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Method of replacing much of the mouse cortex with human “organoids” enables studies of brain diseases in a living nervous system

The role of physical fitness in cognitive reserve and brain maintenance remains unclear. We investigated the associations of muscular and aerobic fitness (VO(2)max) with markers of brain health and cognition in 353 cognitively unimpaired older adults (mean age = 72.77 ± 7.95 years; 177 females). Muscular fitness comprised handgrip strength, appendicular skeletal muscle mass, and Timed-Up-and-Go performance. Blood biomarkers of Alzheimer's pathology (Aβ(1-42)/Aβ(1-40), p-tau(217), GFAP) and...

Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer's disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer's disease and exists in common variants that confer decreased, neutral, or increased risk. Here we...

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Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and...

Hutchinson‑Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by mutations in the LMNA gene. High mobility group A1 (HMGA1) exhibits differential expression patterns across aging models. However, its roles and mechanisms in aging remain unclear. Here, we show a positive correlation between HMGA1 and the heterochromatin protein HP1β in multiple tissues of Lmna^(G609G/G609G), a classic genetic mouse model of HGPS to recapitulate typical premature aging features, and...

Intracellular pathogens are ideal candidates for modelling the pathophysiology of chronic infection, as they hide within host cells and avoid immune clearance by reshaping cellular fate. This study unveils how the intracellular pathogen Mycobacterium abscessus (Mab) reprograms alveolar macrophages towards a senescent state -a multifaced phenotype marked by proliferative arrest, distinctive morphological shifts, activation of DNA damage signalling cascade, and secretion of senescence-associated...

Chronic activation of the cGAS-STING pathway drives inflammaging and cellular senescence. Although nuclear envelope (NE) barrier failure leading to cytoplasmic chromatin leakage is a key trigger, the molecular mechanisms governing STING activity at the NE during aging remain poorly understood. Here, we identify lamin A/C (LMNA) as a critical NE scaffold that orchestrates STING regulation by recruiting both STING and Casein Kinase 2 (CK2α). We demonstrate that LMNA facilitates the phosphorylation...

Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated...

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Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and...

Age-related neurodegenerative diseases are characterized by progressive DNA damage in post-mitotic neurons against a backdrop of deteriorating circadian rhythms, yet the molecular link between these conjoined features of brain aging remains unclear. We propose the TyrRS cascade as that link: a signaling architecture in which the noncanonical nuclear functions of tyrosyl-tRNA synthetase (TyrRS/YARS1) schedule neuronal genome maintenance across the day through three coregulated streams,...

The accumulation of lipid droplets in microglia has been reported to increase in response to ageing and age-related diseases like Alzheimer's disease. The present study investigates changes in lipid droplet dynamics with increasing age in the mouse and the similarly sized long-lived rodent, the naked mole rat (Heterocephalus glaber). We show that the naked mole rat contains large amounts of microglial lipid droplets in the CA1 and CA3 region of the hippocampus with an age-dependent increase in...

Mild cognitive impairment (MCI) is an important prodromal stage of Alzheimer's disease, and its early identification is critical for risk assessment and timely intervention. Resting-state functional magnetic resonance imaging (rs-fMRI) can noninvasively characterize brain functional activity and connectivity. However, most existing methods rely on static second-order functional connectivity, limiting their ability to capture dynamic coordination and high-order interactions among multiple brain...

Alzheimer's disease is widely depicted as a linear cascade from amyloid-β accumulation to Tau pathology and neurodegeneration. We propose instead that the disease unfolds through discrete molecular, cellular and network phases organized around biological inflection points. At these thresholds, stress-driven loss of homeostasis produces qualitative shifts in cellular behavior that alters disease progression. These altered states spread across local tissue-domains, accumulate as a mosaic across...

Apolipoprotein E (APOE) genotype is the strongest genetic determinant of late-onset Alzheimer's disease (AD) risk. Of its three common isoforms, E4 increases AD risk and promotes inflammatory and metabolic dysregulation, whereas E2 is protective and is associated with altered lipid handling and immune function. Microglia express APOE in response to stress or injury and exhibit isoform-dependent transcriptional profiles, but the specific contribution of microglial APOE to these phenotypes remains...

N-terminal acetylation (NTA) is a ubiquitous eukaryotic post-translational modification catalyzed by Nα-acetyltransferases (NATs). Among the eight NAT families, the NatA complex-composed of the catalytic subunit NAA10 and auxiliary subunit NAA15-mediates N-terminal acetylation of ~40% of mammalian proteins. Pathogenic mutations in NAA10 or NAA15 disrupt NatA complex integrity or enzymatic activity, resulting in NAA10- or NAA15-related syndromes. Both disorders share overlapping clinical...

Dysregulated dopamine (DA) signaling and redox homeostasis contributes to multiple neuropsychiatric and neurodegenerative disorders. Polymorphisms that influence the activity of catechol-O-methyltransferase (COMT), an enzyme critical for degrading DA in the dorsolateral prefrontal cortex, have been implicated in behavioral and neuropsychiatric alterations associated with schizophrenia (SCZ). Adverse neuropsychiatric effects have also been reported in Parkinson's disease (PD) patients...

Aging is accompanied by molecular hallmarks conserved from yeast to humans. One such hallmark, senescence, is an irreversible nondividing state that promotes aging. We previously reported that mutants of the yeast Anaphase Promoting Complex (APC) shorten the lifespan of both dividing and nondividing cells. Here, we propose that activation of the APC will promote the maintenance of quiescent yeast cells, thereby delaying senescence and aging. We observed that APC activity in aging quiescent cells...