The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50987 | GEO | 2014/12/20
SECONDARY ACCESSION(S): PRJNA219481
REPOSITORIES: GEO
Similar Datasets
Project description:The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD+ deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a highfat diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of pro-inflammatory gene expression both in the liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice. Groups of 28 week old male C57BL/6J mice were maintained on ad libitum AIN-93G SD diet, or an ad libitum AIN-93G diet supplemented with SRT1720 for the rest of their lives. SRT1720 was added at a dose of 1.33 g drug per kg of chow, formulated to provide daily doses of approximately 100 mg drug per kg bodyweight to the mice. 5 mice from each group were selected and RNA was extracted from both muscle and liver tissue using 1.0mm glass beads in a Precellys 24 Tissue Homogenizer and Qiagen RNeasy Mini Kits for Fibrous Tissue according to manufacturer's specifications. Quality and quantity of the total RNA was checked with the Agilent 2100 bioanalyzer using RNA 6000 Nano chips. RNA samples were labeled using the Illumina TotalPrep RNA Amplification Kit. In short, 0.5ug of total RNA was first converted into single-stranded cDNA with reverse transcriptase using an oligo-dT primer containing the T7 RNA polymerase promoter site and then copied to produce double-stranded cDNA molecules. The double stranded cDNA was cleaned and concentrated with the supplied columns and used in an overnight in-vitro transcription reaction where single-stranded RNA (cRNA) was generated and labeled by incorporation of biotin-16-UTP. Arrays were hybridized using a total of 0.75ug of biotin-labeled cRNA at 58 degrees C for 16 hours to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips. Each BeadChip has ~24,000 well-annotated RefSeq transcripts with approximately 30-fold redundancy. The arrays were washed, blocked and the biotin labeled cRNA was detected by staining with streptavidin-Cy3. Arrays were scanned at a resolution of 0.8um using the Beadstation 500 X from Illumina and the data was extracted using the Illumina GenomeStudio software(v1.6.0). Any spots at or below the background were filtered out using an Illumina detection p value of 0.02 and above. The natural log of all remaining scores were used to find the avg and std of each array and the z-score normalization was calculated and presented below. Z-score = (raw value - avg)/std.
2014-12-20 | E-GEOD-50987 | biostudies-arrayexpress
Project description:Activation of Sirt1, the mammalian homolog of an NAD+-dependent deacetylase known to modulate lifespan in lower organisms, is thought to hold promise as a strategy for delaying aging in mammals. SRT1720, a novel compound developed as a specific and potent activator of Sirt1, has shown promising effects to glucose homeostasis in short-term studies of rats and mice. Here we show SRT1720 extends both mean and maximum lifespan of mice fed a high-fat diet and has concrete benefits to health including reduced liver steatosis and increased insulin sensitivity and locomotor activity. Gene expression profiles and markers of inflammation and apoptosis were also restored to levels more reflective of standard diet controls. Furthermore, the benefits incurred by SRT1720 occurred in the absence of any observable toxicity. The current findings provide hope that safe and effective treatments may be developed to mitigate age-related diseases and enhance lifespan in humans. Male C57BL/6J mice obtained at 12 weeks of age were maintained on a standard purified mouse diet (AIN-93G) until 56 weeks of age prior to the start of the experiment. Beginning at 56 weeks of age, the SD group was fed a standard AIN-93G diet for the duration of the study. Three separate groups were placed on a high-fat diet (HFD) (AIN-93G modified by the addition of hydrogenated coconut oil to provide 60% of calories from fat) or HFD + 30mg/kg body weight SRT1720 (HFD-L) or 100mg/kg body weight SRT1720 (HFD-H) and remained on those diets throughout the study. All mice were fed ad libitum. Food intake and body weight were measured biweekly for the duration of the study.
2011-08-17 | E-GEOD-19102 | biostudies-arrayexpress
Project description:Activation of Sirt1, the mammalian homolog of an NAD+-dependent deacetylase known to modulate lifespan in lower organisms, is thought to hold promise as a strategy for delaying aging in mammals. SRT1720, a novel compound developed as a specific and potent activator of Sirt1, has shown promising effects to glucose homeostasis in short-term studies of rats and mice. Here we show SRT1720 extends both mean and maximum lifespan of mice fed a high-fat diet and has concrete benefits to health including reduced liver steatosis and increased insulin sensitivity and locomotor activity. Gene expression profiles and markers of inflammation and apoptosis were also restored to levels more reflective of standard diet controls. Furthermore, the benefits incurred by SRT1720 occurred in the absence of any observable toxicity. The current findings provide hope that safe and effective treatments may be developed to mitigate age-related diseases and enhance lifespan in humans.
2011-08-18 | GSE19102 | GEO
Project description:The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 6 (SIRT6), an NAD+-dependent deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. Here we show that MDL-800 is a specific SIRT6 activator that has health and lifespan benefits in adult mice fed a standard diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after MDL-800 supplementation. Treatment with MDL-800 induced synthesis of anti-oxidation related proteins, and this rejuvenated HSCs and ISCs in aged mice. Inhibition of pro-inflammatory gene expression in both liver and muscle of MDL-800-treated animals was noted. MDL-800 lowered the level of NF-kB pathway and improved fatty acid metabolism in liver. Combined with our previous work, the current study further supports the beneficial effects of MDL-800 on health across the lifespan in mice.
2023-01-30 | GSE144749 | GEO
Project description:Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans. Key words: Sirtuins, lifespan, healthspan, osteoporosis, muscle wasting, inflammation
2014-09-22 | GSE49000 | GEO
Project description:The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet
| PRJNA219481 | ENA
Project description:Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans. Key words: Sirtuins, lifespan, healthspan, osteoporosis, muscle wasting, inflammation Groups of 28 week old male C57BL6/J mice were maintained for the rest of their lives or until sacrifice on either an ad libitum AIN-93G SD diet, an ad libitum AIN-93G diet supplemented with SRT2104 or a caloric restricted AIN-93G diet consisting of 60% of what the ad lib animals ate. SRT2104 was added at a dose of 1.33 g drug per kg of chow, formulated to provide daily doses of approximately 100 mg drug per kg bodyweight to the mice. 5 mice from each group were selected after 41 weeks and RNA was extracted from both muscle and liver tissue using 1.0mm glass beads in a Precellys 24 Tissue Homogenizer and Qiagen RNeasy Mini Kits for Fibrous Tissue according to manufacturer's specifications. Quality and quantity of the total RNA was checked with the Agilent 2100 bioanalyzer using RNA 6000 Nano chips. RNA samples were labeled using the Illumina TotalPrep RNA Amplification Kit. In short, 0.5ug of total RNA was first converted into single-stranded cDNA with reverse transcriptase using an oligo-dT primer containing the T7 RNA polymerase promoter site and then copied to produce double-stranded cDNA molecules. The double stranded cDNA was cleaned and concentrated with the supplied columns and used in an overnight in-vitro transcription reaction where single-stranded RNA (cRNA) was generated and labeled by incorporation of biotin-16-UTP. Arrays were hybridized using a total of 0.75ug of biotin-labeled cRNA at 58 degrees C for 16 hours to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips. Each BeadChip has ~24,000 well-annotated RefSeq transcripts with approximately 30-fold redundancy. The arrays were washed, blocked and the biotin labeled cRNA was detected by staining with streptavidin-Cy3. Arrays were scanned at a resolution of 0.8um using the Beadstation 500 X from Illumina and the data was extracted using the Illumina GenomeStudio software(v1.6.0). Any spots at or below the background were filtered out using an Illumina detection p value of 0.02 and above. The natural log of all remaining scores were used to find the avg and std of each array and the z-score normalization was calculated and presented below. Z-score = (raw value - avg)/std.
2014-09-22 | E-GEOD-49000 | biostudies-arrayexpress
Project description:Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low protein, high carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets, or to a control diet. At age 15 months, patterns of RNA expression in the hippocampus were similar between CR and LPHC diets for genes associated with longevity, cytokines and dendrite morphogenesis. Nutrient sensing proteins including SIRT1, mTOR and PGC1α were also influenced by diet, however the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. CR and LPHC diets led to modest improvements in the Barnes Maze and Novel Object Recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.
2018-10-18 | GSE111778 | GEO
Project description:The SIRT1 deacetylase is one of the best-studied potential mediators of some of the anti-aging effects of calorie restriction (CR); but its role in CR-dependent lifespan extension has not been demonstrated. We previously found that mice lacking both copies of SIRT1 displayed a shorter median lifespan than wild type mice on an ad libitum diet. Here we report that median lifespan extension in CR heterozygote SIRT1+/- mice was identical (51%) to that observed in wild type mice but SIRT1+/- mice displayed a higher frequency of some certain pathologies. Although larger studies in different genetic backgrounds are necessary , these results provide strong initial evidence for the requirement of SIRT1 for the anti-aging effects of CR, but suggest that its high expression is not required for CR-induced lifespan extension. Key words: SIRT1, caloric restriction, lifespan, anti-aging 2-5 month old male mice of 3 different genotypes (SIRT1+/+, SIRT1+/-, and SIRT1-/-) that had normal, reduced or no expression of SIRT1 were treated with either a 40% caloric restricted diet (CR) or an ad libitum diet (AL). 2-4 replicates of each experimental condition were used in the analysis.
2014-04-25 | E-GEOD-46895 | biostudies-arrayexpress
Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).
2011-12-05 | E-GEOD-31647 | biostudies-arrayexpress