Supplements

Why It Matters

EPA and DHA are the biologically active omega-3s — they resolve inflammation, build brain cell membranes (DHA is ~40% of brain phospholipids), protect cardiovascular health, and support retinal function. Plant-based ALA (from flax, chia, walnuts) converts to EPA at only 5–10% and to DHA at <1%. Vegetarians and low-fish eaters consistently have inadequate EPA/DHA levels.

Algae vs. Fish Oil

A 2025 randomized double-blind trial (74 adults, 14 weeks) confirmed algae oil is statistically non-inferior to fish oil for bioavailability of both DHA and EPA in plasma phospholipids. Algae oil is also free from mercury, PCBs, and other ocean contaminants. It tends to be higher in DHA than EPA (opposite of fish oil), which is arguably preferable for brain health.

Vitamin D is a steroid hormone, not just a bone vitamin. It modulates innate and adaptive immunity, regulates autoimmunity risk (MS, Type 1 diabetes, psoriasis), and influences gene expression across hundreds of pathways. The USDA found no dietary pattern provides adequate vitamin D from food alone.

UVB on bare skin synthesizes vitamin D, but this requires midday sun on bare arms/legs — which indoor-heavy lifestyles rarely provide consistently. See Light & Circadian for the sunlight angle.

Form: D3 (cholecalciferol) is significantly more effective at raising serum 25(OH)D than D2 (ergocalciferol). Take with a meal containing fat for absorption.

K2 directs calcium into bones and away from arteries by activating osteocalcin (bone mineralization) and Matrix Gla Protein (prevents arterial calcification). Without K2, supplemental D3 + calcium can actually worsen arterial calcification. A 3-year RCT in 244 postmenopausal women showed 180 mcg MK-7 daily halted age-related arterial stiffening.

Magnesium is a cofactor in 300+ enzymatic reactions including CYP450 function (Phase I liver detox), ATP production, DNA repair, GABA receptor function (sleep/calm), and muscle relaxation. An estimated 2.4 billion people (31% globally) don't meet recommended magnesium intake. A landmark 2018 review called subclinical magnesium deficiency "a principal driver of cardiovascular disease."

Modern Diet Problem

Soil depletion has reduced magnesium in crops 20–30% since the 1950s. Refined grains strip 80–97% of magnesium. Water treatment removes it from drinking water.

Forms Matter

Creatine is the body's rapid-energy currency. Phosphocreatine acts as a local battery — instantly donating a phosphate group to regenerate ATP. Your brain uses ~20% of your total energy budget despite being ~2% of body mass. Vegetarians have measurably lower muscle AND brain creatine stores, confirmed via MRS brain imaging.

Where the Benefit Is Strongest

Kidney Fears Are Overblown

A 2025 systematic review and meta-analysis found creatine does NOT harm kidney function in healthy individuals. The serum creatinine increase is a measurement artifact — creatine, not creatinine.

Who needs it: Vegans (20–86% deficient per meta-analysis), vegetarians (10–40%), older adults, anyone on metformin or long-term PPIs. B12 deficiency causes irreversible neurological damage — myelin degeneration, peripheral neuropathy, cognitive impairment — and damage can be silent for years before symptoms appear.

Form matters: Methylcobalamin is the bioactive form (already methylated — no conversion needed). Cyanocobalamin is cheaper but requires conversion and contains a cyanide molecule that must be detoxified.

Who needs it: Menstruating women, vegetarians, endurance athletes. Vegetarians absorb non-heme iron at 2–20% vs. 15–35% for heme iron.

The absorption hack: Vitamin C increases non-heme iron absorption by 8–20x by reducing ferric to ferrous iron. Citrus, peppers, tomatoes with iron-rich foods.

Zinc

Critical for T-cell immunity, wound healing, thyroid hormone production, testosterone synthesis, and taste/smell. Vegetarian diets are lower in bioavailable zinc because phytates in grains and legumes inhibit absorption.

Dose: 15–30 mg zinc picolinate or bisglycinate, with food. Balance with 2 mg copper per 30 mg zinc if supplementing long-term. Pumpkin seeds are the best vegetarian food source.

Choline

Essential for liver function (phosphatidylcholine is required for VLDL export from the liver — without it, fat accumulates → NAFLD), brain function (precursor to acetylcholine), and methylation. The USDA flagged it as a nutrient of concern for all vegetarian patterns.

Iodine

A structural component of T3 and T4 thyroid hormones. If you use sea salt, Himalayan salt, or kosher salt instead of iodized table salt, you're getting essentially zero iodine from that source. Dose: 150 mcg daily. Be cautious with kelp supplements — they can contain 2,000+ mcg, enough to suppress thyroid function.

Selenium

Essential for thyroid function (selenoproteins convert T4 → active T3), glutathione peroxidase activity, and immune function. The Brazil nut hack: 1–2 Brazil nuts daily provides ~70–90 mcg selenium. One of the rare cases where a single food covers the entire requirement. Dose: 100–200 mcg daily. Do not exceed 400 mcg (toxicity risk).

Glycine

Glycine is one of glutathione's three amino acids, a critical substrate for Phase II amino acid conjugation in liver detox, a building block for collagen, and it improves sleep quality by lowering core body temperature. Dose: 3–5g daily. Can be taken before bed. Pairs with NAC for the GlyNAC protocol.

The body's glutathione factory. Provides the rate-limiting amino acid for your master antioxidant.

Mechanism

NAC is deacetylated to cysteine — the rate-limiting amino acid for glutathione (GSH) synthesis. Glutathione is the body's master antioxidant and central to Phase II detoxification. Every toxin your liver processes draws on glutathione reserves. NAC keeps the tank full. It's also a direct free radical scavenger and a mucolytic (breaks disulfide bonds in mucus).

Evidence by Condition

The active compound in turmeric. The most-studied natural Nrf2 activator — with real caveats.

Mechanism — Nrf2/ARE Activation

Under normal conditions, Nrf2 is held captive in the cytoplasm by Keap1. Curcumin promotes Nrf2 dissociation via PKC-delta-mediated phosphorylation of p62. Nrf2 translocates to the nucleus and switches on protective genes including HO-1, GST, and NQO1 (a Phase II detox enzyme).

Secondary — NF-kB Suppression

Curcumin inhibits NF-kB, the master inflammation switch. Reduces IL-6, TNF-alpha, and COX-2.

Bioavailability — The Critical Challenge

The most potent natural inducer of Phase II detox enzymes. Found in broccoli sprouts.

Mechanism — Keap1/Nrf2

Sulforaphane modifies cysteine residues on Keap1, causing it to release Nrf2. Different molecular trigger than curcumin (which works via p62 phosphorylation), which is why stacking the two gives broader Nrf2 activation than either alone. Most potent known natural inducer of NQO1 and other Phase II detoxification enzymes. These convert fat-soluble toxins (EDCs from microplastics, heavy metals, pollutants) into water-soluble compounds your body can excrete.

Unlike curcumin, no PAINS issue. Sulforaphane has ~80% natural bioavailability from broccoli sprouts and is not a PAINS compound. A 2025 comprehensive analysis identified 84 registered clinical trials.

Sourcing Comparison

Flavonoid with antioxidant, anti-inflammatory, mast cell stabilizing, and senolytic activity.

Strongest Use Case — Allergies

Quercetin stabilizes mast cells and inhibits histamine release — working upstream of antihistamines like cetirizine. A 2022 double-blind RCT found quercetin significantly improved allergic rhinitis symptoms. A 2025 systematic review & meta-analysis of 18 studies confirmed benefit beyond conventional treatment.

Senolytic connection: Quercetin is part of the Mayo Clinic dasatinib + quercetin senolytic combination. Connects to NAD+ & Aging via potential CD38 inhibition.

Liver-specific. Prescription drug in Germany, supplement in the US.

Silymarin protects liver cells directly — stabilizes hepatocyte membranes, stimulates protein synthesis (regeneration), scavenges free radicals in liver tissue, and has anti-fibrotic activity.

An alkaloid from goldenseal, barberry, and Coptis. One of the most evidence-backed natural compounds for metabolic health — often called "nature's metformin" (with caveats).

Mechanism — AMPK Activation

Berberine activates AMP-activated protein kinase (AMPK), the same metabolic master switch triggered by fasting and exercise. AMPK activation increases glucose uptake (GLUT4 translocation), enhances fatty acid oxidation, and inhibits hepatic gluconeogenesis. Mechanism involves mitochondrial complex I inhibition, raising the AMP:ATP ratio — mimicking an energy deficit without caloric restriction.

Secondary — NF-kB Suppression + Gut Microbiome

Poor systemic bioavailability (<1%) may actually be a feature. Much stays in the gut where it modulates the microbiome — increasing short-chain fatty acid producers (Akkermansia muciniphila) and reducing endotoxin producers. This gut-mediated mechanism explains a significant portion of the metabolic benefits.

Clinical Evidence — Blood Glucose & Metabolic Syndrome

Social Media Hype vs. Reality

The core SIRT1 activation claim was a lab artifact — the fluorescent tag in the assay interacted with the compound. GSK paid $720 million for Sirtris Pharmaceuticals based on this flawed assay and shuttered the program in 2013. The NIA Interventions Testing Program found no lifespan extension in mice across multiple trials. Bioavailability is near-zero (<5 ng/mL in plasma after oral dosing).

A 2024 review concluded: "no conclusive clinical evidence to advocate its recommendation in any healthcare setting."

Mixed human evidence, expensive, significant conflicts of interest (the Sinclair and Sirtris pattern repeating with NMN). The mechanism is real — boosting NAD+ precursors — but the outcome data in humans is weaker than the hype.

See the full NAD+ & Aging article for the detailed breakdown of NMN vs. NR, dosing, and whether it's worth it over lifestyle interventions.

Calcium D-Glucarate

Mechanism is sound: Inhibits beta-glucuronidase, a bacterial enzyme in the gut that reverses Phase II glucuronidation and causes toxins your liver already cleared to be reabsorbed. The biochemistry is solid.

Human data is weak: As Memorial Sloan Kettering notes, there are no robust human clinical trials. The mechanism predicts it should work for recirculation reduction; we just don't have outcome data. Dose (if trying): 200–500 mg daily with meals.

Chitosan (Microplastic Binder)

Chitosan is a positively-charged biopolymer that binds negatively-charged microplastic particles in the gut. A 2025 rat study showed >100% MP excretion (meaning it pulled out previously stored MPs from tissue). A 2025 human pilot (n=10) showed a 47% increase in MP excretion.

GI Binders (Activated Charcoal, Zeolite, Bentonite Clay)

Situational, not daily. Bind everything including nutrients and medications. Keep on hand for acute exposures (food poisoning, suspected toxin exposure). Always take 2+ hours away from medications, vitamins, and food. Not a daily supplement.