Aging, Lifespan & Longevity

Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer's disease

9 hours 23 minutes ago
Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer's disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic...
Julie C Lauterborn

Fostering healthy aging: the interdependency of infections, immunity and frailty

1 day 9 hours ago
Untangling the interdependency of infections, immunity and frailty may help to clarify their roles in the maintenance of health in aging individuals, and the recent COVID-19 pandemic has further highlighted such priority. In this scoping review we aimed to systematically collect the evidence on 1) the impact of common infections such as influenza, pneumonia and varicella zoster on frailty development, and 2) the role played by frailty in the response to immunization of older adults. Findings are...
Davide L Vetrano

Spermidine inhibits vascular calcification in chronic kidney disease through modulation of SIRT1 signaling pathway

1 day 9 hours ago
Vascular calcification is a common pathologic condition in patients with chronic kidney disease (CKD) and aging individuals. It has been established that vascular calcification is a gene-regulated biological process resembling osteogenesis involving osteogenic differentiation. However, there is no efficient treatment available for vascular calcification so far. The natural polyamine spermidine has been demonstrated to increase life span and protect against cardiovascular disease. It is unclear...
Xiaoyu Liu

The changing health needs of the UK population

2 days 9 hours ago
The demographics of the UK population are changing and so is the need for health care. In this Health Policy, we explore the current health of the population, the changing health needs, and future threats to health. Relative to other high-income countries, the UK is lagging on many health outcomes, such as life expectancy and infant mortality, and there is a growing burden of mental illness. Successes exist, such as the striking improvements in oral health, but inequalities in health persist as...
Martin McKee

Purifying selection on noncoding deletions of human regulatory loci detected using their cellular pleiotropy

3 days 9 hours ago
Genomic deletions provide a powerful loss-of-function model in noncoding regions to assess the role of purifying selection on genetic variation. Regulatory element function is characterized by nonuniform tissue and cell type activity, necessarily linking the study of fitness consequences from regulatory variants to their corresponding cellular activity. We generated a callset of deletions from genomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used deletions from The 1000...
David W Radke

Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

3 days 9 hours ago
GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression...
Sukhleen Kour

The quest to understand aging during and after COVID-19

4 days 9 hours ago
Over the past year, Cell Stem Cell has introduced early-career researchers impacted by the COVID-19 pandemic and subsequent closures to our readers. One year since our first introductions, we've invited several participants to reflect on their experiences and key issues. In this Story, Weiqi Zhang discusses her lab's research focus and how they found opportunities during COVID-19 shutdowns to provide new resources for the aging research community.
Weiqi Zhang

AHNAK controls 53BP1-mediated p53 response by restraining 53BP1 oligomerization and phase separation

4 days 9 hours ago
p53-binding protein 1 (53BP1) regulates both the DNA damage response and p53 signaling. Although 53BP1's function is well established in DNA double-strand break repair, how its role in p53 signaling is modulated remains poorly understood. Here, we identify the scaffolding protein AHNAK as a G1 phase-enriched interactor of 53BP1. We demonstrate that AHNAK binds to the 53BP1 oligomerization domain and controls its multimerization potential. Loss of AHNAK results in hyper-accumulation of 53BP1 on...
Indrajeet Ghodke

TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs

4 days 9 hours ago
53BP1 influences genome stability via two independent mechanisms: (1) regulating DNA double-strand break (DSB) repair and (2) enhancing p53 activity. We discovered a protein, Tudor-interacting repair regulator (TIRR), that associates with the 53BP1 Tudor domain and prevents its recruitment to DSBs. Here, we elucidate how TIRR affects 53BP1 function beyond its recruitment to DSBs and biochemically links the two distinct roles of 53BP1. Loss of TIRR causes an aberrant increase in the gene...
Nishita Parnandi

BRAF(V600E)-induced senescence drives Langerhans cell histiocytosis pathophysiology

4 days 9 hours ago
Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAF^(V600E). We recently discovered that the BRAF^(V600E) mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAF^(V600E) mutation in HPCs leads to LCH is not...
Camille Bigenwald

Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease

4 days 9 hours ago
Selective neurodegeneration is a critical causal factor in Alzheimer's disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of ApoE-which has a robust genetic linkage to AD-correlated strongly, on a cell-by-cell...
Kelly A Zalocusky

Common genetic associations between age-related diseases

4 days 9 hours ago
Age is a common risk factor in many diseases, but the molecular basis for this relationship is elusive. In this study we identified 4 disease clusters from 116 diseases in the UK Biobank data, defined by their age-of-onset profiles, and found that diseases with the same onset profile are genetically more similar, suggesting a common etiology. This similarity was not explained by disease categories, co-occurrences or disease cause-effect relationships. Two of the four disease clusters had an...
Handan Melike Dönertaş

5-HT6R null mutatrion induces synaptic and cognitive defects

4 days 9 hours ago
Serotonin 6 receptor (5-HT6R) is a promising target for a variety of human diseases, such as Alzheimer's disease (AD) and schizophrenia. However, the detailed mechanism underlying 5-HT6R activity in the central nervous system (CNS) is not fully understood. In the present study, 5-HT6R null mutant (5-HT6R^(-/-) ) mice were found to exhibit cognitive deficiencies and abnormal anxiety levels. 5-HT6R is considered to be specifically localized on the primary cilia. We found that the loss of 5-HT6R...
Zehui Sun

Acceleration of ageing via disturbing mTOR-regulated proteostasis by a new ageing-associated gene PC4

5 days 9 hours ago
Research on ageing-associated genes is important for investigating ageing and anti-ageing strategies. Here, we firstly reported that the human positive cofactor 4 (PC4), a multifunctional and highly conserved nucleoprotein, is accumulated and activated during ageing and causes global accelerated ageing process by disrupting proteostasis. Mechanistically, PC4 interacts with Sin3-HDAC complex and inhibits its deacetylated activity, leads to hyper-acetylation of the histones at the promoters of...
Long Chen

Oocyte-derived microvilli control female fertility by optimizing ovarian follicle selection in mice

5 days 9 hours ago
Crosstalk between oocytes and surrounding somatic cells is crucial for mammalian oogenesis, but the structural mechanisms on oocytes to control female reproduction remain unknown. Here we combine endogenous-fluorescent tracing mouse models with a high-resolution live-cell imaging system to characterize oocyte-derived mushroom-like microvilli (Oo-Mvi), which mediate germ-somatic communication in mice. We perform 3D live-cell imaging to show that Oo-Mvi exhibit cellular characteristics that fit an...
Yan Zhang

Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer's disease

5 days 9 hours ago
Alzheimer's disease (AD) is a leading cause of dementia in elderly individuals and therapeutic options for AD are very limited. Over-activation of N-methyl-D-aspartate (NMDA) receptors, amyloid β (Aβ) aggregation, a decrease in cerebral blood flow (CBF), and downstream pathological events play important roles in the disease progression of AD. In the present study, MN-08, a novel memantine nitrate, was found to inhibit Aβ accumulation, prevent neuronal and dendritic spine loss, and consequently...
Liangmiao Wu
4 hours 9 minutes ago
Aging, Lifespan & Longevity
(Rejuvenation[TitleAbstract] OR Rejuvenate[TitleAbstract] OR Senescent[TitleAbstract] OR Senescence[TitleAbstract] OR Aging[TitleAbstract] OR Ageing[TitleAbstract] OR Lifespan[TitleAbstract] O…: Latest results from PubMed
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