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A lysosomal surveillance response to stress extends healthspan

1 month 3 weeks ago
Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H^(+)-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive...
Terytty Yang Li

A host organelle integrates stolen chloroplasts for animal photosynthesis

1 month 3 weeks ago
Eukaryotic life evolved over a billion years ago when ancient cells engulfed and integrated prokaryotes to become modern mitochondria and chloroplasts. Sacoglossan "solar-powered" sea slugs possess the ability to acquire organelles within a single lifetime by selectively retaining consumed chloroplasts that remain photosynthetically active for nearly a year. The mechanism for this "animal photosynthesis" remains unknown. Here, we discovered that foreign chloroplasts are housed within novel,...
Corey A H Allard

Systematic profiling reveals betaine as an exercise mimetic for geroprotection

1 month 3 weeks ago
Exercise has well-established health benefits, yet its molecular underpinnings remain incompletely understood. We conducted an integrated multi-omics analysis to compare the effects of acute vs. long-term exercise in healthy males. Acute exercise induced transient responses, whereas repeated exercise triggered adaptive changes, notably reducing cellular senescence and inflammation and enhancing betaine metabolism. Exercise-driven betaine enrichment, partly mediated by renal biosynthesis, exerts...
Lingling Geng

Cellular senescence in chronic obstructive pulmonary disease: Molecular mechanisms and therapeutic interventions

1 month 3 weeks ago
Chronic obstructive pulmonary disease (COPD) is the world's fourth highest reason for mortality, accounting for 3.5 million deaths in 2021, and about 5 % of total global deaths. Emphysema and chronic bronchitis are the two major pathologies of COPD. Tobacco smoke, dust, vapors, and fumes, outdoor air pollutants, genetic factors, ageing, infections, and asthma are the risk factors of COPD. On the other hand, senescence is permanent halt in cell cycle accompanied by phenotypic alterations due to...
Sapana Subedi

A lysosomal surveillance response to stress extends healthspan

1 month 3 weeks ago
Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H^(+)-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive...
Terytty Yang Li

Overexpression of the Dicer family genes influences lifespan and stress resistance in a tissue-, sex-, and stressor-specific manner in Drosophila melanogaster

1 month 3 weeks ago
Small non-coding RNAs coordinate essential cellular processes, including gene expression regulation, genome stability maintenance, and transposon suppression. These processes determine aging, lifespan, and resistance of cells and organisms to stress. In this work, we conducted a comprehensive study of the geroprotective effects of overexpression of two Dicer family genes (Dcr-1 and Dcr-2, which are responsible for the biogenesis of miRNAs and siRNAs) in different tissues of Drosophila...
Ekaterina Proshkina

Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro

1 month 3 weeks ago
Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1...
Anna Podleśny-Drabiniok

Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer's disease and frontotemporal dementia

1 month 3 weeks ago
Nucleocytoplasmic transport defects are observed in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here, we assess mRNA nucleocytoplasmic localization by performing transcriptome-wide profiling on nuclear and cytoplasmic fractions of human iPSC-derived cortical neurons from healthy individuals compared to those with familial AD or FTD. We find that AD- and FTD-causing mutations induce significant changes in mRNA nucleocytoplasmic distribution. We additionally observe the...
Christy Hung

A Dock8-dependent mechanosensitive central actin pool maintains T cell shape and protects nucleus during migration

1 month 3 weeks ago
Immune cells navigate through complex tissue architectures by extensive cellular deformation, low adhesion, and high cell velocities. Loss-of-function mutations in Dedicator of Cytokinesis 8 (Dock8) are associated with immunodeficiency as immune cells becoming entangled during migration through dense environments, but their migration on two-dimensional surfaces remains entirely intact. Here we investigated the specific cytoskeletal defect of Dock8-deficient activated T cells and describe a...
Connie Shen

Identifying the target, mechanism, and agonist of alpha-ketoglutaric acid in delaying mesenchymal stem cell senescence

1 month 3 weeks ago
α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed...
Zhao Cui

Contribution of glutamatergic projections to neurons in the nonhuman primate substantia nigra pars reticulata for reactive inhibition

1 month 3 weeks ago
The basal ganglia play a crucial role in action selection by facilitating desired movements and suppressing unwanted ones. The substantia nigra pars reticulata (SNr), a key output nucleus, facilitates movement through disinhibition of the superior colliculus (SC). However, its role in action suppression, particularly in primates, remains less clear. We investigated whether individual SNr neurons in three male macaque monkeys bidirectionally modulate their activity to both facilitate and suppress...
Atsushi Yoshida

Mitochondrial protein nmd regulates lipophagy and general autophagy during development

1 month 3 weeks ago
Lipophagy engulfs lipid droplets and delivers them to lysosomes for degradation. We found that lipophagy levels were low in most fly tissues, except for the prothoracic gland (PG) during larval development. Therefore, we performed a small-scale screening in the PG to identify regulators of lipophagy. We discovered that the loss of nmd, a gene encoding a mitochondrial AAA-ATPase, led to developmental failure and reduced lipophagy in the PG. Further studies indicated that nmd was not only required...
Wei Wang

Focal adhesion-derived liquid-liquid phase separations regulate mRNA translation

1 month 3 weeks ago
Liquid-liquid phase separation (LLPS) has emerged as a major organizing principle in cells. Recent work showed that multiple components of integrin-mediated focal adhesions, including p130Cas can form LLPS, which govern adhesion dynamics and related cell behaviors. In this study, we found that the focal adhesion protein p130Cas drives the formation of structures with the characteristics of LLPS that bud from focal adhesions into the cytoplasm. Condensing concentrated cytoplasm around...
Abhishek Kumar