Academy

Insulin/IGF-1 Signaling Pathway and Longevity in C. elegans

Overview: The Insulin/IGF-1 signaling (IIS) pathway is a core regulator of growth, metabolism and lifespan in animals. In the nematode Caenorhabditis elegans, this pathway controls key transcription factors that drive stress responses and aging.

Key Components:

1. DAF-2 receptor: Acts like the insulin receptor; it senses insulin-like peptides in the worm.
2. AGE-1/PI3K: A kinase that generates lipid signals (PIP3) after DAF-2 activation.
3. PDK-1, AKT-1/2, SGK-1: Downstream kinases that transmit signals by phosphorylation.
4. DAF-16/FOXO: A transcription factor normally held inactive in the cytoplasm by phosphorylation.
5. SKN-1/Nrf2: Another transcription factor that controls detoxification and oxidative stress genes.

Mechanism of Longevity Control:

• Under high IIS activity (e.g., abundant nutrients), DAF-2 signaling leads to phosphorylation of DAF-16 and SKN-1, keeping them out of the nucleus and limiting stress-resistance gene expression.
• Under reduced IIS (dietary restriction or genetic inhibition), kinases are less active, allowing DAF-16 and SKN-1 to move into the nucleus.
• In the nucleus, these factors bind DNA and turn on genes that boost antioxidant defenses (like SOD and glutathione), heat-shock proteins and metabolic regulators, thus extending lifespan.

Relevance to Plant Extracts:

Natural compounds such as flavonoids and polyphenols can mimic reduced IIS and directly or indirectly modulate this pathway. By influencing kinase activity or enhancing stress-response factors, these extracts promote nuclear localization of DAF-16/FOXO and SKN-1/Nrf2, triggering longevity programs.

Applications:

1. Discovery of dietary supplements that safely activate longevity pathways.
2. Screening small molecules for anti-aging drug leads using C. elegans as a high-throughput model.
3. Studying the cross-talk between metabolism, stress resistance and aging in more complex organisms.