Hallmarks of aging: An expanding universe

Cell, Journal Year: 2023, Volume and Issue: 186(2), P. 243 - 278

Published: Jan. 1, 2023

Language: Английский

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Melatonin inhibits ferroptosis and delays age-related cataract by regulating SIRT6/p-Nrf2/GPX4 and SIRT6/NCOA4/FTH1 pathways

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 157, P. 114048 - 114048

Published: Dec. 1, 2022

Cataracts are the main cause of reversible blindness worldwide. The ageing lens caused by ultraviolet B (UVB) radiation is mostly related to oxidative stress (OS). Little known about whether OS induced UVB enhances sensitivity epithelial cells ferroptotic stress, which may be a new mechanism leading age-related cataracts (ARCs).Ferroptosis was detected transmission electron microscopy (TEM), iron assay, lipid peroxidation (MDA) real-time PCR, western blotting, and immunofluorescence. Genetic engineering technology used investigate regulatory relationship among Sirtuin 6 (SIRT6), nuclear factor erythroid 2-related 2 (Nrf2), receptor coactivator 4 (NCOA4), glutathione peroxidase (GPX4) ferritin heavy chain (FTH1). Knockdown overexpression SIRT6 locally in vivo rats were performed probe ferroptosis ARCs.Here, we observed that can drastically induce vitro. Surprisingly, inhibition direct reason melatonin rescued B-3, SRA01/04 HEK-293 T survival; pan-caspase inhibitor Z-Vad-FMK did not significantly reverse death UVB-irradiated compared with UVB+DMSO group. an upstream regulator phosphorylated Nrf2 (p-Nrf2) NCOA4 cells. Melatonin inhibited through SIRT6/p-Nrf2/GPX4 SIRT6/COA4/FTH1 pathways neutralize toxicity, protected against vitro delayed cataract formation exposure rats.Our findings reveal novel causal role pathogenesis ARCs, raises possibility selectively targeting activation resistance as latent antioxidative therapeutic strategy for ARCs.

Language: Английский

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Epigenetics, DNA damage, and aging

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

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Sirt6 attenuates chondrocyte senescence and osteoarthritis progression

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 10, 2022

Sirt6 has been implicated as a key regulator in aging-related diseases, including osteoarthritis. However, its functional role and molecular mechanism chondrocyte senescence osteoarthritis pathophysiology remain largely undefined. Here we show that deficiency exaggerates progression, whereas intra-articular injection of adenovirus-Sirt6 markedly attenuates surgical destabilization medial meniscus-induced Mechanistically, can directly interact with STAT5 deacetylate STAT5, thus inhibiting the IL-15/JAK3-induced translocation from cytoplasm to nucleus, which inactivates IL-15/JAK3/STAT5 signaling. Mass spectrometry revealed deacetylated conserved lysine 163 on STAT5. Mutation arginine abolished regulatory effect Sirt6. In vivo, specific ablation chondrocytes exacerbated Pharmacological activation substantially alleviated senescence. Taken together, by Targeting represents promising new approach for

Language: Английский

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Regulation of ribosomal RNA gene copy number, transcription and nucleolus organization in eukaryotes

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(6), P. 414 - 429

Published: Feb. 2, 2023

Language: Английский

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SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases

Aging and Disease, Journal Year: 2022, Volume and Issue: 13(6), P. 1787 - 1787

Published: Jan. 1, 2022

As an important NAD⁺-dependent enzyme, SIRT6 has received significant attention since its discovery. In view of observations that SIRT6-deficient animals exhibit genomic instability and metabolic disorders undergo early death, long been considered a protein longevity. Recently, growing evidence demonstrated functions as deacetylase, mono-ADP-ribosyltransferase fatty deacylase participates in variety cellular signaling pathways from DNA damage repair the stage to disease progression. this review, we elaborate on specific substrates molecular mechanisms various physiological pathological processes detail, emphasizing links aging (genomic damage, telomere integrity, repair), metabolism (glycolysis, gluconeogenesis, insulin secretion lipid synthesis, lipolysis, thermogenesis), inflammation cardiovascular diseases (atherosclerosis, cardiac hypertrophy, heart failure, ischemia-reperfusion injury). addition, most recent advances regarding modulators (agonists inhibitors) potential therapeutic agents for SIRT6-mediated are reviewed.

Language: Английский

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SIRT6 is a key regulator of mitochondrial function in the brain

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 18, 2023

Abstract The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it critical roles the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics metabolomics approaches characterize functions of mouse brains. Our analysis reveals that is a central regulator mitochondrial activity brain. deficiency leads with global downregulation mitochondria-related genes pronounced changes metabolite content. We suggest affects through interaction transcription factor YY1 that, together, regulate gene expression. Moreover, target include SIRT3 SIRT4, which are significantly downregulated SIRT6-deficient results demonstrate lack decreased expression metabolomic TCA cycle byproducts, including increased ROS production, reduced number, impaired membrane potential can be partially rescued by restoring SIRT4 levels. Importantly, observed brains also occurring aging human particularly patients Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic lateral sclerosis disease. Overall, our levels neurodegeneration initiate dysfunction altering expression, decay.

Language: Английский

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SIRT1 and SIRT6: The role in aging-related diseases

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1869(7), P. 166815 - 166815

Published: July 26, 2023

Aging is characterized by progressive functional deterioration with increased risk of mortality. It a complex biological process driven multitude intertwined mechanisms such as DNA damage, chronic inflammation, and metabolic dysfunction. Sirtuins (SIRTs) are family NAD+-dependent enzymes that regulate fundamental functions from genomic stability lifespan to energy metabolism tumorigenesis. Of the seven mammalian SIRT isotypes (SIRT1-7), SIRT1 SIRT6 well-recognized for regulating signaling pathways related aging. Herein, we review protective role in aging-related diseases at molecular, cellular, tissue, whole-organism levels. We also discuss therapeutic potential modulators treatment these challenges thereof.

Language: Английский

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Genomic Instability and Epigenetic Changes during Aging

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

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SIRT6 Ameliorates Cancer Cachexia–Associated Adipose Wasting by Suppressing TNFR2 Signalling in Mice

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 1, 2025

ABSTRACT Background Cachexia is a wasting syndrome associated with imbalanced energy metabolism and loss of adipose muscle tissues contributes to morbidity mortality in ageing as well patients severe chronic diseases, including cancer. At present, there are no treatments addressing cachexia that have reached validation be used the clinic. In this study, we investigate protective role SIRT6, an important regulator homeostasis health preservation, against Lewis lung carcinoma (LLC)–induced cachexia. Methods SIRT6 levels serum from gastric cancer ( n = 22, 65.27 ± 12.50 years old, 40.9% females) healthy controls 63.50 10.77 45.4% were measured evaluate correlation between circulating development. Ten‐week‐old transgenic (TG) wild type (WT) male mice injected LLC cells (1.5 × 10 6 per mouse) effects on cachexia‐associated browning lipolysis underlying mechanisms. We explored effect LLC‐conditioned medium induced mature adipocytes, differentiated primary mouse embryonic fibroblasts (MEFs). evaluated vitro activator by treatment MDL800. Results concentrations significantly higher non‐cachectic (3.41 0.30 ng/mL) compared cachectic (3.20 0.23 ng/mL, p < 0.01), suggesting negative level overexpression ameliorated tumour‐induced expenditure white (eWAT mass loss: 66% WT vs. 32% TG; iWAT 69% 40% TG) through suppression lipolysis. LLC‐induced cachexia, tumour necrosis factor‐α receptor 2 (TNFR2) mediated inhibition lipolytic signalling, because difference knockout group was almost eliminated TNFR2 neutralizing antibody. Increased concentration found (690.41 pg/mL 1166.98 patients, 0.05). A selective pharmaceutical activator, MDL800, could completely reverse adipocytes. Conclusion unexpected beneficial function demonstrating increased expression or activity capable protecting host tissue wasting, providing concept future therapies for

Language: Английский

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