Aging, Lifespan & Longevity

Non-enzymatic function of WRN RECQL helicase regulates removal of topoisomerase-I-DNA covalent complexes and triggers NF-κB signaling in cancer

18 hours 51 minutes ago
Mutation in Werner (WRN) RECQL helicase is associated with premature aging syndrome (Werner syndrome, WS) and predisposition to multiple cancers. In patients with solid cancers, deficiency of the WRN RECQL helicase is paradoxically associated with enhanced overall survival in response to treatment with TOP1 inhibitors, which stabilize pathological TOP1-DNA-covalent-complexes (TOP1cc) on the genome. However, the underlying mechanism of WRN in development of chemoresistance to TOP1 inhibitors is...
Pooja Gupta

DNA methylation clocks for dogs and humans

1 day 18 hours ago
SignificanceEpigenetic estimators of age (known as clocks) allow one to identify interventions that slow or reverse aging. Previous epigenetic clocks only applied to one species at a time. Here, we describe epigenetic clocks that apply to both dogs and humans. These clocks, which measure methylation levels in highly conserved stretches of the DNA, promise to increase the likelihood that interventions that reverse epigenetic age in one species will have the same effect in the other.
Steve Horvath

Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation

1 day 18 hours ago
Mammals differ more than 100-fold in maximum lifespan. Here, we conducted comparative transcriptomics on 26 species with diverse lifespans. We identified thousands of genes with expression levels negatively or positively correlated with a species' maximum lifespan (Neg- or Pos-MLS genes). Neg-MLS genes are primarily involved in energy metabolism and inflammation. Pos-MLS genes show enrichment in DNA repair, microtubule organization, and RNA transport. Expression of Neg- and Pos-MLS genes is...
J Yuyang Lu

Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis

1 day 18 hours ago
Cleavage of membrane proteins in the lipid bilayer by intramembrane proteases is crucial for health and disease. Although different lipid environments can potently modulate their activity, how this is linked to their structural dynamics is unclear. Here we show that the carboxy-peptidase-like activity of the archaeal intramembrane protease PSH, a homolog of the Alzheimer's disease-associated presenilin/γ-secretase is impaired in micelles and promoted in a lipid bilayer. Comparative molecular...
Lukas P Feilen

Distinct designer diamines promote mitophagy, and thereby enhance healthspan in <em>C. elegans</em> and protect human cells against oxidative damage

1 day 18 hours ago
Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population. Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of...
Vijigisha Srivastava

A male pheromone that improves the quality of the oogenic germline

2 days 18 hours ago
SignificanceAging animals, particularly females, suffer from diminished reproductive ability, likely due to high costs of germline maintenance. Potential remedies may be found in signals exchanged by members of opposite sexes to promote reproductive success. We show that in the nematode Caenorhabditis elegans, male pheromone facilitates healthy oocyte aging. This pheromone increases germline proliferation and physiological cell death, which is required to maintain oocyte quality. We show that...
Erin Z Aprison

Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast

2 days 18 hours ago
In yeast, actin cables are F-actin bundles that are essential for cell division through their function as tracks for cargo movement from mother to daughter cell. Actin cables also affect yeast lifespan by promoting transport and inheritance of higher-functioning mitochondria to daughter cells. Here, we report that actin cable stability declines with age. Our genome-wide screen for genes that affect actin cable stability identified the open reading frame YKL075C. Deletion of YKL075C results in...
Cierra N Sing

Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells

2 days 18 hours ago
Hematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Here, we present an integrated analysis of transcriptome and chromatin accessibility of aged HSCs and downstream progenitors. Alterations in chromatin accessibility preferentially take place in HSCs with aging, which gradually resolve with differentiation. Differentially open accessible regions (open DARs) in aged HSCs are enriched for enhancers and show enrichment of binding motifs of the STAT, ATF, and CNC...
Naoki Itokawa

Age-related memory vulnerability to interfering stimuli is caused by gradual loss of MAPK-dependent protection in Drosophila

2 days 18 hours ago
Age-related memory impairment (AMI) is a common phenomenon across species. Vulnerability to interfering stimuli has been proposed to be an important cause of AMI. However, the molecular mechanisms underlying this vulnerability-related AMI remain unknown. Here we show that learning-activated MAPK signals are gradually lost with age, leading to vulnerability-related AMI in Drosophila. Young flies (2- or 3-day-old) exhibited a significant increase in phosphorylated MAPK levels within 15 min after...
Han Mo

Intermittent methionine restriction reduces IGF-1 levels and produces similar healthspan benefits to continuous methionine restriction

2 days 18 hours ago
A sustained state of methionine restriction (MR) dramatically extends the healthspan of several model organisms. For example, continuously methionine-restricted rodents have less age-related pathology and are up to 45% longer-lived than controls. Promisingly, MR is feasible for humans, and studies have suggested that methionine-restricted individuals may receive similar benefits to rodents. However, long-term adherence to a methionine-restricted diet is likely to be challenging for many...
Jason D Plummer

Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease

2 days 18 hours ago
We developed an endophenotype disease module-based methodology for Alzheimer's disease (AD) drug repurposing and identified sildenafil as a potential disease risk modifier. Based on retrospective case-control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, we found that sildenafil usage was significantly associated with a 69% reduced risk of AD (hazard ratio = 0.31, 95% confidence interval 0.25-0.39, P<1.0×10^(-8)). Propensity score stratified analyses...
Jiansong Fang

Alzheimer's disease associated AKAP9 I2558M mutation alters posttranslational modification and interactome of tau and cellular functions in CRISPR-edited human neuronal cells

4 days 18 hours ago
Alzheimer's disease (AD) is a pervasive neurodegeneration disease with high heritability. In this study, we employed CRISPR-Cas9-engineered technology to investigate the effects of a rare mutation (rs144662445) in the A kinase anchoring protein 9 (AKAP9) gene, which is associated with AD in African Americans (AA), on tau pathology and the tau interactome in SH-SY5Y P301L neuron-like cells. The mutation significantly increased the level of phosphorylated tau, specifically at the site...
Yang You

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

5 days 18 hours ago
Dyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human iPSC-derived AT2 (iAT2) cells to model how short...
Rafael Jesus Fernandez

Central tolerance is impaired in the middle-aged thymic environment

5 days 18 hours ago
One of the earliest hallmarks of immune aging is thymus involution, which not only reduces the number of newly generated and exported T cells, but also alters the composition and organization of the thymus microenvironment. Thymic T-cell export continues into adulthood, yet the impact of thymus involution on the quality of newly generated T-cell clones is not well established. Notably, the number and proportion of medullary thymic epithelial cells (mTECs) and expression of tissue-restricted...
Jessica N Lancaster

Topical therapy for regression and melanoma prevention of congenital giant nevi

5 days 18 hours ago
Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models...
Yeon Sook Choi

PERSIST platform provides programmable RNA regulation using CRISPR endoRNases

5 days 18 hours ago
Regulated transgene expression is an integral component of gene therapies, cell therapies and biomanufacturing. However, transcription factor-based regulation, upon which most applications are based, suffers from complications such as epigenetic silencing that limit expression longevity and reliability. Constitutive transgene transcription paired with post-transcriptional gene regulation could combat silencing, but few such RNA- or protein-level platforms exist. Here we develop an RNA-regulation...
Breanna DiAndreth

Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ

5 days 18 hours ago
Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear...
Yi Liu

Establishment of H3K9-methylated heterochromatin and its functions in tissue differentiation and maintenance

5 days 18 hours ago
Heterochromatin is characterized by dimethylated or trimethylated histone H3 Lys9 (H3K9me2 or H3K9me3, respectively) and is found at transposable elements, satellite repeats and genes, where it ensures their transcriptional silencing. The histone methyltransferases (HMTs) that methylate H3K9 - in mammals Suppressor of variegation 3-9 homologue 1 (SUV39H1), SUV39H2, SET domain bifurcated 1 (SETDB1), SETDB2, G9A and G9A-like protein (GLP) - and the 'readers' of H3K9me2 or H3K9me3 are highly...
Jan Padeken
3 hours 44 minutes ago
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