Aggregator

Alzheimer's disease (AD) is a growing health problem worldwide, particularly in the developed world due to an ageing population. Glutamate excitotoxicity plays a major role in the pathophysiology of AD, and glutamate re-uptake is controlled by excitatory amino acid transporters (EAATs). The EAAT2 isoform is the predominant transporter involved in glutamate reuptake, therefore EAAT1 has not been the focus of AD research. We investigated the layer-specific expression of EAAT1 in human medial...

Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism-Dementia (Guam PD) and cultured neurons...

Metabotropic glutamate receptors (mGluRs) are widely expressed throughout the central nervous system. They are linked to G-protein coupled receptors and are known to modulate synaptic transmission. The data regarding their expression in auditory structures are not systematic and mainly originate from physiological studies where expression was used to support physiological findings. MGluRs are classified into three groups based on their sequence homology, G protein-coupling, and ligand...

Alzheimer's disease (AD) is a growing health problem worldwide, particularly in the developed world due to an ageing population. Glutamate excitotoxicity plays a major role in the pathophysiology of AD, and glutamate re-uptake is controlled by excitatory amino acid transporters (EAATs). The EAAT2 isoform is the predominant transporter involved in glutamate reuptake, therefore EAAT1 has not been the focus of AD research. We investigated the layer-specific expression of EAAT1 in human medial...

Skin aging, often called as premature skin aging, is the hastened deterioration of the skin resulting from multiple factors, including UV radiation, environmental contaminants, inadequate nutrition, stress, etc. Dietary phytochemicals, present in fruits, vegetables, and other plant-derived meals, have gained interest due to their efficiency to eradicate free radicals and lowering the release of inflammatory mediators which accounts for premature skin aging. Several dietary phytochemicals, i.e.,...

Macroautophagy/autophagy, an evolutionarily conserved cellular degradation pathway, involves phagophores that sequester cytoplasmic constituents and mature into autophagosomes for subsequent lysosomal delivery. The ATG8 gene family, comprising the MAP1LC3/LC3 and GABARAP/GBR subfamilies in mammals, encodes ubiquitin-like proteins that are conjugated to phagophore membranes during autophagosome biogenesis. A central question in the field is how Atg8-family proteins are precisely involved in...

No abstract

The geroscience hypothesis proposes that underlying biological processes, such as the accumulation of senescent cells, have deleterious effects on multiple tissues and increase the risk of many chronic conditions with aging. Senescent cells produce heterogenous biomarkers, also called senescence-associated secretory phenotype (SASP). Circulating concentrations of senescence biomarkers may reflect an underlying burden of senescent cells in various tissues. Plasma levels of these proteins have...

Extracellular vesicles (EVs) play crucial roles in aging. In this National Institutes on Aging-funded study, we sought to identify circulating extracellular vesicle (EV) biomarkers indicative of longevity. The plasma EV proteome of 48 older adults (mean age 77.2 ± 1.7 years [range 72-80]; 50% female, 50% Black, 50% < 2-year survival, 50% ≥ 10-year survival) was analyzed by high-resolution mass spectrometry and flow cytometry. The ability of EV peptides to predict longevity was evaluated in...

The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses Braf^(V600E) melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has...

Calorie restriction (CR) is a dietary intervention used to promote health and longevity^(1,2). CR causes various metabolic changes in both the production and the circulation of metabolites¹; however, it remains unclear which altered metabolites account for the physiological benefits of CR. Here we use metabolomics to analyse metabolites that exhibit changes in abundance during CR and perform subsequent functional validation. We show that lithocholic acid (LCA) is one of the metabolites that...

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk¹. Brain ageing is complex and is accompanied by many cellular changes². Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of...

Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing¹. However, the molecular details of how LCA activates AMPK and induces these biological effects are unclear. Here we show that LCA enhances the activity of sirtuins to deacetylate and subsequently inhibit vacuolar H^(+)-ATPase (v-ATPase), which leads to AMPK activation through the lysosomal glucose-sensing pathway. Proteomics analyses of proteins...

No abstract

No abstract

The pathological deposition of proteins is a hallmark of several devastating neurodegenerative diseases. These pathological deposits comprise aggregates of proteins that adopt distinct structures named strains. However, the molecular factors responsible for the formation of distinct aggregate strains are unknown. Here, we show that the serine/threonine kinase GSK3β catalyzes the aggregation of the protein tau into Alzheimer's disease (AD)-like filaments. We demonstrate that phosphorylation by...

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a...

Biological aging clocks produce age estimates that can track with age-related health outcomes. This study aimed to benchmark machine learning algorithms, including regularized regression, kernel-based methods, and ensembles, for developing metabolomic aging clocks from nuclear magnetic resonance spectroscopy data. The UK Biobank data, including 168 plasma metabolites from up to N = 225,212 middle-aged and older adults (mean age, 56.97 years), were used to train and internally validate 17...

But ancient DNA from bony lesions suggests original bacterial strains may not have spread sexually

CONCLUSION: Multimorbidity is strongly associated with accelerated kidney function decline in older age. Individuals with cardiometabolic multimorbidity exhibit a particularly increased risk. Increased monitoring and timely interventions may preserve kidney function and reduce cardiovascular risks in individuals presenting with conditions that are characteristic of high-risk multimorbidity patterns.