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Molecular features of human pathological tau distinguish tauopathy-associated dementias
In Alzheimer's disease (AD), pathological tau protein shows a progressive accumulation of post-translational modifications (PTMs), reflecting disease severity, progression, and prion-like activity. Although many neurodegenerative diseases with dementia display tau aggregates, the pathological proteoforms of tau protein from each disease type remain unknown. Here, using a quantitative mass spectrometry-based proteomics platform, FLEXITau, deep characterization of pathological tau protein isolated...
Targeting the Nrf2/HO-1 aixs: a therapeutic strategy against regulated cell death in Alzheimer's disease
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, chronic neuroinflammation, and dysregulation of multiple regulated cell death pathways. Aging, as the primary risk factor for AD, is accompanied by the accumulation of oxidative stress, which serves as a pivotal contributor to AD pathogenesis and is intricately linked to the activation of diverse cell...
Therapeutic efficacy of synthetic analogues of gut hormones in a mouse model of Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative condition characterised by amyloid-β pathology, neuroinflammation, synaptic dysfunction and cognitive decline. Few pharmacological interventions are available, offering only symptomatic relief, and approval for a number of anti-amyloid biologics is limited, with concerns about safety, cost and efficacy. Here we investigated the effects of 8-10 weeks treatment with liraglutide, NAcGIP[Lys(37)PAL] and Xenin-25[Lys(13)PAL], long-lasting analogues of...
Clonal expansion of cytotoxic CD8⁺ T cells in lecanemab-associated ARIA
Amyloid-related imaging abnormalities (ARIA) are the principal safety concern limiting anti-amyloid therapies for Alzheimer's disease, yet their biology remains unclear. Here we show, through multi-omic profiling of peripheral blood from three ARIA+ patients and matched controls, that ARIA is associated with coordinated reprogramming of CD8 + T cells. CD8+ effector memory (TEM) and terminally differentiated (TEMRA) subsets were expanded, clonally enriched, and transcriptionally primed for...
Hallmarks of cancer-Then and now, and beyond
Cancer presents a remarkably instructive perturbation of mechanisms manifesting in our biology that have gone awry, eliciting a malady that is inexorably increasing in incidence and societal burden concomitant with healthier aging. The wealth of knowledge and data forthcoming from decades of cancer research can be organized into conceptually distinct but interconnected parametric dimensions that define the mechanistic foundation of the disease: aberrantly acquired functional capabilities (the...
Fanconi Anaemia as a Human Model of Accelerated Epigenetic and Immune Ageing
Fanconi anaemia (FA) is a DNA-repair disorder that compresses multiple hallmarks of ageing into childhood and early adulthood. Persistent genomic instability in FA precipitates oxidative stress, inflammatory remodelling, and metabolic reprogramming, which together erode epigenetic integrity and immune competence. Here we provide evidence FA-specific DNA-repair failure is linked to mitochondrial metabolism, nutrient-sensing networks, and immune dysfunction. In this context, we discuss how these...
Targeting the Nrf2/HO-1 aixs: a therapeutic strategy against regulated cell death in Alzheimer's disease
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, chronic neuroinflammation, and dysregulation of multiple regulated cell death pathways. Aging, as the primary risk factor for AD, is accompanied by the accumulation of oxidative stress, which serves as a pivotal contributor to AD pathogenesis and is intricately linked to the activation of diverse cell...
Ageing and Liver Immune Cells
Ageing is associated with a dysregulated immune system that contributes to vulnerability in older adults to infection, malignancies, autoimmune diseases, and inflammatory disorders. This immune dysfunction can be categorised into two processes: progressive decline in immune responsiveness (immunosenescence) and chronic low-grade systemic inflammation (inflammaging). These processes perpetuate a cycle wherein persistent inflammation accelerates immune cell exhaustion and senescence, while...
Single-cell Aging Clocks: A Precision Tool for Dissecting and Targeting the Aging Process
Biological age, an indicator of an individual's health status, was initially measured using bulk tissue aging clocks. However, by averaging molecular signals across thousands of cells, these tools mask the cellular heterogeneity that characterizes aging. Recent single-cell aging clocks, enabled by high-resolution omics technologies, address this limitation. In this review, we provide a systematic overview of these tools, covering their computational foundations and the key biological insights...
Short-term high-fat diet impairs anterograde and retrograde memory consolidation, but not retrieval in aged rats
CONCLUSION: These findings demonstrate that short-term consumption of ultraprocessed HFD selectively impairs consolidation while sparing retrieval of hippocampal- and amygdala-dependent memory in aging. These findings are important because identifying the specific memory processes that are disrupted, rather than global memory dysfunction, helps narrow mechanistic targets and informs the development of more precise interventions to mitigate diet-related cognitive decline in aging.
Lactate transmission from hypoxic tumor cells promotes macrophage senescence and M2 polarization via the DNMT1-NHE7 axis to accelerate endometrial cancer progression
Although hypoxia is a well-known key driver of metabolic reprogramming in endometrial cancer (EC), its role in lactate-mediated macrophage activation remains unclear. This study investigates whether hypoxia-mediated lactate metabolism reprogramming facilitated EC progression via macrophages. Our data demonstrated that hypoxia-inducible factor 1 subunit alpha (HIF1A) drives a lactate-regulated metabolic cascade, elevating glycolytic genes and monocarboxylate transporter 3 (MCT3) in EC cells to...
The human pathome shows sex and tissue specific aging patterns
Little is known about tissue-specific changes that occur with aging in humans. Using the description of 33 million histological samples we extract thousands of age- and mortality-associated features from text narratives that we call The Human Pathome (pathoage.com). Notably, we can broadly determine when post-development aging starts at the organism and tissue level, indicating a sexual dimorphism with females aging earlier but slower and males aging later but faster. We employ unsupervised...
Briefing Chat: What Brazilian centenarians could reveal about the science of ageing
No abstract
Patterns of cognitive and motor decline in Alzheimer's Disease (AD) and ageing in healthy populations
No abstract
Single-cell immune atlas of mouse testes unveils metabolic reprogramming of FOLR2 + macrophages in orchestrating testicular immunity during aging
Immune cells play a crucial role in maintaining tissue homeostasis during aging. However, the dynamics and functions of immune cells in testicular aging have not been well elucidated. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to analyze CD45-enriched immune cells isolated from young and old mice testis. This approach yielded a comprehensive dataset comprising 6622 immune cells, encompassing macrophages, monocytes, and T cells. Our analysis revealed a significant decline...
Associations of external environment with life-space mobility among community-dwelling older adults: the potential mediating role of intrinsic capacity
CONCLUSIONS: The life-space mobility of older adults living in the community was moderately low. The external environment was associated with life-space mobility both directly and indirectly through intrinsic capacity. To improve the functional ability of community-dwelling older adults, attention should be given to enhancing their life-space mobility, optimizing the external environment, and strengthening intrinsic capacity. These efforts will contribute to achieving the goal of healthy aging.
REV-ERB-alpha and -beta coordinately regulate astrocyte reactivity and proteostatic function
The molecular circadian clock is a ubiquitous transcriptional-translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α (Nr1d1) and REV-ERB-β (Nr1d2) are components of the core circadian clock which regulate metabolism, neuroinflammatory responses, synaptic pruning, and protein aggregation, though the cell type-specific effects and relative compensatory effects of REV-ERB-α AND -β in the brain are unknown. To study...
Fn14 is an activity-dependent, Bmal1-regulated cytokine receptor that induces rod-like microglia and restricts neuronal activity in vivo
Cytokines and their receptors play important roles in brain development and aging-related disease, but their functions within the healthy adult brain remain poorly understood. Here, we show that pyramidal neurons in hippocampal CA1 induce Fn14 expression in response to activity and environmental enrichment. Once expressed, Fn14 dampens the activity of these neurons most prominently at the daily transition between light and dark. Fn14 expression in CA1 neurons is regulated by the circadian...
Early-life NAD(+) deficiency programs skeletal muscle aging by sustained suppression of hyaluronic acid synthesis beginning in childhood
Nicotinamide adenine dinucleotide (NAD^(+)) levels decline with age, which has been associated with the development of aging-associated diseases. However, it remains unknown whether low NAD^(+) levels in early life affect aging. This study demonstrates that deficiency of NAD synthetase (NADS), a critical enzyme of the deamidated NAD^(+) biosynthesis pathway, drastically reduced NAD^(+) levels in skeletal muscle and impaired muscle function at a young age. Intriguingly, NAD^(+) levels were...
Five energy metabolism pathways show distinct regional distributions and lifespan trajectories in the human brain
Energy metabolism involves a series of biochemical reactions that generate ATP, utilizing substrates such as glucose and oxygen supplied via cerebral blood flow. Energy substrates are metabolized in multiple interrelated pathways that are cell- and organelle-specific. These pathways not only generate energy but are also fundamental to the production of essential biomolecules required for neuronal function and survival. How these complex biochemical processes are spatially distributed across the...