Featured
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Article
| Open AccessDietary thiols accelerate aging of C. elegans
Reactive oxygen species are required for the long lifespan, and glutathione is an antioxidant. Here the authors show that limiting the consumption of dietary thiols, including those naturally derived from the microbiota, increases proteotoxic stress resistance in worms and human cells, and extends C. elegans lifespan.
- Ivan Gusarov
- , Ilya Shamovsky
- & Evgeny Nudler
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Article
| Open AccessThe long lives of primates and the ‘invariant rate of ageing’ hypothesis
The ‘invariant rate of ageing’ hypothesis suggests that the rate of ageing tends to be constant within species. Here, Colchero et al. find support for the hypothesis across primates, including humans, suggesting biological constraints on the rate of ageing.
- Fernando Colchero
- , José Manuel Aburto
- & Susan C. Alberts
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Article
| Open AccessRestoration of energy homeostasis by SIRT6 extends healthy lifespan
Aging is associated with increased frailty and disrupted energy homeostasis. Here, the authors show that SIRT6 overexpression extends the lifespan of male and female mice and demonstrate that SIRT6 optimizes energy homeostasis in old age, which delays frailty and preserves healthy aging.
- A. Roichman
- , S. Elhanati
- & H. Y. Cohen
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Article
| Open AccessCaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution
Natural selection may favor traits underlying aging-related diseases if they benefit the young. Wang et al. find that oxidative activation of CaMKII provides physiological benefits critical to the initial and continued success of vertebrates but at the cost of disease, frailty, and shortened lifespan.
- Qinchuan Wang
- , Erick O. Hernández-Ochoa
- & Mark E. Anderson
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Article
| Open AccessIn vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche
Short term systemic expression of the reprogramming factors Oct-3/4, Sox2, Klf4, c-Myc (OSKM) rejuvenates aging cells and promotes tissue regeneration. Here the authors show that myofiber-specific expression of OSKM accelerates muscle regeneration by reducing secretion of muscle stem cell quiescence promoting Wnt4.
- Chao Wang
- , Ruben Rabadan Ros
- & Juan Carlos Izpisua Belmonte
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Review Article
| Open AccessImportance of circadian timing for aging and longevity
Circadian clocks link physiologic processes to environmental conditions and a mismatch between internal and external rhythms has negative effects on organismal health. In this review, the authors discuss the interactions between circadian clocks and dietary interventions targeted to promote healthy aging.
- Victoria A. Acosta-Rodríguez
- , Filipa Rijo-Ferreira
- & Joseph S. Takahashi
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Article
| Open AccessThe genomic loci of specific human tRNA genes exhibit ageing-related DNA hypermethylation
The epigenome has been shown to change with age, potentially impacting on ageing-related disease. Here the authors investigate the DNA methylation state of the genomic loci of human tRNA and observe enrichment for age-related DNA hypermethylation at tRNA loci.
- Richard J. Acton
- , Wei Yuan
- & Christopher G. Bell
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Article
| Open AccessInactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism
Histone acetylations are important epigenetic marks for transcriptional activation and respond to metabolic changes. Here the authors develop a lifespan screen and show that inactivation of the histone deacetylase complex activates longevity and protects against stress via trehalose metabolism.
- Ruofan Yu
- , Xiaohua Cao
- & Weiwei Dang
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Article
| Open AccessMutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.
- Takeshi Fujino
- , Susumu Goyama
- & Toshio Kitamura
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Article
| Open AccessDietary restriction transforms the mammalian protein persulfidome in a tissue-specific and cystathionine γ-lyase-dependent manner
Dietary restriction (DR) can increase protein persulfidation but the tissue specificity of this process is not well understood. Here, the authors compare organ-specific protein persulfidomes in young and aged mice under DR, and show that DR-dependent persulfidome changes depend on cystathionine γ-lyase.
- Nazmin Bithi
- , Christopher Link
- & Christopher Hine
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Article
| Open AccessThe decrease of intraflagellar transport impairs sensory perception and metabolism in ageing
Sensory perception and metabolic homeostasis are known to deteriorate with ageing, while mechanisms underlying their deterioration remain poorly understood. Here, the authors demonstrate that decrease of intraflagellar transport in the cilia of sensory neurons impairs sensory perception and metabolism in ageing C. elegans.
- Yincong Zhang
- , Xiaona Zhang
- & Yidong Shen
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Article
| Open AccessMutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation
Aging is associated with declining protein homeostasis. Here, using a chemical mutagenesis screen for lifespan extension in C. elegans, the authors report that inhibition of the integrated stress response enhances longevity and protein homeostasis in a manner dependent on kin-35, without reducing protein synthesis.
- Maxime J. Derisbourg
- , Laura E. Wester
- & Martin S. Denzel
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Article
| Open AccessDNA methylation predicts age and provides insight into exceptional longevity of bats
DNA methylation profiles from 26 bat species accurately predicts chronological age, while longevity-related methylation patterns across the genome suggest that bat longevity results from augmented immune response and cancer suppression.
- Gerald S. Wilkinson
- , Danielle M. Adams
- & Steve Horvath
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Article
| Open AccessAntagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging
Sarcopenia is the age-associated functional decline and atrophy of muscle fibers, and it has been proposed that it might be counteracted by inducing myofiber hypertrophy. Here, the authors show that expression levels of the ubiquitin ligase UBR4 are increased with ageing, and that whilst its genetic ablation rescues muscle atrophy, it is also associated with reduced protein quality and impaired force production in Drosophila and mouse models.
- Liam C. Hunt
- , Bronwen Schadeberg
- & Fabio Demontis
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Article
| Open AccessFunctional regeneration and repair of tendons using biomimetic scaffolds loaded with recombinant periostin
The regeneration of functional tendons remains a clinical challenge. Here the authors develop a biomimetic scaffold loaded with recombinant periostin and demonstrate its functionality in promoting tendon stem/progenitor cell recruitment and tenogenic differentiation, and tendon regeneration in a rat full-cut Achilles tendon defect model.
- Yu Wang
- , Shanshan Jin
- & Yan Liu
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Article
| Open AccessMaintenance of type 2 glycolytic myofibers with age by Mib1-Actn3 axis
Muscle atrophy is associated with ageing, but the underlying molecular mechanisms are not well understood. Here, they authors show that ablation of the E3 ubiquitin ligase Mib1 is important for myofibre maintenance via a mechanism that involves targeting and degradation of Actn3, and that Mib1 ablation in mice induces muscle atrophy which can be rescued by knockown of Actn3 expression.
- Ji-Yun Seo
- , Jong-Seol Kang
- & Young-Yun Kong
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Article
| Open AccessProteome-wide and matrisome-specific alterations during human pancreas development and maturation
The pancreatic extracellular matrix (ECM) is known to differ between species, age groups and physiological states, but its compositional changes throughout human life are not well understood. Here, the authors study how the proteome of pancreatic ECM changes during human development and maturation.
- Zihui Li
- , Daniel M. Tremmel
- & Lingjun Li
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Article
| Open AccessNiche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1
Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential and associated dormancy. Here the authors show that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1, and that decline of netrin-1 production during ageing leads to decreased Neo1 mediated HSC self-renewal.
- Simon Renders
- , Arthur Flohr Svendsen
- & Andreas Trumpp
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Review Article
| Open AccessMechanisms of muscle atrophy and hypertrophy: implications in health and disease
Loss of muscle mass is associated with ageing and with a number of diseases such as cancer. Here, the authors review the signaling pathways that modulate protein synthesis and degradation and gain or loss of muscle mass, and discuss therapeutic implications and future directions for the field.
- Roberta Sartori
- , Vanina Romanello
- & Marco Sandri
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Article
| Open AccessSteroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases
Sul-2 is a steroid sulfatase in c.elegans. Here the authors show that, in the absence of sul-2 enzymatic activity, worm lifespan is increased, and that chemical inhibition ameliorates symptoms of neurodegenerative disorders in worms and mice.
- Mercedes M. Pérez-Jiménez
- , José M. Monje-Moreno
- & Manuel J. Muñoz
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Article
| Open AccessAlpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations
α-ketoglutarate is an intermediate of the Krebs Cycle that was recently reported to extend lifespan in C.Elegans. Here, the authors show that administration of α-ketoglutarate to mice reduces age-related bone loss, by ameliorating senescence of bone-marrow derived mesenchymal stem cells.
- Yuan Wang
- , Peng Deng
- & Quan Yuan
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Article
| Open AccessAge and life expectancy clocks based on machine learning analysis of mouse frailty
The discovery of interventions that slow aging could be accelerated by employing non-invasive biometrics that predict biological age or life expectancy. Here the authors use longitudinal frailty data from naturally aging mice to develop two such tools, that are responsive to interventions.
- Michael B. Schultz
- , Alice E. Kane
- & David A. Sinclair
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Article
| Open AccessThe neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia
mTORC1 expression is increased during ageing of muscle, and on the other hand, its activation promotes muscle hypertrophy. Here, the authors assess whether mTORC1 has positive or negative effects on ageing, and show that its long-term inhibition preserves muscle mass and function and neuromuscular junction integrity, whereas muscle-specific activation is associated with sarcopenia.
- Daniel J. Ham
- , Anastasiya Börsch
- & Markus A. Rüegg
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Article
| Open AccessThe precursor of PI(3,4,5)P3 alleviates aging by activating daf-18(Pten) and independent of daf-16
Phosphatidylinositol 3-kinase catalyzes the reaction from PI(4,5)P2 to PI(3,4,5)P3 and is encoded by the age-1 gene known to regulate lifespan. Here the researchers found that the metabolite myo-inositol, which can be converted to PI(3,4,5)P3 extends worm lifespan and alleviates worm as well as mouse health decline during aging.
- Dawei Shi
- , Xian Xia
- & Jing-Dong J. Han
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Article
| Open AccessPharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain
Blood–brain barrier dysfunction occurs in ageing and in neurodegenerative diseases. Here, the authors use scRNA-seq to identify transcriptomic changes in endothelial cell subtypes in the aged mouse brain, some of which may generalize to human and can be reversed by treatment with a GLP-1R agonist.
- Lei Zhao
- , Zhongqi Li
- & Ho Ko
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Article
| Open AccessSenolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation
Organ transplantation involving aged donors is often confounded by reduced post-transplantation organ survival. By studying both human organs and mouse transplantation models, here the authors show that pretreating the donors with senolytics to reduce mitochondria DNA and pro-inflammatory dendritic cells may help promote survival of aged organs.
- Jasper Iske
- , Midas Seyda
- & Stefan G. Tullius
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Article
| Open AccessInhibition of inflammatory CCR2 signaling promotes aged muscle regeneration and strength recovery after injury
Chronic inflammation is a feature of age-related regenerative decline in skeletal muscles, but how it directly affects resident muscle stem cell fate and function is unclear. Here, the authors show that Ccr2 signaling in muscle stem cell derived progenitors represses terminal myogenic differentiation, and that targeting Ccr2 on aged myogenic progenitors rejuvenates aged skeletal muscle healing and function.
- Roméo S. Blanc
- , Jacob G. Kallenbach
- & Joe V. Chakkalakal
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Article
| Open AccessAge-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy
Autophagic activity declines with age in several tissues and is linked to aging-associated functional decline and pathologies. Here the authors show that Rubicon, a negative regulator of autophagy, decreases in adipocytes with age, and its loss leads to adipocyte dysfunction via excess autophagic degradation of SRC-1 and TIF2.
- Tadashi Yamamuro
- , Tsuyoshi Kawabata
- & Tamotsu Yoshimori
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Article
| Open AccessAssociations of cardiovascular biomarkers and plasma albumin with exceptional survival to the highest ages
Supercentenarians are approaching the current longevity limit by avoiding or surviving major illness, thus identifying biomarkers for exceptional survival might provide insights into the protection against disease of aging. Here, the authors show low NT-proBNP and high albumin in plasma are the biological correlates of survival to the highest ages.
- Takumi Hirata
- , Yasumichi Arai
- & Nobuyoshi Hirose
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Article
| Open AccessMultivariate genomic scan implicates novel loci and haem metabolism in human ageing
Ageing phenotypes are of great interest but are difficult to study genetically, partly due to the sample sizes required. Here, the authors present a multivariate framework to combine GWAS summary statistics and increase statistical power, identifying additional loci enriched for aging.
- Paul R. H. J. Timmers
- , James F. Wilson
- & Joris Deelen
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Article
| Open AccessPiwi reduction in the aged niche eliminates germline stem cells via Toll-GSK3 signaling
Retrotransposons are known to be involved in aging. Here the authors show that the retrotransposon silencer Piwi contributes to germline stem cell loss during aging in Drosophila.
- Kun-Yang Lin
- , Wen-Der Wang
- & Hwei-Jan Hsu
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Article
| Open AccessImpaired peroxisomal import in Drosophila oenocytes causes cardiac dysfunction by inducing upd3 as a peroxikine
Aging is the major risk factor for cardiovascular diseases due to chronic, low-grade inflammation stemmed from pro-inflammatory factors circulating in the body. Here, the authors identify a role of hepatocyte specific peroxisomal import in mediating non-autonomous regulation of cardiac aging, through upregulation of IL6-like inflammatory cytokine.
- Kerui Huang
- , Ting Miao
- & Hua Bai
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Article
| Open AccessVesicular transport mediates the uptake of cytoplasmic proteins into mitochondria in Drosophila melanogaster
Mitochondrial dynamics change during ageing, with larger mitochondria and altered protein import in older animals. Here the authors show that Dosmit protein mediates mitochondrial morphology with Rab32 by inducing double-membraned vesicles that regulate protein trafficking into mitochondria.
- Po-Lin Chen
- , Kai-Ting Huang
- & Chun-Hong Chen
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Article
| Open AccessNaked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties
Naked mole rats are the longest-lived rodents and produce very-high-molecular-mass hyaluronan (vHMM-HA). Here the authors show that naked mole rat vHMM-HA is better at protecting mouse and human cells from cell cycle arrest and cell death, compared to the high-molecular-mass hyaluronan produced by these species.
- Masaki Takasugi
- , Denis Firsanov
- & Vera Gorbunova
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Article
| Open AccessA single-cell transcriptomic landscape of primate arterial aging
Arterial degeneration, closely associated with cardiovascular diseases, is driven by aging-related vascular cell-specific transcriptomics changes. This study provides a single-cell transcriptomic atlas for senile aortic and coronary arteries and underscores FOXO3A-based the transcriptional network in vasoprotection during aging.
- Weiqi Zhang
- , Shu Zhang
- & Jing Qu
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Article
| Open AccessCircadian regulation of mitochondrial uncoupling and lifespan
Disruption of different components of molecular circadian clocks has varying effects on health and lifespan of model organisms. Here the authors show that loss of period extends life in drosophila melanogaster.
- Matt Ulgherait
- , Anna Chen
- & Mimi Shirasu-Hiza
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Article
| Open AccessTransient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells
Aging involves gradual loss of tissue function, and transcription factor (TF) expression can ameliorate this in progeroid mice. Here the authors show that transient TF expression reverses age-associated epigenetic marks, inflammatory profiles and restores regenerative potential in naturally aged human cells.
- Tapash Jay Sarkar
- , Marco Quarta
- & Vittorio Sebastiano
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Article
| Open AccessSexual-dimorphism in human immune system aging
Whether the immune system aging differs between men and women is barely known. Here the authors characterize gene expression, chromatin state and immune subset composition in the blood of healthy humans 22 to 93 years of age, uncovering shared as well as sex-unique alterations, and create a web resource to interactively explore the data.
- Eladio J. Márquez
- , Cheng-han Chung
- & Duygu Ucar
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Article
| Open AccessLoss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis
Mutations in the hexosamine pathway key enzyme glutamine fructose-6-phosphate amidotransferase (GFAT-1) improve protein quality control and extend C. elegans lifespan. Here the authors present the crystal structures of full-length human GFAT-1 alone and with bound ligands and perform activity assays, which show that gain-of-function in the longevity-associated G451E variant is caused by a loss of feedback regulation.
- Sabine Ruegenberg
- , Moritz Horn
- & Martin S. Denzel
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Article
| Open AccessThe Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.
- Mark Pinese
- , Paul Lacaze
- & David M. Thomas
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Article
| Open AccessDAF-16/FOXO requires Protein Phosphatase 4 to initiate transcription of stress resistance and longevity promoting genes
The transcription factor DAF-16/FOXO mediates a wide variety of aging-preventive responses by driving the expression of stress resistance and longevity promoting genes. Here the authors show that transcriptional initiation at many DAF-16/FOXO target genes requires the dephosphorylation of SPT-5 by Protein Phosphatase 4.
- Ilke Sen
- , Xin Zhou
- & Christian G. Riedel
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Article
| Open AccessGut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway
Intestinal aging is associated with declines in structure and absorption of nutrients. Here, the authors show that aging related intestinal decline is mediated by activation of the mTORC1-p38MAPK-p53 pathway in intestinal stem cells and can be ameliorated by abrogating mTORC1 or p38MAPK activity.
- Dan He
- , Hongguang Wu
- & Baojie Li
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Article
| Open AccessMitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities
Sarcopenia is the loss of muscle mass and strength associated with physical disability during ageing. Here, the authors analyse muscle biopsies from 119 patients with sarcopenia and age-matched controls of different ethnic groups and find transcriptional signatures indicating mitochondrial dysfunction, associated with reduced mitochondria numbers and lower NAD+ levels in older individuals with sarcopenia.
- Eugenia Migliavacca
- , Stacey K. H. Tay
- & Jerome N. Feige
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Article
| Open AccessSenescent cell turnover slows with age providing an explanation for the Gompertz law
One of the underlying causes of aging is the accumulation of senescent cells, but their turnover rates and dynamics during ageing are unknown. Here the authors measure and model senescent cell production and removal and explore implications for mortality.
- Omer Karin
- , Amit Agrawal
- & Uri Alon
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Article
| Open AccessA fln-2 mutation affects lethal pathology and lifespan in C. elegans
C. elegans is a commonly used model organism in the study of ageing, and differences in genetic background can result in varying strain longevity. Here the authors demonstrate that a background mutation in fln-2 affects life-limiting pharyngeal infection and that in the mutant background the beneficial effect of sir-2.1 over-expression is suppressed.
- Yuan Zhao
- , Hongyuan Wang
- & David Gems
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Article
| Open AccessHydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans
Hydralazine is a drug used in the treatment of heart failure and cancer, and it has recently been shown to promote lifespan in C. elegans. Here, the authors elucidate the mechanism of action of hydralazine, and show that it targets PKA to promote mitochondrial function via Sirtuin1/5.
- Esmaeil Dehghan
- , Mohammad Goodarzi
- & Hamid Mirzaei
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Article
| Open AccessA secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing
Decreased autophagy is a hallmark of ageing, but its inter-tissue regulation is poorly understood. Here, Zhou et al. identify mir-83 in C. elegans, which is transported across tissues and suppresses autophagy, contributing to age-related decline.
- Yifei Zhou
- , Xueqing Wang
- & Yidong Shen
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Article
| Open AccessGWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation
Mosaic loss of chromosome Y (mLOY) is associated with age and smoking but also genetic factors play a role. Here, Terao et al. perform GWAS for mLOY in 95,380 Japanese men and identify 46 loci that overlap with hematopoietic stem cell enhancers and transcription factor binding sites critical for hematopoiesis.
- Chikashi Terao
- , Yukihide Momozawa
- & Yoichiro Kamatani
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Article
| Open AccessAgeing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells
Age-related tissue alterations have been associated with a decline in stem cell number and function. Here the authors report a single cell multi-omics study of mouse muscle stem cells, combining single cell transcriptome and DNA methylome profiling and find that aged cells have a global increase of uncoordinated transcriptional heterogeneity biased towards genes regulating cell-niche interactions.
- Irene Hernando-Herraez
- , Brendan Evano
- & Wolf Reik