Low-density lipoprotein cholesterol and lifespan: A Mendelian randomization study.

Area of Science:

• Genetics
• Cardiovascular Health
• Longevity Research

Background:

• The impact of long-term low-density lipoprotein cholesterol (LDL-c) reduction on lifespan in the general population remains unclear.
• Previous research has not established whether lowering LDL-c benefits individuals without pre-existing cardiovascular risk factors.

Purpose of the Study:

• To investigate the association between genetically determined LDL-c levels and lifespan in a general population.
• To examine the gene-specific effects of LDL-c modification on longevity, focusing on key drug targets.

Main Methods:

• Utilized Mendelian randomization with genetic variants proxying LDL-c levels from the Global Lipids Genetics Consortium (n=173,082).
• Assessed lifespan association (n=1,012,240) and replicated findings using longevity as an outcome (90th vs. 60th percentile age).
• Analyzed gene-specific effects for HMGCR, NPC1L1, and PCSK9 targets.

Main Results:

• A one-standard deviation increase in genetically proxied LDL-c was associated with a 1.2-year reduction in lifespan (P=3.83×10⁻¹²).
• Longevity analysis showed a significant inverse association between LDL-c and survival to older age (OR=0.72, P=7.83×10⁻⁸).
• PCSK9 inhibition showed a significant effect on lifespan reduction (-0.99 years, P=6.80×10⁻⁶), while HMGCR and NPC1L1 were underpowered.

Conclusions:

• Higher LDL-c levels are genetically associated with reduced lifespan and longevity in the general population.
• LDL-c lowering therapies likely provide a net lifespan benefit, particularly PCSK9 inhibitors.
• Further randomized controlled trials are needed to confirm clinical practice modifications.