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ATP Synthase, a Target for Dementia and Aging?

James W Larrick1,2, Jasmine W Larrick1, Andrew R Mendelsohn1,2

  • 11 Panorama Research Institute , Sunnyvale, California.

Rejuvenation Research
|February 21, 2018
PubMed

Insights

Aging increases the risk of fatal diseases like Alzheimer's dementia (AD). J147, a therapeutic molecule, targets mitochondrial ATP synthase, potentially offering a new avenue for AD treatment and lifespan extension.

Area of Science:

  • Gerontology and Neurodegenerative Diseases
  • Mitochondrial Biology
  • Drug Discovery

Background:

  • Advancing age is the primary risk factor for major life-threatening diseases, including Alzheimer's dementia (AD).
  • Current AD therapies offer limited efficacy, primarily symptomatic relief without halting disease progression.
  • J147 is a therapeutic molecule demonstrating efficacy in rescuing cognitive deficits in aged AD mouse models.

Purpose of the Study:

  • To elucidate the mechanism of action for J147, a promising therapeutic candidate for Alzheimer's dementia.
  • To investigate the molecular targets and pathways modulated by J147 in the context of aging and cognitive decline.

Main Methods:

  • Mechanistic studies were performed to identify the molecular target of J147.
  • Investigated the effects of J147 on mitochondrial alpha-F1-ATP synthase (ATP5A) activity.
  • Assessed the downstream signaling pathways, including intracellular calcium modulation, AMP-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR) signaling.

Main Results:

  • J147 was identified to target the mitochondrial alpha-F1-ATP synthase (ATP5A).
  • Modest inhibition of ATP synthase by J147 modulates intracellular calcium levels.
  • This modulation activates AMP-activated protein kinase (AMPK), leading to the inhibition of mammalian target of rapamycin (mTOR).

Conclusions:

  • J147's mechanism involves the modulation of mitochondrial ATP synthase, impacting key cellular signaling pathways.
  • The identified pathway (ATP synthase inhibition -> calcium modulation -> AMPK activation -> mTOR inhibition) is a known mechanism for lifespan extension.
  • These findings suggest J147 as a potential therapeutic agent for Alzheimer's dementia and possibly for promoting longevity.
Keywords:
agingantioxidantslongevitymitochondrianeurodegeneration

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