The secret to living to 100 is high cholesterol?
In a nutshell
High cholesterol is linked to greater longevity, not heart disease
LDL is a weak predictor of heart attacks
Cholesterol is essential and protective
I came across the provocative title of this article after a conversation with a friend about her cholesterol. Around the same time I stumbled across a thread on X that provided useful links I hadn’t previously encountered. This article provides those links for anyone interested in reading more on the subject. I’ll cover:
Cholesterol and longevity
Low cholesterol increases the likelihood of death
"If cholesterol does not cause heart disease, then what does?"
Before going there, let’s remind ourselves of a couple of things. There is no such thing as good and bad cholesterol, there is just cholesterol. LDL and HDL are not cholesterol, they are lipoproteins used to carry cholesterol around our bodies.
Cholesterol and longevity
The AMORIS (Apolipoprotein-related MOrtality RISk) study is the main source of data behind my provocative article title. It provides data on 812,000 Swedish individuals collected during routine health checks between 1985 and 1996. The study design is provided in reference 1.
Subsequently, researchers analyzed biomarkers from ~44,000 participants (followed up to 35 years) and identified factors linked to reaching age 100 years of age [2]. Their key findings are as follows:
Higher total cholesterol and iron are linked to greater likelihood of reaching 100
Lower levels of glucose, creatinine, uric acid, aspartate aminotransferase (ASAT/AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LD), and total iron-binding capacity (TIBC) are associated with greater likelihood of reaching 100
In short, the data suggest that higher cholesterol correlates with longer life, not shorter.
Low cholesterol increases the likelihood of death
A 2019 study showed that all-cause deaths associated with cholesterol, follow a “U”-shaped curve [3]. The safest level of cholesterol is in the middle at the bottom of the “U”. Levels below and above that middle are associated with more death.
The authors point out that the relationship between low cholesterol and death is stronger than that with high cholesterol. It appears, therefore, that the risk of death is higher at low levels than at high levels.
"If cholesterol does not cause heart disease, then what does?"
If LDL causes heart disease, then people with heart attacks should have high LDL. In 2009, Sachdeva and colleagues looked at 136,905 patients hospitalised with coronary artery disease across 541 hospitals [4]. They concluded that many patients had "normal" or low LDL levels, suggesting that factors beyond LDL (e.g., insulin resistance and hyperinsulinemia, inflammation, and low HDL) were more important.
In a recent study [5] of ~28,024 initially healthy women looking at more than 50 factors for their link to heart disease, scientists calculated the following relative risks:
Diabetes - highest risk factor at 11
Metabolic syndrome - 6
High blood pressure - 5
Obesity - 4
Smoking - 4
Inflammation (CRP biomarker) - 3
LDL - 1
LDL is, therefore, one of the things least likely to be associated with heart disease. Everything else listed above is more likely (3-11 times) to indicate a likelihood of heart disease.
Nevertheless, these associations do not alone indicate causation. What do the data indicate may be the cause?
Insulin resistance and hyperinsulinemia
At the top of the list are diabetes (11x) metabolic syndrome (6x), high blood pressure (5x), and obesity (4x). I’ve argued in the past that diabetes, high blood pressure, and obesity are manifestations of metabolic syndrome caused by insulin resistance and hyperinsulinemia.
It turns out that we’ve known this for more than 50 years. In 1975, Joseph Kraft tested 14,384 patients and discovered that insulin resistance is detectable 10 to 20 years before blood sugar moves on a standard test [6]. Kraft went on to publish a later book in which he links hyperinsulinemia to a broad range of metabolic issues (the things we call chronic disease) [7].
Inflammation
Inflammation measured as C-reactive protein (CRP) ranked high on the list above. Its relative risk three times higher than LDL.
In 2008, 17,802 patients with normal LDL but elevated CRP had significantly higher cardiovascular risk [8]. In 2017, another trial showed that reducing inflammation alone, without touching cholesterol, reduced heart attacks by 15%. They had the answer. Inflammation. Not cholesterol.
Their cholesterol was fine. Their inflammation was killing them.
Summary
Cholesterol is not our enemy. Quite the opposite, it is one of the most important molecules in our body and our cells produce it because it is essential for:
Building cell membranes
Producing vital hormones including vitamin D, testosterone, estrogen, and cortisol
Creating bile acids for fat digestion
Supporting brain function (the human brain is 25% cholesterol by dry weight)
When an artery is damaged, irrespective of the cause, cholesterol is sent to help with the repair. This is analogous to firemen racing to a house blaze, it is not an attack. Cholesterol is there to fix the problem.
High cholesterol, especially in the context of otherwise good metabolic health, is not the villain it’s been made out to be. Focusing on hyperinsulinemia, insulin resistance, chronic inflammation, and overall metabolic health is more promising for long-term heart health and longevity.
References
Walldius G, Malmström H, Jungner I, et al. Cohort Profile: The AMORIS cohort. International Journal of Epidemiology. 2017;46(4):1103–1103i. doi:10.1093/ije/dyw333
Murata S, et al. Blood biomarker profiles and exceptional longevity: comparison of centenarians and non-centenarians in a 35-year follow-up of the Swedish AMORIS cohort. GeroScience. 2024;46(2):1693-1702. doi:10.1007/s11357-023-00936-w (with correction).
Yi, SW., Yi, JJ. & Ohrr, H. Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults. Sci Rep9, 1596 (2019). https://doi.org/10.1038/s41598-018-38461-y
Sachdeva, A., Cannon, C., Deedwania, PC., LaBresh, K., Smith, SC., Dai, D., Hernandez, A., & Fonarow, GC. (2009). Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. American Heart Journal, 157(1), 111-117. https://doi.org/10.1016/j.ahj.2008.08.010
Dugani SB, Moorthy MV, Li C, et al. Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women. JAMA Cardiol. 2021;6(4):437–447. doi:10.1001/jamacardio.2020.7073
Joseph R. Kraft, Detection of Diabetes Mellitus In Situ (Occult Diabetes), Laboratory Medicine, Volume 6, Issue 2, 1 February 1975, Pages 10–22, https://doi.org/10.1093/labmed/6.2.10
Kraft JR. (2008) Diabetes Epidemic & You. Trafford Publishing
Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207. doi: 10.1056/NEJMoa0807646
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119-1131. doi: 10.1056/NEJMoa1707914