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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...

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...

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...

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...

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 (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...

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 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...

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...

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.

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...

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...

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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...

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.

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...

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...

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...

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...