Regulation of cellular senescence and metabolic health by dietary protein
膳食蛋白质调节细胞衰老和代谢健康
基本信息
- 批准号:10678729
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-03 至 2026-04-02
- 项目状态:未结题
- 来源:
- 关键词:Adipose tissueAffectAgeAgingApoptoticAutomobile DrivingBiology of AgingBranched-Chain Amino AcidsCardiovascular DiseasesCell AgingCell Culture TechniquesCell Cycle ArrestCellsComplexConsumptionCultured CellsDNA DamageDasatinibDevelopmentDiabetes MellitusDietDietary InterventionDietary ProteinsDiseaseEatingFRAP1 geneFacultyFellowshipFemaleFibroblastsGene ExpressionGeneticGoalsHealthHealthcare SystemsHomeostasisHormone ResponsiveHumanImpairmentIn VitroIndividualInflammationInflammatoryInterventionIsoleucineLeucineLifeLiverLongevityMacronutrients NutritionMalignant NeoplasmsMediatingMentorshipMetabolicMetabolic dysfunctionMetabolismMethodsMitochondriaMolecularMusMuscleNatureObese MicePathologyPathway interactionsPersonsPharmaceutical PreparationsPhenotypePopulationPredispositionProcessProtein KinaseProteinsPublic HealthQuality of lifeQuercetinRegimenResearch PersonnelResistanceRisk FactorsRodentRoleSignal TransductionSirolimusStimulusStressSupplementationTestingTissuesTrainingUnited StatesValineage relatedagedcell growth regulationdiet-induced obesitydietarydietary manipulationexperimental studyfamily burdenfibroblast growth factor 21frailtyhealthspanhealthy aginghuman old age (65+)improvedin vivoinsightmTOR Inhibitormalemembermiddle agemortalitypharmacologicprematurepreventprotein intakeresponsesenescenceskillsstressortenure tracktranscriptome
项目摘要
PROJECT SUMMARY The number of people over age 65 has more than tripled over the past century, placing
great burdens on families and the healthcare system. Extending healthspan, the portion of the life that is relatively
free from major deficits that impair quality of life, may be the most efficacious way to prevent or delay aging and age-
related diseases to reduce such burdens. However, without fully understanding the mechanisms driving aging,
identifying and developing effective and translatable interventions to improve health and longevity in humans will
likely remain limited.
A hallmark of aging, cellular senescence (CS), is an apoptotic-resistant, cell-cycle arrested state induced by
various stressors. Senescent cells release pro-inflammatory soluble factors collectively called the senescence-
associated secretory phenotype (SASP), which can induce premature CS in healthy cells and promote age-related
pathologies. CS can be cleared by genetic or pharmacological (i.e., senolytic drugs) methods, which leads to
improvements in metabolic health and reductions age-related diseases.
Protein restriction (PR) improves many aspects of metabolic health in both humans and mice, and extends
mouse lifespan, specifically through the reduced consumption of the branched-chain amino acids (i.e. leucine,
isoleucine and valine; BCAAs). In preliminary studies, I have found that a diet low in BCAAs (BCAA-R) reduces CS
in aged and diet-induced obese mice as well as cell culture. The mechanisms by which protein promotes CS, and
conversely the mechanisms by which PR and BCAA-R promote healthy aging and reduce CS, are unknown.
One mechanism by which BCAA-R may function to reduce CS is the protein kinase mTORC1, which is
stimulated by protein and BCAAs. mTORC1 activity promotes the SASP, while the mTOR inhibitor rapamycin inhibits
the SASP. BCAA-R has been shown to reduce mTORC1 signaling in the liver and muscle of male mice. Another
factor required for PR is fibroblast growth factor 21 (FGF21), which is also induced by BCAA-R. In vitro, FGF21 has
been shown to protect against CS burden. In this proposal, I will test if diet affects CS clearance by assessing if
senolytics will have the greatest effect on metabolic health and frailty in aged mice eating a high protein diet. I also
will test if BCAAs drive high-protein-induced CS and metabolic dysfunction through activation of mTORC1 in vivo and
in vitro. Finally, I will test if the action of BCAA-R on FGF21 in the whole body or in specific tissues mediates the
effects of a BCAA-R on metabolic health and CS in diet-induced obese mice.
Together, these aims will examine multiple mechanisms by which dietary protein and the BCAAs modulate to
impact CS burden. I will be completing this fellowship under the mentorship of my sponsor, Dr. Dudley Lamming, an
expert in aging biology and metabolism, and my co-sponsor, Dr. Paul Robbins, a world-leading expert in CS.
Completing these aims and the accompanying individualized training plan will help me develop the skills necessary
to become a successful tenure track faculty member focused on the biology of aging and cellular senescence.
在过去的一个世纪里,65岁以上的人口数量增加了两倍多
项目成果
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