity and plasticity of aging and also accurately predict aging-related adverse outcomes. Epigenetic age models are based on DNA methylation levels at selected genomic sites and can be significant predictors of mortality and healthy/unhealthy aging. However, the biological function of DNA methylation at selected sites is yet to be determined. Frailty is a syndrome resulting from decreased physiological reserves and resilience. The frailty index is a probability-based extension of the concept of frailty. Defined as the proportion of health deficits, the frailty index quantifies the progression of unhealthy aging. The frailty index is currently the best predictor of mortality. It is associated with various biological factors and provides insight into the biological processes of aging. Investigation of the multi-omics factors associated with the frailty index will provide further insight.

Gut dysbiosis is a common feature associated with the chronic inflammation of HIV infection. Toward understanding the interplay of chronic treated HIV infection, dysbiosis, and systemic inflammation, we investigated longitudinal fecal microbiome changes and plasma inflammatory markers in the nonhuman primate model. Following simian immunodeficiency virus (SIV) infection in rhesus macaques, significant changes were observed in several members of the phylum Firmicutes along with an increase in Bacteroidetes. Viral suppression with antiretroviral therapy (ART) resulted in an early but partial recovery of compositional changes and butyrate producing genes in the gut microbiome. Over the course of chronic SIV infection and long-term ART, however, the specific loss of Faecalibacterium prausnitzii and Treponema succinifaciens significantly correlated with an increase in plasma inflammatory cytokines including IL-6, G-CSF, I-TAC, and MIG. Further, the loss of T. succinifaciens correlated with an increase in circulating biomarkers of gut epithelial barrier damage (IFABP) and microbial translocation (LBP and sCD14). As F. prausnitzii and T. succinifaciens are major short-chain fatty acid producing bacteria, their sustained loss during chronic SV-ART may contribute to gut inflammation and metabolic alterations despite effective long-term control of viremia. A better understanding of the correlations between the anti-inflammatory bacterial community and healthy gut barrier functions in the setting of long-term ART may have a major impact on the clinical management of inflammatory comorbidities in HIV-infected individuals.

from lifetime exposures to pathogens in concert with impaired immune responses, poses an obstinate challenge to the health span of the growing elderly population. Older adults are not only at a greater risk for age-related diseases, but also for more severe infections. Of note, pneumonia, influenza, sepsis, and recently severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused significant mortality among elders. Several factors contribute to the increased morbidity/mortality of older adults, including loss of naïve lymphocytes, exhaustion of adaptive immunity, and a skew toward proinflammatory responses. Additionally, loss of intestinal homeostasis and perturbations in epithelial barrier protective immune functions have recently emerged as key factors underlying chronic inflammation and age-related comorbidities.

HIV-associated inflammation has been implicated in the premature aging and increased risk of age-associated comorbidities in cART-treated individuals. However, the immune mechanisms underlying the chronic inflammatory state of cART-suppressed HIV infection remain unclear. Here, we investigated the role of γδT cells, a group of innate IL-17 producing T lymphocytes, in the development of systemic inflammation and leaky gut phenotype during cART-suppressed SIV infection of macaques. Plasma levels of inflammatory mediators, intestinal epithelial barrier disruption (IEBD) and microbial translocation (MT) biomarkers, and Th1/Th17-type cytokine functions were longitudinally assessed in blood and gut mucosa of SIV-infected, cART-suppressed macaques. Among the various gut mucosal IL-17/IL-22-producing T lymphocyte subsets including Th17, γδT, CD161+ CD8+ T, and MAIT cells, a specific decline in the Vδ2 subset of γδT cells and impaired IL-17/IL-22 production in γδT cells significantly correlated with the subsequent increase in plasma IEBD/MT markers (IFABP, LPS-binding protein, and sCD14) and pro-inflammatory cytokines (IL-6, IL-1β, IP10, etc.) despite continued viral suppression during long-term cART. Further, the plasma inflammatory cytokine signature during long-term cART was distinct from acute SIV infection and resembled the inflammatory cytokine profile of uninfected aging (inflammaging) macaques. Overall, our data suggest that during cART-suppressed chronic SIV infection, dysregulation of IL-17/IL-22 cytokine effector functions and decline of Vδ2 γδT cell subsets may contribute to gut epithelial barrier disruption and development of a distinct plasma inflammatory signature characteristic of inflammaging. Our results advance the current understanding of the impact of chronic HIV/SIV infection on γδT cell functions and demonstrate that in the setting of long-term cART, the loss of epithelial barrier-protective functions of Vδ2 T cells and ensuing IEBD/MT occurs before the hallmark expansion of Vδ1 subsets and skewed Vδ2/Vδ1 ratio. Thus, our work suggests that novel therapeutic approaches toward restoring IL-17/IL-22 cytokine functions of intestinal Vδ2 T cells may be beneficial in preserving gut epithelial barrier function and reducing chronic inflammation in HIV-infected individuals.