Black pepper (piperine) — The Bioavailability Enhancer

Piperine acts primarily as a bioenhancer by inhibiting key drug-metabolising enzymes in the liver and intestines, notably cytochrome P450 3A4 (CYP3A4) and UDP-glucuronosyltransferases (UGTs). It also inhibits P-glycoprotein (P-gp), an efflux pump that normally prevents the absorption of various compounds. By slowing the glucuronidation and clearance of target molecules, piperine significantly extends their half-life and serum concentration. In preclinical models, piperine has also been shown to exhibit mild anti-inflammatory and antioxidant properties, potentially modulating NF-κB pathways, though its primary relevance to longevity is strictly pharmacokinetic.

Human trials primarily investigate piperine as an adjuvant rather than a standalone therapy. The most famous study demonstrated that 20 mg of piperine co-administered with 2 g of curcumin increased curcumin bioavailability by 2,000% in healthy human volunteers. No published human longevity trials exist for piperine alone. Animal/in-vitro evidence only for direct longevity effects.

5–20 mg per day, typically taken simultaneously with the target molecule (e.g., curcumin or resveratrol). Higher doses are not generally recommended due to the risk of excessive drug interactions. Unestablished as a standalone longevity intervention.

Piperine is generally well-tolerated at standard doses (5–20 mg) but carries a significant risk of drug interactions. Because it inhibits CYP3A4 and P-glycoprotein, it can inadvertently increase the blood levels and toxicity of prescription medications, including statins, blood thinners, and certain cardiovascular drugs. It should be used with caution or avoided by individuals taking narrow-therapeutic-index medications.

Key Papers