Siim Land’s Longevity Protocol — Evidence-Based (2025-2026)

Siim Land’s Longevity Protocol — Evidence-Based (2025-2026)

Overall evidence: Grade C

Every supplement independently graded on human evidence — dose, the rationale, and where the science actually lands.

16 items · grade mix 1A / 3B / 11C / 1D · 26 peer-reviewed citations · last reviewed 2026-07-18

Bottom line

Siim Land is a bestselling longevity/metabolic-health author (Metabolic Autophagy) whose 2025 stack is built around methylation support, glutathione/antioxidant capacity, and metabolic control rather than exotic anti-aging compounds. His confirmed daily core (creatine, glycine, collagen, omega-3, magnesium, taurine, TMG) is low-risk, cheap, and broadly evidence-aligned for its specific endpoints, and he sensibly cycles the more speculative items (NMN, berberine, sulforaphane). The honest problem is framing: most items are supported only for surrogate outcomes (biomarkers, strength, skin, blood pressure), and several headline longevity claims (taurine, NMN, glucosamine, vitamin K2) rest on animal or observational data that recent RCTs have failed to confirm.

A B C D
A — Strong human evidence B — Moderate evidence C — Preliminary / mixed D — Weak / refuted
Educational only — not medical advice. Grades reflect the strength of published human evidence, not a recommendation to take (or avoid) anything — check each item’s verdict tag for direction. Prescription medications and any new supplement should be discussed with your doctor.
B+

Creatine monohydrate

Supports
Dose3-5 g/day (~100 mg/kg)TimingDaily, any time

Why Longevity takes it: Muscle, strength and cognition; spares methyl groups for DNA repair. — Supplement List 2025; YouTube tier-list

What the evidence says: The best-evidenced item here: many RCTs and meta-analyses confirm creatine augments strength and lean mass with resistance training, and it plausibly supports cognition under stress/sleep loss. But longevity benefit is extrapolated from muscle/brain surrogates; no trial shows it extends human lifespan. Very safe.

Key studies: PMID 37432300PMID 34199420PMID 39519498
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C

Glycine

Mixed
Dose10-15 g/dayTimingBefore bed

Why Longevity takes it: Glutathione synthesis; offsets methionine load from high-protein diet; sleep. — Supplement List 2025; sleep-stack posts

What the evidence says: Glycine is a genuine glutathione precursor, and the GlyNAC RCT in older adults improved oxidative-stress and physical-function biomarkers over 16 weeks. But those are surrogate endpoints from one small single-center group, not hard outcomes, and glycine-alone human longevity data are absent. Cheap and reasonable.

Key studies: PMID 35975308PMID 34587244
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C

NAC (N-acetylcysteine, as GlyNAC)

Mixed
Dose600 mg-1.8 g/day (paired with glycine)TimingCycled, not confirmed daily

Why Longevity takes it: Cysteine donor to rebuild glutathione and lower oxidative stress with age. — YouTube tier-list; podcast

What the evidence says: NAC's aging case rides almost entirely on the same small GlyNAC trials from the Sekhar group, which show biomarker and function gains but no mortality endpoints and await independent replication. NAC reliably raises glutathione, yet broad anti-aging claims are premature. Low-risk; early-stage single-lab evidence.

Key studies: PMID 35975308PMID 34587244
B

Magnesium

Supports
Dose400 mg elemental/dayTimingEvening

Why Longevity takes it: Enzyme cofactor; heart health, sleep, stress resilience. — Supplement List 2025

What the evidence says: Multiple double-blind RCTs and a 2024 umbrella meta-analysis show ~400 mg/day modestly lowers blood pressure (~2 mmHg systolic), a real CV-risk surrogate, and correcting deficiency is worthwhile. The effect is small and it is not a proven lifespan intervention. A safe staple.

Key studies: PMID 27402922PMID 39280209
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C

Omega-3 (EPA/DHA fish oil)

Mixed
Dose2-3 g combined EPA+DHA/dayTimingDaily with food

Why Longevity takes it: Heart and brain health; anti-inflammatory. — Supplement List 2025

What the evidence says: The 2020 Cochrane review (86 RCTs, ~163,000 people) found long-chain omega-3s have little or no effect on all-cause mortality or CV events, with only a small reduction in coronary heart disease events and reliable triglyceride lowering. Best justified for elevated triglycerides, not lifespan.

Key studies: PMID 32114706
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B

Vitamin D3

Mixed
Dose5000 IU/dayTimingCycled, with K2 and fat

Why Longevity takes it: Immune and bone health; correct widespread deficiency. — Supplement List 2025 (cycled tier)

What the evidence says: VITAL (25,871 people) found 2000 IU/day did not reduce cancer incidence or major CV events, though a cancer-mortality signal emerged in latency analyses. Benefit appears confined to correcting deficiency; 5000 IU in a replete person has no proven longevity payoff.

Key studies: PMID 30415629PMID 31733345
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C

Vitamin K2 (MK-7)

Mixed
Dose120 mcg/dayTimingCycled, with D3

Why Longevity takes it: Activates matrix-Gla protein to direct calcium to bone and away from arteries. — Supplement List 2025 (cycled tier)

What the evidence says: Mechanistically K2 activates matrix-Gla protein and observational data look favorable, but the randomized 2022 Circulation trial (AVADEC) found K2+D did not slow aortic valve calcification. The cardiovascular claim is largely unproven in RCTs. Promising biology, disappointing hard endpoints.

Key studies: PMID 35465686PMID 34785587
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D

Taurine

Unproven
Dose3-6 g/dayTimingDaily

Why Longevity takes it: Replace age-related taurine decline; reported mitochondrial/anti-senescence effects. — YouTube longevity videos (post-2023 Science paper)

What the evidence says: The viral 2023 Science paper showed taurine extends healthspan/lifespan in mice and healthspan in monkeys, and blood taurine falls with age in humans, but the human evidence is only correlational and the authors call for trials. No human RCT shows taurine slows aging. Animal-data-driven hype ahead of clinical evidence.

Key studies: PMID 37289866
C

TMG (trimethylglycine / betaine)

Mixed
Dose1-2 g/dayTimingDaily (pairs with creatine)

Why Longevity takes it: Methylation support; lowers homocysteine, replenishing methyl groups used by creatine. — Supplement List 2025

What the evidence says: Betaine reliably lowers homocysteine, but homocysteine-lowering has repeatedly failed to reduce cardiovascular events, and high-dose betaine can raise LDL/total cholesterol. It corrects a biomarker of unproven causal value. Modest and low-cost.

Key studies: PMID 36717385
C

Glucosamine (sulfate/HCl)

Mixed
Dose~1.5 g/dayTimingDiscussed/tier-list

Why Longevity takes it: Large observational mortality and CVD benefit; joint health. — YouTube tier-list; podcast

What the evidence says: Large cohorts (UK Biobank ~495,000; a US NHANES cohort) associate habitual glucosamine use with ~15% lower all-cause and CV mortality, a striking but purely observational signal likely inflated by healthy-user bias. No RCT has tested glucosamine for mortality. Cheap and safe; hypothesis-generating only.

Key studies: PMID 32253185PMID 33219063
C

Sulforaphane (broccoli sprout extract)

Mixed
Dose~10-30 mg sulforaphane equivalent/dayTimingDiscussed/tier-list

Why Longevity takes it: Nrf2 activation for antioxidant and detox support. — YouTube longevity videos; podcast

What the evidence says: Sulforaphane activates the Nrf2 pathway, and small RCTs show effects on fasting glucose (a 2025 Nature Microbiology trial) and liver enzymes. These are short-term biomarker endpoints, not aging outcomes, and bioavailability varies widely. Low-risk with an interesting mechanism but thin clinical evidence.

Key studies: PMID 39929977PMID 36618707
C

CoQ10 (ubiquinol)

Mixed
Dose100-200 mg/dayTimingDiscussed/tier-list

Why Longevity takes it: Mitochondrial bioenergetics and antioxidant support that declines with age. — YouTube tier-list; podcast

What the evidence says: CoQ10's best longevity-adjacent data come from the Swedish KiSel-10 trial, where selenium PLUS CoQ10 (not CoQ10 alone) reduced CV mortality in selenium-deplete elderly. It is not established for healthy replete adults. The signal is confounded by co-supplementation and a low-selenium context.

Key studies: PMID 36480969PMID 36014852
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A

Berberine

Supports
Dose1 g/day (often 500 mg x2)TimingCycled, before carb meals

Why Longevity takes it: Metabolic health; glucose and lipid control (natures metformin). — Supplement List 2025 (cycled tier)

What the evidence says: A meta-analysis of 46 RCTs confirms berberine ~1 g/day meaningfully lowers HbA1c, fasting glucose and LDL, with near-pharmaceutical metabolic effects. Crucially this is glycemic/lipid control, NOT a demonstrated longevity benefit, and GI side effects plus drug interactions are real. Strong for the metabolic claim only; cycle it like a drug.

Key studies: PMID 34956436
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C

NMN / NR

Mixed
Dose350 mg/dayTimingCycled, morning

Why Longevity takes it: Boost NAD+ for cellular energy and repair. — Supplement List 2025 (cycled tier)

What the evidence says: NMN raises NAD+, and small RCTs report gains in muscle insulin sensitivity (Science 2021) and some physical-function measures, but results are inconsistent, short-term and on surrogate endpoints, with no human lifespan data. Regulatory status is unsettled. Marketing far exceeds the human evidence.

Key studies: PMID 36482258PMID 33888596
C

Collagen peptides

Mixed
Dose10-15 g/dayTimingMorning, in shake

Why Longevity takes it: Skin, joint and connective-tissue health; glycine source. — Supplement List 2025

What the evidence says: Multiple RCTs show 10-15 g/day collagen improves skin hydration, elasticity and density, reasonably solid for those cosmetic endpoints. But skin appearance is not healthspan, and there is no evidence collagen extends life or prevents disease. Safe and effective for its actual (skin/joint) claim.

Key studies: PMID 31627309PMID 37822045
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C

Electrolytes (sodium/potassium/magnesium)

Mixed
DoseTo need during fasting/low-carbTimingDuring fasting, low-carb, exercise

Why Longevity takes it: Prevent deficiency, cramps and fatigue during fasting/keto; hydration. — Metabolic Autophagy; fasting/keto content

What the evidence says: The strongest electrolyte outcome data is the SSaSS trial (NEJM 2021), where potassium-enriched salt substitution cut stroke and death in older hypertensive adults, but that is sodium-for-potassium swapping in a high-risk group, not the hydration dosing Land recommends. For replete healthy people, added electrolytes relieve deficiency symptoms but have no proven longevity effect.

Key studies: PMID 34459569

How this stack works

Land's stack targets methylation (glycine, TMG, and creatine's methyl demand), glutathione/antioxidant capacity (glycine + NAC), and metabolic control (berberine, electrolytes for fasting/keto), layered on standard basics.

Evidence summary

Across 16 items the modal grade is C (biomarker, observational, or animal data); only creatine (B+), magnesium (B), vitamin D3 (B) and berberine (A, metabolic-only) reach solid RCT support, and not one item has direct human lifespan- or healthspan-extension evidence. Overall C.

Risks & interactions

Berberine should be cycled (GI upset, drug interactions); high-dose betaine/TMG can raise LDL; taurine and NMN are unproven for longevity; vitamin K2's hard-endpoint RCT (AVADEC) was negative. Generally low-risk otherwise, but added electrolytes/salt are only useful in fasting/keto or genuine deficiency.

Who this is for

A sober, above-average template for people already doing the basics who want a methylation/glutathione angle. The confirmed daily core (creatine, glycine, collagen, omega-3, magnesium) is reasonable; the cycled/tier-list items (berberine, NMN, sulforaphane, glucosamine) are optional experiments, not proven longevity levers.

Sources

  1. Singh P (2023). Taurine deficiency as a driver of aging. Science. doi:10.1126/science.abn9257 · PMID 37289866
  2. Kumar P (2023). Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial. J Gerontol A Biol Sci Med Sci. doi:10.1093/gerona/glac135 · PMID 35975308
  3. Sekhar RV (2021). GlyNAC Supplementation Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Aging Hallmarks, Metabolic Defects, Muscle Strength, Cognitive Decline, and Body Composition. J Nutr. doi:10.1093/jn/nxab309 · PMID 34587244
  4. Guo J (2021). The Effect of Berberine on Metabolic Profiles in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis of RCTs. Oxid Med Cell Longev. doi:10.1155/2021/2074610 · PMID 34956436
  5. Burke R (2023). The Effects of Creatine Supplementation Combined with Resistance Training on Regional Measures of Muscle Hypertrophy: A Systematic Review with Meta-Analysis. Nutrients. doi:10.3390/nu15092116 · PMID 37432300
  6. Forbes SC (2021). Meta-Analysis Examining the Importance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults. Nutrients. doi:10.3390/nu13061912 · PMID 34199420
  7. Wang Z (2024). Effects of Creatine Supplementation and Resistance Training on Muscle Strength Gains in Adults <50 Years of Age: A Systematic Review and Meta-Analysis. Nutrients. doi:10.3390/nu16213665 · PMID 39519498
  8. Zhang X (2016). Effects of Magnesium Supplementation on Blood Pressure: A Meta-Analysis of Randomized Double-Blind Placebo-Controlled Trials. Hypertension. doi:10.1161/HYPERTENSIONAHA.116.07664 · PMID 27402922
  9. Alharran AM (2024). Impact of Magnesium Supplementation on Blood Pressure: An Umbrella Meta-Analysis of Randomized Controlled Trials. Curr Ther Res Clin Exp. doi:10.1016/j.curtheres.2024.100755 · PMID 39280209
  10. Abdelhamid AS (2020). Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. doi:10.1002/14651858.CD003177.pub5 · PMID 32114706
  11. Manson JE (2019). Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease (VITAL). N Engl J Med. doi:10.1056/NEJMoa1809944 · PMID 30415629
  12. Manson JE (2019). Principal results of the VITamin D and OmegA-3 TriaL (VITAL) and updated meta-analyses of relevant vitamin D trials. J Steroid Biochem Mol Biol. doi:10.1016/j.jsbmb.2019.105522 · PMID 31733345
  13. Li ZH (2020). Associations of regular glucosamine use with all-cause and cause-specific mortality: a large prospective cohort study. Ann Rheum Dis. doi:10.1136/annrheumdis-2020-217176 · PMID 32253185
  14. King DE (2020). Glucosamine/Chondroitin and Mortality in a US NHANES Cohort. J Am Board Fam Med. doi:10.3122/jabfm.2020.06.200110 · PMID 33219063
  15. Diederichsen ACP (2022). Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial (AVADEC). Circulation. doi:10.1161/CIRCULATIONAHA.121.057008 · PMID 35465686
  16. Hariri E (2021). Vitamin K-a neglected player in cardiovascular health: a narrative review. Open Heart. doi:10.1136/openhrt-2021-001715 · PMID 34785587
  17. Lu XT (2023). Effects of low-dose B vitamins plus betaine supplementation on lowering homocysteine concentrations among Chinese adults with hyperhomocysteinemia: a randomized controlled trial. Eur J Nutr. doi:10.1007/s00394-023-03087-y · PMID 36717385
  18. Yi L (2022). The efficacy and safety of beta-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, dose-dependent clinical trial. Geroscience. doi:10.1007/s11357-022-00705-1 · PMID 36482258
  19. Yoshino M (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. doi:10.1126/science.abe9985 · PMID 33888596
  20. Bolke L (2019). A Collagen Supplement Improves Skin Hydration, Elasticity, Roughness, and Density: Results of a Randomized, Placebo-Controlled, Blind Study. Nutrients. doi:10.3390/nu11102494 · PMID 31627309
  21. Seong SH (2023). Low-molecular-weight collagen peptides supplement promotes a healthy skin: A randomized, double-blinded, placebo-controlled study. J Cosmet Dermatol. doi:10.1111/jocd.16026 · PMID 37822045
  22. Dwibedi C (2025). Effect of broccoli sprout extract and baseline gut microbiota on fasting blood glucose in prediabetes: a randomized, placebo-controlled trial. Nat Microbiol. doi:10.1038/s41564-025-01932-w · PMID 39929977
  23. Satomi S (2022). Effects of broccoli sprout supplements enriched in glucoraphanin on liver functions in healthy middle-aged adults with high-normal serum hepatic biomarkers: A randomized controlled trial. Front Nutr. doi:10.3389/fnut.2022.1077271 · PMID 36618707
  24. An P (2022). Micronutrient Supplementation to Reduce Cardiovascular Risk. J Am Coll Cardiol. doi:10.1016/j.jacc.2022.09.048 · PMID 36480969
  25. Opstad TB (2022). Selenium and Coenzyme Q10 Intervention Prevents Telomere Attrition, with Association to Reduced Cardiovascular Mortality (KiSel-10 sub-study). Nutrients. doi:10.3390/nu14163346 · PMID 36014852
  26. Neal B (2021). Effect of Salt Substitution on Cardiovascular Events and Death (SSaSS). N Engl J Med. doi:10.1056/NEJMoa2105675 · PMID 34459569

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