Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease

降低线粒体 ATP 合酶活性可延缓衰老和阿尔茨海默病

基本信息

  • 批准号:
    10618893
  • 负责人:
  • 金额:
    $ 91.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-01 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT Aging is the biggest risk factor for Alzheimer's disease (AD) and related dementias (ADRD). However, the underlying molecular mechanism that link mechanisms of aging to ADRDs are unknown. To develop geroprotectors, drugs that target aging and could be used to treat ADRDs we developed a neuro-centric geroscience platform to identify Gero-Neuro-Protectors (GNP), geroprotectors that extend lifespan and simultaneously protect neurons from multiple age associated toxicities. GNPs should make ideal treatments for ADRDs. Increasing lifespan alone, without treating dementia, will only delay disease onset or even prolong disease duration, and thus worsen the ADRD problem, which is the consequence of ever increasing lifespans. We present a proof of principle GNP, J147 and show that it extends lifespan, prevents memory loss, and even restores memory when treatment is initiated in 20-24 month old wild type or symptomatic APPswe mice. We propose a testable model in which J147 protects neurons from ongoing proteotoxic stress by lowering ATP synthase activity, shifting energy metabolism towards glycolysis accompanied by accumulation of acetyl-CoA. Accumulating acetyl-CoA leads to increased H3K9 histone acetylation and protects synapse related gene expression from transcriptional drift -the age-associated deterioration of transcriptional programs- and consequently from functional decline. In the following proposal we will test this model in detail by conducting neuropathology, electrophysiology and behavioral assays in aged wild type mice and two mouse models of ADRD. We show that these effects are evolutionarily conserved and that lowering ATP synthase activity extends lifespan in M. musculus, D. melanogaster and C. elegans. As both, ATP synthase and the age- associated transcriptional drift of synaptic genes are evolutionarily conserved from M. musculus to C. elegans we will use C. elegans to identify the chromatin remodeling factor that controls synapse related gene expression in aging and how it respond to mitochondrial insults. We will validate the role of the identified factor in controlling chromatin on synaptic promoters in primary neurons, aged wild type mice and mouse models of ADRD. Finally, we will expand our GNP concept to profile geroprotective compounds identified by the intervention testing program (ITP) for their ability to protect neurons from different age-associated toxicities and to identify combinations of geroprotectors that are complementary in their protective effects. Because ADRDs are complex diseases with multiple pathological aspects that are unlikely to be addressable by a single drug, we predict rationally designed combinations of geroprotectors to outperform individual geroprotectors. Together these studies will provide deep insights into how aging and ADRDs compromise synapse function and how this can be addressed by treatment with single GNPs or rational GNP combinations.
摘要

项目成果

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Michael Petrascheck其他文献

Michael Petrascheck的其他文献

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{{ truncateString('Michael Petrascheck', 18)}}的其他基金

Lifespan extension by reverse fasting
通过反向禁食延长寿命
  • 批准号:
    10575272
  • 财政年份:
    2023
  • 资助金额:
    $ 91.1万
  • 项目类别:
Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease
降低线粒体 ATP 合酶活性可延缓衰老和阿尔茨海默病
  • 批准号:
    10437597
  • 财政年份:
    2020
  • 资助金额:
    $ 91.1万
  • 项目类别:
Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease
降低线粒体 ATP 合酶活性可延缓衰老和阿尔茨海默病
  • 批准号:
    10653496
  • 财政年份:
    2020
  • 资助金额:
    $ 91.1万
  • 项目类别:
Mechanisms of mRNA translation that modulate protein aggregation
调节蛋白质聚集的 mRNA 翻译机制
  • 批准号:
    9585954
  • 财政年份:
    2018
  • 资助金额:
    $ 91.1万
  • 项目类别:
Modulation of Sensory Perception to Treat Age Related Disease
调节感官知觉来治疗与年龄相关的疾病
  • 批准号:
    8145486
  • 财政年份:
    2011
  • 资助金额:
    $ 91.1万
  • 项目类别:

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