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

The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm DOI
David Gems, João Pedro de Magalhães

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 70, P. 101407 - 101407

Published: July 13, 2021

Language: Английский

Citations

103
Sensitive Activatable Nanoprobes for Real‐Time Ratiometric Magnetic Resonance Imaging of Reactive Oxygen Species and Ameliorating Inflammation In Vivo DOI

Xilan Li,

Yun Liu, Xiaowei Qi

et al.

Advanced Materials, Journal Year: 2022, Volume and Issue: 34(19)

Published: March 11, 2022

Imaging-guided real-time monitoring of the treatment process inflammatory diseases is important for timely adjustment planning to lower unnecessary side effects and improve outcomes. However, it difficult reflect dynamic changes inflammation in vivo with enough tissue penetration depth. Here a novel nanotheranostic agent (denominated TMSN@PM) platelet membrane (PM)-coated, tempol-grafted, manganese-doped, mesoporous silica nanoparticles developed. The PM endows TMSN@PM ability target sites, which are verified by fluorescence imaging Cyanine5 carboxylic acid (Cy5)-labeled TMSN@PM. Under environment (mild acidity excess reactive oxygen species (ROS)), can scavenge ROS, thereby alleviating inflammation, degrade, release manganese ions enhanced magnetic resonance (MRI). relaxation (ΔR1 ) almost linearly correlated concentration H2 O2 , degree inflammation. This method offers non-invasive imaging-based strategy early prediction therapeutic outcomes therapy, may contribute precision medicine terms prognostic stratification future.

Language: Английский

Citations

93
Flavonoids—Natural Gifts to Promote Health and Longevity DOI Open Access
Xiaolan Fan,

Ziqiang Fan,

Ziyue Yang

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(4), P. 2176 - 2176

Published: Feb. 16, 2022

The aging of mammals is accompanied by the progressive atrophy tissues and organs accumulation random damage to macromolecular DNA, protein, lipids. Flavonoids have excellent antioxidant, anti-inflammatory, neuroprotective effects. Recent studies shown that flavonoids can delay prolong a healthy lifespan eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), maintaining metabolic homeostasis. However, only few systematic described in clinical treatment for anti-aging, which needs be explored further. This review first highlights association between damage. Then, we discuss advances role flavonoid molecules prolonging health span organisms. study may provide crucial information drug design developmental applications based on flavonoids.

Language: Английский

Citations

88
The hyperfunction theory: An emerging paradigm for the biology of aging DOI
David Gems

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 74, P. 101557 - 101557

Published: Jan. 3, 2022

Language: Английский

Citations

87
The energetic cost of allostasis and allostatic load DOI Creative Commons
Natalia Bobba-Alves, Robert‐Paul Juster, Martin Picard

et al.

Psychoneuroendocrinology, Journal Year: 2022, Volume and Issue: 146, P. 105951 - 105951

Published: Oct. 8, 2022

Chronic psychosocial stress increases disease risk and mortality, but the underlying mechanisms remain largely unclear. Here we outline an energy-based model for transduction of chronic into over time. The energetic allostatic load (EMAL) emphasizes cost allostasis load, where "load" is additional burden required to support stress-induced energy needs. Living organisms have a limited capacity consume energy. Overconsumption by brain-body processes leads hypermetabolism, defined as excess expenditure above organism's optimum. In turn, hypermetabolism accelerates physiological decline in cells, laboratory animals, humans, may drive biological aging. Therefore, propose that transition from adaptive maladaptive states, overload arises when added competes with longevity-promoting growth, maintenance, repair. Mechanistically, restriction maintenance repair progressive wear-and-tear molecular organ systems. proposed makes testable predictions around physiological, cellular, sub-cellular transduce mortality. We also highlight new avenues quantify its link health across lifespan, via integration systemic cellular measurements together classic biomarkers.

Language: Английский

Citations

85
Genome-wide RNA polymerase stalling shapes the transcriptome during aging DOI Creative Commons
Àkos Gyenis, Jiang Chang, Joris J. P. G. Demmers

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(2), P. 268 - 279

Published: Jan. 19, 2023

Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and polymerase II chromatin immunoprecipitation followed by to elucidate the underlying mechanisms triggering gene wild-type aged mice. We found that 2-year-old liver, 40% of elongating polymerases are stalled, lowering productive transcription skewing transcriptional output a gene-length-dependent fashion. demonstrate this stress caused endogenous DNA damage explains majority aging most mainly postmitotic organs, specifically affecting hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function cellular resilience. Age-related evolutionary conserved from nematodes humans. Thus, accumulation stochastic during deteriorates basal transcription, which establishes age-related transcriptome causes dysfunction key pathways, disclosing functionally underlies major aspects normal aging.

Language: Английский

Citations

85
Epigenetics, DNA damage, and aging DOI Creative Commons

Carolina Soto-Palma,

Laura J. Niedernhofer, Christopher Faulk

et al.

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(16)

Published: Aug. 14, 2022

Over the course of a human lifespan, genome integrity erodes, leading to an increased abundance several types chromatin changes. The DNA lesions (chemical perturbations nucleotides) increases with age, as does number genomic mutations and transcriptional disruptions caused by replication or transcription those lesions, respectively. At epigenetic level, precise methylation patterns degrade, likely causing increasingly stochastic variations in gene expression. Similarly, tight regulation histone modifications begins unravel. instability these mechanisms allows transposon element reactivation remobilization, further mutations, dysregulation, cytoplasmic fragments. This cumulative promotes cell signaling events that drive fate decisions extracellular communications known disrupt tissue homeostasis regeneration. In this Review, we focus on age-related changes their interactions instigate events.

Language: Английский

Citations

81
A NPAS4–NuA4 complex couples synaptic activity to DNA repair DOI Creative Commons
Elizabeth A. Pollina,

Daniel T. Gilliam,

Andrew T. Landau

et al.

Nature, Journal Year: 2023, Volume and Issue: 614(7949), P. 732 - 741

Published: Feb. 15, 2023

Abstract Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of genome across long lifespan postmitotic neurons 1–5 . Whether have acquired specialized protection mechanisms that enable them withstand decades potentially damaging stimuli during periods heightened unknown. Here we identify activity-dependent DNA repair mechanism in which a new form NuA4–TIP60 chromatin modifier assembles activated around inducible, neuronal-specific transcription factor NPAS4. We purify this complex from brain and demonstrate its functions eliciting changes neuronal transcriptomes circuitry. By characterizing landscape activity-induced double-strand breaks brain, show NPAS4–NuA4 binds recurrently damaged regulatory elements recruits additional machinery stimulate their repair. Gene bound by are partially protected against age-dependent accumulation somatic mutations. Impaired signalling leads cascade cellular defects, including dysregulated transcriptional responses, loss control over inhibition instability, all culminate reduce organismal lifespan. In addition, mutations several components NuA4 reported lead neurodevelopmental autism spectrum disorders. Together, these findings couples directly preservation, disruption may contribute developmental disorders, neurodegeneration ageing.

Language: Английский

Citations

80
Aging, oxidative stress and degenerative diseases: mechanisms, complications and emerging therapeutic strategies DOI
Mani Raj Chaudhary, Sakshi Chaudhary, Yogita Sharma

et al.

Biogerontology, Journal Year: 2023, Volume and Issue: 24(5), P. 609 - 662

Published: July 30, 2023

Language: Английский

Citations

75
Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration DOI Creative Commons
Vishnu Dileep, Carles A. Boix, Hansruedi Mathys

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4404 - 4421.e20

Published: Sept. 1, 2023

Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer's disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq human postmortem prefrontal cortex samples and found that excitatory AD were enriched for somatic mosaic gene fusions. Gene fusions particularly damage repair senescence signatures. In addition, structural variations burdened DSBs CK-p25 mouse model neurodegeneration. Neurons also had elevated levels cohesin along progressive multiscale disruption 3D organization aligned transcriptional changes synaptic, neuronal development, histone genes. Overall, this study demonstrates stability by as steps progression diseases.

Language: Английский

Citations

65