A New Translational Rat Model for Evaluating Anti-Aging Interventions

用于评估抗衰老干预措施的新转化大鼠模型

• 批准号: 10665539
• 负责人: STEVEN N. AUSTAD
• 金额: $ 22.96万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10665539
• 关键词: African; Aging; Alzheimer' s Disease; Animals; Biological Assay; Biology; Blood; Breeding; Cancer Intervention; Clinic; Code; Cognitive; Data; Dose; Estradiol; Fatty Liver; Female; Functional disorder; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Hand Strength; Health; Human; Human Biology; Hybrids; Inbred Strain; Inbreeding; Intervention; Intervention Studies; Laboratory Rat; Life; Long-Term Effects; Longevity; Metabolic; Mitochondria; Mitochondrial Proteins; Modeling; Monkeys; Mothers; Mouse Strains; Mus; Muscle; Norway; Nuclear; Nucleotides; Obese Mice; Outcome; Pathology; Pharmaceutical Preparations; Phase; Physiological; Physiology; Plasma; Population; Process; Proteins; Rattus; Research; Research Infrastructure; Research Personnel; Ribosomes; Scheme; Sex Differences; Site; Specificity; Standardization; Stress; Supplementation; Testing; Time; Tissues; Transfer RNA; Translating; age related; anti aging; blood glucose regulation; bone; cognitive capacity; design; diet-induced obesity; endurance exercise; improved; insulin sensitivity; inter-institutional; male; metabolic abnormality assessment; mitochondrial genome; mouse model; novel; pharmacologic; programs; sex; therapy development; translation to humans

We propose to develop as sustainable aging research infrastructure, a new and unique genetically heterogeneous laboratory rat model that can be used to evaluate putative life- and health-extending interventions. The rat has numerous advantages over the mouse for interventional aging research including more human-like physiology and pathophysiology, more cognitive sophistication, and greater genetic diversity compared with standard mouse strains. Inspired by the UM-HET3 mice used by the Interventions testing program, our rat model (OKC-HETb/w) will also be populations of genetically heterogeneous F2 descendants of 4 divergent, inbred strains. A significant difference from the UM-HET3 mice, our breeding scheme takes advantage of the rat’s substantial mitochondrial genomic diversity compared with the mouse to create a population half of which carries the BN strain mitochondria (OKC-HETb), the other half carries the WKY strain mitochondria (OKC- HETw). These mitochondrial genomes mimic great human mitochondrial diversity in that they differ at 95 nucleotides involving 11 of 13 mitochondrial protein-coding genes, 5 tRNA’s and both ribosomal subunits. Our preliminary data show that the OKC-HETb and OKC-HETw rats respond differently to exercise endurance, grip strength, and responsiveness to 17α-estradiol. As a proof of principle, we will evaluate in the OKC-HETb/w rat an anti-aging intervention (17α-estradiol) that was previously found to enhance the longevity of male mice only. An intriguing outcome of our project will be to verify whether or not, this sex-specificity is also seen in our rat model. In the R21 phase of this project we will produce the OKC-HETb/w rats and (1) characterize energetics-based health assays at whole animal and cellular levels under standard and stressed (HFD) conditions in both sexes in both mitochondrial genotypes, (2) determine the dose of 17α-estradiol that will yield blood levels comparable to those found at effective life-extending doses in the ITP study and the short-term effects of 17α-estradiol on metabolic parameters in diet-induced obese mice of both sexes, and (3) provide investigators with tissues as well as young and old OKC-HETb/w. In the R33 phase, we will use the information gained in the R21 phase to: (1) determine the effect of 17α-estradiol on the longevity and age-related pathology in both sexes and both mitochondrial genotypes and (2) determine the long-term effects of 17α-estradiol on age-related changes in metabolic and health parameters, again, in both sexes and both mitochondrial genotypes.

我们建议发展一个可持续的老龄化研究基础设施，一个新的和独特的基因