Key Findings
Lifespan Extension: Berberine significantly extended lifespan in C. elegans at concentrations of 1μM (19% increase), 10μM (28% increase), and 100μM (18% increase), with 10μM showing optimal effects.
Healthspan Improvements: At 10μM, berberine reduced age pigments (lipofuscin accumulation), increased locomotory ability (body bends per minute), and maintained fertility unchanged compared to controls.
Molecular Mechanism
ROS Generation: Berberine generates beneficial reactive oxygen species (ROS), measured using DCF-DA fluorescence. This ROS production was completely blocked by N-acetyl-l-cysteine (NAC), which also eliminated berberine’s lifespan benefits.
PMK-1/SKN-1 Pathway Activation:
- Berberine activates PMK-1 (p38 MAPK) through ROS-dependent phosphorylation
- PMK-1 subsequently activates SKN-1 (Nrf2 ortholog), a transcription factor controlling stress response
- SKN-1 upregulates detoxification genes: gst-4, gst-10, and gcs-1
- Mutations in either pmk-1 or skn-1 completely abolished berberine’s lifespan extension
Neurodegeneration Protection
Polyglutamine Disease Model: Berberine improved motility and reduced polyQ35 protein aggregation in AM140 strain muscle cells. Protection required intact PMK-1/SKN-1 signaling.
Alzheimer’s Disease Models: Berberine extended lifespan in two Alzheimer’s models expressing human Aβ1-42:
- CL4176 (rapid paralysis strain)
- CL2006 (slow paralysis strain)
- Protection was lost in pmk-1 and skn-1 deficient worms
Paradigm Shift in ROS Biology
The study reinforces that mild ROS generation acts as beneficial signaling rather than purely damaging. Previous paradigms viewed ROS solely as harmful aging accelerators, but this work demonstrates ROS can activate protective pathways leading to longevity.
Experimental Design
Strains Used: Wild-type N2, skn-1 mutants (zu67, zu135), pmk-1 mutant (km25), neurodegenerative disease models (AM140, CL4176, CL2006)
Key Measurements: Lifespan assays, locomotion analysis, ROS detection, gene expression (qPCR), protein phosphorylation (Western blot), fluorescent reporter activity
Controls: NAC (ROS scavenger), RNAi knockdowns, genetic mutants, multiple independent replicates
Clinical Implications
Berberine, already used in traditional Chinese and Ayurvedic medicine, demonstrates therapeutic potential for aging and neurodegeneration through evolutionarily conserved pathways. The PMK-1/SKN-1 pathway exists in mammals, suggesting translational relevance.
TL;DR: Berberine extends C. elegans lifespan by 28% at 10μM through beneficial ROS generation that activates the PMK-1/SKN-1 stress response pathway, leading to upregulation of detoxification genes and protection against polyglutamine and Alzheimer’s disease models. This challenges the traditional view of ROS as purely harmful and suggests berberine’s therapeutic potential for aging and neurodegeneration.
Source:
https://www.sciencedirect.com/science/article/pii/S0167494324003200