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A growing body of evidence implicates the menopausal transition as a neurobiological inflection point in women's brain aging and Alzheimer's disease (AD) vulnerability. Menopause is a midlife neuroendocrine transition characterized by a decline in sex steroid hormones and widespread systemic effects. The brain is not a passive recipient of ovarian hormones but an active endocrine-sensing organ. Menopause, however, does not act in isolation: the ovarian-brain axis is established embryonically,...

Oxidative stress and lipid peroxidation are increasingly recognized as age-related drivers of neurodegeneration, with Parkinson's disease (PD) representing a condition of heightened vulnerability. Among lipid peroxidation products, reactive aldehydes including 4-hydroxy-2-nonenal, malondialdehyde, acrolein, 4-hydroxy-2-hexenal, and crotonaldehyde have emerged not only as biomarkers of oxidative damage, but also as active mediators of neuronal dysfunction. Owing to their electrophilic nature,...

Cryogenic electron microscopy has revealed endpoint structures of ex vivo amyloid filaments, but how amyloids assemble and evolve in living organisms-and how these transitions affect physiology-remains poorly understood. Here, we map the age-dependent structural landscape of Orb2 amyloid, a synaptic translation regulator required for long-term memory, across the adult lifespan of Drosophila melanogaster. By determining multiple Orb2 amyloid structures, we uncover a dynamic, age-linked...

A growing body of evidence implicates the menopausal transition as a neurobiological inflection point in women's brain aging and Alzheimer's disease (AD) vulnerability. Menopause is a midlife neuroendocrine transition characterized by a decline in sex steroid hormones and widespread systemic effects. The brain is not a passive recipient of ovarian hormones but an active endocrine-sensing organ. Menopause, however, does not act in isolation: the ovarian-brain axis is established embryonically,...

Oxidative stress and lipid peroxidation are increasingly recognized as age-related drivers of neurodegeneration, with Parkinson's disease (PD) representing a condition of heightened vulnerability. Among lipid peroxidation products, reactive aldehydes including 4-hydroxy-2-nonenal, malondialdehyde, acrolein, 4-hydroxy-2-hexenal, and crotonaldehyde have emerged not only as biomarkers of oxidative damage, but also as active mediators of neuronal dysfunction. Owing to their electrophilic nature,...

CONCLUSION: This study provides the first multivariate genomic characterization of vascular ageing using Genomic SEM, uncovering loci newly implicated in vascular ageing, convergent putative causal genes, and cellular substrates that link vascular biology to systemic ageing and may inform precision prevention of age-related vascular disorders.

Chaperone-mediated autophagy (CMA), regulated by its lysosomal receptor LAMP2A, is a key pathway for αSynuclein (αSyn) clearance and a direct target of αSyn-related neurotoxicity. Rodent studies show that LAMP2A enhancement reverses neurodegeneration, whereas its deficiency accelerates pathology. To test translational relevance, we examined whether increasing LAMP2A expression in nonhuman primates could mitigate α-synucleinopathy induced by injections of Parkinson's disease patient-derived Lewy...

Cross-modal associative memory impairment is one of the earliest cognitive markers of neurodegenerative disorders and may be particularly sensitive to the detection of Mild Cognitive Impairment (MCI). The Italian Face-Name Association Test (ItFNAT) assesses face-name associative memory through immediate recall (IR), delayed free (DFR), and total recall (DTR), and qualitative indices. This study provides psychometric properties, discriminative capacity, and diagnostic accuracy in older adults. A...

Cells exhibit innate reparative communication, enabling the exchange of bioactive molecules and, in some cases, entire organelles. Harnessing this endogenous process of intercellular organelle transfer represents an emerging therapeutic paradigm for restoring cellular function in diseases driven by organelle dysfunction. Mitochondrial transfer has gained prominence for its ability to restore bioenergetic capacity, mitigate oxidative stress, and rescue metabolic function in cells with impaired...

CONCLUSION: Cognitive advantages observed in women in midlife did not translate into lower dementia risk. Further research incorporating biological, psychosocial and life-course factors, as well as the timing and heterogeneity of underlying disease processes, is needed to better understand sex differences in cognitive ageing and dementia.

The microstructure of cells within the human cerebral cortex varies across the cortical ribbon, where changes in cytoarchitecture and myeloarchitecture are thought to endow each region of the cortex with its unique function. While fine-scale relative to a cell, these changes at the population level impact architectural properties of the cortex measurable in vivo by noninvasive MRI, such as the thickness and myelin content of the cortex. This raises the question of whether or not we can use these...

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The human nigrostriatal pathway, comprising dopaminergic neurons in the ventral midbrain that project to the dorsolateral striatum, is essential for motor control and selectively vulnerable in Parkinson's disease. How this circuit assembles during human development remains poorly understood, and in vitro models capturing its long-range connectivity and spatial organization have been lacking. Here, we establish a compartmentalized, human stem cell-based model of the nigrostriatal pathway by...

CONCLUSIONS: Using a novel graph-based SV calling pipeline, we identify high-quality SVs across a large and ancestrally diverse cohort. Our analyses reveal both common and rare SVs associated with AD. These findings provide valuable insights into the genetic architecture of AD, emphasizing the value of including diverse populations in AD genomic studies.

Aberrant activation of the STING signaling pathway is involved with aging-related inflammation, yet no STING-targeting therapeutics are clinically approved. Here, we identify Omaveloxolone, an FDA-approved drug for Friedreich's ataxia, as a potent STING degrader (DC(50) = 118 nM, D(max) = 98.6%) via high-throughput screening. Omaveloxolone binds non-covalently to the base of the STING ligand-binding domain (LBD) with high affinity (K(D) = 21.4 nM) and exhibits crowbar-like behavior consistent...

During mitotic growth, Saccharomyces cerevisiae cells age by dividing asymmetrically, producing young daughter cells while retaining age-associated damage in the mother cell, which will eventually become senescent. Gametogenesis naturally and fully resets precursor cell lifespan, even for replicatively aged cells. However, the mechanisms responsible for gametogenic rejuvenation have remained mysterious. This is partly due to the existing methods to quantify lifespan resetting in this context,...

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In mammals, oocytes initiate meiosis during fetal development and then enter a prolonged meiotic arrest. During this female-specific long-term arrest, chromosome cohesion mediated by nonrenewable REC8 cohesin gradually deteriorates, predisposing oocytes to age-associated chromosome segregation errors when meiosis resumes for maturation in adulthood. Female-specific factors that counteract this deterioration remain unknown. Here we identify OMC1 as an oocyte-specific chromosomal protein required...

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CONCLUSION: Cognitive frailty is independently associated with a significantly increases elevated risk of hip fractures in older Chinese older adults, highlighting it as a clinically important and modifiable risk factor. These findings underscore the need for integrated screening protocols that simultaneously assess both cognitive and physical frailty in geriatric care settings.