Bryan Johnson, who has spent years and millions of dollars measuring and re-engineering his own biology, recently revealed something that had eluded him for over a decade: chronically low ferritin, the protein that reflects the body's stored iron. His hemoglobin and hematocrit — the numbers most doctors check first — looked normal, so the low ferritin was repeatedly dismissed as inconsequential.
Earlier this year, a new medical team went looking for why. A colonoscopy came back clean. A more thorough workup — upper endoscopy, biopsies, antibody testing — found the actual cause: autoimmune gastritis, a condition where the immune system attacks the stomach's acid-producing cells, which also impairs vitamin B12 absorption. It's a real, diagnosable disease affecting an estimated 2 to 5 percent of people, and it's why his iron deficiency was ultimately corrected with an intravenous infusion rather than any oral formulation.
That's a specific medical story, not a referendum on supplement quality — no pill, however well-formulated, reliably works around a stomach that can't produce enough acid to begin the absorption process in the first place. But the broader pattern his case surfaced — low ferritin hiding behind a normal hemoglobin, and iron absorption being far more tightly regulated than "just take a pill" suggests — is exactly the terrain most people dealing with iron issues are standing on, even without an autoimmune diagnosis.
The "Rusty Nail" Problem
Most over-the-counter iron comes as ferrous sulfate or ferrous oxide — inorganic metal salts that, chemically, aren't far off from swallowing rust. In the stomach's acidic environment, these forms oxidize quickly, generating free radicals that irritate the gut lining directly. That irritation is the mechanism behind the nausea, cramping, and constipation these supplements are notorious for.
It's also self-defeating: these forms are absorbed so poorly — commonly cited bioavailability is under 10% — that most people are taking on the full side-effect burden for a small fraction of the intended benefit.
The Hepcidin Blockade — And Its Real Limits
There's a second, less visible layer to why iron supplementation fails, and it has nothing to do with which iron salt is on the label: a hormone called hepcidin.
Hepcidin is the body's master iron regulator. It acts on ferroportin, the channel that exports iron out of gut cells and into the bloodstream — and when the body senses inflammation, or already has adequate iron stores, hepcidin rises and shuts that channel down. Iron can get into the gut cell just fine and still never reach circulation if hepcidin has closed the door on the way out.
Where Iron Form Genuinely Matters
None of that makes iron form irrelevant — it matters enormously for the much more common scenario: ordinary iron deficiency without an underlying absorption disorder, where tolerability and getting iron into the gut cell efficiently are the real bottlenecks.
Iron bisglycinate — iron chelated to the amino acid glycine, commercialized as Ferrochel® — is absorbed through the PEPT-1 dipeptide transporter, a separate, higher-capacity route from the DMT-1 channel that plain iron salts compete for and easily saturate. It's recognized by the World Health Organization as a suitable iron fortification form specifically because it delivers meaningfully better bioavailability with less gastric irritation than iron salts.
Liposomal iron has an even more direct case behind it. Multiple randomized controlled trials — including recent pediatric studies — show liposomal iron improving hemoglobin and iron status with substantially fewer GI side effects than ferrous sulfate or ferrous ascorbate. The most striking comparison: a randomized trial in adults with chronic kidney disease found that oral liposomal iron produced hemoglobin improvements comparable to intravenous iron over three months — a genuinely high bar for an oral supplement to clear.
| Form | How It's Absorbed | What the Evidence Shows |
|---|---|---|
| Ferrous Sulfate / Oxide | DMT-1 channel; easily saturated, pH-dependent | Cheap, but bioavailability under 10%; frequent GI side effects |
| Iron Bisglycinate | PEPT-1 dipeptide transporter; bypasses the DMT-1 bottleneck | WHO-recognized; better tolerated and absorbed in repeated trials |
| Liposomal Iron | Endocytosis; largely bypasses pH-dependent uptake | Matched IV iron on hemoglobin improvement in a 3-month CKD trial |
All three deliver "iron." Only some of them get a meaningful fraction of it into your bloodstream without a fight.
The Cofactors That Finish the Job
Iron absorption is only the first step. Vitamin C helps convert dietary iron into the form the gut absorbs more readily and assists it across the intestinal wall — which is why pairing the two, rather than taking them at arbitrary separate times, measurably improves uptake.
Iron also isn't enough on its own to build a red blood cell. Hemoglobin synthesis, and the cell division involved in making new red blood cells in the first place, depend on vitamin B12 and folate — which is why unexplained anemia sometimes turns out to be a B12 or folate problem wearing an iron-deficiency costume, and why comprehensive formulas pair iron with the active, methylated forms of both (methylcobalamin and 5-MTHF) rather than iron alone.
The Verdict
For most people whose iron supplement "isn't working," the fix really is about form: a chelate like bisglycinate or a well-designed liposomal formulation solves the tolerability and absorption-efficiency problems that make cheap iron salts fail, and the evidence behind both is real and repeated.
But Bryan Johnson's case is a useful check on how far that logic goes. Persistent, unexplained low ferritin — especially alongside a stubbornly normal hemoglobin — is worth real medical investigation, not just a better bottle. Sometimes the answer is a smarter supplement. Sometimes it's a diagnosis nobody had gotten around to looking for.