Treatment with a selective histone deacetylase (HDAC) 1 and 2 inhibitor in aged mice rejuvenates multiple organ systems DOI Open Access
Alessandra Tammaro,

Eileen G. Daniels,

Iman M. Hu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 31, 2023

ABSTRACT The process of aging increases the risk developing age-related diseases, which come at great societal healthcare costs and suffering to individuals. Meanwhile, targeting basic mechanisms can reduce diseases during aging, essentially resulting in a ‘healthy aging’ process. Multiple pathways exist, over past decades have systematically been confirmed through gene knockout or overexpression studies mammals ability increase healthy lifespan. In this work, we perform transcriptome-based drug screening identify small molecules that mimic transcriptional profiles long-lived genetic interventions mammals. We one molecule whose effects diverse known longevity interventions: compound 60 (Cmpd60), is selective inhibitor histone deacetylase 1 (HDAC1) 2 (HDAC2). line with this, battery molecular, phenotypic, bioinformatic analyses, multiple disease cell animal models, find Cmpd60 treatment rejuvenates organ systems. These included kidney, brain, heart. renal reduced partial epithelial-mesenchymal transition (EMT) vitro decreased fibrosis vivo . For dementia-related expression , were recapitulated when treating APPSWE-1349 Alzheimer mouse. cardiac activated favorable developmental improved ventricular cardiomyocyte contraction relaxation model hypertrophy. Our work establishes systemic, two-week an HDAC1/2 serves as multi-tissue, intervention This holds potential for translation towards therapeutics promote humans.

Language: Английский

ATF4 in cellular stress, ferroptosis, and cancer DOI
Hu Tang, Rui Kang, Jiao Liu

et al.

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(4), P. 1025 - 1041

Published: Feb. 21, 2024

Language: Английский

Citations

26
Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders DOI Creative Commons

Antonis Roussos,

Katerina Kitopoulou,

Fivos Borbolis

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(3), P. 478 - 478

Published: March 5, 2023

In recent years, advances in science and technology have improved our quality of life, enabling us to tackle diseases increase human life expectancy. However, longevity is accompanied by an accretion the frequency age-related neurodegenerative diseases, creating a growing burden, with pervasive social impact for societies. The cost managing such chronic disorders lack effective treatments highlight need decipher their molecular genetic underpinnings, order discover new therapeutic targets. this effort, nematode Caenorhabditis elegans serves as powerful tool recapitulate several disease-related phenotypes provides highly malleable model that allows implementation multidisciplinary approaches, addition large-scale pharmacological screens. Its anatomical transparency use co-expressed fluorescent proteins track progress neurodegeneration. Moreover, functional conservation neuronal processes, along high homology between genomes, render C. extremely suitable study disorders. This review describes models used neurodegeneration underscores contribution effort dissect basis identify novel gene targets potential.

Language: Английский

Citations

28
Tracking cell-type-specific temporal dynamics in human and mouse brains DOI Creative Commons
Ziyu Lu,

Melissa Zhang,

Jasper Lee

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4345 - 4364.e24

Published: Sept. 1, 2023

Progenitor cells are critical in preserving organismal homeostasis, yet their diversity and dynamics the aged brain remain underexplored. We introduced TrackerSci, a single-cell genomic method that combines newborn cell labeling combinatorial indexing to characterize transcriptome chromatin landscape of proliferating progenitor vivo. Using we investigated mouse brains across various ages model Alzheimer's disease. Our dataset revealed diverse types epigenetic signatures. further quantified aging-associated shifts cell-type-specific proliferation differentiation deciphered associated molecular programs. Extending our study human brain, identified conserved genetic signatures species pinpointed region-specific cellular dynamics, such as reduced oligodendrogenesis cerebellum. anticipate TrackerSci will be broadly applicable unveil temporal systems.

Language: Английский

Citations

19
Unveiling the Therapeutic Potential of Folate-Dependent One-Carbon Metabolism in Cancer and Neurodegeneration DOI Open Access
Ana Filipa Sobral, Andrea Cunha, Vera Silva

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9339 - 9339

Published: Aug. 28, 2024

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) playing a pivotal role. Folate, B vitamin, key cofactor in this pathway, supporting DNA synthesis, methylation and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability preventing carcinogenesis. Additionally, neurodevelopment, essential neural tube closure central nervous system formation. Thus, dysregulation of can contribute to pathologies such as cancer, severe birth defects, neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk its potential therapeutic target. antifolate drugs that inhibit enzymes 1C strategies targeting receptors are current options. However, cancer complex, varying among types dietary contexts. conditions, including Alzheimer's Parkinson's diseases, deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing neuronal damage. Clinical trials folic acid supplementation show mixed outcomes, underscoring the complexities neuroprotective effects. This review integrates knowledge neurodegeneration, exploring molecular mechanisms, clinical implications, strategies, which provide information advancing treatments.

Language: Английский

Citations

5
Topoisomerase inhibitor amonafide enhances defense responses to promote longevity in C. elegans DOI Creative Commons

Iman M. Hu,

Ana Serna‐Gallego,

Stacia Everts

et al.

GeroScience, Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

Abstract Aging is a major risk factor for disease, and developing effective pharmaceutical interventions to improve healthspan promote longevity has become high priority society. One of the molecular pathways related in various model organisms revolves around lowering AKT1 levels. This prompted our silico drug screen small molecules capable mimicking transcriptional effects knockdown. We found topoisomerase inhibitors as top candidate longevity-drug class. Evaluating multiple compounds from this class C. elegans revealed that inhibitor amonafide greatest benefit on lifespan. Intriguingly, effect was not solely dependent DAF-16/FOXO , canonical pathway lifespan extension via inhibition. performed RNA-seq amonafide-treated worms more youthful signature, including activation diverse cellular defense pathways. mitochondrial unfolded protein response (UPR mt ) regulator afts-1 be crucial both improved extended upon treatment. Moreover, partially immune transcription zip-2 integrated stress atf-4 . further examined potential age-related disease. Treating Parkinson’s disease with mobility. In conclusion, we identified novel geroprotector, which activates mitochondrial-, pathogen-, xenobiotic-associated responses that—though studies are needed—may serve therapy.

Language: Английский

Citations

0
ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor DOI Creative Commons

Adrien Corne,

Florine Adolphe, Jérôme Estaquier

et al.

Biology, Journal Year: 2024, Volume and Issue: 13(3), P. 146 - 146

Published: Feb. 26, 2024

Cellular integrated stress response (ISR), the mitochondrial unfolded protein (UPRmt), and IFN signaling are associated with viral infections. Activating transcription factor 4 (ATF4) plays a pivotal role in these pathways controls expression of many genes involved redox processes, amino acid metabolism, misfolding, autophagy, apoptosis. The precise ATF4 during infection is unclear depends on cell hosts, agents, models. Furthermore, can be hijacked by pathogens to favor replication. In this review, we summarize ATF4-mediated infections, focusing human immunodeficiency virus 1 (HIV-1). We examine consequences activation for HIV-1 replication reactivation. autophagy apoptosis explored as context programmed deaths contribute depletion CD4 T cells. also participate establishment innate adaptive immunity that essential host control finally discuss putative paralogue, named ATF5, infection. This review underlines at crossroads multiple processes reflecting host–pathogen interactions.

Language: Английский

Citations

3
Repurposing nucleoside reverse transcriptase inhibitors (NRTIs) to slow aging DOI Creative Commons

Thomas Brochard,

Rebecca L. McIntyre, Riekelt H. Houtkooper

et al.

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 92, P. 102132 - 102132

Published: Nov. 19, 2023

Repurposing drugs already approved in the clinic to be used off-label as geroprotectors, compounds that combat mechanisms of aging, are a promising way rapidly reduce age-related disease incidence society. Several recent studies have found class drugs-nucleoside reverse transcriptase inhibitors (NRTIs)-originally developed treatments for cancers and human immunodeficiency virus (HIV) infection, could repurposed slow aging process. Interestingly, these propose complementary target multiple hallmarks aging. At molecular level, NRTIs repress LINE-1 elements, reducing DNA damage, benefiting hallmark 'Genomic Instability'. organellar inhibit mitochondrial translation, activate ATF-4, suppress cytosolic extend lifespan worms manner related 'Loss Proteostasis' Meanwhile, at cellular P2X7-mediated activation inflammasome, inflammation improving 'Altered Intercellular Communication'. Future development health will need balance out toxic side effects with beneficial effects, which may occur part through hormesis.

Language: Английский

Citations

8
Low-dose naltrexone extends healthspan and lifespan in C. elegans via SKN-1 activation DOI Creative Commons
Weisha Li, Rebecca L. McIntyre, Bauke V. Schomakers

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(6), P. 109949 - 109949

Published: May 8, 2024

Highlights•Low-dose naltrexone (LDN) extends the healthspan and lifespan in C. elegans•LDN promotes nuclear translocation of transcription factor SKN-1•Lifespan extension LDN depend on SKN-1•LDN activates oxidative stress response certain immunity genesSummaryAs global aging population rises, finding effective interventions to improve health is crucial. Drug repurposing, utilizing existing drugs for new purposes, presents a promising strategy rapid implementation. We explored from Library Integrated Network-based Cellular Signatures (LINCS) based several selection criteria. Low-dose has gained attention treating various diseases, yet its impact longevity remains underexplored. Our study elegans demonstrated that low dose, but not high extended lifespan. This effect was mediated through SKN-1 (NRF2 mammals) signaling, influencing innate immune gene expression upregulating responses. With LDN's side effects profile, our findings underscore potential as geroprotector, suggesting further exploration promoting healthy humans warranted.Graphical abstract

Language: Английский

Citations

2
HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice DOI Creative Commons
Alessandra Tammaro,

Eileen G. Daniels,

Iman M. Hu

et al.

iScience, Journal Year: 2023, Volume and Issue: 27(1), P. 108681 - 108681

Published: Dec. 12, 2023

Aging increases the risk of age-related diseases, imposing substantial healthcare and personal costs. Targeting fundamental aging mechanisms pharmacologically can promote healthy reduce this disease susceptibility. In work, we employed transcriptome-based drug screening to identify compounds emulating transcriptional signatures long-lived genetic interventions. We discovered compound 60 (Cmpd60), a selective histone deacetylase 1 2 (HDAC1/2) inhibitor, mimicking diverse longevity extensive molecular, phenotypic, bioinformatic assessments using various cell aged mouse models, found Cmpd60 treatment improve phenotypes in multiple organs. reduces renal epithelial-mesenchymal transition fibrosis kidney, diminishes dementia-related gene expression brain, enhances cardiac contractility relaxation for heart. sum, our two-week HDAC1/2 inhibitor mice establishes multi-tissue, intervention mammals, holding promise therapeutic translation humans.

Language: Английский

Citations

6
Novel insights into the activating transcription factor 4 in Alzheimer’s disease and associated aging-related diseases: Mechanisms and therapeutic implications DOI
Nan Zhang, Jianfei Nao,

Shun Zhang

et al.

Frontiers in Neuroendocrinology, Journal Year: 2024, Volume and Issue: 74, P. 101144 - 101144

Published: May 24, 2024

Language: Английский

Citations

0