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Apolipoprotein E (ApoE) mediates the bidirectional transport of lipids between cells. In the brain, this includes the transfer of lipids from neurons to glia. ApoE4, a major risk factor for Alzheimer's disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) confer resistance to disease, yet little is known regarding how these variants affect lipid trafficking. Here, we explored how lipoprotein particles containing different ApoE...

Using natural experiments, we have previously reported that live-attenuated herpes zoster (HZ) vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, we find that HZ vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. Exploratory analyses suggest that the effects are not driven by a specific dementia type. Our approach takes advantage of the fact that individuals who had...

Cognitive impairment in people with Parkinson disease (PD) imposes a substantial societal burden: PD affects over 1% of the population aged 65 years and older, and 24-31% of individuals with this condition develop dementia and another 26% present with mild cognitive impairment. Given the increasing prevalence of PD in light of an ageing population, the challenge of PD-associated cognitive impairment is likely to intensify. In this Review, we highlight the latest research advances in...

One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are...

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Brain aging is a major factor in cognitive decline and Alzheimer's disease (AD) progression. Aging-induced microglial senescence critically drives inflammaging and brain aging processes. Nevertheless, the underlying reasons and mechanisms that promote microglial aging remain unclear. This study explores how 27-hydroxycholesterol (27-OHC), a key oxysterol, accelerates brain aging by promoting microglial senescence, iron overload, and neuroinflammation. Clinically, we observed a significant...

The aging brain exhibits an increased inflammatory potential which in turn elicits behavioral changes e.g., social withdrawal. Social isolation is a risk factor for additional health complications, and interventions which can mitigate these negative facets of aging can improve longevity and quality of life in old age. The circadian system critically regulates neuroimmune function and behavior, but circadian rhythms also degrade with age, resulting in lower amplitude oscillations in activity and...

Torque teno virus (TTV) is a ubiquitous virus whose viremia increases in conditions of immune dysfunction and aging, suggesting its potential role as a biomarker of immunosenescence. This study investigated the association between TTV viremia and all-cause mortality risk over seven years in a hospitalized older cohort, and its relationship with inflammatory markers including osteopontin (OPN) and growth differentiation factor 15 (GDF15). Data from 956 patients were analyzed, with high TTV load...

CONCLUSIONS: Elevated serum Cu/Zn ratio predicts adverse outcomes and sarcopenia, highlighting its value as a biomarker for clinical risk in older adults.

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial...

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, but the molecular mechanisms underlying its course remain incompletely understood. We measured 4789 cerebrospinal fluid proteins in 1040 samples from 438 individuals with MS and controls followed longitudinally. To isolate disease-related biology, we adjusted for normal aging, sex, while also measuring residual effects of demographic and genetic covariates. Here we show that 3714 proteins are significantly...

Cognitive impairment in people with Parkinson disease (PD) imposes a substantial societal burden: PD affects over 1% of the population aged 65 years and older, and 24-31% of individuals with this condition develop dementia and another 26% present with mild cognitive impairment. Given the increasing prevalence of PD in light of an ageing population, the challenge of PD-associated cognitive impairment is likely to intensify. In this Review, we highlight the latest research advances in...

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CONCLUSIONS: This study highlights significant gaps in knowledge, training, and interdisciplinary collaboration in the care of OAWH. While both geriatricians and HIV specialists recognize the unique needs of this population, barriers such as insufficient training and role ambiguity hinder progress. Our findings support earlier, biologically informed interventions and integration of geriatrics into routine HIV care; targeted training and institutional support appear warranted.

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing...

The Alzheimer's disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine-based inhibitory motif domain-containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective...

In the later stages of Parkinson's disease, patients often manifest levodopa-induced dyskinesia (LID), compromising their quality of life. The pathophysiology underlying LID is poorly understood, and treatment options are limited. To move toward filling this treatment gap, the intrinsic and synaptic changes in striatal spiny projection neurons (SPNs) triggered by the sustained elevation of dopamine (DA) during dyskinesia were characterized using electrophysiological, pharmacological, molecular,...

Neurofluids, including cerebrospinal fluid (CSF) and interstitial fluid, circulate through regulated central nervous system pathways to clear cerebral waste and support brain health, with elevated CSF flow hyperdynamicity and regurgitation through the cerebral aqueduct associating with aging and neurodegeneration. Sleep exerts state-dependent effects on neurofluid circulation, yet similar modulation during unique waking states, such as meditation, remains underexplored. Notably, mindfulness...

Aberrant proteostasis in alveolar type 2 epithelial cells (AEC2s) contributes to idiopathic pulmonary fibrosis (IPF), but the role of the ubiquitin-proteasome system (UPS) is unclear. Here, we show that UPS disruption in AEC2s amplifies profibrotic signaling to macrophages through macrophage migration inhibitory factor (MIF) family proteins in several models. Modeling UPS disruption with an AEC2-specific cullin 3 (Cul3) deletion produced spontaneous fibrosis in a physiological aging mouse model...

Alzheimer's disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice....