By Jerry and Lisa Meloche, Pharm.D., Owners, Compounding Pharmacists
Cholesterol has been a central focus of cardiovascular risk assessment for decades. In clinical practice, elevated low-density lipo-protein cholesterol (LDL-C) is consistently identified as a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD), and lipid-lowering therapies have reduced rates of heart attacks and strokes in numerous randomized controlled trials. Standard guidelines generally recommend LDL-C targets based on individual cardiovascular risk. Despite this well-established framework, recent research has prompted a nuanced re-examination of how cholesterol levels relate to longevity, particularly in individuals at very advanced age.
The Sardinian Longevity Study:
Methods and Findings
A new observational study conducted in Sardinia’s Blue Zone — a region noted for an unusually high prevalence of individuals living into their 90s and beyond — explored the relationship between cholesterol levels and survival in extremely old adults. The cohort consisted of 168 nonagenarians (81 men and 87 women) with all four grandparents born within the Blue Zone. Baseline fasting lipid profiles were obtained once, including total cholesterol and LDL-C, and survival was tracked prospectively over approximately six years.
A key finding of the study was that individuals with moderate elevations in LDL-C (defined as an LDL-C level ≥ 130 mg/dL) demonstrated significantly longer median survival compared with those whose LDL-C was below this threshold. Specifically:
• Median survival for individuals with LDL-C ≥ 130mg/dL was 3.82 ± 1.88 years, compared with 2.79 ± 1.56 years for those with LDL-C below this level (p < 0.0001).
• Cox regression analysis revealed that participants with moderate LDL-C elevations had a 40% lower risk of mortality during follow-up than those with lower LDL-C (odds ratio 0.60; 95% confidence interval 0.405–0.891).
These results challenge a simplistic interpretation that lower cholesterol uniformly confers superior survival in all age groups.
Interpreting the “Cholesterol Paradox”
The authors described their observations as a “cholesterol paradox” — substantial LDL-C levels that would ordinarily be considered elevated appeared correlated with greater longevity in this particular population. Several hypotheses have been proposed to explain these findings:
1. Age-Specific Biology.
Cholesterol participates in foundational physiological processes including cell membrane integrity, hormone synthesis, and vitamin D metabolism. In very advanced age, higher LDL-C might reflect preserved metabolic capacity rather than pathology.
2. Reverse Causality.
Lower cholesterol levels in the very old could represent a marker of frailty or underlying illness rather than a risk factor causing adverse outcomes. Some longitudinal data suggest that cholesterol values decline prior to death in older adults, indicating that low cholesterol may sometimes be a consequence — not a cause — of declining health.
3. Heterogeneous Effects Across Age Spectra.
Epidemiological evidence demonstrates that in younger and middle-aged adults, high LDL-C correlates with increased risk of cardiovascular mortality. For example, the Framingham cohort showed a consistent positive association between elevated cholesterol and long-term risk of coronary and total mortality in younger populations.
In contrast, among the oldest old (e.g., ≥ 85 years), some cohort studies have reported no significant association or even inverse associations between lipid levels and all-cause mortality. These observations underscore that the prognostic meaning of cholesterol measurements may differ markedly by age and health context.
Clinical Context and Caution
While the Sardinian Blue Zone study provides intriguing evidence about cholesterol and survival in advanced age, several key limitations should be acknowledged:
• Observational design: The data do not establish causation, and unmeasured factors such as diet, genetic background, lifestyle, and comorbidities could contribute to observed associations.
• Single measurement: Cholesterol was measured only at baseline, and lifelong lipid trajectories were not captured.
• Small sample size: The cohort was limited to 168 individuals, primarily in a unique geographic and cultural setting, which may restrict generalizability.
Other high-quality research, including large population studies and genetic analyses, generally supports the conclusion that lifelong exposure to high LDL-C is associated with increased risk of atherosclerotic cardiovascular disease and reduced lifespan in middle-aged and younger adults. Mendelian randomization studies suggest that genetically elevated LDL-C reduces lifespan across broad populations, and lipid-lowering therapies are known to improve cardiovascular outcomes in many patient groups.
Integrating Evidence for Practice
Clinicians interpreting cholesterol data should consider:
• Age and health status: Risk stratification differs substantially between mid-life individuals and those of advanced age.
• Comprehensive risk assessment: Cholesterol values should be interpreted in the context of overall cardiovascular risk, including blood pressure,
smoking status, diabetes, and family history.
• Individualized decision-making: Shared decision-making between patient and clinician incorporating patient values, risk tolerance, and life expectancy is essential.
Cholesterol remains an important biomarker for cardiovascular risk, but its relationship with longevity is complex and influenced by age, health status, and possibly genetic and environmental factors. Continued research, particularly large longitudinal studies across diverse populations, is necessary to refine our understanding of lipid biology and its implications for longevity.
• Single measurement: Cholesterol was measured only at baseline, and lifelong lipid trajectories were not captured.
• Small sample size: The cohort was limited to 168 individuals, primarily in a unique geographic and cultural setting, which may restrict generalizability.
Other high-quality research, including large population studies and genetic analyses, generally supports the conclusion that lifelong exposure to high LDL-C is associated with increased risk of atherosclerotic cardiovascular disease and reduced lifespan in middle-aged and younger adults. Mendelian randomization studies suggest that genetically elevated LDL-C reduces lifespan across broad populations, and lipid-lowering therapies are known to improve cardiovascular outcomes in many patient groups.
Integrating Evidence for Practice
Clinicians interpreting cholesterol data should consider:
• Age and health status: Risk stratification differs substantially between mid-life individuals and those of advanced age.
• Comprehensive risk assessment: Cholesterol values should be interpreted in the context of overall cardiovascular risk, including blood pressure, smoking status, diabetes, and family history.
• Individualized decision-making: Shared decision-making between patient and clinician incorporating patient values, risk tolerance, and life expectancy is essential.
Cholesterol remains an important biomarker for cardiovascular risk, but its relationship with longevity is complex and influenced by age, health status, and possibly genetic and environmental factors. Continued research, particularly large longitudinal studies across diverse populations, is necessary to refine our understanding of lipid biology and its implications for longevity.
Creative Scripts Compounding Pharmacy
239-261-0050
600 Goodlette Road North #108
Naples, FL 34102
www.creativescripts.net
Reference
Pes, G. M., Dore, M. P., Errigo, A., Poulain, M., & Carru, C. (2024). The cholesterol paradox in long-livers from a Sardinia longevity hot spot (Blue Zone). Nutrients, 16(3), 467. https://doi.org/10.3390/nu16030467
Reference
Pes, G. M., Dore, M. P., Errigo, A., Poulain, M., & Carru, C. (2024). The cholesterol paradox in long-livers from a Sardinia longevity hot spot (Blue Zone). Nutrients, 16(3), 467. https://doi.org/10.3390/nu16030467