Vitamin B12

Vitamin essential for nerve function and red blood cells

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What is Vitamin B12?

Vitamin B12 (cobalamin) is a water-soluble vitamin essential for DNA synthesis, red blood cell formation, neurological function, and the methylation cycle. Unlike most vitamins, B12 is found almost exclusively in animal products (meat, fish, eggs, dairy), making vegetarians and vegans particularly susceptible to deficiency. B12 is absorbed in the small intestine with the help of intrinsic factor (a protein produced by stomach parietal cells), and deficiency can result from either dietary insufficiency or malabsorption.

Here's the critical insight:B12 deficiency is insidious and often misdiagnosed. It can take 5-10 years to develop after B12 intake stops, because the liver stores 2-5 mg (enough for 3-5 years). Early symptoms—fatigue, brain fog, mood changes—are nonspecific and often attributed to aging or stress. But if left untreated, B12 deficiency causes irreversible neurological damage:peripheral neuropathy, cognitive decline, dementia, and spinal cord degeneration (subacute combined degeneration). Standard reference ranges (>200 pg/mL) are too low;functional medicine practitioners target >400-500 pg/mL to prevent subclinical deficiency.

Serum B12 measures total B12 in blood, but it's not always reliable. Some people have normal serum B12 but functional deficiency at the cellular level. Methylmalonic acid (MMA) and homocysteine are more sensitive functional markers:they rise when B12 is insufficient for cellular metabolism. If serum B12 is borderline (200-400 pg/mL) and you have symptoms, check MMA and homocysteine to confirm deficiency.

Why Vitamin B12 Matters for Longevity

Neurological health:B12 is essential for myelin sheath formation around nerves. Deficiency causes irreversible nerve damage, peripheral neuropathy, cognitive decline, dementia.
DNA synthesis and cell division:B12 is required for synthesis of nucleotides. Deficiency impairs rapidly dividing cells (bone marrow, gut lining) causing megaloblastic anemia.
Methylation cycle:B12 (as methylcobalamin) is a cofactor for methionine synthase, converting homocysteine→methionine. Deficiency raises homocysteine, a risk factor for cardiovascular disease, stroke, Alzheimer's.
Red blood cell formation:B12 deficiency causes macrocytic anemia (large, immature red blood cells) leading to fatigue, weakness, shortness of breath.
Energy production:B12 (as adenosylcobalamin) is required for conversion of methylmalonyl-CoA to succinyl-CoA in the Krebs cycle. Deficiency impairs mitochondrial energy production.
Mood and mental health:B12 supports neurotransmitter synthesis. Deficiency linked to depression, anxiety, cognitive decline, and increased dementia risk.

Optimal vs Standard Ranges

Range Type	Level	Significance
Optimal (Longevity)	500-1000 pg/mL	Target range for optimal brain health, energy, and methylation. Many functional medicine doctors target >600 pg/mL.
Adequate (Standard)	400-500 pg/mL	Meets standard guidelines but may be suboptimal for some individuals, especially if symptoms present.
Suboptimal	200-400 pg/mL	Low-normal range. May have subclinical deficiency with elevated MMA/homocysteine. Consider supplementation if symptomatic.
Deficient	<200 pg/mL	Frank deficiency. High risk of anemia, neuropathy, cognitive impairment. Requires immediate B12 replacement (sublingual or injection).

Standard lab range: neuropathy

How to Optimize Vitamin B12

1. Very High

>1000 pg/mL

2. Seen with supplementation. Generally not harmful (B12 is water-soluble, excess excreted). Very high levels (>2000 pg/mL) rare;may indicate liver disease, kidney disease, or myeloproliferative disorders.

B12 Supplementation (Dose and Form)

3. Methylcobalamin or hydroxocobalamin:Preferred forms. Methylcobalamin is the active form used in methylation;hydroxocobalamin is converted to both methyl- and adenosyl-cobalamin. | Cyanocobalamin:Synthetic form, most common in supplements. Requires conversion to active forms. Generally effective but methylcobalamin may be superior for neurological issues. | Sublingual B12:1000-5000 mcg daily. Bypasses stomach absorption issues. Effective for most people with mild-moderate deficiency. | B12 injections (IM):1000 mcg weekly or monthly for severe deficiency, pernicious anemia, or malabsorption. Most effective for rapid repletion. | Maintenance dose:500-1000 mcg/day sublingual or 1000 mcg/month injection after repletion.

Identify and Treat Underlying Cause

4. Pernicious anemia (autoimmune):Antibodies destroy stomach parietal cells → no intrinsic factor → can't absorb B12. Requires lifelong B12 injections or very high-dose oral (1000-2000 mcg/day can overcome lack of intrinsic factor via passive diffusion). Check anti-intrinsic factor antibodies, anti-parietal cell antibodies. | Atrophic gastritis:Reduced stomach acid impairs B12 release from food. Common in elderly, H. pylori infection, long-term PPI use. May need B12 supplementation. | Metformin:Impairs B12 absorption in ~30% of diabetics on long-term metformin. Check B12 annually if on metformin;supplement if needed. | Dietary insufficiency:Vegetarians/vegans must supplement B12 (no reliable plant sources except fortified foods). | Malabsorption:Celiac disease, Crohn's disease, gastric bypass, pancreatic insufficiency impair B12 absorption.

Optimize Methylation Cofactors

5. B12 works synergistically with folate in the methylation cycle. Deficiency of either causes elevated homocysteine. | Folate (methylfolate):400-800 mcg/day. Required for methylation cycle. Use methylfolate (5-MTHF) if MTHFR gene variant. | Vitamin B6:25-50 mg/day. Cofactor for homocysteine metabolism via transsulfuration pathway. | Betaine (TMG):500-2000 mg/day. Alternative methyl donor;can lower homocysteine if B12/folate insufficient.

Address Elevated Homocysteine (if >10 mcmol/L)

Symptoms of Abnormal Vitamin B12

Low Vitamin B12

Elevated homocysteine indicates functional B12 or folate deficiency even if serum levels appear normal.
Target:Homocysteine <7-8 mcmol/L optimal;<10 acceptable. Levels >15 increase CVD risk by 50-100%.
B12 + folate + B6 supplementation effectively lowers homocysteine. Retest in 3 months.

High Vitamin B12

Methylmalonic acid (MMA):Most sensitive marker of B12 deficiency. Rises before serum B12 drops.
Normal MMA:<250 nmol/L. Elevated MMA confirms functional B12 deficiency.
If serum B12 is 200-400 pg/mL but you have symptoms (fatigue, neuropathy, cognitive issues), check MMA and homocysteine.

Causes of Abnormal Vitamin B12

Low Levels

Deficiency <200 pg/mL causes anemia and neurological symptoms. Levels 200-400 pg/mL may cause subclinical deficiency (check MMA/homocysteine).

High Levels

High B12 (>1000 pg/mL) from supplementation is generally harmless. Very high B12 (>2000 pg/mL) without supplementation may indicate:
Liver disease (impaired B12 clearance)
Kidney disease (reduced excretion)
Myeloproliferative disorders (leukemia, polycythemia vera)
Rarely, excessive supplementation

When to Retest

Very high unsupplemented B12 should prompt evaluation for underlying disease, but is not directly harmful.

Scientific Evidence

Dietary insufficiency:Vegetarian/vegan diet without B12 supplementation. No reliable plant sources of B12.|Pernicious anemia:Autoimmune destruction of gastric parietal cells → no intrinsic factor → B12 malabsorption. Most common in elderly, Northern Europeans.|Atrophic gastritis:Age-related or H. pylori-induced stomach atrophy reduces acid and intrinsic factor. Common in elderly.|Medications:Metformin (30% of long-term users develop deficiency), PPIs (omeprazole, pantoprazole), H2 blockers (ranitidine).|Malabsorption:Celiac disease, Crohn's disease, gastric bypass, pancreatic insufficiency, bacterial overgrowth (SIBO).|Alcohol abuse:Damages stomach lining, impairs absorption.|Aging:Reduced stomach acid and intrinsic factor production after age 50.|Nitrous oxide exposure:Inactivates B12 (anesthesia, recreational use).

Liver disease:Hepatitis, cirrhosis (impaired B12 clearance).|Kidney disease:Chronic kidney failure (reduced excretion).|Myeloproliferative disorders:Leukemia, polycythemia vera (increased B12-binding proteins).|Excessive B12 supplementation:>1000 mcg/day (generally harmless, water-soluble).

Source:Baseline:Check serum B12 if symptoms of deficiency (fatigue, neuropathy, cognitive issues) or risk factors (vegetarian/vegan, elderly, on metformin/PPIs).|If borderline (200-400 pg/mL):Check MMA and homocysteine to confirm functional deficiency.|After starting supplementation:Retest in 3 months to ensure adequate repletion. Goal >500 pg/mL.|Annual screening:For vegetarians/vegans, elderly (>60), patients on metformin or PPIs.|If treating pernicious anemia:Monitor B12 and MMA to ensure adequacy of injection schedule (may need monthly injections lifelong).|If elevated homocysteine:Retest 3 months after B12/folate/B6 supplementation to confirm normalization.

B12 Deficiency Prevalence

B12 deficiency affects 10-15% of adults >60 due to atrophic gastritis and reduced intrinsic factor. Vegetarians/vegans have 50-90% prevalence if not supplementing. Metformin users have 30% risk. Subclinical deficiency (B12 200-400 pg/mL with elevated MMA) is much more common.

Source:Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr. 2009;89(2):693S-696S.

B12 and Cognitive Decline

B12 deficiency causes brain atrophy, cognitive decline, and dementia. Observational studies show low B12 (<300 pg/mL) associated with 2-3x higher Alzheimer's risk. B12 supplementation slows brain atrophy by 30-50% in elderly with high homocysteine and prevents progression from MCI to dementia.

Source:Smith AD, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment. PLoS One. 2010;5(9):e12244.

B12 and Cardiovascular Disease (via Homocysteine)

B12 deficiency raises homocysteine, which damages endothelium and increases CVD risk. Meta-analyses show homocysteine >10 mcmol/L associated with 50% higher CVD risk. B12/folate/B6 supplementation lowers homocysteine by 25-30% but CVD benefit in RCTs is modest (likely because started too late in disease process).

Source:Wald DS, et al. Homocysteine and cardiovascular disease:evidence on causality from a meta-analysis. BMJ. 2002;325(7374):1202.

B12 and Peripheral Neuropathy

B12 deficiency is a common cause of peripheral neuropathy (tingling, numbness, pain in hands/feet). Early treatment with B12 injections can reverse neuropathy, but delayed treatment may result in permanent nerve damage. Methylcobalamin form may be superior to cyanocobalamin for neurological issues.

Source:Healton EB, et al. Neurologic aspects of cobalamin deficiency. Medicine. 1991;70(4):229-245.

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Superpower	✓	$199	100+ (150 with ratios)
WHOOP Advanced Labs	✓	$349	65
Labcorp OnDemand	—	$398	30+
Life Extension	—	$486	40+
Everlywell	✓	$468	83
Mito Health	✓	$349	100+
InsideTracker	—	$680	54
Function Health	✓	$365	100+
Marek Health Base	—	$250	65
Marek Health Comprehensive	✓	$495	70+
Marek Health Complete	✓	$895	100+
Marek Health Executive	✓	$1950	150+
Blueprint	—	$399	100+
Quest Health	—	$Varies	75+
Empirical Health	✓	$190	100+
Oura Health Panels	—	$99	50
SiPhox Health	✓	$125	60
Hims Labs Base	✓	$199	50
Hims Labs Advanced	✓	$499	120+
Healthspan	—	$4188	80+
Vitality Blueprint Standard	✓	$375	85
Vitality Blueprint Elite	✓	$700	129