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Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of...

Whether new neurons contribute to human cognition in old age remains debated. Recently in Cell Stem Cell, Tosoni et al.¹ show that immature-neuron transcriptional programs persist in the aged dentate gyrus and that their molecular state, not simply their abundance, tracks Alzheimer's pathology and cognitive resilience.

Lysine63 polyubiquitination is a prevalent post-translational modification in the central nervous system. Deficiency of CYLD, a lysine63-specific deubiquitinase, is linked to synaptic dysfunction and neurodegenerative disorders. However, our understanding of how CYLD contributes to the manifestation of neuronal deficits, particularly in the context of ageing, remains limited. Here, we report that CYLD-1 is essential for physiological lifespan in the nematode Caenorhabditis elegans. Neuronal...

The decline of glomerular filtration is a hallmark of aging. Methylglyoxal (MG) is a uremic toxin known to induce aging-like changes; however, whether its mechanism of action is similar remains unclear. We compare the underlying mechanisms of MG and aging using Drosophila nephrocytes as a model. In addition to lower body weight, reduced locomotion, and shorter lifespans, MG caused filtration defects and induced cellular senescence in nephrocytes similar to the effects of aging, with a...

CONCLUSIONS: EAA captures biological ageing signatures relevant to neurological disease, but interpretation is context dependent. Current evidence does not support routine clinical use. Improved standardisation and validation may clarify the role of epigenetic ageing in neurological disease vulnerability.

Older adults bear a substantial and increasing share of the cancer burden in Asia, yet its temporal trends, geographical heterogeneity, and inequalities remain insufficiently characterised. Using estimates from the Global Burden of Disease Study 2023, we assessed cancer incidence, mortality, and disability-adjusted life-years (DALYs) among adults aged 65 years and older across 34 Asian countries from 1990 to 2023, and examined demographic and epidemiological drivers, variations by location,...

Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of...

Mitochondrial dysfunction, impaired proteostasis, and reduced stress resistance and resilience are aging hallmarks. At the core of these hallmarks, the mitochondrial unfolded protein response (mtUPR) is a transcriptional pathway that restores mitochondrial proteostasis in response to proteotoxicity. Although the mtUPR is well studied in invertebrates and cell culture models, how the mtUPR is engaged in aged mammalian tissue is poorly defined. Here, we defined the extent to which repeated...

CONCLUSION: This study reveals immune dysregulation characterized by hyperinflammation-immunosenescence coexistence; a preliminary prediction model (TP, NLR, age, viral coinfection) requires prospective multicenter validation.

BACKGROUND: Existing research on social participation and later-life mental health often relies on fragmented classifications, pays insufficient attention to family-oriented contributory activities, and gives limited consideration to subgroup heterogeneity. To address these gaps, this study develops a contributory-developmental framework of social participation and examines the differential associations between various types of social participation and depressive symptoms among Chinese older...

A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes remain unclear. CXCL13 is a chemokine that shapes germinal center (GC) organization, but the regulation of human-specific CXCL13^(+) T follicular helper (Tfh) cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in Tfh cells, the cell type that provides help to B cells in...

The medial prefrontal cortex (mPFC) weighs options during decision-making, but its role in inferring competing emotional states and how this process changes with age, remain unclear. We recorded brain activity with functional MRI while 20 young and 40 older adults inferred the emotions of actors shown in ecological yet controlled social interactions. Socially shared representations about the timing, accuracy, and uncertainty of emotional inferences were defined using response distributions from...

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Aging research has made remarkable progress in describing aging through the genetic architecture of longevity, epigenetic clocks, proteomic signatures, and systems-level analyses. Yet a critical dimension remains underrepresented: the role of genome integrity, germline and somatic mutation accumulation in individual-specific vulnerability, frailty, and multimorbidity across the life course. The need for individual-level thinking has deep roots, from Darwin's emphasis on individual variation in...

Selective autophagy maintains organelle and proteome homeostasis through receptor-mediated degradation of damaged membranes and aggregation-prone proteins. Although autophagy dysfunction and endoplasmic reticulum (ER) abnormalities are prominent features of Alzheimer's disease (AD), whether reticulophagy directly contributes to amyloid precursor protein (APP) turnover has remained unclear. We identify FAM134B/RETREG1 as a specific receptor that recognizes ER-localized APP and promotes its...

CONCLUSIONS: Older Chinese adults in the UK exhibit diverse PA patterns and face a range of barriers, underscoring the need to consider their varied needs and experiences when designing interventions. Factors influencing PA engagement align with the COM-B framework, highlighting the importance of addressing capability, opportunity, and motivation. These findings provide a practical evidence base to inform behaviour change interventions, supporting the development of culturally tailored...

CONCLUSION: Long-term PA shows a clear dose-response relationship with sarcopenia risk in later life. While sustained activity across adulthood confers the greatest benefit, initiating PA even later in life remains associated with lower odds of sarcopenia.

Arterial stiffness is a hallmark of vascular aging and a major risk factor for cardiovascular disease. While immune aging-typically characterized by reduced T cell receptor (TCR) diversity and CD8^(+) memory expansion-contributes to this process, growing evidence suggests that peripheral immune dysregulation may impair vascular function through mechanisms distinct from classical immunosenescence. To investigate this, we profiled peripheral TCRβ repertoires from 563 adults without clinically...

A newly discovered genetic clock acts as the master timekeeper for development, orchestrating crucial bursts of gene activity throughout a worm’s growth. When the clock is disrupted, development stops, offering fresh clues about how growth-related disorders may arise.