WHAT IS A TRULY NATURAL LEVEL OF LDL?

WHAT IS A TRULY NATURAL LEVEL OF LDL?

The following is written by Pablo Corral MD (on X as @drpablocorral) and it's an excellent summary of an important question everyone should pay close to. Especially if someone likes to say they live/eat in a way that tries to mimic our early ancestors, they should be aware of this too and follow suit completely if being consistent.

How much LDL-C did our ancestors actually have?

The evidence exists — five independent lines, all converging on the same uncomfortable answer.....

1️⃣ The term newborn. Before any dietary or metabolic influence, a healthy neonate arrives with LDL-C of ~30–50 mg/dL. That is the LDLR operating without environmental interference. Everything that rises after birth is acquired.

2️⃣ The Tsimane (Kaplan et al., Lancet 2017) — forager-horticulturalists of the Bolivian Amazon — have a LDL-C between 70 to 90 mg/dL and the lowest prevalence of coronary atherosclerosis ever recorded in any human population. Five times less than the U.S. in adults over 75. And their LDL is rising as roads and processed food arrive.

3️⃣ PCSK9 loss-of-function variants. African American carriers of nonsense mutations (Y142X/C679X, ~2% frequency): −28% LDL-C and −88% CHD risk over 15 years (Cohen et al., NEJM 2006). Homozygous LOF carriers live with LDL-C of ~15–30 mg/dL. Perfectly healthy. Nature already ran the trial.

4️⃣ Evolutionary genetics. Recent positive selection signals exist on gain-of-function PCSK9 variants that raise LDL-C — likely adaptive in food-scarce ancestral environments. Modern hypercholesterolemia is not "normal." It is an ancestral survival advantage turned pathological by evolutionary mismatch.

5️⃣ Great apes in natural habitat: ~40–70 mg/dL LDL-C. Same genome. Different environment.

👆 Bonus — Lp(a). The KIV-2 repeat expansion that raises Lp(a) is a derived, recent variant. Low-Lp(a) alleles are ancestral. Elevated Lp(a) is a textbook antagonistic pleiotropy signal — possibly protective against bleeding early in life, atherogenic over decades

📍The convergent estimate: ancestral LDL-C was ~30–70 mg/dL.

📍An LDL-C of 130 mg/dL (or even 100mg/dL) is not "normal." It is normal for a Western society in evolutionary mismatch. Targets of <55 mg/dL in high-risk patients — which still feel aggressive to many clinicians — are, ironically, closer to the ancestral phenotype than what we call "normal LDL" in daily practice.

🤔 The question is not "is it safe to lower LDL this much?"

The question is: why did we let it rise this high?

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ADDED COMMENTARY FROM DR CHONG:

More thoughts on the idea of "evolutionary mismatch": A vast majority of us have a mismatch between our genetics and our modern environment. Many people carry ancestral genetic programming that evolved to traffic and conserve fuel as efficiently as possible, because many of our ancestral lines were exposed to prolonged risk of famine. The people who survived were the ones whose biology was really good at holding on to things and they have passed this on to most of us. But now we live in an environment of abundance, and when we eat the way we do, and move so much less on average (even a daily one hour workout is nowhere near what we used to do) on a regular basis, it overloads what is still a very conservative system, and one consequence of that is LDL rising well above what our arteries were designed to handle long-term. It's an unfortunate situation that is hard to remedy unless we are able to completely change our lives in terms of how we eat and how we move. I fully believe that, except for the unfortunate few whose genetics are just too strong to fully overcome (such as some people with FH or severe polygenic risks or very high Lp(a)), most people can technically change to eating and moving and living in a way that matches their body's design well enough that their plaque can stabilize. However, for the rest, or for those who are unable to make and sustain such changes, living in the healthiest way they can PLUS using whatever additional tools work well enough for them to recreate this ancestral environment in their bodies, is the safest and most effective approach to this very treatable disease.