Gene

PCSK9

Last updated 2026-07-02· Last reviewed 2026-07-02· 1 min read

Reviewed by the Ultimate Longevity Bible editorial team. Educational reference — not medical advice. See disclaimer.

Biology

Hepatic PCSK9 binds LDLR on the hepatocyte surface → LDLR internalised and degraded → less LDL clearance from blood → serum LDL rises.
Loss-of-function PCSK9 variants → more LDLR at the hepatocyte surface → more LDL clearance → lower serum LDL.

Human genetics

~2–3% of African-American individuals carry the R46L loss-of-function variant.
Carriers have ~30% lower LDL-C from birth and ~50% lower lifetime CHD risk — one of the strongest naturally-occurring cardio-protective variants known.
Homozygous gain-of-function variants cause severe hypercholesterolaemia.

Therapeutic exploitation

Alirocumab, evolocumab: monoclonal antibodies against PCSK9.
Inclisiran: siRNA silencing PCSK9 mRNA in hepatocytes — twice-yearly dosing.
FOURIER, ODYSSEY OUTCOMES trials: substantial cardiovascular-outcome reduction on top of statin therapy.

Longevity relevance

The PCSK9 story is a paradigmatic example of Mendelian randomisation guiding pharmaceutical development — natural loss-of-function humans demonstrated safety and efficacy of a therapeutic approach decades before the drugs were developed.