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

Molecular mechanisms of aging and anti-aging strategies DOI Creative Commons
Yumeng Li,

Xutong Tian,

Juyue Luo

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: May 24, 2024

Abstract Aging is a complex and multifaceted process involving variety of interrelated molecular mechanisms cellular systems. Phenotypically, the biological aging accompanied by gradual loss function systemic deterioration multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, protein balance, deregulated nutrient sensing, altered intercellular communication, dysbiosis. These age-related changes may be alleviated intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, targeted longevity genes. In this review, we summarise key historical progress exploration important causes anti-aging strategies recent decades, which provides basis for further understanding reversibility phenotypes, application prospect synthetic biotechnology therapy also prospected.

Language: Английский

Citations

53
Stress, epigenetics, and aging: Unraveling the intricate crosstalk DOI Creative Commons
Zeming Wu, Jing Qu, Weiqi Zhang

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 84(1), P. 34 - 54

Published: Nov. 13, 2023

Language: Английский

Citations

52
Role of hypoxia in cellular senescence DOI Creative Commons
Haoyu Gao, Eugenie Nepovimová, Zbyněk Heger

et al.

Pharmacological Research, Journal Year: 2023, Volume and Issue: 194, P. 106841 - 106841

Published: June 28, 2023

Senescent cells persist and continuously secrete proinflammatory tissue-remodeling molecules that poison surrounding cells, leading to various age-related diseases, including diabetes, atherosclerosis, Alzheimer's disease. The underlying mechanism of cellular senescence has not yet been fully explored. Emerging evidence indicates hypoxia is involved in the regulation senescence. Hypoxia-inducible factor (HIF)- 1α accumulates under hypoxic conditions regulates by modulating levels markers p16, p53, lamin B1, cyclin D1. Hypoxia a critical condition for maintaining tumor immune evasion, which promoted driving expression genetic factors (such as p53 CD47) while triggering immunosenescence. Under conditions, autophagy activated targeting BCL-2/adenovirus E1B 19-kDa interacting protein 3, subsequently induces p21WAF1/CIP1 well p16Ink4a increases β-galactosidase (β-gal) activity, thereby inducing Deletion p21 gene activity response regulator poly (ADP-ribose) polymerase-1 (PARP-1) level nonhomologous end joining (NHEJ) proteins, repairs DNA double-strand breaks, alleviates Moreover, associated with intestinal dysbiosis an accumulation D-galactose derived from gut microbiota. Chronic leads striking reduction amount Lactobacillus D-galactose-degrading enzymes gut, producing excess reactive oxygen species (ROS) bone marrow mesenchymal stem cells. Exosomal microRNAs (miRNAs) long noncoding RNAs (lncRNAs) play important roles miR-424-5p are decreased hypoxia, whereas lncRNA-MALAT1 increased, both induce present review focuses on recent advances understanding role effects HIFs, PARP-1, microbiota, exosomal mRNA hypoxia-mediated cell specifically discussed. This our provides new clues anti-aging processes treatment aging-related diseases.

Language: Английский

Citations

51
Genomic Instability and Epigenetic Changes during Aging DOI Open Access

Lucía López-Gil,

Amparo Pascual‐Ahuir, Markus Proft

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14279 - 14279

Published: Sept. 19, 2023

Aging is considered the deterioration of physiological functions along with an increased mortality rate. This scientific review focuses on central importance genomic instability during aging process, encompassing a range cellular and molecular changes that occur advancing age. In particular, this revision addresses genetic epigenetic alterations contribute to instability, such as telomere shortening, DNA damage accumulation, decreased repair capacity. Furthermore, explores aging, including modifications histones, methylation patterns, role non-coding RNAs. Finally, discusses organization chromatin its contribution heterochromatin loss, remodeling, in nucleosome histone abundance. conclusion, highlights fundamental plays process underscores need for continued research into these complex biological mechanisms.

Language: Английский

Citations

46
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

Citations

46