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Conserved lipid metabolic reprogramming confers hypoxic and aging resilience
Wei I Jiang1, Goncalo Dias do Vale2, Quentinn Pearce3,4
1Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Biorxiv : the Preprint Server for Biology
|September 18, 2025
Summary
Arctic ground squirrels show resilience to extreme conditions by downregulating triglycerides and upregulating malonic acid. This metabolic adaptation enhances survival during hypoxia and may protect against aging and APOE4-related diseases.
Area of Science:
- Cellular Metabolism
- Neuroscience
- Comparative Physiology
Background:
- Arctic ground squirrels (AGS) are extreme hibernators with remarkable resilience to hypoxia and hypothermia.
- The cellular mechanisms underlying AGS resilience are not well understood.
- AGS serve as a valuable model for studying metabolic adaptation.
Purpose of the Study:
- To investigate the metabolic adaptations in AGS neural stem cells (NSCs) contributing to their resilience.
- To explore the role of lipid metabolism in cellular adaptation to hypoxia.
- To determine if inhibiting lipid biosynthesis confers resilience in other model organisms and against specific pathologies.
Main Methods:
- Lipidomic and metabolomic profiling of AGS and murine NSCs.
- Inhibition of lipid biosynthesis in AGS NSCs and *C. elegans*.
- Assessment of hypoxic survival and mitochondrial fission in *C. elegans*.
- Evaluation of APOE4-induced pathologies and aging in *C. elegans*.
Main Results:
- AGS NSCs show downregulated triglycerides and upregulated malonic acid compared to murine NSCs.
- Inhibiting lipid biosynthesis in AGS NSCs mimicked hypoxic resilience.
- Hypoxia downregulated lipid biosynthesis enzymes in *C. elegans*.
- Inhibiting lipid biosynthesis in *C. elegans* enhanced hypoxic survival and reduced mitochondrial fission.
- Inhibiting lipid biosynthesis protected *C. elegans* against APOE4 pathologies and aging.
Conclusions:
- Triglyceride downregulation is a conserved metabolic resilience mechanism.
- This mechanism offers protective strategies for neural tissues against hypoxia, ischemia, and aging.
- Targeting lipid biosynthesis may be a therapeutic approach for neurological disorders and age-related conditions.
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