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The complexity of Alzheimer's disease (AD) manifests in diverse clinical phenotypes, including cognitive impairment and neuropsychiatric symptoms. However, the etiology of these phenotypes remains elusive. To address this, the PsychAD project generated a population-level single-nucleus RNA sequencing dataset comprising over 6 million nuclei from the prefrontal cortex of >1,000 individual brains, covering a variety of disease phenotypes. Here, leveraging this dataset, we developed a computational...

Nearly a century ago, restricting diet during early-life periods was suggested to extend lifespan in rats and in Daphnia^(1,2). The effect of juvenile diet on adult physiology and lifespan has subsequently been described in other model organisms, including fruit flies^(3-5) and mice^(6-8); however, its mechanism remains poorly understood. Here, using Drosophila as a model, we show that restricting protein intake during the larval stage (early-life protein restriction; ePR) promotes adult...

Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing¹. mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor²; however, this function of mTORC1 is resistant to rapamycin inhibition³. TOP mRNAs are exceptionally abundant, and thus impose a...

Centuries ago, Thomas Sydenham famously wrote, "A man is as old as his arteries", highlighting the importance of the vasculature for health and healthy aging. Here, we review recent developments in vascular aging research, focusing on how microvascular aging drives tissue dysfunction and the emerging therapeutic opportunities for vascular rejuvenation. Although macrovascular aging has long been studied, microvascular aging remains an emerging frontier. Recent single-cell and multiomic...

Changes in cell type composition play an important role in human health and disease. Recent advances in single-cell technology have enabled the measurement of cell type composition at increasing cell lineage resolution across large cohorts of individuals. Yet this raises new challenges for statistical analysis of these compositional data to identify changes in cell type frequency. We introduce crumblr ( DiseaseNeurogenomics.github.io/crumblr ), a scalable statistical method for analyzing count...

Disrupted rest-activity rhythms have been associated with aging and chronic disease, yet longitudinal evidence from free-living populations has been lacking. Here we integrate multi-year Fitbit activity data from the All of Us Research Program with clinical biomarker-derived PhenoAge from 2,222 participants (8,447 person-years). Through high-dimensional digital phenotyping, we show that circadian rest-activity rhythm intensity, timing, and stability are associated with biological aging...

The human brain undergoes profound changes from early development through late adulthood, shaping cognition, behaviour and vulnerability to disease^(1,2). Understanding how these changes are organized within specific brain regions and cell types is essential for interpreting normal ageing and its relationship to psychiatric and neurodegenerative disorders. The dorsolateral prefrontal cortex has a central role in higher cognitive functions and is particularly sensitive to age-related decline³,...

Neurodegenerative and neuropsychiatric diseases impose a considerable societal and public health burden. However, our understanding of the molecular mechanisms underlying these highly complex conditions remains limited^(1,2). Here, to gain deeper insights into the aetiology of different brain diseases, we used specimens from 1,494 unique donors to generate a population-scale single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, comprising over 6.3 million individual...

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Parkinson's disease (PD) is characterized by abnormal oscillatory activity and altered interregional coupling within the cortico-subthalamic (M1-STN) circuit. Transcranial magneto-acoustic stimulation (TMAS) combines focused ultrasound with a static magnetic field, but its modeled physical responses and circuit-level effects remain incompletely characterized. We integrated multiphysics simulations with behavioral testing, simultaneous M1-STN local field potential recordings, Golgi-Cox staining,...

Chronic inflammation is a common feature of aging and is observed across various age-related neurodegenerative diseases, including Alzheimer's disease (AD). Diffusion magnetic resonance imaging (dMRI) metrics of white matter microstructure are hypothesized to be sensitive to inflammation, though few studies have assessed this relationship in non-clinical populations. This cross-sectional study of 457 dementia-free older adults (M(age)=63.82) examined associations of plasma markers related to...

Studies of centenarians and supercentenarians provide insight into aging and substrates of cognitive impairment at the extreme limits of age. In this study, we examined pathologic findings in 15 centenarians (99-109 years) and 7 supercentenarians (111-115 years) who underwent autopsy at our institution during a 25-year period between 2000 and 2025 and compared them with a cohort of 24 older adults (70-90 years) who underwent autopsy during 2024-2025. Of the 22 centenarians and supercentenarians,...

BACKGROUND: Skin aging is driven by multiple interconnected pathological processes. However, existing evidence remains fragmented across studies of individual mechanisms and compounds, hindering the discovery of novel targets and the repurposing of established drug targets.This review systematically summarizes the fundamental mechanisms and categorizes current antiaging pharmacological strategies corresponding to these mechanisms, aiming to provide a theoretical framework for future drug...

Alzheimer's disease is widely conceptualized as a biological continuum initiated by amyloid-β (Aβ) accumulation, followed by tau aggregation and neurodegeneration. Although the ATN framework is commonly used to define disease stages, its static biomarker categories may not fully capture the dynamic pathological transitions that determine the optimal window for anti-Aβ therapies. Here, we introduce a Biological Continuum framework that distinguishes dynamic pathological cascades from static...

Exosomes offer a promising vehicle for noninvasive diagnosis of neurodegenerative diseases by carrying multiple biomarkers across the blood-brain barrier. However, traditional exosome analysis often misses subtle genotype-specific variations because of weak signals from a few exosomes, reliance on markers, and limited understanding of disease signatures. Here, we present a sound way to understand Alzheimer's disease through label-free surface-enhanced Raman scattering (SERS) profiling of...

The ketogenic diet (KD) elevates β-hydroxybutyrate (β-HB), an energy metabolite and signaling molecule with immunomodulatory effects, and has been associated with cognitive and metabolic effects in some preclinical and clinical studies. However, clinical evidence for ketogenic and ketone-based interventions in cognitive aging and Alzheimer's disease remains mixed, and long-term carbohydrate restriction may be difficult to implement in older adults. Dietary supplements that elevate β-HB, such as...

Spontaneous neuronal oscillations support large-scale brain communication and are sensitive to adult aging, yet how their moment-to-moment dynamics change across the adult lifespan and relate to cognition remains unclear. Here, we used resting-state magnetoencephalography (MEG) and time-delay embedded hidden Markov modelling to characterize transient oscillatory brain states in 617 healthy adults aged 18-88 years. Aging was associated with a frequency- and region-specific reorganization of...

Age is a critical determinant of COVID-19 severity, yet the underlying metabolic mechanisms driving disease progression remain poorly understood. Using a well-characterized Syrian hamster model, we investigated how aging shapes intestinal and systemic sterol metabolism during SARS-CoV-2 infection. Young (7-10 weeks) and aged (12 months) hamsters were intranasally infected, and clinical outcomes were integrated with virological, histopathological, and lipidomic profiles across intestinal tissues,...

CONCLUSIONS: Better CVH, as measured by the LE8 score, was associated with fewer and a slower accumulation of age-related health deficits in older adults. These findings suggest that promoting CVH may help delay functional decline and support healthier aging trajectories.