Formation of memory assemblies through the DNA-sensing TLR9 pathway DOI Creative Commons
Vladimir Jovasevic, Elizabeth Wood, Ana Cicvaric

et al.

Nature, Journal Year: 2024, Volume and Issue: 628(8006), P. 145 - 153

Published: March 27, 2024

Abstract As hippocampal neurons respond to diverse types of information 1 , a subset assembles into microcircuits representing memory 2 . Those typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage 3–5 Here we found discrete clusters excitatory CA1 with persistent double-stranded (dsDNA) breaks, nuclear envelope ruptures and perinuclear release histone dsDNA fragments hours after learning. Following these early events, some acquired an inflammatory phenotype involving activation TLR9 signalling accumulation centrosomal repair complexes 6 Neuron-specific knockdown Tlr9 impaired while blunting contextual fear conditioning-induced changes gene expression specific neurons. Notably, had essential role centrosome function, including repair, ciliogenesis build-up perineuronal nets. We demonstrate novel cascade learning-induced events neuronal undergoing TLR9-mediated their recruitment circuits. With compromised this fundamental mechanism becomes gateway genomic instability cognitive impairments implicated accelerated senescence, psychiatric disorders neurodegenerative disorders. Maintaining the integrity thus emerges as promising preventive strategy for neurocognitive deficits.

Language: Английский

Telomere dysfunction in ageing and age-related diseases DOI Open Access
Francesca Rossiello, Diana Jurk, João F. Passos

et al.

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(2), P. 135 - 147

Published: Feb. 1, 2022

Language: Английский

Citations

457
Somatic mutation rates scale with lifespan across mammals DOI Creative Commons
Alex Cagan, Adrian Baez‐Ortega, Natalia Brzozowska

et al.

Nature, Journal Year: 2022, Volume and Issue: 604(7906), P. 517 - 524

Published: April 13, 2022

Abstract The rates and patterns of somatic mutation in normal tissues are largely unknown outside humans 1–7 . Comparative analyses can shed light on the diversity mutagenesis across species, long-standing hypotheses about evolution their role cancer ageing. Here we performed whole-genome sequencing 208 intestinal crypts from 56 individuals to study landscape 16 mammalian species. We found that was dominated by seemingly endogenous mutational processes all including 5-methylcytosine deamination oxidative damage. With some differences, signatures other species resembled those described 8 , although relative contribution each signature varied Notably, rate per year greatly exhibited a strong inverse relationship with lifespan, no life-history trait studied showing comparable association. Despite widely different life histories among examined—including variation around 30-fold lifespan 40,000-fold body mass—the burden at end only factor 3. These data unveil common mammals, suggest evolutionarily constrained may be contributing

Language: Английский

Citations

334
Atrial fibrillation DOI Creative Commons
Bianca J.J.M. Brundel, Xun Ai, Mellanie True Hills

et al.

Nature Reviews Disease Primers, Journal Year: 2022, Volume and Issue: 8(1)

Published: April 7, 2022

Atrial fibrillation (AF) is the most common cardiac arrhythmia despite substantial efforts to understand pathophysiology of condition and develop improved treatments. Identifying underlying causative mechanisms AF in individual patients difficult efficacy current therapies suboptimal. Consequently, incidence steadily rising there a pressing need for novel therapies. Research has revealed that defects specific molecular pathways underlie pathogenesis, resulting electrical conduction disorders drive AF. The severity this so-called electropathology correlates with stage disease progression determines response treatment. Therefore, unravelling expected fuel development innovative personalized diagnostic tools mechanism-based Moreover, co-creation studies implement prerequisite successful management. Currently, various treatment modalities targeting AF-related electropathology, including lifestyle changes, pharmaceutical nutraceutical therapy, substrate-based ablative neuromodulation, are available maintain sinus rhythm might offer holistic strategy treat increasing prevalence as populations age. This Primer provides an overview epidemiology, AF, approaches treatments, highlights important directions improve understanding management patients.

Language: Английский

Citations

311
Meta-hallmarks of aging and cancer DOI Creative Commons
Carlos López-Otı́n, Federico Pietrocola, David Roiz‐Valle

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(1), P. 12 - 35

Published: Jan. 1, 2023

Language: Английский

Citations

286
Chemotherapy Side-Effects: Not All DNA Damage Is Equal DOI Open Access
Winnie M. C. van den Boogaard, Daphne S. J. Komninos, Wilbert P. Vermeij

et al.

Cancers, Journal Year: 2022, Volume and Issue: 14(3), P. 627 - 627

Published: Jan. 26, 2022

Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment later in life they are frequently confronted with the severe negative side-effects their life-saving treatment. The occurrence numerous features accelerated aging, seriously affecting quality life, has now become one most pressing problems associated (pediatric) Chemotherapies target damage DNA, causing mutations or genome instability, a major hallmark both aging. there types chemotherapeutic drugs that genotoxic interfere DNA metabolism different ways, each own biodistribution, kinetics, biological fate. Depending on type lesion produced (e.g., interference replication RNA transcription), organ cell inflicted cycle differentiation status, metabolic state, activity clearance detoxification mechanisms, cellular condition micro-environment), degree exposure, outcomes can largely differ. These considerations provide conceptual framework which classes chemotherapeutics contribute development toxicities aging systems. Here, we summarize observed ex-cancer patients discuss might be responsible.

Language: Английский

Citations

265
The landscape of aging DOI Open Access
Yusheng Cai, Wei Song, Jiaming Li

et al.

Science China Life Sciences, Journal Year: 2022, Volume and Issue: 65(12), P. 2354 - 2454

Published: Sept. 2, 2022

Language: Английский

Citations

243
Making sense of the ageing methylome DOI
Kirsten Seale, Steve Horvath, Andrew E. Teschendorff

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(10), P. 585 - 605

Published: May 2, 2022

Language: Английский

Citations

176
The p53 network: cellular and systemic DNA damage responses in cancer and aging DOI
Pavana Lakshmi Vaddavalli, Björn Schumacher

Trends in Genetics, Journal Year: 2022, Volume and Issue: 38(6), P. 598 - 612

Published: March 25, 2022

Language: Английский

Citations

160
From imbalance to impairment: the central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration DOI Creative Commons
Sheryar Afzal, Aimi Syamima Abdul Manap, Ali Attiq

et al.

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 18, 2023

Increased production and buildup of reactive oxygen species (ROS) can lead to various health issues, including metabolic problems, cancers, neurological conditions. Our bodies counteract ROS with biological antioxidants such as SOD, CAT, GPx, which help prevent cellular damage. However, if there is an imbalance between these antioxidants, it result in oxidative stress. This cause genetic epigenetic changes at the molecular level. review delves into how plays a role disorders caused by We also look animal models used for researching pathways. study offers insights mechanism, pathology, changes, assist drug development disease understanding.

Language: Английский

Citations

125
Connecting aging biology and inflammation in the omics era DOI Creative Commons
Keenan A. Walker, Nathan Basisty,

David M. Wilson

et al.

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(14)

Published: July 14, 2022

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood solid tissues, termed inflammaging. Inflammaging has been implicated pathogenesis many age-associated chronic diseases as well loss physical cognitive function. The search for mechanisms underlie inflammaging focused initially on hallmarks aging, but it rapidly expanding multiple directions. Here, we discuss threads connecting cellular senescence mitochondrial dysfunction impaired mitophagy DNA damage, which may act hub We explore emerging multi-omics efforts aspire define complexity - identify molecular signatures novel targets interventions aimed at counteracting excessive inflammation its deleterious consequences while preserving physiological immune response. Finally, review evidence involved brain aging neurodegenerative diseases. Our goal broaden research agenda with an eye new therapeutic opportunities.

Language: Английский

Citations

113