AMPK/SIRT1/PGC-1α Signaling Pathway: Molecular Mechanisms and Targeted Strategies From Energy Homeostasis Regulation to Disease Therapy.
Level 5 - mechanism / opinion, no new human data
Narrative review of preclinical and molecular mechanisms without systematic review or new human data
PubMed 41268687 · doi:10.1111/cns.70657
What was done
This narrative review synthesized molecular, cellular, and preclinical evidence examining the regulation and function of the AMPK/SIRT1/PGC-1α signaling cascade. The authors evaluated its role in cellular energy homeostasis and mapped disease-specific pathophysiological mechanisms across conditions including Alzheimer's disease, Parkinson's disease, diabetes, stroke, cardiovascular injury, and chronic kidney disease, along with potential therapeutic activators.
What was found
The abstract reports no numerical findings or effect sizes. It describes a mechanistic positive feedback loop in which AMPK activation increases NAD+ to activate SIRT1, which deacetylates and activates PGC-1α to drive mitochondrial biogenesis. Dysregulation of this pathway is reported to promote amyloid-beta production via BACE1/γ-secretase in Alzheimer's models, impair α-synuclein clearance in Parkinson's models, disrupt GLUT4 translocation in diabetes, and enhance fibrosis and inflammation via NLRP3 and TGF-β/Smad3 signaling.
Why it matters
The paper synthesizes how a central metabolic sensor connects diverse chronic and neurodegenerative diseases, providing a mechanistic framework for evaluating multi-target therapies like metformin, resveratrol, and lifestyle interventions.
Limits
As a narrative review, the paper does not use systematic search criteria, quality appraisal, or meta-analytic pooling. The reported findings rely predominantly on preclinical and in vitro models rather than direct human clinical trials, and no quantitative outcomes are provided in the abstract.
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