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Targeting mechanisms of inter-organelle communication to promote healthy aging

细胞器间通讯的靶向机制促进健康衰老

基本信息

批准号：
9886173
负责人：
Kristopher Burkewitz
金额：
$ 24.2万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886173
关键词：
5&apos -AMP-activated protein kinase ATF6 gene Address Age Age of Onset Aging Animals Automobile Driving Behavior Biological Biological Process CREB1 gene Caenorhabditis elegans Cardiovascular Diseases Cells Cellular Metabolic Process Cellular biology Clinical Communication Coupled Data Defect Diabetes Mellitus Dietary Intervention Disease Elderly Endoplasmic Reticulum Fertility Gene Expression Genes Genetic Genetic Models Goals Growth Health Homeostasis Immunity Individual Intervention Knowledge Link Longevity Malignant Neoplasms Mammalian Cell Mediating Mediator of activation protein Membrane Metabolic Metabolism Microscopy Mitochondria Modeling Molecular Morbidity - disease rate Morphology Neurodegenerative Disorders Nuclear Onset of illness Organelles Osteoporosis Output Pathology Pathway interactions Patients Phase Physiology Play Protein Kinase Proteins Public Health Regulation Reproduction Resolution Risk Factors Role Shapes Signal Transduction Site Stroke System Testing Therapeutic Training Transcription Coactivator Transgenic Organisms Translating age related aged comorbidity design detection of nutrient differential expression functional decline gene therapy healthy aging improved in vivo in vivo monitoring insight lipid metabolism metabolomics mitochondrial metabolism novel prevent proteostasis response sensor side effect targeted treatment therapeutic development tool transcription factor

项目摘要

Project Summary/Abstract Age-onset diseases including cancer, neurodegenerative disease, diabetes, cardiovascular disease, stroke, and osteoporosis are generating a public health burden that is quickly becoming insurmountable. Exacerbating this problem, co-morbidities are common among the elderly. The ideal therapeutic strategy to confront this crisis is to target a unifying risk factor, but patient age is the only risk factor common to all these diseases. Fortunately, it is increasingly clear that the biological processes of aging are malleable, thus the rate and quality of aging may be improved. Genetic and nutritional interventions causing real or perceived energy- depletion are robust, conserved mechanisms to promote healthier aging. Unfortunately these interventions, e.g. activation of the molecular low-energy sensor AMPK, also carry clinically unacceptable side effects, such as suppressed immunity and fertility. Translating these findings into therapeutics thus requires identification of downstream mechanisms that are sufficient for healthier aging. Through a genetic model of longevity in C. elegans via activation of AMPK, we demonstrated that the negative side-effects of energy-depletion can be uncoupled from the positive effects on healthy aging. Using unbiased, systems-level approaches, we found that the longevity-specific mechanism involves downstream regulation of mitochondrial dynamics and metabolic functions, and we now demonstrate that regulation of mitochondrial dynamics is causal to AMPK longevity. New data indicate that perturbing the unfolded protein response (UPR), which mediates homeostasis of the endoplasmic reticulum (ER), interacts with the AMPK pathway to extend lifespan through a mechanism that also requires mitochondrial remodeling. Given recent studies showing that the ER physically interacts with mitochondria to regulate organelle morphology and metabolic signaling, these data suggest a new paradigm in aging: ER/mitochondrial regulation of longevity occurs through an integrated metabolic mechanism. Physical changes in mitochondrial networks are a hallmark of aging, but how organelle dynamics are mechanistically involved in longevity is unknown. By genetically inactivating mediators of mitochondrial remodeling (fission/fusion), Aim 1 will define how mitochondrial dynamics drive the changes in mitochondrial metabolism associated with low-energy longevity. Through novel transgenics and training in high-resolution microscopy in Aim 2, I will test the hypothesis that UPRER perturbations promote altered mitochondrial morphology and signaling between organelles. Finally in the R00 phase, Aim 3 will build on the tools and insights developed in Aims 1 and 2 to identify genetic mechanisms in C. elegans by which ER-mitochondrial inter-organelle communication can be directly targeted to extend healthy lifespan and protect metabolic homeostasis. Taken together, the goal of this proposal is to identify how evolutionarily conserved energy-sensing pathways coordinately modulate inter-organelle signaling and metabolic function to promote longevity.

项目总结/文摘