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Every compound, protocol, and pathway mapped by evidence. From proven to experimental. The most comprehensive longevity guide on the internet.
Published in Cell (2013) and expanded in 2023, these nine hallmarks represent the fundamental biological processes that drive aging. Every longevity intervention targets one or more of these pathways.
Accumulated DNA damage from endogenous and exogenous sources overwhelms repair mechanisms, driving mutations that impair cellular function and increase cancer risk.
Interventions
Mechanism: Supports DNA repair enzymes (PARPs), activates Nrf2 antioxidant pathways, and upregulates base-excision repair.
Progressive shortening of protective chromosome caps with each cell division. Critically short telomeres trigger senescence or apoptosis, depleting regenerative capacity.
Interventions
Mechanism: Astragaloside IV activates telomerase; Vitamin D correlates with longer leukocyte telomere length; aerobic exercise preserves telomere length via telomerase upregulation.
Age-related changes in DNA methylation, histone modification, and chromatin remodeling alter gene expression patterns, silencing protective genes and activating harmful ones.
Interventions
Mechanism: AKG is a cofactor for TET demethylases; folate supplies methyl groups for proper methylation; berberine modulates AMPK-dependent epigenetic regulators.
Decline in the protein quality-control network (chaperones, proteasome, autophagy) leads to accumulation of misfolded and aggregated proteins, driving neurodegeneration and cellular dysfunction.
Interventions
Mechanism: Spermidine induces autophagy via eIF5A hypusination; time-restricted eating activates AMPK/ULK1 autophagy cascade; supports proteasomal clearance of damaged proteins.
Overactive growth-promoting pathways (mTOR, insulin/IGF-1) and diminished longevity pathways (AMPK, sirtuins) accelerate aging. Caloric restriction counteracts this hallmark most robustly.
Interventions
Mechanism: Rapamycin directly inhibits mTORC1; metformin and berberine activate AMPK, mimicking caloric restriction and improving insulin sensitivity.
Age-related decline in mitochondrial membrane potential, electron transport efficiency, and mitochondrial biogenesis reduces ATP output and increases reactive oxygen species.
Interventions
Mechanism: CoQ10 restores electron transport chain efficiency; PQQ stimulates mitochondrial biogenesis via PGC-1alpha; NAD+ precursors fuel sirtuin-mediated mitophagy.
Permanently growth-arrested cells accumulate with age, secreting inflammatory cytokines (SASP) that damage surrounding tissue, promote fibrosis, and drive chronic inflammation.
Interventions
Mechanism: Senolytics selectively induce apoptosis in senescent cells by targeting anti-apoptotic pathways (BCL-2/BCL-xL). Fisetin is the most potent natural senolytic identified to date.
Decline in the number and function of adult stem cells impairs tissue repair and regeneration across all organ systems, reducing the body's ability to maintain homeostasis.
Interventions
Mechanism: GHK-Cu resets gene expression toward a younger profile; exercise stimulates muscle satellite cells; fasting triggers stem cell regeneration via PKA pathway inhibition.
Chronic low-grade inflammation (inflammaging), impaired endocrine signaling, and altered extracellular matrix composition disrupt tissue coordination and immune surveillance.
Interventions
Mechanism: Omega-3 resolves inflammation via specialized pro-resolving mediators; curcumin inhibits NF-kB; sulforaphane activates Nrf2 to suppress pro-inflammatory gene expression.
32 compounds evaluated by mechanism, evidence quality, dosage, and risk level. Filter, sort, and compare to build your own evidence-based protocol.
| Compound ↑ | Evidence | Risk |
|---|---|---|
Alpha-Ketoglutarate (AKG) Epigenetic | Emerging | Low |
Apigenin Polyphenol | Emerging | Low |
Astragaloside IV (TA-65) Telomere | Emerging | Low |
Berberine mTOR | Strong | Low-Moderate |
C60 (Buckminsterfullerene) Antioxidant | Preclinical | High |
Collagen Peptides Structural | Strong | Low |
CoQ10 (Ubiquinol) Mitochondrial | Strong | Low |
Creatine Amino Acid | Strong | Low |
Curcumin Anti-inflammatory | Moderate | Low |
Dasatinib Senolytic | Moderate | High |
Epitalon (Epithalon) Peptide | Preclinical | Moderate |
Ergothioneine Antioxidant | Emerging | Low |
Fisetin Senolytic | Emerging | Low |
GHK-Cu (Copper Peptide) Peptide | Emerging | Low-Moderate |
Glycine Amino Acid | Moderate | Low |
Hyaluronic Acid Structural | Moderate | Low |
Magnesium Anti-inflammatory | Strong | Low |
Metformin mTOR | Strong | Low-Moderate |
NAC (N-Acetyl Cysteine) Antioxidant | Strong | Low |
NMN (Nicotinamide Mononucleotide) NAD+ | Moderate | Low |
NR (Nicotinamide Riboside) NAD+ | Moderate | Low |
Omega-3 (EPA/DHA) Anti-inflammatory | Strong | Low |
PQQ (Pyrroloquinoline Quinone) Mitochondrial | Emerging | Low |
Pterostilbene Polyphenol | Emerging | Low |
Quercetin Senolytic | Moderate | Low |
Rapamycin mTOR | Strong | High |
Resveratrol Polyphenol | Moderate | Low |
Spermidine Epigenetic | Moderate | Low |
Sulforaphane Antioxidant | Moderate | Low |
Taurine Amino Acid | Strong | Low |
Urolithin A Mitochondrial | Moderate | Low |
Vitamin D3 Anti-inflammatory | Strong | Low |
Key Study References
Bryan Johnson spends an estimated $2M+ per year on his Blueprint longevity program. We analyzed his published supplement stack and separated what is evidence-based from what is experimental or unproven.
Includes full medical team, daily measurements, custom compounding, plasma exchange, and gene therapy experiments.
His published stack includes 50+ supplements, prescription medications, and experimental compounds taken in precise timing windows.
Claims a biological age 20+ years younger than his chronological age, measured by DunedinPACE and other epigenetic clocks.
Daily Nutrition
Exercise Protocol
Green = evidence-based. Red = experimental or insufficient evidence for the claim.
| Supplement | Dose | Status |
|---|---|---|
| NMN | Undisclosed (est. 1g) | Evidence-Based |
| Lithium (microdose) | 1 mg | Experimental |
| Rapamycin (Rx) | 6 mg biweekly | Evidence-Based |
| Metformin | 1500 mg | Evidence-Based |
| Acarbose | 200 mg | Evidence-Based |
| Spermidine | 10 mg | Evidence-Based |
| CoQ10 | 100 mg | Evidence-Based |
| EPA/DHA | 2 g | Evidence-Based |
| Vitamin D | 2000 IU | Evidence-Based |
| Collagen peptides | Unknown | Evidence-Based |
| DHEA | 25 mg | Experimental |
| Lycopene | 10 mg | Experimental |
| Cocoa flavanols | 500 mg | Evidence-Based |
| Creatine | 2.5 g | Evidence-Based |
| Ashwagandha | 600 mg | Experimental |
| Fisetin | Cycled | Experimental |
80% of the benefit for 0.003% of the cost
The vast majority of Bryan Johnson's results come from things that cost almost nothing: caloric restriction, consistent exercise, good sleep hygiene, and a whole-food plant-rich diet. His basic supplement stack (Vitamin D, Omega-3, Creatine, CoQ10) costs under $80/month. The $2M funds MRI machines, a personal chef, a team of 30+ doctors, and experimental therapies that add marginal benefit at extreme cost.
Core essentials: Vitamin D, Omega-3, Mag, Creatine. Captures an estimated 60% of supplement benefit.
Add NMN, CoQ10, Berberine. Targets NAD+, mitochondria, and nutrient sensing. ~80% of benefit.
Sleep 7-8 hrs, exercise 150+ min/wk, eat whole foods, manage stress. These outperform any supplement.
Ranked by the strength of evidence linking each food to extended healthspan. Blue Zone staples are marked. These foods outperform most supplements.
Okinawa, Sardinia, Nicoya, Ikaria, Loma Linda
Meat consumed ~5x per month in small portions
Beans, lentils, chickpeas are the cornerstone
Okinawans practice hara hachi bu (eat until 80% full)
1-2 glasses with food (Sardinia, Ikaria)
| # | Food | Blue Zone |
|---|---|---|
| 1 | Extra-Virgin Olive Oil Oleocanthal, hydroxytyrosol, oleic acid | ● |
| 2 | Wild Blueberries Anthocyanins, pterostilbene, quercetin | ● |
| 3 | Wild-Caught Salmon EPA/DHA omega-3, astaxanthin | ● |
| 4 | Broccoli Sprouts Sulforaphane (50-100x more than broccoli) | ● |
| 5 | Walnuts ALA omega-3, polyphenols, melatonin | ● |
| 6 | Green Tea (Matcha) EGCG, L-theanine, catechins | ● |
| 7 | Turmeric (whole root) Curcumin, ar-turmerone, bisdemethoxycurcumin | ● |
| 8 | Dark Chocolate (>85%) Epicatechin, theobromine, polyphenols | ● |
| 9 | Pomegranate Ellagitannins (converted to Urolithin A by gut bacteria) | ● |
| 10 | Fermented Foods (kimchi, sauerkraut, natto) Spermidine, Vitamin K2, probiotics, nattokinase | ● |
| 11 | Sardines / Anchovies EPA/DHA, calcium, CoQ10, selenium | ● |
| 12 | Mushrooms (Lion's Mane, Shiitake) Ergothioneine, beta-glucans, hericenones | ● |
| 13 | Legumes (lentils, black beans) Fiber, resistant starch, folate, polyphenols | ● |
| 14 | Avocado Oleic acid, glutathione, potassium, lutein | ● |
| 15 | Cruciferous Vegetables Sulforaphane, indole-3-carbinol, DIM | ● |
| 16 | Bone Broth Glycine, proline, collagen, minerals | ● |
| 17 | Sweet Potatoes Beta-carotene, anthocyanins, fiber | ● |
| 18 | Eggs (pastured) Choline, lutein, zeaxanthin, complete protein | ● |
| 19 | Flaxseeds ALA, lignans, fiber | ● |
| 20 | Garlic / Aged Garlic Allicin, S-allyl cysteine, ajoene | ● |
Time-Restricted Eating (TRE)
Caloric Restriction (CR)
The frontier of longevity science. These interventions range from promising clinical trials to highly speculative research. Proceed with caution and medical supervision.
Partial cellular reprogramming using Oct4, Sox2, Klf4, and c-Myc (OSKM) factors can reverse epigenetic age without losing cell identity. Altos Labs and Retro Biosciences are investing billions.
Dasatinib (100 mg) + Quercetin (1000 mg) taken for 3 consecutive days, repeated monthly. Selectively clears senescent cells that drive inflammation and tissue damage.
Therapeutic plasma exchange (TPE) replaces aged plasma with saline and albumin. The key insight: it is the removal of pro-aging factors in old blood, not the addition of young blood, that drives rejuvenation.
Repeated exposure to 100% oxygen at 2 ATA in a pressurized chamber. Creates a hyperoxia-hypoxia cycle that stimulates stem cells, lengthens telomeres, and clears senescent cells.
Deliberate cold exposure (cold plunge, cryotherapy) and heat exposure (sauna) activate hormetic stress pathways that improve resilience, reduce inflammation, and activate heat/cold shock proteins.
Short amino acid chains with targeted biological activity. Popular in the longevity community but largely unregulated and under-studied in humans.
Rapamycin (sirolimus) is the only compound that consistently extends lifespan across yeast, worms, flies, and mammals. Low-dose, pulsed protocols are now being tested in humans for aging.
Epigenetic clocks measure DNA methylation patterns at specific CpG sites to calculate your biological age. The pace-of-aging metric (DunedinPACE) measures how fast you are aging right now.
Four tiers from essential to experimental. Start at Tier 1 and only move up once you have the basics dialed in. The most expensive tier is not the most important.
The absolute foundation. These four have extensive safety data, strong evidence, and address the most common deficiencies.
50%+ are deficient. Regulates 1,000+ genes. Reduced cancer mortality 25% (VITAL trial).
Anti-inflammatory. Preserves telomeres. Reduces cardiovascular risk. Most people get far too little.
Cofactor for 600+ enzymes. Improves sleep, reduces inflammation. Almost everyone is deficient.
Neuroprotective. Prevents sarcopenia. One of the most studied and safest supplements in existence.
Add these once Tier 1 is locked in. Good human data, reasonable safety profiles, targeting specific aging mechanisms.
NAD+ restoration. Human trials show improved insulin sensitivity and vascular function.
Declines 50% with age. KiSel-10 trial: 53% reduction in cardiovascular mortality over 12 years.
Natural AMPK activator. Comparable to metformin in glucose-lowering trials. Also improves lipids.
For the serious biohacker. Promising preclinical data with early human signals. The risk-reward shifts here.
Autophagy inducer. Epidemiological data links intake to reduced mortality. Safe track record in food.
Most potent natural senolytic. Intermittent dosing mimics mouse study protocol. Inexpensive.
Mitophagy activator. ATLAS trial showed improved mitochondrial markers. Gut-dependent, so supplementation ensures levels.
The complete stack with monitoring. Includes prescription compounds. Requires a physician comfortable with longevity medicine.
The foundation plus the experimental layer.
Most robust lifespan extension in mammals. Requires regular blood monitoring for lipids and immune markers.
TAME trial ongoing. Reduces all-cause mortality in diabetics below non-diabetic controls.
You cannot optimize what you do not measure. Essential for any serious protocol.
Track actual aging rate vs. chronological age. The ultimate feedback loop.
You cannot optimize what you do not measure. These tests and biomarkers tell you how fast you are actually aging, regardless of your birthday.
Measures IgG glycosylation patterns. Responsive to lifestyle changes within months. Widely used in longevity research.
Turnaround: 3-4 weeks
Uses DunedinPACE and principal component clocks. Most comprehensive epigenetic age test available commercially.
Turnaround: 3-5 weeks
Measures cumulative pace of aging and biological age. Founded by MIT aging researcher Leonard Guarente.
Turnaround: 4-6 weeks
Uses the original Horvath 2013 clock. Well-validated but less responsive to short-term interventions.
Turnaround: 3-4 weeks
These biomarkers provide the best window into your aging trajectory. Optimal ranges are more aggressive than standard “normal” lab ranges because the goal is healthspan, not just absence of disease.
| Marker | Optimal Range | Free? |
|---|---|---|
| hsCRP | < 0.5 mg/L | Specialty |
| Homocysteine | < 7 umol/L | Specialty |
| Fasting Insulin | < 5 uIU/mL | Specialty |
| IGF-1 | 100-150 ng/mL | Specialty |
| HbA1c | < 5.2% | Specialty |
| ApoB | < 60 mg/dL | Specialty |
| Vitamin D (25-OH) | 50-70 ng/mL | Standard Panel |
| Omega-3 Index | > 8% | Specialty |
| Fasting Glucose | < 85 mg/dL | Standard Panel |
| GGT | < 20 U/L | Standard Panel |
Your annual physical typically includes fasting glucose, basic lipids, CBC, and metabolic panel. Ask your doctor to add HbA1c and Vitamin D, which are often covered by insurance. These alone provide valuable baseline data.
Services like InsideTracker ($249+), Marek Health, or direct-to-consumer labs (Quest, Ulta Labs) provide hsCRP, ApoB, insulin, homocysteine, Omega-3 index, and hormone panels without a doctor's order in most US states.
Use Biorank to find the highest-quality, evidence-based supplements at the best value. Every product scored on the same rigorous methodology.
This page is for educational and informational purposes only. It is not medical advice and should not replace consultation with a qualified healthcare provider. Some compounds discussed (rapamycin, metformin, dasatinib) are prescription medications with significant side effects and contraindications. Experimental therapies carry unknown risks. Always consult your physician before starting any new supplement, medication, or health protocol. Individual responses vary. Biorank does not diagnose, treat, cure, or prevent any disease. The studies cited are for reference only and do not constitute endorsement of any specific product or therapy.