Instalab ResearchCholesterol plays roles that are often overlooked in public conversation. It is a structural component of every cell membrane, helping cells maintain their shape and function. It is the raw material for steroid hormones, including cortisol, testosterone, and estrogen. It is required for the production of vitamin D and bile acids that digest dietary fat. Roughly one fifth of the body’s cholesterol resides in the brain, where it is critical for nerve signaling and synaptic stability.
If cholesterol levels become too low, these biological systems could theoretically be compromised. The question is whether clinical research confirms this theoretical concern.
The relationship between cholesterol and mortality is not linear. Large-scale cohort studies in older adults have revealed that both very high and very low levels of low-density lipoprotein cholesterol (LDL-C) are linked with increased death risk. In a study of over 12,000 older adults, very low LDL-C was associated with greater mortality from non-cardiovascular causes such as cancer and infections, even though high LDL-C increased cardiovascular deaths. Importantly, when early deaths were excluded from analysis, much of the non-cardiovascular association disappeared, suggesting that low cholesterol was often a marker of underlying illness rather than a cause of death.
This illustrates the “U-shaped curve”: too high is dangerous, too low may be problematic, and there is a middle range that appears healthiest.
The possibility that low cholesterol increases cancer risk has been debated for decades. Early studies noted associations between low serum cholesterol and higher rates of cancers such as lung and digestive cancers. However, later evidence from massive cohorts, including over 360,000 men in the Multiple Risk Factor Intervention Trial, showed that the apparent link was largely explained by reverse causation: preclinical cancers lower cholesterol, not the other way around.
Still, cholesterol is vital for cell division, and there is active research on whether disruption in cholesterol metabolism affects tumor biology. Interestingly, some studies suggest the opposite effect: in the Prostate Cancer Prevention Trial, men with low cholesterol had a significantly lower risk of developing high-grade prostate cancer. These findings highlight that the cholesterol–cancer connection is not one of simple cause and effect.
One of the few consistent risks associated with very low cholesterol is hemorrhagic stroke. A systematic review of randomized controlled trials and cohort studies found that people with total cholesterol below about 5 mmol/L (193 mg/dL) had nearly double the risk of hemorrhagic stroke. This risk, however, was confined to a small fraction of the population and was outweighed by the cardiovascular benefits of lower cholesterol overall. More recent meta-analyses confirm that while very low LDL-C may slightly increase hemorrhagic stroke risk, it substantially reduces ischemic stroke and heart attack risk, making the net benefit clear.
The brain’s reliance on cholesterol has fueled concerns about psychiatric risks of low cholesterol. Some early observational studies linked very low cholesterol with higher rates of suicide and violent behavior. More recent, larger studies have found that the association is inconsistent, often explained by confounding factors such as underlying depression or chronic illness.
Genetic studies and randomized trials lowering LDL-C have not demonstrated consistent psychiatric harms. The weight of evidence suggests that while low cholesterol can coexist with psychiatric symptoms, it is not a direct driver of them.
Cholesterol supports the immune system by stabilizing cell membranes and participating in signaling pathways used by white blood cells. Some cohort studies of older adults have found associations between low cholesterol and higher risk of infection-related mortality. However, these associations again appear strongest in frail or chronically ill populations, suggesting that low cholesterol is more a marker of poor health than a cause of vulnerability.
The most rigorous evidence comes from randomized controlled trials of statins and newer drugs such as PCSK9 inhibitors. In the ODYSSEY OUTCOMES trial, more than 18,000 patients with recent acute coronary syndrome were treated with alirocumab plus statins. Many achieved LDL-C levels as low as 15 mg/dL, yet they experienced significantly fewer heart attacks and strokes than those on statins alone. There was no increase in cancer, psychiatric disease, or overall mortality in the very low cholesterol group.
Meta-analyses of statin trials involving hundreds of thousands of participants consistently show that “lower is better” for LDL-C when it comes to reducing cardiovascular events. The benefits of LDL-C lowering persist even at very low levels, with little evidence of harm.
It is important to separate two situations. In one, cholesterol is lowered intentionally through medication or lifestyle, and outcomes are overwhelmingly positive. In the other, cholesterol is naturally low due to chronic illness, malnutrition, or liver disease, and outcomes are often poor. In the second case, low cholesterol is a symptom of declining health, not the cause of it.
This distinction explains why randomized trials, which involve relatively healthy participants whose cholesterol is actively lowered, show benefits, while observational studies of sick populations sometimes show harms.
