SIRT6 Is a Key Regulator of Pancreatic β-Cell Survival and Function During Aging
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ABSTRACT:
PROVIDER: PRJNA1214259 | ENA |
REPOSITORIES: ENA
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Project description:SIRT6 has been implicated in anti-aging at the organismal level; however, its role in pancreatic beta cell aging is unclear. This study investigated the role of SIRT6 in pancreatic beta cell aging using conditional SIRT6 transgenic overexpression mice at 10 and 16 months of age. Our data show that SIRT6 has a strong protective function against aging-associated oxidative stress, DNA damage, and multiple forms of cell death.
2025-08-23 | GSE287696 | GEO
Project description:The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Unexpectedly, our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain. SIRT6 deficiency in the brain leads to mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolite content. We suggest that SIRT6 affects mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and 4 levels. Importantly, the changes we observed in SIRT6 deficient brains are also occurring in aging human brains and particularly in patients with Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that the reduced levels of SIRT6 in the aging brain and neurodegeneration initiate mitochondrial dysfunction by altering gene expression, ROS production and mitochondrial decay.
2023-02-03 | GSE221077 | GEO
Project description:SIRT6 is a key regulator of mitochondrial function in the brain
| PRJNA912711 | ENA
Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-κB. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging. comparison of wild type, Sirt6-/- and Sirt6-/- RelA-/- MEF cells
2011-05-11 | E-GEOD-28585 | biostudies-arrayexpress
Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-?B. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging. comparison of wild type, RelA -/- and Sirt6-/- MEF cells
2011-05-11 | E-GEOD-28638 | biostudies-arrayexpress
Project description:Aging is one of the important risk factors for Intervertebral disc degeneration, a major contributor to chronic low back and neck pain. Our recent work has demonstrated a promising role for SIRT6, a nuclear NAD⁺- dependent deacetylase and defatty acylase, in maintaining intervertebral disc health with aging. We therefore investigated whether SIRT6 activation improves outcomes of disc health by studying the spinal phenotype of 24-month-old mice treated with a well-studied agonist, MDL-800, for 6 months. Histological studies revealed healthy disc tissue morphology, enhanced cell viability, and lower degeneration scores in mice treated with MDL-800. Further mechanistic insights revealed that SIRT6 activation decreased H3K9ac levels, improved cell phenotype and matrix quality, and reduced the SASP burden in the disc, characterized by decreased abundance of p21, IL-6 and TGF-b. Tissue RNA-Seq, in vitro measurements of histone 3 modifications, and multi-omics ATAC-seq/RNA-seq analyses revealed that SIRT6 activation altered the epigenetic status (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscape of disc cells. Notably, MDL-800 treatment increased LC3II levels, indicating enhanced autophagic flux in nucleus pulposus cells. Furthermore, plasma LC-MS and NMR analyses revealed minimal systemic metabolic changes. ScRNA sequencing of splenocytes and bone marrow cells showed a decrease in the proportions of B cells, T cells, and granulocytes, without an altered systemic cytokine profile, indicating good tolerance and the absence of systemic inflammation following MDL-800 treatment. Our study demonstrates that SIRT6 activation modulates autophagy and cell senescence in the disc, underscoring the feasibility of targeting SIRT6 activation as a promising pharmacological strategy to maintain disc health in the aging spine.
2026-03-04 | GSE320197 | GEO
Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-κB. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging.
2011-05-11 | GSE28585 | GEO
Project description:Sirtuins (Sirt) are a family of enzymes that modify chromatin and other proteins to affect gene activity. Loss of Sirt6 leads to a progeria-like phenotype in mice, but the target of SIRT6 action has been elusive. Here we show that Sirt6 binds to thousands of gene promoters in a stress-inducible fashion, guided by the stress-responsive transcription factor NF-κB. Chromatin profiling by ChIP-chip analysis of Sirt6 and NF-KB component RelA combined with expression array data of wildtype, Sirt6 knockout and Sirt6 RelA double knockout cells demonstrates that RelA recruits Sirt6 to NF-KB targets in response to TNF-a induction and that many of these targets are important for senescence and aging.
2011-05-11 | GSE28638 | GEO
Project description:Aging is one of the important risk factors for Intervertebral disc degeneration, a major contributor to chronic low back and neck pain. Our recent work has demonstrated a promising role for SIRT6, a nuclear NAD⁺- dependent deacetylase and defatty acylase, in maintaining intervertebral disc health with aging. We therefore investigated whether SIRT6 activation improves outcomes of disc health by studying the spinal phenotype of 24-month-old mice treated with a well-studied agonist, MDL-800, for 6 months. Histological studies revealed healthy disc tissue morphology, enhanced cell viability, and lower degeneration scores in mice treated with MDL-800. Further mechanistic insights revealed that SIRT6 activation decreased H3K9ac levels, improved cell phenotype and matrix quality, and reduced the SASP burden in the disc, characterized by decreased abundance of p21, IL-6 and TGF-b. Tissue RNA-Seq, in vitro measurements of histone 3 modifications, and multi-omics ATAC-seq/RNA-seq analyses revealed that SIRT6 activation altered the epigenetic status (decreased H3K9ac, H3K36me3, and H3K79me2) and transcriptomic landscape of disc cells. Notably, MDL-800 treatment increased LC3II levels, indicating enhanced autophagic flux in nucleus pulposus cells. Furthermore, plasma LC-MS and NMR analyses revealed minimal systemic metabolic changes. ScRNA sequencing of splenocytes and bone marrow cells showed a decrease in the proportions of B cells, T cells, and granulocytes, without an altered systemic cytokine profile, indicating good tolerance and the absence of systemic inflammation following MDL-800 treatment. Our study demonstrates that SIRT6 activation modulates autophagy and cell senescence in the disc, underscoring the feasibility of targeting SIRT6 activation as a promising pharmacological strategy to maintain disc health in the aging spine.
2026-03-04 | GSE320429 | GEO
Project description:Telomere length is important for the maintaining the individual health of a species. However, recent studies have indicated that the telomere length of somatic cells can be drastically decreased in the offspring receiving in vitro fertilization (IVF) therapy, however, the underlying molecular mechanism remains unknown. Sirt6 is a NAD+-dependent epigenetic regulator that has recently been found to play an important role in maintaining telomere stability. Here, we report for the first time that NAD+ levels are significantly lower in blastocysts cultured in vitro than that in blastocysts developed in vivo, leading to impaired Sirt6 function, further triggering telomere shortening of the inner cell mass and possibly affecting newborn offspring. This phenotype could be effectively mitigated by supplementation with NMN, a precursor of NAD+, during in vitro culture.While it could not be achieved in Sirt6 conditional knockout embryos. Our results reveal the mechanism by which in vitro culture induces telomere shortening in preimplantation embryos, providing a potential target for improving in vitro culture conditions.
2025-07-07 | GSE280684 | GEO