Untangling determinants of health and lifespan
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA511484 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The impact of chronic caloric restriction (CR) on health and survival in model organisms is complex and its underlying molecular mechanisms are poorly understood. Genetic background, sex, degree of CR and diet composition are expected modifiers of survival outcomes of this intervention. A recent study in mice addressed the impact of diet composition and feeding patterns used in nonhuman primates. It was found that, while diet composition alone did not impact longevity, fasting and calories were determinant for increased survival. We use here a combined physiological, multi-omics (transcriptomics-metabolomics), and integrated pathway analyses to gain insight into core and specific pathways associated with liver healthspan and lifespan. Main findings show that liver longevity pathways associated with CR predominantly correspond to detoxification, molecular turnover-repair-maintenance, and energy supply processes. Differential responses on lifespan extension provided by the different feeding strategies unveiled a distinct pattern of longevity pathways that centered around amino acid, fatty acid and nucleic acid metabolisms. Glycine-serine-threonine metabolism was a unique metabolic hub associated with lifespan whereas short-chain fatty acids and essential PUFAs metabolism were unique to healthspan. Nonhuman primate serum metabolomics data essentially recapitulated key features in mice.
2020-07-13 | GSE124294 | 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: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.
2014-12-20 | GSE50987 | 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 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:Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets led to hyperphagia, obesity and reduced lifespan. These effects were not due to elevated BCAA per se or hepatic mTOR activation, but rather the shift in balance between dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and was linked to central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averted the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes were not due to intrinsic toxicity; rather, to hyperphagia driven by AA imbalance.
2019-03-11 | GSE114855 | GEO
Project description:The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming material with dynamic properties shaping the structure and function of the cell. The proper function of actin is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis (1–5). The breakdown of these cellular processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton (5–9). However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator promoting actin health and longevity. Interestingly, overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are through preservation of actin, downstream of the function of BET-1 as a transcriptional regulator. Together, our discovery attributes assigns a key role of BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
2023-06-01 | E-MTAB-12289 | biostudies-arrayexpress
Project description:The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming material with dynamic properties shaping the structure and function of the cell. The proper function of actin is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis (1–5). The breakdown of these cellular processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton (5–9). However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator promoting actin health and longevity. Interestingly, overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are through preservation of actin, downstream of the function of BET-1 as a transcriptional regulator. Together, our discovery attributes assigns a key role of BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
2023-06-01 | E-MTAB-11786 | biostudies-arrayexpress
Project description:A key challenge in aging research is to extend lifespan in tandem with slowing down functional decline so that the life with good health (healthspan) can be extended. Here, we show that clearance of a small number of cells, which highly express p21Cip1 (p21high), starting from 20 months improves cardiac and metabolic function, and extends both median and maximum lifespan in mice. Importantly, by assessing health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting morbidity compression and healthspan extension. Mechanistically, p21high cells encompass several cell types, with a conserved pro-inflammatory signature. Clearance of p21high cells reduces inflammation, and rejuvenates transcriptomic signatures of various tissues to younger states. These findings demonstrate the feasibility of morbidity compression in mice, and indicate p21high cells as a therapeutic target for healthy aging.
2024-06-13 | GSE269660 | GEO
Project description:This work is an implementation science study that examines different aspects of implementing a single intervention. The intervention consists of asking community health centers to implement an outreach strategy to screen patients for colorectal cancer and for social determinants of health in community health centers at the same contact point. These are both clinical targets that the CHCs feel that their patients need and want to offer at a higher rate. The intervention consists of outreach to patients in need of colorectal cancer screening (CRC) to offer fecal immunochemical test (FIT) screening and screening for social determinants of health (SDOH). In this implementation science study, the intervention is an evidence-based intervention being implemented in real-world clinical practice. The intervention is the outreach to offer FIT and SDOH, conducted by clinic staff. Both evidence-based screening activities-FIT and SDOH screening-are used in the practices included in the study but pairing them is intended to increase efficiency and patient-centeredness by addressing health related social needs that may impact patients’ ability to engage in cancer screening. The study aims to test the effect of implementing the intervention on clinical and process outcomes. Clinical outcomes are CRC screening and SDOH screening. Analysis of process outcomes includes measuring what organizational factors influence implementation.
| 2354406 | ecrin-mdr-crc
Project description:During aging, the loss of metabolic homeostasis drives a myriad of pathologies. A central regulator of cellular energy, the AMP-activated protein kinase (AMPK), orchestrates organismal metabolism. However, direct genetic manipulations of the AMPK complex in mice have, so far, produced detrimental phenotypes. Here, as an alternative approach, we alter energy homeostasis by manipulating the upstream nucleotide pool. Using the turquoise killifish, we mutate APRT, a key enzyme in AMP biosynthesis, and extend the lifespan of heterozygous males. Next, applying an integrated omics approach identify that metabolic functions are rejuvenated in old mutants, which also display a fasting-like metabolic profile and resistance to high-fat diet. On the cellular level, heterozygous cells exhibit enhanced nutrient sensitivity, reduced ATP levels, and AMPK ¬activation. Finally, lifelong intermittent fasting abolishes the longevity benefits. Our findings suggest that perturbing AMP biosynthesis may modulate vertebrate lifespan, and propose APRT as a promising target for promoting metabolic health.
2023-05-23 | GSE190757 | GEO