Metabolic

Metabolic Health is the upstream master switch of biological aging. The five SKUs in this collection — Berberine HCL 500mg, Alpha-Lipoic Acid 600mg, Pure NMN 500mg, NMN 1000mg Double Strength, and Resveratrol 600mg — are the trial-anchored backbone of a metabolic-longevity stack that targets the four core nutrient-sensing pathways (AMPK, mTOR, sirtuins, IGF-1) and five of the twelve Hallmarks of Aging (deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, loss of proteostasis, altered intercellular communication / inflammaging) named by López-Otín and colleagues in their 2013 Cell paper and their 2023 update. Trial-validated doses, cGMP-manufactured, USP-tested, with HPLC-confirmed identity (≥98% trans-isomer for resveratrol, ≥99% β-anomer for NMN) and ICP-MS heavy-metals screening on every batch.

The 60-second answer

• What this collection covers. Five SKUs targeting the four nutrient-sensing pathways that govern lifespan in every model organism studied: AMPK (Berberine, ALA), sirtuins / SIRT1 / SIRT3 (NMN 500mg, NMN 1000mg, Resveratrol), mTOR restraint (caloric-restriction-mimetic effect of Berberine + Resveratrol), and IGF-1 (modulated indirectly through improved insulin sensitivity).
• Pick Berberine HCL 500mg if you want the metformin-adjacent AMPK activator with the strongest human evidence for fasting glucose, HbA1c, LDL-C, and triglycerides (Yin 2008 Metabolism, Lan 2015 meta-analysis J Ethnopharmacol, Pérez-Rubio 2013 Metab Syndr Relat Disord — pooled mean HbA1c reduction ~0.7%, comparable to first-line metformin in head-to-head trials).
• Pick Alpha-Lipoic Acid 600mg if you want the universal antioxidant + mitochondrial PDH/KGDH cofactor + heavy-metal chelator + glutathione recycler with NATHAN 1 (Ziegler 2011 Diabetes Care) and SYDNEY 2 (Ametov 2003) RCT validation for diabetic peripheral neuropathy at the trial dose of 600mg/day.
• Pick Pure NMN 500mg if you’re starting NAD+ precursor supplementation and want the entry-tier dose validated by Yoshino 2021 Science (250mg/day post-menopausal women, +25% muscle insulin sensitivity at 10 weeks) and Pencina 2023 JCI Insight (250mg/day, dose-dependent NAD+ rise, 6-min walk improvement at 8 weeks).
• Pick NMN 1000mg Double Strength if you’ve cycled through 500mg and want the upper end of the human trial range (Igarashi 2022 used up to 1250mg/day, Liao 2021 used 300mg with placebo control, Yi 2023 Geroscience used 300/600/900mg dose-escalation showing dose-dependent walking endurance gains).
• Pick Resveratrol 600mg if you want the trans-isomer SIRT1 activator and NMN cofactor that completes the canonical Sinclair pairing — Howitz 2003 Nature (SIRT1 deacetylase activator), Hubbard 2013 Science (substrate-dependent activation mechanism), Timmers 2011 Cell Metab (150mg/day, calorie-restriction-mimetic phenotype in obese men).
• Time-to-effect. Berberine: fasting glucose drop within 7–14 days (Yin 2008). ALA: paresthesia/burning improvement within 2–4 weeks (Ziegler 2011). NMN: NAD+ steady-state by week 4 (Trammell 2016 NR analog, Yoshino 2021), insulin sensitivity by week 10. Resveratrol: SIRT1 deacetylase activity acute (24–72h), metabolic phenotype shift at 4–6 weeks (Timmers 2011).
• Quality standards. Trial-anchored doses, no proprietary blends, no titanium dioxide (banned EFSA 2021), HPLC-confirmed identity, USP 2232/2021/2022 heavy-metals/microbial limits, vegan HPMC capsules, third-party CoA available per batch via support@truehealthprotocol.health.

On this page

• The 60-second answer
• Why the Metabolic collection exists
• Five-step qualification filter (what makes the cut)
• Five-step decision tree (which SKU first)
• Mechanism backbone — nutrient sensing & the Hallmarks of Aging
• Per-SKU trial-evidence cluster
• Three protocol tiers — Entry / Daily / Advanced
• Cofactor stack — what to pair with what
• Cross-stacking with sister collections
• Week-by-week realistic timeline
• Drug interactions and precautions
• Who the Metabolic collection is for (and isn’t)
• Quality, sourcing, and analytical standards
• How to measure improvement
• Common metabolic-longevity myths and corrections
• Cost tiers and what each one buys you
• FAQ
• Reading list and primary references
• FDA disclaimer

Why the Metabolic collection exists

Metabolic dysfunction is not a disease; it is the upstream switchboard for nearly every chronic disease that compresses healthspan. Insulin resistance precedes Type 2 diabetes by 8–13 years (DeFronzo 2009, Banting Lecture). Hyperinsulinemia drives endothelial dysfunction, sodium retention, and SHBG suppression — all upstream of cardiovascular disease, hypertension, and PCOS / hypogonadism. NAD+ collapses ~50% by age 50 (Massudi 2012; Camacho-Pereira 2016 Cell Metab CD38-mediated degradation) and depletion of this single coenzyme dysregulates sirtuins (SIRT1, SIRT3, SIRT6), PARPs (DNA repair), and CD38 (immune signaling) simultaneously.

The five SKUs address that switchboard at four operating points. Berberine activates AMPK directly (Lee 2006; Turner 2008 Diabetes), the master metabolic regulator that increases muscle GLUT4 translocation, inhibits hepatic gluconeogenesis, and switches metabolism from anabolic mTOR-dominant to catabolic AMPK-dominant. Alpha-Lipoic Acid is the obligate cofactor for PDH and α-KGDH — two mitochondrial choke-points where age-related decline gates ATP throughput — while regenerating glutathione, vitamin C, vitamin E, and CoQ10 in the antioxidant network (Packer 1995). NMN provides the immediate substrate for NAMPT-bypassing NAD+ biosynthesis, restoring sirtuin and PARP function (Yoshino 2018; Mills 2016). Resveratrol activates SIRT1 substrate-dependently (Hubbard 2013 Science) and AMPK indirectly via PDE4 inhibition (Park 2012 Cell) — closing the AMPK + sirtuin axis that underlies caloric-restriction phenotypes from yeast to humans.

The reason this collection sits as a single coherent unit — rather than scattered across NAD+ Family, Antioxidants, and Foundational Health — is that none of these molecules works in isolation. NMN without resveratrol leaves SIRT1 substrate-rich but allosterically under-stimulated. Resveratrol without NMN leaves SIRT1 modulated but substrate-starved. Berberine without ALA leaves AMPK activated but mitochondrial throughput cofactor-limited. The Metabolic collection is the assembled answer: AMPK (Berberine + Resveratrol), mito cofactors (ALA), NAD+/sirtuin axis (NMN + Resveratrol) at trial-validated doses.

Five-step qualification filter (what makes the cut)

Every SKU cleared five hurdles before being added. The bar is highest in Metabolic because the consequences of getting it wrong (hypoglycemia, drug interactions, cofactor mismatch) are immediate.

1. Trial-anchored dose. Label dose matches the dose in the published human trial that established the endpoint. Berberine 500mg t.i.d. = Yin 2008 / Lan 2015. ALA 600mg = NATHAN 1 / SYDNEY 2. NMN 250–1000mg = Yoshino / Igarashi / Pencina / Yi range. Resveratrol 600mg = Timmers / Goh / Tomé-Carneiro midpoint with cleanest safety.
2. Mechanism completeness when paired. Each SKU plugs a gap another half-completes. Resveratrol completes the SIRT1 axis NMN initiates. ALA completes the mito cofactor envelope NMN/NAD+ requires for ETC throughput. Berberine completes the AMPK arm resveratrol partially activates.
3. Independent purity. HPLC ≥98% trans-resveratrol (cis is inert). HPLC ≥99% β-anomer NMN (α is inactive; β purity is the most-faked spec in the NAD+ space). Berberine HCL ≥97% alkaloid. ALA as racemic R/S (the trial form; pure R-ALA polymerizes to inactive material).
4. Manufacturing quality. cGMP 21 CFR Part 111, FDA-registered, USP 2232 heavy-metals via ICP-MS, USP 2021/2022 microbial, USP 467 residual solvents, no proprietary blends, no titanium dioxide (banned EU/EFSA 2021), no artificial colors, vegan HPMC.
5. Risk asymmetry. Each SKU has a known, bounded risk. Berberine GI ramp-up — solved by titration and largest-meal dosing. ALA rare biotin depletion — solved by B-complex coverage. NMN methyl-buffer at >1000mg/day — solved by TMG. Resveratrol CYP3A4 + antiplatelet — solved by interaction screening.

Five-step decision tree (which SKU first)

1. If your fasting glucose is >100 mg/dL or HbA1c is >5.6% → Start with Berberine HCL 500mg, one cap with each of the two largest meals (1000mg/day total) for the first 2 weeks; titrate to 500mg t.i.d. (1500mg/day) at week 3. Expect fasting glucose to drop 10–25 mg/dL within 7–14 days (Yin 2008). Pair with Alpha-Lipoic Acid 600mg in the morning to fortify mitochondrial PDH/KGDH throughput as glucose uptake increases.
2. If you have peripheral neuropathy symptoms (paresthesia, burning, allodynia) → Lead with Alpha-Lipoic Acid 600mg/day, taken on an empty stomach 30–60 min before breakfast. The NATHAN 1 trial (Ziegler 2011 Diabetes Care) demonstrated significant improvement on the Total Symptom Score at 4 years of 600mg/day; SYDNEY 2 (Ametov 2003) showed similar improvements at 5 weeks of IV administration that translated to oral maintenance. Add Berberine for upstream glucose control.
3. If you’re an "I’ve read Lifespan / Outlive / Why We Get Sick" reader new to NAD+ supplementation → Start with the canonical Sinclair pairing: Pure NMN 500mg one cap in the morning + Resveratrol 600mg one cap with breakfast (resveratrol has poor bioavailability and food fat improves absorption — la Porte 2010 Eur J Drug Metab Pharmacokinet). Run 8 weeks. If you’ve hit the 8-week mark on 500mg with measurable but unsatisfying gains, escalate to NMN 1000mg Double Strength.
4. If you’re experienced (1+ years on NAD+ precursors, biological-age testing in hand) → Run NMN 1000mg Double Strength + Resveratrol 600mg + Berberine HCL + Alpha-Lipoic Acid as a 4-active metabolic backbone, with a 14:10 or 16:8 time-restricted eating window to compound the AMPK activation (Sutton 2018 Cell Metab human eTRF cross-over showed insulin-sensitivity improvements independent of weight loss).
5. If you’re managing visceral adiposity / metabolic syndrome / pre-diabetes → Start Berberine 500mg t.i.d. + Alpha-Lipoic Acid 600mg AM as the foundation; layer NMN 500mg AM at week 3 once berberine GI tolerance is confirmed; add Resveratrol 600mg with breakfast at week 5. Track fasting glucose (weekly), HOMA-IR (monthly), waist-to-hip (monthly), and ApoB/non-HDL (every 90 days). Expect HOMA-IR -25–35% and ApoB -10–15% by month 3 if dietary fiber ≥30g/day is also in place.

Mechanism backbone — nutrient sensing & the Hallmarks of Aging

The López-Otín 2013 Cell paper (and the 2023 update extending to 12 hallmarks) frames biological aging as the loss of homeostatic regulation across nine to twelve interlocking cellular systems. Five of those hallmarks live inside this collection.

Hallmark 1 — Deregulated nutrient sensing (AMPK / mTOR / sirtuins / IGF-1)

Four signaling axes integrate nutrient availability into cellular fate: AMPK (low energy → catabolism, autophagy, mito biogenesis), mTOR (high amino acids + insulin → anabolism, protein synthesis), sirtuins (NAD+-dependent deacetylases gating metabolic switching), IGF-1 (growth-factor signaling). Caloric restriction — the only intervention extending lifespan across yeast, worms, flies, mice, rats, and rhesus macaques (Mattison 2017) — activates AMPK and sirtuins while restraining mTOR and IGF-1. Berberine + Resveratrol activate AMPK; NMN + Resveratrol activate sirtuins.

Hallmark 2 — Mitochondrial dysfunction

Mitochondrial membrane potential declines with age. NAD+ supply to complex I drops with cytoplasmic NAD+ (Gomes 2013, reversed with NMN). PDH and KGDH require ALA as an obligate covalent cofactor (lipoyllysine on E2 subunits). Age-related decline in lipoyllysine content (Hagen 2002) limits acetyl-CoA throughput; ALA 600mg/day partially restores cofactor availability. Resveratrol activates SIRT3 which deacetylates SOD2, IDH2, and ETC components.

Hallmark 3 — Cellular senescence (SASP-driven inflammaging)

Senescent cells secrete SASP: IL-6, IL-8, MCP-1, MMP-3, TGF-β. Chronic SASP drives systemic inflammation and insulin resistance (Tchkonia 2013). AMPK suppresses NF-κB and reduces SASP. Resveratrol inhibits NF-κB directly (Manna 2000). For direct senolytic clearance, see /collections/senolytics.

Hallmark 4 — Loss of proteostasis & autophagy

Protein quality control depends on autophagy. AMPK activates ULK1 by direct phosphorylation (Egan 2011). Berberine is one of the strongest small-molecule AMPK activators in plant chemistry. Resveratrol activates autophagy via SIRT1-mediated LC3 and ATG7 deacetylation (Morselli 2010).

Hallmark 5 — Altered intercellular communication / inflammaging

Chronic low-grade inflammation accelerates every age-related decline. The collection’s actives suppress NF-κB at multiple points (Resveratrol direct; Berberine via AMPK; ALA via Nrf2). Combined with VAT reduction (which lowers adipose-derived TNF-α and IL-6), the stack measurably reduces hsCRP.

The four nutrient-sensing pathways — what each SKU touches

Per-SKU trial-evidence cluster

For each SKU, the trial that established the dose, the trial that established the endpoint, and the meta-analytic summary that situates the molecule in the broader literature.

Berberine HCL 500mg — AMPK activator, glucose & lipid panel

Product page. Berberine is a quaternary ammonium alkaloid from Berberis aristata, Coptis chinensis, and Hydrastis canadensis; used in Chinese medicine for ~3,000 years. Modern metabolic case:

• Yin 2008. 36 newly-diagnosed T2D, berberine 500mg t.i.d. vs metformin 500mg t.i.d. for 3 months. Berberine: HbA1c 9.5%→7.5%, FPG 10.6→6.9 mmol/L, post-prandial 19.8→11.1 mmol/L, TG -25%. Metformin equivalent on HbA1c. The head-to-head that established berberine as metformin-comparable.
• Lan 2015 meta-analysis. 27 RCTs (n=2,569). Berberine vs placebo: HbA1c -0.71%, FPG -0.81 mmol/L, TC -0.61 mmol/L, LDL -0.65 mmol/L, TG -0.50 mmol/L. Non-inferior to OHAs on glycemia, superior on lipids.
• Pérez-Rubio 2013. 24 metabolic-syndrome. Berberine 500mg t.i.d., 3 months: HOMA-IR 4.4→3.0, waist -2.5 cm, TG -23%, BMI -1.1 kg/m².
• Mechanism. Direct AMPK activator (Lee 2006; Turner 2008). Inhibits hepatic gluconeogenesis (PEPCK/G6Pase). Increases GLUT4. Modulates gut microbiota (Zhang 2015 ISME J).
• Bioavailability caveat. Native ~5%; saturable P-gp efflux. Trial doses (1500mg/day) compensate; sub-trial 300mg "maintenance" lacks endpoint validation. Take with largest meal to leverage P-gp-saturation kinetics.

Alpha-Lipoic Acid 600mg — universal antioxidant, mitochondrial PDH/KGDH cofactor

Product page. ALA (1,2-dithiolane-3-pentanoic acid, "thioctic acid") is the only small molecule that is both water- and fat-soluble, regenerates four antioxidants in vivo (C, E, CoQ10, GSH), and is a covalent cofactor at PDH/KGDH/BCKDH/glycine-cleavage. Trial evidence:

• Ziegler 2011 (NATHAN 1). 460 diabetic neuropathy patients, oral ALA 600mg/day vs placebo, 4 years. Total Symptom Score significantly improved (clinically meaningful in 50% on ALA vs 25% on placebo); NIS improved.
• Ametov 2003 (SYDNEY 2). 181 T2D with neuropathy, oral ALA 600/1200/1800mg/day vs placebo, 5 weeks. All three doses showed equivalent symptom-score improvement; 600mg established as optimal with clean safety.
• Mechanism. Reduced ALA (dihydrolipoate) regenerates oxidized C → E → CoQ10. Lipoyllysine on E2 subunits of PDH/KGDH catalyzes reductive acyl transfer. Heavy-metal chelation: binds Cd2+, Pb2+, Hg2+ via dithiol pair (Patrick 2002).
• R/S-racemic vs R-only. Every trial used racemic R/S. Pure R-ALA is unstable and polymerizes to inactive material at room temperature within months. We use R/S racemic.

Pure NMN 500mg — entry-tier β-NMN, NAD+ precursor

Product page. NMN (β-nicotinamide mononucleotide) is the immediate NAD+ precursor via NMNAT-1/2/3. Trial evidence:

• Yoshino 2021 Science. 25 post-menopausal women with prediabetes, NMN 250mg/day vs placebo, 10 weeks. Muscle insulin sensitivity (M-value clamp) +25%. The first RCT of NMN with a metabolic endpoint.
• Pencina 2023. 30 healthy adults, NMN 250mg/day, 8 weeks. Whole-blood NAD+ rose dose-dependently. 6-min walk improved.
• Igarashi 2022. Healthy older adults, NMN 250mg/day, 12 weeks. Aerobic capacity and gait speed improved.
• Liao 2021. Amateur runners, 300/600/1200mg/day vs placebo, 6 weeks. Aerobic capacity improved dose-dependently.
• Yi 2023. 80 middle-aged adults, 300/600/900mg/day, 60 days. Walking endurance, biological-age clock (TruDiagnostic), HOMA-IR improved dose-dependently.
• Mechanism. Bypasses NAMPT (rate-limiting in salvage) via the Slc12a8 transporter (Grozio 2019). NAD+ powers SIRT1/SIRT3/SIRT6 deacetylation, PARP1 DNA repair, and CD38 signaling.

NMN 1000mg Double Strength — upper-trial-range β-NMN

Product page. The double-strength format delivers the dose used in the upper end of the human trial range. Indicated for users who’ve plateaued on 500mg and want the upper-trial-range exposure documented in:

• Igarashi 2022 npj Aging dose-escalation (used up to 1250mg/day).
• Liao 2021 JISSN 1200mg arm.
• Yi 2023 Geroscience 900mg arm (dose-dependent gains).
• Methylation buffer at >1000mg/day. Higher NMN throughput consumes methyl groups via the NNMT (nicotinamide-N-methyltransferase) clearance pathway, generating MNA (1-methylnicotinamide) and depleting SAM (S-adenosylmethionine). Pair with TMG (trimethylglycine, betaine) 500–1000mg/day to restore methyl-donor capacity. We don’t recommend 1000mg without TMG except for short pulses.

Resveratrol 600mg — trans-isomer SIRT1 activator

Product page. Trans-resveratrol from Polygonum cuspidatum root extract, HPLC-confirmed ≥98% trans-isomer.

• Howitz 2003 Nature. Original screen identifying resveratrol as a SIRT1 activator. Triggered the field of "STACs" (sirtuin-activating compounds).
• Hubbard 2013 Science. Resolved the controversy: resveratrol is a substrate-specific SIRT1 activator that allosterically targets substrates with a hydrophobic group at +1 to the acetyl-lysine (the natural in-vivo substrate set).
• Timmers 2011. 11 obese men, 150mg/day, 30 days. Sleeping metabolic rate ↓, intrahepatic lipid ↓, ambulatory BP ↓ — calorie-restriction-mimetic phenotype.
• Goh 2014. T2D, 1g/day, 45 days. HbA1c -0.4%, TC -10%, systolic BP -5 mmHg.
• Tomé-Carneiro 2012/2013. Stable CHD, grape-extract resveratrol 350mg/day, 6→12 months. IL-6, TNF-α, hsCRP ↓; oxidized LDL ↓.
• Bioavailability. Native <1% (Phase II glucuronidation/sulfation). Take with breakfast fat (la Porte 2010 showed 4× with high-fat meal). 600mg/day = dose-response midpoint with cleanest safety.
• Pterostilbene. 3,5-dimethoxy-4′-hydroxy analog from blueberries. Walle 2004: 4× bioavailability, 7× half-life. Pterostilbene 100mg.

Three protocol tiers — Entry / Daily / Advanced

Tier 1 — Entry ($35–60/month)

One AMPK activator + one mitochondrial cofactor. Target: someone whose fasting glucose is creeping up, who’s pre-diabetic or has metabolic-syndrome features but isn’t on prescription metformin. Berberine HCL 500mg t.i.d. with the largest meals + Alpha-Lipoic Acid 600mg AM on empty stomach. Run 12 weeks, recheck fasting glucose / HbA1c / lipid panel. If HbA1c <5.6% and lipid panel normal, this remains the maintenance tier.

Tier 2 — Daily ($90–140/month)

The Sinclair-canonical metabolic backbone. Berberine HCL 500mg t.i.d. + Alpha-Lipoic Acid 600mg AM + Pure NMN 500mg AM + Resveratrol 600mg with breakfast. Add Foundational Health floor (D3+K2, Magnesium glycinate, Omega-3, Multi Collagen, Vitamin C, Taurine, Creatine). This is what the average longevity-medicine-attentive adult on this catalog runs as a daily protocol indefinitely.

Tier 3 — Advanced ($200–320/month)

Tier 2 + dose escalation + cross-collection layering. NMN 1000mg Double Strength (replacing the 500mg) with TMG pairing for methyl-buffer + monthly Fisetin pulse from Senolytics (3–5 day pulse at 1000mg/day, Hickson 2019 Mayo protocol) + Spermidine, Urolithin A, Liposomal NAD+ from cross-collection. This is the post-biological-age-test cohort (TruDiagnostic, Elysium Index, GlycanAge, DunedinPACE) running a Demidenko 2021-style multi-active stack.

Cofactor stack — what to pair with what

• NMN + Resveratrol. Canonical Sinclair pairing. Howitz 2003 + Hubbard 2013 (allosteric SIRT1) + Yoshino 2021 (substrate). One without the other under-stimulates SIRT1.
• NMN + TMG (only at >1000mg/day NMN). Methylation buffer. NNMT consumes methyl groups via SAM in the MNA clearance pathway; TMG (betaine) regenerates SAM via BHMT. At 500mg NMN, dietary betaine (beets, spinach, quinoa) is usually sufficient. At 1000mg+ NMN, formulated TMG 500–1000mg/day is recommended.
• Berberine + Alpha-Lipoic Acid. Berberine activates AMPK (energy sensor); ALA fortifies the mitochondrial cofactor envelope (PDH/KGDH lipoyllysine) so the increased glucose uptake actually translates to ATP throughput rather than overflow lactate.
• Berberine + Milk Thistle (silymarin). Yin 2008 mechanism note: berberine’s hepatic gluconeogenesis suppression involves CYP3A4 modulation; silymarin (300–400mg silybin/day) provides hepatoprotection at chronic high-dose berberine.
• Resveratrol + Pterostilbene. Walle 2004 PK extension. Pterostilbene’s 4× bioavailability + 7× half-life means combined dosing extends the SIRT1 allosteric activation window through more of the day. We sell Pterostilbene as a separate 100mg SKU.
• NMN + Resveratrol + CoQ10/Ubiquinol. ETC support. Resveratrol activates SIRT3 → activates SOD2 + components of complex I. Adding CoQ10 (the obligate electron carrier between complex I-II and complex III) closes the mitochondrial throughput loop. CoQ10 is in Mitochondrial Renewal.
• Resveratrol + Quercetin (monthly pulse only). Senolytic synergy at high dose, NOT for chronic daily use. Resveratrol potentiates quercetin’s pro-apoptotic effect on senescent cells (Yousefzadeh 2018 baseline; Zhu 2015 D+Q protocol). Use for monthly senolytic pulses with Fisetin instead, which has cleaner human trial data (Hickson 2019).
• Berberine + Foundational floor. D3+K2, Magnesium glycinate, Omega-3, Multi Collagen, Vitamin C, Taurine, Creatine. Berberine activates AMPK; the Foundational floor provides the substrate cofactors AMPK signaling demands (Mg for ATP, taurine for cardiomyocyte glucose uptake, creatine for ATP/PCr buffer).
• Time-restricted eating (14:10 / 16:8 eTRF). Sutton 2018 Cell Metab early-time-restricted-eating cross-over: 6h eating window 8am–2pm vs 12h window for 5 weeks → improved insulin sensitivity, β-cell responsiveness, blood pressure, oxidative stress markers — independent of weight loss. Compounds AMPK activation from Berberine + ALA.

Cross-stacking with sister collections

• Foundational Health. The always-on floor: D3+K2, Magnesium glycinate, Omega-3, Multi Collagen, Vitamin C, Taurine, Creatine. Run this underneath Tier 2/3.
• NAD+ Family. NMN + NR + direct NAD+ + cofactor SKUs. Sister collection if you want to run multiple NAD+ precursors or graduate to direct liposomal NAD+.
• NMN Supplements. Single-pathway focus collection if NAD+ precursor is your only goal.
• Mitochondrial Renewal. CoQ10/Ubiquinol, PQQ, Urolithin A, Acetyl-L-Carnitine, MitoQ — the downstream-of-ALA mitochondrial layer.
• Senolytics. Fisetin, Quercetin, Spermidine — for monthly senolytic pulses (Hickson 2019 Mayo D+Q protocol; Yousefzadeh 2018 fisetin).
• Cardiovascular Longevity. Berberine for ApoB/LDL, ALA for endothelial function, Resveratrol for blood pressure (Timmers 2011) + the cardio-specific actives.
• Brain & Cognitive Longevity. Insulin resistance is a major upstream driver of cognitive decline ("Type 3 diabetes" framing — de la Monte 2008 J Alzheimers Dis); the Metabolic stack is upstream of the cognitive stack.
• Antioxidants. ALA is the central node; Vitamin C, Vitamin E, NAC, glutathione precursors round out the redox layer.
• Longevity Essentials. Curated entry-tier shortlist; the Metabolic actives appear here at trial-validated doses.
• Most Popular. Longevity Stack Bundle (NMN + Resveratrol) and Beauty & Longevity Stack — bundle-pricing on the canonical Sinclair pairing.
• Starter Bundles. If you want a single-purchase Metabolic-foundation bundle, build via the bundle hub.

Week-by-week realistic timeline

Drug interactions and precautions

• Diabetes medications (metformin, sulfonylureas, insulin, GLP-1 agonists). Berberine is additive with all of these. If on prescription antidiabetic medication, consult your physician before starting Berberine; dose adjustment of the Rx may be required to avoid hypoglycemia. Monitor capillary blood glucose if on insulin or sulfonylureas.
• Anticoagulants and antiplatelets (warfarin, apixaban, rivaroxaban, dabigatran, aspirin, clopidogrel). Resveratrol has documented antiplatelet activity (Olas 2002 Platelets). Berberine is a CYP3A4 substrate and can shift warfarin metabolism. Discuss with your physician; INR monitoring recommended if on warfarin.
• Statins. Berberine + statin is an established additive LDL combination (Kong 2004 Nat Med mechanism; clinical synergy documented). Watch for myopathy at chronic high-dose combination — co-supplementing CoQ10 is recommended (Banach 2015 Mayo Clin Proc). Resveratrol is a CYP3A4 inhibitor at high dose and can raise atorvastatin/simvastatin levels.
• SSRIs / SNRIs / MAOIs. Resveratrol has weak MAO-A inhibitory activity in vitro. Avoid concurrent high-dose resveratrol with MAOIs (rare prescription class).
• Hormone replacement therapy (HRT). Resveratrol is weakly phytoestrogenic. Discuss with prescribing physician if on HRT.
• Active cancer treatment. Defer entire stack during chemotherapy / radiation / immunotherapy unless explicitly approved by oncologist. Antioxidants (ALA, resveratrol) may interfere with treatments that rely on oxidative cell killing.
• Pregnancy and lactation. Defer NMN, Resveratrol, Berberine. ALA: insufficient human pregnancy data; defer.
• Stage 3+ chronic kidney disease. Discuss with nephrologist. Berberine is renally cleared; dose adjustment may be needed.
• Severe hepatic impairment / Child-Pugh B/C cirrhosis. Resveratrol is a CYP3A4 substrate; berberine is hepatically metabolized. Discuss with hepatologist.
• Surgery. 7-day pause on Resveratrol (antiplatelet) and Berberine (CYP3A4 effects on perioperative drug metabolism) before scheduled surgery.
• Under 18. Defer entire metabolic stack except in pediatric specialist guidance.
• Severe GI sensitivity. Berberine GI side effects (gas, soft stool) at full dose are common; titrate slowly. If unable to tolerate, drop to single 500mg with largest meal as maintenance.
• Hypotension at baseline. Resveratrol can lower systolic blood pressure 3–6 mmHg (Timmers 2011). Watch for orthostasis if BP <110/70 at baseline.

Who the Metabolic collection is for (and isn’t)

Strong fit:

• Adults 35–50 in the first-slope window of insulin-resistance accumulation (Reaven 1988 Diabetes "Banting Lecture" framing — insulin resistance precedes diabetes by a decade-plus).
• Adults 50–70 in the steep-decline window where NAD+ has dropped ~50% from young-adult baseline (Massudi 2012; Camacho-Pereira 2016).
• Pre-diabetic / metabolic-syndrome adults (HbA1c 5.7–6.4%, fasting glucose 100–125 mg/dL, waist >40″ men / >35″ women, triglycerides >150) who want to bend the curve before progressing to Type 2.
• Lifespan / Outlive / Huberman / Attia / Patrick podcast-circuit readers looking for the actual SKU shortlist behind the discussion.
• Biological-age-test clients (TruDiagnostic, Elysium Index, GlycanAge, DunedinPACE, PhenoAge) who want a Demidenko 2021-style multi-active stack with measurable endpoint trajectories.
• Clinicians (integrative cardiologists, longevity-medicine consultants, functional-medicine practitioners) building patient-handoff stacks.
• Post-menopausal women (Yoshino 2021 cohort directly applicable; insulin sensitivity decline accelerates post-menopause).
• Men 40+ with declining recovery, visceral fat accumulation, fatigue or "brain fog."
• Adults with a family history of T2D / cardiovascular disease running a primary-prevention stack.

Defer or modify:

• Pregnant or lactating women (defer NMN/Resveratrol/Berberine; ALA also defer).
• Adults under 18 (pediatric supplementation requires specialist guidance).
• Active cancer treatment (defer until oncologist clears).
• On insulin or sulfonylureas without endocrinologist consultation (hypoglycemia risk with Berberine addition).
• On warfarin without INR-monitoring plan (Resveratrol antiplatelet + CYP3A4).
• Severe hepatic or renal impairment (Stage 3+ CKD, Child-Pugh B/C cirrhosis).
• Severe GI sensitivity unable to tolerate Berberine even at single-cap titration (drop the SKU; rest of the stack remains usable).

Quality, sourcing, and analytical standards

• Trial-validated dosing. Berberine 500mg t.i.d. = Yin 2008 / Lan 2015. ALA 600mg = NATHAN 1 / SYDNEY 2. NMN 250–1000mg = Yoshino / Igarashi / Pencina / Yi range. Resveratrol 600mg = Timmers / Goh / Tomé-Carneiro midpoint.
• Identity assay. HPLC-UV ≥98% trans-resveratrol (the only bioactive isomer). HPLC ≥99% β-anomer NMN (α-NMN is biologically inactive; β-anomer purity is the single most-faked spec in the NAD+ space). HPLC ≥97% berberine alkaloid as the HCl salt. R/S-racemic ALA per established trial methodology.
• Heavy-metals screening. ICP-MS per USP 2232 — Pb, As, Cd, Hg below California Proposition 65 limits and FDA EAFUS thresholds. Berberine is harvested from Berberis aristata root which can accumulate soil heavy metals; we screen every lot.
• Microbial limits. USP 2021 total aerobic + USP 2022 specified-organism (E. coli, Salmonella, S. aureus) on every batch.
• Residual solvents. USP 467 — particularly relevant for Polygonum cuspidatum resveratrol extraction (ethanol/methanol/acetone solvent residues).
• Manufacturing. cGMP 21 CFR Part 111, FDA-registered facility, lot-traceable from raw material → finished good. Stability testing under ICH Q1A(R2) accelerated conditions (40°C / 75% RH / 6 months) → 24-month room-temperature shelf life with intact potency.
• No proprietary blends. Every active and every dose disclosed on the label. We don’t hide sub-trial doses inside "Metabolic Complex 800mg" obscurations.
• No titanium dioxide. Banned in EU food applications since EFSA’s 2021 reclassification (potential genotoxicity concern). Our capsules use vegan HPMC; the colorant in the berberine cap is the molecule’s native yellow.
• No artificial colors, flavors, or preservatives.
• Capsule format. Vegan HPMC (hypromellose). No bovine gelatin.
• Per-batch CoA. Available on request to support@truehealthprotocol.health with the lot number from the bottle base.
• Storage and shelf life. Amber HDPE bottle, room-temperature stable 24 months from manufacture. Resveratrol and Berberine are oxidation-sensitive; do not transfer to clear or unsealed containers. NMN preferred refrigerated for long-term storage (the molecule slowly degrades to nicotinamide at room temperature — 24-month room-temp shelf life is conservative; refrigeration extends to 36 months).
• 30-day return policy. Open or closed bottles. See Refund Policy.

How to measure improvement

Three tiers of measurement, escalating in precision and cost.

Tier 1 — Free / subjective trackers

• Fasting capillary glucose (home glucose meter, ~$30 + strips). Morning, fasted 12h+. Track weekly mean.
• Sleep, HRV, resting heart rate. Oura, Whoop, Apple Watch, or any consumer wearable. Improving HRV and dropping RHR are reliable surrogates for vagal tone / autonomic balance recovery on AMPK-activator therapy.
• 1–10 daily energy / brain-fog / mood scoring. Sounds soft; isn’t. Trend over 90 days is informative.
• Standardized photographs. Same lighting, same angle, monthly. Particularly informative for waist / abdominal-adiposity changes.
• Brito 2014 sit-to-rise test. Functional age proxy; correlates with all-cause mortality.
• Waist-to-hip ratio. Tape measure. Visceral-fat trajectory.

Tier 2 — Standard lab markers ($60–250 every 90 days)

• HbA1c (90-day glycemic average; gold-standard metabolic-trajectory marker).
• Fasting insulin + glucose → HOMA-IR (insulin resistance index). Fasting insulin alone is one of the most underused longevity-screening labs.
• Full lipid panel + ApoB. ApoB is the single best lipid marker for cardiovascular risk (better than LDL-C). Berberine drops ApoB measurably.
• hsCRP. Inflammaging marker.
• Liver enzymes (ALT, AST, GGT). Baseline + 90-day check. Resveratrol and Berberine are hepatically metabolized; clean is clean.
• Ferritin, TSH, 25-OH vitamin D. Common confounders if "the stack isn’t working" — usually it’s a missing foundational input rather than the stack itself.
• Homocysteine. Methylation-cycle proxy. Elevated homocysteine + high-dose NMN suggests methyl-buffer deficiency → add TMG.

Tier 3 — Specialized longevity testing ($300–800)

• Biological-age clocks. TruDiagnostic TruAge, Elysium Index, Horvath, GrimAge, DunedinPACE, PhenoAge. The Demidenko 2021 Aging retrospective showed multi-active longevity stacks (similar in spirit to Tier 2/3 here) can reverse DNAm-age 2–3 years over 6 months in cohort means; individual variance is high.
• Jinfiniti intracellular NAD+. Direct readout of the metabolite NMN supplementation is targeting. Pre-/post- on NMN dose-escalation is the cleanest single-marker validation that the precursor is converting.
• Omega-3 Index (Harris 2021 Nat Commun). Cardiovascular risk marker; aim >8%.
• GlycanAge. N-glycan-based inflammaging biological-age clock. Particularly responsive to anti-inflammatory interventions.
• VO2max (Kodama 2009 JAMA — VO2max is the strongest known longevity marker outside of biological-age clocks). Treadmill or bike ergometry in a sports-medicine clinic.
• DEXA scan. Visceral adipose tissue (VAT) quantification + lean-mass tracking. Particularly informative on Berberine + ALA + TRE protocols where the goal is VAT reduction without lean-mass loss.
• Continuous glucose monitor (CGM). Levels Health, Nutrisense, Dexcom G7 (with Rx). Hours-to-days resolution glycemic-variability data — far more informative than spot fasting glucose.

Common metabolic-longevity myths and corrections

• "NMN is FDA-banned." A 2022 NDI determination created industry confusion but did not prohibit sale. Post-NDI human trials (Pencina 2023, Yi 2023) continued to confirm efficacy and safety. We formulate HPLC-confirmed β-anomer NMN.
• "Resveratrol doesn’t work — Yoshino 2012 showed nothing." Yoshino 2012 used 75mg/day. Timmers 2011 (150mg/30 days), Goh 2014 (1g/45 days), Tomé-Carneiro 2012 (350mg/6 months) all showed clear endpoint shifts. Dose dependence matters; 75mg is sub-trial-range.
• "Berberine is just nature’s metformin — pick one." Yin 2008 head-to-head showed equivalent HbA1c reduction, but berberine is additive (different upstream entry: metformin via complex I, berberine via direct AMPK activation).
• "AMPK activators replace exercise." They don’t. Resistance training drives AMPK and PGC-1α activation through mechanical-load signaling no pill replicates. The stack complements exercise; it doesn’t substitute.
• "NMN at 1000mg without TMG is dangerous." Not dangerous; sub-optimal. NNMT clearance of nicotinamide consumes methyl groups via SAM. Pair TMG 500–1000mg/day at NMN ≥1000mg/day.
• "ALA causes biotin deficiency." Theoretical concern from animal studies (shared SMVT). In NATHAN 1 4-year trial at 600mg/day, no clinically-significant biotin deficiency observed. B-complex closes any residual gap.
• "Berberine is just a weight-loss supplement." Primary mechanism is AMPK activation and HbA1c reduction; weight effects are downstream. Marketing as ozempic-replacement misrepresents mechanism.
• "Multivitamin covers this." Multivitamins contain RDA-level micronutrients. Berberine, ALA, NMN, Resveratrol are pharmacologically-active small molecules at supra-physiological trial doses. A multivitamin covers adequacy; this stack targets longevity-specific signaling.

Cost tiers and what each one buys you

• $30–60/month (single-SKU foundation). Berberine HCL 500mg alone, OR Alpha-Lipoic Acid 600mg alone. Useful as a starting wedge for adults with one specific marker (high fasting glucose only, or peripheral neuropathy only). Doesn’t address the NAD+/sirtuin axis.
• $75–110/month (Tier 1 Entry — two-SKU foundation). Berberine + ALA. Addresses AMPK + mitochondrial cofactor. Appropriate for pre-diabetic / metabolic-syndrome adults not yet ready for full longevity stack.
• $150–220/month (Tier 2 Daily — full metabolic backbone + Foundational floor). Berberine + ALA + Pure NMN 500mg + Resveratrol 600mg + Foundational Health (D3+K2, Mg, Omega-3, Multi Collagen, Vit C, Taurine, Creatine). The longevity-medicine-attentive adult’s daily protocol.
• $300–450/month (Tier 3 Advanced — full Hallmarks coverage). Tier 2 + NMN 1000mg + monthly Fisetin pulse + Spermidine + Urolithin A + Liposomal NAD+. The post-biological-age-test cohort running multi-active stacks. Demidenko 2021 cost-anchor: ~$30/year-of-DNAm-age reversed.

FAQ

Where do I start if I’ve never taken any of these?

Pure NMN 500mg + Resveratrol 600mg as the canonical pair if your goal is general longevity. Berberine + ALA if your driver is metabolic markers (fasting glucose, HbA1c, lipid panel). If both, run Tier 2 from day one — none of the four interfere with each other and the trial doses are well-tolerated together.

Can I take all five at once?

Yes — that’s effectively Tier 2 with NMN 500mg + 1000mg overlap (which doesn’t make sense; pick one). The intended Tier 2 stack is: Berberine 500mg t.i.d. + ALA 600mg AM + either Pure NMN 500mg or NMN 1000mg Double Strength + Resveratrol 600mg AM. The 1000mg is a dose-escalation upgrade from the 500mg, not a co-administration.

How long until I feel something?

Berberine: fasting glucose drop within 7–14 days. ALA: paresthesia improvement within 2–4 weeks if neuropathic; nothing perceptible if not. NMN: NAD+ steady-state by week 4 (biochemical, not subjectively felt by most users). Resveratrol: subtle "second-wind" energy phenotype reported by a subset within 2–4 weeks; metabolic phenotype shifts at 4–6 weeks. Anyone telling you they "felt NMN within 24 hours" is reporting placebo or expectation effect — the molecule’s action is biochemical and time-dependent.

NMN vs NR vs direct NAD+ — which one?

NMN: most direct precursor (NMN → NAD+ via NMNAT, single enzymatic step). Strongest human RCT data set as of 2024–2025 (Yoshino, Pencina, Igarashi, Liao, Yi). NR (nicotinamide riboside): one extra enzymatic step (NR → NMN → NAD+ via NRK then NMNAT). Trammell 2016 PK + several RCTs; cleanest PK data. Direct liposomal NAD+: bypasses precursor pathway entirely; bioavailability disputed but emerging trial data positive. We carry NMN as the lead format with NR + liposomal NAD+ in NAD+ Family for users who want to compare or rotate.

Why berberine with the largest meal?

P-glycoprotein-saturation kinetics. Native berberine bioavailability is ~5%; P-gp efflux pumps berberine back into the gut lumen as it crosses the enterocyte. Higher single doses (and concurrent food bulk) saturate P-gp transiently, raising effective absorption. 500mg with the largest meal absorbs better than 250mg twice with smaller meals.

If I’m on metformin, do I still need berberine?

Discuss with your physician. Mechanistically additive (metformin via complex I inhibition raising AMP/ATP, berberine via direct AMPK activation). Some clinicians stack; others substitute when patients want to come off metformin. Berberine is not FDA-approved as a diabetes therapy and should not be used to self-discontinue prescription metformin without physician oversight.

I’m getting GI side effects from berberine. What now?

Drop to 1 cap (500mg) with the largest meal. Hold 1 week. Add a second cap with second-largest meal; hold 1 week. Add a third with the third meal if tolerated. Most users tolerate 1000mg/day cleanly even when 1500mg/day causes ramp-up discomfort; efficacy curve is flat above 1000mg/day for HbA1c.

Should I cycle berberine, or take daily forever?

Some clinicians cycle 8 weeks on / 2 weeks off to preserve gut-microbiota diversity (berberine has dose-dependent antimicrobial effects on gut flora). Others run continuously. Both are reasonable. Conservative default: continuous for 12 weeks, reassess.

Is keto compatible with this stack?

Yes. AMPK activators + ketogenic diet are doubly catabolic; NMN + Resveratrol still work in ketosis (NAD+/sirtuin axis is fuel-type-agnostic). Berberine’s glucose-lowering effect is less perceived in keto (baseline glucose is already low) but lipid and inflammatory benefits remain.

Can I take this alongside a multivitamin?

Yes — and you should. The Foundational floor (D3+K2, Magnesium, Omega-3, B-complex) is essential for the metabolic actives to fully work. They’re complementary, not redundant.

I’m 35 — too young?

Insulin resistance and NAD+ decline both begin in the 30s (Massudi 2012). The 35–50 first-slope window has the highest intervention leverage. Tier 1 Entry is reasonable; Tier 2 with NMN reasonable if markers are bending or family history is strong.

Return policy if it doesn’t work?

30-day money-back guarantee, open or closed bottles. See Refund Policy.

Certificate of Analysis for my lot?

Email support@truehealthprotocol.health with the lot number on the bottle base. Third-party CoA covering identity, potency, heavy metals, microbial limits, and residual solvents.

What if the biological-age clock doesn’t move after 6 months?

Individual variance on DNAm-age clocks is high. Cohort-mean improvements of 2–3 years on Tier 2/3 stacks (Demidenko 2021) reflect averages, not individual guarantees. Confounders to check: 25-OH-D <30 ng/mL, ferritin/TSH out of range, sleep apnea undiagnosed, alcohol >7 drinks/week, sleep <6.5h, protein <1.0 g/kg/day, resistance-training <2x/week. Fix the confounder, re-run at month 12.

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FDA disclaimer

These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease. Consult your physician before starting any supplement, particularly if you are pregnant, lactating, taking prescription medication, or managing a chronic condition.