aging hallmark

Amyloid plaques composed of fibrils of misfolded Aβ peptides are pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aβ fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how Aβ fibril structures in situ differ in Aβ plaque of different mouse models expressing familial mutations in the AβPP gene...

Denervated myofibers and senescent cells are hallmarks of skeletal muscle aging. However, sparse research has examined how resistance training affects these outcomes. We investigated the effects of unilateral leg extensor resistance training (2 days/week for 8 weeks) on denervated myofibers, senescent cells, and associated protein markers in apparently healthy middle-aged participants (MA, 55 ± 8 years old, 17 females, 9 males). We obtained dual-leg vastus lateralis (VL) muscle cross-sectional area (mCSA), VL biopsies, and strength assessments before and after training...

Human ageing, along with the ageing of conventional model organisms, is depicted as a continuous and progressive decline of biological capabilities accompanied by an exponentially increasing mortality risk. However, not all organisms experience ageing identically and our understanding of the phenomenon is coloured by human-centric views. Ageing is multifaceted and influences a diverse range of species in varying ways. Some undergo swift declines post-reproduction, while others exhibit insubstantial changes throughout their existence...

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice...

Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks...

During aging, microglia - the resident macrophages of the brain - exhibit dystrophic phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia dystrophy have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis...

Studies of the aging transcriptome focus on genes that change with age. But what can we learn from age-invariant genes-those that remain unchanged throughout the aging process? These genes also have a practical application: they serve as reference genes (often called housekeeping genes) in expression studies. Reference genes have mostly been identified and validated in young organisms, and no systematic investigation has been done across the lifespan. Here, we build upon a common pipeline for identifying reference genes in RNA-seq datasets to identify age-invariant genes across seventeen C57BL/6 mouse tissues (brain, lung, bone marrow, muscle, white blood cells, heart, small intestine, kidney, liver, pancreas, skin, brown, gonadal, marrow, and subcutaneous adipose tissue) spanning 1 to 21+ months of age...

In the last decade cellular senescence, a hallmark of aging, has come into focus for pharmacologically targeting aging processes. Senolytics are one of these interventive strategies that have advanced into clinical trials, creating an unmet need for minimally invasive biomarkers of senescent cell load to identify patients at need for senotherapy. We created a landscape of miRNA and mRNA expression in five human cell types induced to senescence in-vitro and provide proof-of-principle evidence that miRNA expression can track senescence burden dynamically in-vivo using transgenic p21 high senescent cell clearance in HFD fed mice...

Background : A prominent hallmark of aging is inflammaging-the increased expression of innate immune genes without identifiable infection. Model organisms with shorter lifespans, such as the fruit fly, provide an essential platform for probing the mechanisms of inflammaging. Multiple groups have reported that, like mammalian models, old flies have significantly higher levels of expression of anti-microbial peptide genes. However, whether some of these genes-or any others-can serve as reliable markers for assessing and comparing inflammaging in different strains remains unclear...

Cataracts are one of the leading causes of blindness, with an estimated 95 million people affected worldwide. A hallmark of cataract development is lens opacification, typically associated not only with aging but also radiation exposure as encountered by interventional radiologists and astronauts during the long-term space mission. To better understand radiation-induced cataracts, the adverse outcome pathway (AOP) framework was used to structure and evaluate knowledge across biological levels of organization (e...

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment...

AIMS: The vascular aging process accelerated by type 2 diabetes mellitus (T2DM) is responsible for the elevated risk of associated cardiovascular diseases (CVDs). Metabolic disorder-induced immune senescence has been implicated in multi-organ/tissue damage. Herein, we sought to determine the role of immunosenescence in diabetic vascular aging and to investigate the underlying mechanisms. METHODS AND RESULTS: Aging hallmarks of the immune system appear prior to the vasculature in streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM mice or db/db mice...

Copper (Cu) dyshomeostasis has been linked to obesity and related morbidities and also to aging. Cu levels are higher in older or obese individuals, and adipose tissue (AT) Cu levels correlate with body mass index. Aging and obesity induce similar AT functional and structural changes, including an accumulation of senescent cells. To study the effect of Cu-mediated stress-induced premature senescent (Cu-SIPS) on preadipocytes, 3T3-L1 cell line was exposed to a subcytotoxic concentration of copper sulfate. After Cu treatment, preadipocytes acquired typical senescence characteristics including diminished cell proliferation, cell and nuclei enlargement and increased lysosomal mass (higher Lamp2 expression and a slight increased number of cells positive for β-galactosidase associated with senescence (SA-β-Gal))...

Mantle cell lymphoma (MCL) is a rare, incurable non-Hodgkin's lymphoma characterized by naive B cells infiltrating the lymphoid follicle's mantle zone. A key feature of MCL is the cytogenetic abnormality t(11;14) (q13:q14), found in 95% of cases, leading to Cyclin D1 overexpression resulting in uncontrolled cell cycle progression and genetic instability. Occasionally, Cyclin D2 or D3 overexpression can substitute for Cyclin D1, causing similar effects. The transcription factor SOX11 is a hallmark of classical Cyclin D1-positive MCL and also in cases without the typical t(11;14) abnormality, making it an important diagnostic marker...

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that severely affects patients and their families. Genetic and environmental risk factors, such as viral infections, synergize to accelerate the aging-associated neurodegeneration. Genetic risk factors for late-onset AD (LOAD), which accounts for most AD cases, are predominantly implicated in microglial and immune cell functions. As such, microglia play a major role in formation of amyloid beta (Aβ) plaques, the major pathological hallmark of AD...

Tau, a hallmark of Alzheimer's disease, is poorly characterized in cerebral amyloid angiopathy. We aimed to assess the clinico-radiological correlations between tau positron emission tomography scans and cerebral amyloid angiopathy. We assessed cerebral amyloid and hyperphosphorylated tau in patients with probable cerebral amyloid angiopathy ( n = 31) and hypertensive small vessel disease ( n = 27) using 11 C-Pittsburgh compound B and 18 F-T807 positron emission tomography. Multivariable regression models were employed to assess radio-clinical features related to cerebral tau pathology in cerebral amyloid angiopathy...

Vacuole formation is a key hallmark of age-dependent neurodegeneration in the Drosophila brain. Here, we present a protocol to analyze 3D neurodegenerative vacuoles in the whole-mount Drosophila melanogaster brain. We describe steps for whole-brain dissection, staining, 3D imaging, and z-stack image processing using Fiji ImageJ. We then detail procedures for annotating and 3D-reconstructing neurodegenerative vacuoles with WEBKNOSSOS and Python, and performing statistical analysis in Python. This protocol enables measurement of parameters such as the number and volume of each vacuole...

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight...

The efficacy of current treatments is still insufficient for Alzheimer's disease (AD), the most common cause of Dementia. Out of the two pathological hallmarks of AD amyloid-β plaques and neurofibrillary tangles, comprising of tau protein, tau pathology strongly correlates with the symptoms of AD. Previously, screening for inhibitors of tau aggregation that target recombinant tau aggregates have been attempted. Since a recent cryo-EM analysis revealed distinct differences in the folding patterns of heparin-induced recombinant tau filaments and AD tau filaments, this study focused on AD seed-dependent tau aggregation in drug repositioning for AD...

Cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene that encodes cystinosin, a ubiquitous lysosomal cystine/H+ antiporter. The hallmark of the disease is progressive accumulation of cystine and cystine crystals in virtually all tissues. At the kidney level, human cystinosis is characterized by the development of renal Fanconi syndrome and progressive glomerular and interstitial damage leading to end-stage kidney disease in the second or third decade of life. The exact molecular mechanisms involved in the pathogenesis of renal disease in cystinosis are incompletely elucidated...