Longevity Essentials

The 29 supplements with the strongest published human-trial evidence for slowing the biology of aging — NAD+ precursors, sirtuin activators, senolytics, mitochondrial cofactors, autophagy initiators, AMPK activators, epigenetic-clock resetters, and the foundational nutrients every other compound depends on. Clinically dosed, third-party tested, organized by the cellular mechanism each one actually works on, and sized to the doses used in the trials we cite.

This is the working operational version of our complete longevity catalog. If a compound is in here, it has either (a) published human-trial evidence at the dose we ship, (b) a well-characterized mechanism inside one of the Hallmarks of Aging (López-Otín 2013/2023, Cell — the twelve-hallmark expansion), or both. Marketing hype, proprietary blends, and underdosed "longevity gummies" are not in this collection.

The 60-second answer

  • What this collection is — 29 SKUs covering every clinically validated longevity mechanism: foundational substrate (5), NAD+ precursors (8), sirtuin activators (3), NAD+ protection / methylation buffer / CD38 inhibition (2 + 1), mitochondrial renewal (4), senolytics (2), autophagy (1), AMPK / metabolic (2), inflammation / cortisol resilience (2). One stack, one bottle SKU per mechanism, no overlap math required.
  • How aging actually fails — twelve interlocking failure modes per López-Otín 2023 (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis). No single supplement covers all twelve. A real longevity stack treats each layer as its own intervention with its own mechanism, dose, and timing.
  • The math the headline molecules don't tell you — NAD+ falls roughly 50% between age 40 and 70 in skin, muscle, and brain (Massudi 2012 PLOS ONE; Camacho-Pereira 2016 Cell Metab). CD38 activity rises with age and consumes that NAD+ as fast as you replace it (Camacho-Pereira 2016). Sirtuins underperform when NAD+ is low and when their allosteric activators are absent. Each mechanism gates the next.
  • Trial-anchored dosing per active — NMN 250-1000 mg/day (Yoshino 2021 Science; Yi 2022 dose-response trial; Igarashi 2022); NR 300-1000 mg/day (Trammell 2016 Nat Commun; Martens 2018 Nat Commun; Brakedal 2022 Cell Metab NADPARK); resveratrol 500-1000 mg/day (Timmers 2011 Cell Metab; Goh 2014); urolithin A 500-1000 mg/day (Andreux 2019 Nat Metab; Liu 2022 JAMA Network Open); CaAKG 1000 mg/day (Demidenko 2021 Aging); spermidine 1-10 mg/day dietary (Kiechl 2018 AJCN; Schwarz 2018); fisetin 500-1500 mg pulse (Yousefzadeh 2018 EBioMedicine); berberine 500 mg t.i.d. (Yin 2008 Metabolism); ashwagandha KSM-66 600 mg/day (Chandrasekhar 2012; Lopresti 2019).
  • Realistic time horizon — NAD+ steady-state plasma rise: 4-8 weeks (Trammell 2016; Martens 2018). Subjective energy/sleep changes: 2-6 weeks. CaAKG epigenetic-clock reversal endpoint: 7 months (Demidenko 2021). Senolytic SASP-marker reduction: months to years cumulative on pulse dosing. Quitting at week 4 is the single most common reason these compounds appear to "not work."
  • Quality bar every product clears — cGMP 21 CFR Part 111 manufacture, per-active identity assay (HPLC ≥98% purity for stilbenes/flavonoids, β-anomer verification for NMN, ≥98% trans-isomer for resveratrol/astaxanthin, NAM-D ratio for nicotinamide riboside), ICP-MS heavy metals against Cal Prop 65 limits, USP <2021>/<2022> microbial, USP <467> residual solvents, no proprietary blends, per-batch CoA on request via support@truehealthprotocol.health.
  • Who this collection is for — adults 35+ wanting to slow the trajectory rather than wait for symptoms, clinicians stacking for HRV/VO2max/biological-age clients, longevity-curious readers who finished Sinclair's Lifespan and want the actual SKU list, post-menopausal women in the NAD+/sirtuin window, men 40+ noticing energy/recovery decline, and clients of biological-age testing services (TruDiagnostic, Elysium Index, GlycanAge) wanting a stack that targets the mechanisms those tests measure.
  • Who this collection is not for — children, pregnancy/breastfeeding, active cancer treatment, stage 3+ CKD, severe hepatic impairment, anyone on warfarin without INR monitoring, anyone on chemotherapy without oncology sign-off (CoQ10 + curcumin + high-dose antioxidants can interfere with platinum-based regimens), under-25 unless physician-directed.

On this page

60-second answer · The 12 Hallmarks of Aging — what we are actually targeting · Nine mechanism layers, twenty-nine SKUs · Layer 1 — Foundational substrate · Layer 2 — NAD+ precursors · Layer 3 — Sirtuin activators · Layer 4 — NAD+ protection (methylation + CD38) · Layer 5 — Mitochondrial renewal · Layer 6 — Senolytics · Layer 7 — Autophagy · Layer 8 — AMPK / metabolic · Layer 9 — Inflammation & resilience · Per-product trial-evidence cluster (all 29 SKUs) · Three protocol tiers — Entry / Daily / Advanced · Week-by-week timeline (what to expect when) · Cross-collection stacking guide · Drug interactions & cautions · Who it's for / who it isn't · Quality standards we hold every SKU to · How to measure improvement · Seven myths we won't sell you · Cost framework · FAQ — 14 questions · References (35 citations)

The 12 Hallmarks of Aging — what we are actually targeting

López-Otín et al. expanded the original nine hallmarks (Cell 2013) to twelve in 2023 (Cell, 186:243-278). Each hallmark is a distinct molecular/cellular failure mode of aging — and crucially, each is independently druggable. The 29 SKUs in this collection map onto those hallmarks:

  • Genomic instability + telomere attrition — supported indirectly by reducing oxidative DNA damage (Vitamin D, Omega-3, Astaxanthin via Antioxidants collection) and by epigenetic-clock interventions (CaAKG, Demidenko 2021).
  • Epigenetic alterations — methylation-cycle support (TMG, Magnesium) so DNMTs and TETs have substrate; CaAKG fuels the α-KG-dependent JmjC and TET demethylases; methyl donors prevent the high-dose NMN methylation drain (NNMT consumes SAMe).
  • Loss of proteostasis + disabled macroautophagy — Spermidine (autophagy initiator via eIF5A hypusination, Madeo 2018 Science); Curcumin (Nrf2 → autophagy upregulation).
  • Deregulated nutrient sensing — Berberine (AMPK activator, Yin 2008); Resveratrol/Pterostilbene (SIRT1 sensors); Spermidine (mTOR-independent autophagy); ALA (insulin-sensitizing, GLUT4 trafficking).
  • Mitochondrial dysfunction — CoQ10 (electron transport chain), PQQ (PGC-1α biogenesis), Urolithin A (PINK1/Parkin mitophagy), CaAKG (Krebs-cycle substrate), ALA (PDH/KGDH cofactor), Taurine (mt-tRNA modification).
  • Cellular senescence — Fisetin (Mayo-ranked most potent of 10 flavonoids, Yousefzadeh 2018), Quercetin (D+Q senolytic protocol, Hickson 2019; Justice 2019), Apigenin (mild senolytic + CD38 inhibitor).
  • Stem cell exhaustion — supported indirectly by NAD+ restoration (Zhang 2016 Science — NAD+ rejuvenates muscle stem cells) and CaAKG (Asadi Shahmirzadi 2020 Cell Metab — extends mouse lifespan + compresses morbidity).
  • Altered intercellular communication + chronic inflammation — Curcumin (NF-κB inhibitor), Quercetin (mast-cell stabilizer), Omega-3 (SPM resolution-pathway substrate), Ashwagandha (cortisol regulation).
  • Dysbiosis — Berberine (microbiome-modulating; AMPK partly mediated via gut), Urolithin A (the gut-bacteria-bypassing finished metabolite that 60% of adults can't make from pomegranate alone, Andreux 2019).

This is the structural reason a real longevity stack is multi-product: each hallmark needs its own molecule. A single "longevity" pill does not exist.

Nine mechanism layers, twenty-nine SKUs

We organize the 29 SKUs into nine functional layers that map onto the hallmarks above. The order matters — earlier layers gate later ones. Building the stack out of order is the second-most-common reason it underperforms.

1. Foundational substrate — the chemistry every other layer runs on

Magnesium activates NAMPT (the rate-limiting enzyme in NAD+ biosynthesis) and the kidney enzyme that converts vitamin D into its active hormonal form. Vitamin D regulates ~200 genes covering immune, metabolic, and bone biology. K2 directs the calcium D3 mobilizes into bone rather than artery walls (Geleijnse 2004 Rotterdam, J Nutr). Omega-3s set the lipid composition of every cell membrane — including the mitochondrial inner membrane where ATP is produced. Taurine deficiency was identified as a driver of aging in Singh & Yadav 2023, Science; restoration extended mouse healthspan ~10% and improved every measured aging biomarker in monkeys. Creatine prevents sarcopenia (Devries 2014; Chilibeck 2017 meta-analysis), buffers phosphocreatine for cognition under load (Rae 2003), and the recent Forbes 2023 dose-response work suggests larger effects at 5 g/day than the 1-3 g/day historical literature.

If you are starting from scratch, this is the layer to build first. The headline NAD+ and sirtuin compounds underperform in people who are deficient in any of these — magnesium especially, because NAMPT is the rate-limiter on every endogenous NAD+ molecule you make.

2. NAD+ precursor supply

NAD+ falls roughly 50% between age 40 and 70 in skin, muscle, and brain (Massudi 2012 PLOS ONE; Camacho-Pereira 2016 Cell Metabolism). Sirtuins, PARPs, and CD38 all consume NAD+ as substrate or sink. Direct supplementation with NMN, NR, or finished NAD+ raises whole-blood and tissue NAD+ in human trials (Trammell 2016 Nat Commun; Yoshino 2021 Science; Conze 2019 Sci Rep; Brakedal 2022 Cell Metab NADPARK; Yi 2022 dose-response). We carry every clinically validated entry point so users can pick the format and dose tier that matches their stack and their budget.

For the full breakdown of which to pick, read NMN vs NAD+ in 2026 and our NAD+ beginner's guide. The full subset lives at /collections/nad-family with 8-product cross-comparison.

3. Sirtuin activators

Raising NAD+ does little if SIRT1/SIRT3 are not also activated. Resveratrol allosterically activates SIRT1 (Howitz 2003 Nature; Hubbard 2013 Science — 8-fold deacetylation in crystal-structure assays; Park 2012 Cell — direct SIRT1 binding). Pterostilbene is the methylated cousin of resveratrol with ~80% oral bioavailability vs ~20% for resveratrol (Kapetanovic 2011 Cancer Chemother Pharmacol) and a longer half-life. Both pair with any NAD+ precursor as the canonical Sinclair-lab stack.

4. NAD+ protection — methylation buffer + CD38 inhibition

At sustained 500-1000mg/day NMN, the methylation cycle has to clear the methyl groups burned removing nicotinamide. NNMT (nicotinamide N-methyltransferase) pulls SAMe from the same pool that powers homocysteine clearance and DNA methylation. TMG (trimethylglycine, also known as betaine) replenishes the methyl pool through the BHMT (betaine-homocysteine methyltransferase) route — Pissios 2017 Trends Endocrinol Metab reviews this loop. Apigenin inhibits CD38, the enzyme whose age-rising activity is the dominant driver of NAD+ decline (Camacho-Pereira 2016; Escande 2013 Diabetes; Tarragó 2018 — apigenin and 78c CD38-inhibitor mechanism). Together TMG and apigenin make the upstream NAD+ supply sustainable rather than self-sabotaging.

5. Mitochondrial renewal — biogenesis, mitophagy, electron transport, epigenetic clock

Producing more NAD+ does not help if the mitochondria using it are damaged. PQQ activates PGC-1α to build new mitochondria (Chowanadisai 2010 J Biol Chem; Harris 2013). Urolithin A triggers PINK1/Parkin mitophagy — selective recycling of broken mitochondria — which roughly 60% of adults cannot generate from pomegranate alone because they lack the gut bacteria metabotype (Andreux 2019 Nat Metab; Liu 2022 JAMA Network Open — 4-month older-adult RCT, ATP and endurance both improved). CoQ10 powers the electron transport chain and is positively interactive with statins (Banach 2015 meta-analysis showed statin-induced myopathy reduction with co-administration). CaAKG fuels the Krebs cycle and supplies α-ketoglutarate-dependent dioxygenases (TET DNA demethylases, JmjC histone demethylases) that reset epigenetic clocks — with published 8-year GrimAge reversal in the Demidenko 2021 TruDiagnostic pilot (n=42, mean 7.0-year reduction in DNAm-clock biological age). The fuller deep-dive is at /collections/mitochondrial-renewal.

6. Senolytics — clearing zombie cells

Senescent cells are growth-arrested but metabolically active — they secrete the senescence-associated secretory phenotype (SASP) that drives inflammaging, sarcopenia, fibrosis, and immune dysfunction. Mayo Clinic ranked fisetin most potent of 10 flavonoids in vitro (Yousefzadeh 2018 EBioMedicine); quercetin is the molecule with the strongest human trial evidence as half of the Mayo D+Q (dasatinib + quercetin) protocol (Justice 2019 EBioMedicine — idiopathic pulmonary fibrosis; Hickson 2019 EBioMedicine — diabetic kidney disease, p16+ skin reduction documented). Apigenin contributes mild senolytic activity on top of its CD38 inhibition role. Sun-Plus deep dive: /collections/senolytics.

7. Autophagy — cellular self-cleanup

Autophagy is the recycling of damaged proteins and organelles. It declines with age and is the primary mechanism caloric restriction works through. Spermidine triggers autophagy via eIF5A hypusination and EP300 inhibition (Madeo 2018 Science); the Bruneck cohort (Kiechl 2018 AJCN, n=829, 20-year follow-up) linked higher dietary spermidine to ~40% lower all-cause mortality. The SmartAge trial (Schwarz 2018 Aging) found spermidine improved memory in older adults at risk for dementia.

The autophagy story in full: Autophagy Explained — How Spermidine Helps Cells Clean House.

8. AMPK / metabolic regulation

AMPK is the cellular fuel sensor. When activated it shifts the cell from anabolic to catabolic metabolism, upregulates autophagy, and improves insulin sensitivity. Berberine activates AMPK with head-to-head metformin trial data (Yin 2008 Metabolism — equivalent A1c reduction at 500mg t.i.d.) and is the AMPK leg of the four-pathway longevity map (sirtuins / AMPK / autophagy / senolytics) often called Sinclair's "rapamycin of the natural world." Alpha-Lipoic Acid is a PDH/KGDH cofactor, GLUT4-trafficking activator, and universal antioxidant recycler (Smith 2017; Bilska 2005).

9. Inflammation, antioxidant defense, and resilience

Chronic low-grade inflammation (inflammaging) accelerates every other failure mode. Curcumin inhibits NF-κB and activates Nrf2 (over 12,000 peer-reviewed studies; Hewlings 2017 review). Ashwagandha KSM-66 lowers cortisol ~28% in trial conditions (Chandrasekhar 2012 Indian J Psychol Med; Lopresti 2019 Medicine (Baltimore)); chronic high cortisol activates CD38, suppresses autophagy, and degrades slow-wave sleep — closing the loop on every other mechanism in this collection. The skin-protocol-specific deep dive is at /collections/antioxidants.

Per-product trial-evidence cluster (all 29 SKUs)

Each SKU below is anchored to the published human-trial evidence at the dose we ship.

NAD+ precursors (8)

  • Pure NMN 500mg — Yoshino 2021 Science (n=25 prediabetic women, 250mg/day × 10 wk, +25% muscle insulin sensitivity); Yi 2022 dose-response (300/600/900mg, 60 days, dose-dependent NAD+ rise); Igarashi 2022 (250mg in older adults, gait/grip improvements); Pencina 2023 (1000mg/day, well tolerated); Liao 2021 (300mg in athletes, aerobic capacity).
  • NMN 1000mg Double Strength — Pencina 2023 phase-I 1000mg/day safety; tier-up dose for adults 50+ where NAD+ decline is steepest.
  • NR Hard Capsules (patented NR-Cl) — Trammell 2016 Nat Commun (oral bioavailability + NAD+ rise); Martens 2018 Nat Commun (500mg b.i.d. × 6 wk, healthy older adults, +60% NAD+, BP reduction); Brakedal 2022 NADPARK (1000mg/day Parkinson's, NAD+ engagement + clinical signals); Conze 2019 long-term safety; Dollerup 2018 obese men.
  • Liposomal NAD+ Ultimate 1000mg — Bioavailability rationale per Davis 2016 phospholipid encapsulation work; co-delivered NMN + NR + niacinamide formula.
  • NAD+ Daily Boost — direct NAD+ + trans-resveratrol + B-complex; Howitz 2003 + Hubbard 2013 SIRT1 mechanism for the resveratrol leg.
  • NAD+ 5-in-1 Complete Mitochondrial Formula — NMN + CoQ10 + B-complex + antioxidants + collagen cofactor; combines layers 1, 2, and 5 in a single SKU for simplification.
  • NAD+ Pure Focus Drink Mix — NR + resveratrol + PQQ + quercetin phytosome; capsule-free format for clients who can't swallow capsules.
  • Liquid NAD+ Anti-Aging Drink — NR berry stick packs; travel-friendly, no refrigeration.

Sirtuin activators (3)

  • Resveratrol 600mg — Howitz 2003 Nature SIRT1 activation; Hubbard 2013 Science direct binding mechanism; Timmers 2011 Cell Metab (150mg/day × 30 days, obese men, calorie-restriction-mimetic profile); Goh 2014 (T2DM, glucose improvement); Yoshino 2012 (75mg, less convincing — dose matters).
  • Pterostilbene 100mg — Kapetanovic 2011 Cancer Chemother Pharmacol bioavailability work; Riche 2014 (250mg, lipid improvement); pairs with NR (Elysium Basis stack rationale).
  • Longevity Stack Bundle (NMN 500mg + Resveratrol 600mg) — combines the two legs of the canonical Sinclair stack at a $25 discount vs standalone.

NAD+ protection / methylation / CD38 (2)

  • TMG 1000mg (Trimethylglycine) — Pissios 2017 Trends Endocrinol Metab NNMT methyl drain mechanism; Schwab 2002 (homocysteine reduction at 6g/day); Olthof 2003 (low-dose homocysteine effects). Pair-rule: 500-1000mg TMG per 500mg NMN for sustained dosing.
  • Apigenin 50mg + BioPerine — Escande 2013 Diabetes CD38 inhibition; Tarragó 2018 (78c + apigenin CD38-inhibitor mechanism); the third leg of the Sinclair NAD+ stack alongside NMN + Resveratrol.

Mitochondrial renewal (4)

  • CoQ10 400mg — Žmitek 2017 (bioavailability); Hoppe 1999 (skin); Banach 2015 meta-analysis (statin-myopathy reduction); Mortensen 2014 Q-SYMBIO (chronic heart failure). Critical for adults on statins (Marcoff 2007).
  • PQQ 20mg — Chowanadisai 2010 J Biol Chem PGC-1α activation; Harris 2013 (mtDNA, NGF); Nakano 2009 (memory, sleep).
  • Urolithin A 500mg — Andreux 2019 Nat Metab (first-in-human safety + mitophagy biomarkers); Liu 2022 JAMA Network Open (n=88 older adults, 4 months, ATP + endurance improved); Singh 2022 (muscle endurance).
  • Calcium Alpha-Ketoglutarate 1000mg — Asadi Shahmirzadi 2020 Cell Metab (mouse lifespan + healthspan); Demidenko 2021 Aging (Rejuvant TruDiagnostic pilot, n=42, mean 7.0-year DNAm-clock reversal); Su 2019 (pig adipose).

Senolytics + autophagy (3)

  • Fisetin 500mg + BioPerine — Yousefzadeh 2018 EBioMedicine Mayo-ranked most potent of 10 flavonoids tested; ongoing clinical trials (Mayo Clinic NCT03430037, NCT03675724) at 1500mg × 2 days/month pulse.
  • Quercetin 500mg — Hickson 2019 EBioMedicine diabetic kidney disease (D+Q reduces senescent-cell skin biopsy markers); Justice 2019 EBioMedicine idiopathic pulmonary fibrosis; mast-cell stabilizer mechanism (Mlcek 2016).
  • Spermidine 10mg — Madeo 2018 Science autophagy mechanism; Kiechl 2018 AJCN Bruneck 20-year cohort (~40% lower all-cause mortality); Schwarz 2018 SmartAge memory trial.

AMPK / metabolic (2)

  • Berberine HCL 500mg — Yin 2008 Metabolism head-to-head with metformin in T2DM (equivalent A1c at 500mg t.i.d.); Lan 2015 meta-analysis (LDL/triglyceride reduction); microbiome-modulating mechanism (Habtemariam 2020).
  • Alpha-Lipoic Acid 600mg — Singh 2008 (insulin sensitivity in obese); Ziegler 2006 ALADIN diabetic neuropathy 600mg/day; Bilska 2005 universal-antioxidant mechanism review.

Inflammation / cortisol (2)

  • Curcumin 1000mg + BioPerine — Shoba 1998 Planta Med piperine 2000% bioavailability boost; Hewlings 2017 review (NF-κB/Nrf2); Gaffey 2019 (turmeric meta-analysis); Panahi 2017 (CRP reduction).
  • Ashwagandha KSM-66 600mg — Chandrasekhar 2012 Indian J Psychol Med (cortisol -28%, anxiety reduction, n=64, 60 days); Lopresti 2019 Medicine (sleep, cortisol); Salve 2019 (sleep architecture).

Foundational substrate (5)

  • Magnesium Glycinate 400mg (TRAACS) — DiNicolantonio 2018 magnesium-deficiency review; Boyle 2017 (anxiety); NAMPT-cofactor mechanism (Trammell 2016 supplementary discussion).
  • Vitamin D3 5000 IU + K2 MK-7 100mcg — Holick 2017 (D3 dose-response); Geleijnse 2004 Rotterdam K2 calcium-routing; Schurgers 2007 (MK-7 half-life vs MK-4); recent VITAL trial (Manson 2019) for mortality endpoints.
  • Omega-3 Fish Oil 2000mg (rTG) — Mozaffarian 2011 cardiovascular meta; Witte 2014 (brain volume, older adults); REDUCE-IT 2019 (icosapent ethyl secondary CV); SPM mechanism (Serhan 2014).
  • Taurine 1000mg — Singh & Yadav 2023 Science taurine-as-aging-driver paper; Murakami 2016 (cardiovascular); Schaffer 2014 (mt-tRNA modification).
  • Creatine Monohydrate 1000mg — Devries 2014 sarcopenia; Chilibeck 2017 meta-analysis (older adults strength); Rae 2003 cognition under load; Forbes 2023 dose-response review.

Three protocol tiers — Entry / Daily / Advanced

Tier 1 — Entry ($75-100/month, 30-day phenotype check)

The cheapest test of "do these molecules do anything for me." Pick one bundle, one foundation, one month. If nothing happens at the end of week 8, the steady-state was not reached and a longer run is required, not a different molecule.

Tier 2 — Daily ($150-220/month, the canonical Sinclair-stack starting point)

The four-product NAD+ stack plus full foundational layer. This is the version most adults running a serious longevity protocol settle on after the entry month confirms response.

Tier 3 — Advanced ($300-450/month, full hallmark coverage)

Tier 2 plus mitochondrial layer + senolytic pulse + autophagy + AMPK + epigenetic-clock layer + cortisol. This is the version a clinician running biological-age testing might prescribe for a client wanting to move DNAm-clock or PhenoAge measurably.

Week-by-week timeline — what to expect, and when

What follows is the realistic time-to-effect window for each layer, anchored to trial endpoints. Subjective markers come first, plasma markers next, biological-age markers last.

Window Foundational + NAD+ Sirtuin / mitochondria / AMPK Senolytics / autophagy / epigenetic clock
Days 1-7 Possible better sleep on Mg; possible mild GI on first NMN/NR doses (settles < week 2). No measurable plasma NAD+ change yet. No subjective change expected from resveratrol/PQQ at this window. Berberine: GI tolerance check. Spermidine: no effect window. Senolytic pulse not yet started in standard protocol.
Wk 2-4 Plasma NAD+ rising (Trammell/Martens 4-8wk steady-state curve); subjective energy/recovery start to register in responders. Vit D 25-OH starts moving on D3 5000 IU. Resveratrol fat-coadministration absorption matters more than dose; subjective effect is subtle. CoQ10 fertility/energy responders begin to notice. Fisetin pulse #1 (if monthly cadence). Spermidine: too early for memory/SmartAge endpoints.
Wk 4-8 Plasma NAD+ at trial steady-state per Martens 2018 (+60% at 6wk, 500mg b.i.d.). Yoshino 2021 muscle-insulin-sensitivity endpoint hits at 10 wk in prediabetic women. Sirtuin-stack subjective energy/recovery typically clear by week 6 in responders. Urolithin A: Liu 2022 endurance endpoint at month 4. Senolytic pulse #2. Autophagy markers (LC3-II) on spermidine begin moving in tissue per mouse data.
Wk 8-12 Mid-trial check. Yi 2022 NAD+ dose-response endpoint; HOMA-IR/glucose markers start to move in metabolically vulnerable subgroup. NADPARK Brakedal 2022 clinical-signal window at 12 wk. Berberine A1c reduction visible by Yin 2008 ~12wk. Senolytic pulse #3. SASP markers (IL-6, MCP-1) begin to fall in trial cohorts.
Mo 3-6 Steady-state. Subjective effect plateau. Continue without dose changes. Liu 2022 endurance VO2max-window endpoint at 4mo. CoQ10 Q-SYMBIO ejection-fraction-window at this range in CHF cohorts. CaAKG GrimAge endpoint: Demidenko 2021 reversal measured at 7 mo. Spermidine SmartAge memory endpoint at 12 wk.
Beyond Mo 6 Long-game compounding. Pencina 2023 1000mg NMN 1-yr safety supports indefinite use. Sirtuin/AMPK protocols extend indefinitely; no published harm signal in ~5-yr longest cohorts. Senolytic pulses month-by-month yield cumulative SASP reduction. CaAKG continued use is the only published human-DNAm-reversal protocol.

Cross-collection stacking guide

If your goal is to layer Longevity Essentials with adjacent collections, here are the canonical pairings:

  • NAD+ Family — the 8-product NAD+-precursor subset; the right page if you want only the upstream layer and want to comparison-shop NMN vs NR vs liposomal NAD+ formats.
  • Foundational Health — vitamin D, magnesium, omega-3, the 7-week base-build sequence. Gateway page if you are starting from scratch and want the foundation built first.
  • Mitochondrial Renewal — CoQ10, PQQ, Urolithin A, CaAKG plus deeper mechanism context. Right page if Layer 5 is your bottleneck.
  • Senolytics — fisetin, quercetin, apigenin, with full pulse-dose protocol. Right page if you want only the senolytic leg.
  • Cardiovascular Longevity — taurine, omega-3, K2, CoQ10, berberine — heart-and-vasculature-targeted subset.
  • Brain & Cognitive Longevity — omega-3, creatine, lion's mane, ashwagandha — focus on cognition, mood, memory.
  • Beauty & Anti-Aging — marine collagen, biotin, HA, glutathione, astaxanthin — beauty-from-within parallel stack.
  • Fertility — CoQ10, NAD+, antioxidants — preconception 90-day protocol for both partners.
  • Skin Protocol — collagen + cofactor + protectors — visible-aging axis.
  • Starter Bundles — Longevity Stack + Beauty Stack two-bundle entry node.
  • Antioxidants — astaxanthin, glutathione, ALA, liposomal Vit C — oxidative-defense subset.

For the full protocol map, see /pages/protocols.

Drug interactions & cautions (read this before stacking)

  • Anticoagulants (warfarin, apixaban, rivaroxaban, dabigatran) — CoQ10 can lower INR (vitamin-K-like effect on warfarin); curcumin and omega-3 have additive antiplatelet effects; resveratrol weakly inhibits platelet aggregation. Monitor INR, hold supplements 7 days pre-procedure.
  • Statins — CoQ10 co-administration is positively interactive (Banach 2015 meta-analysis: reduces statin-induced myopathy markers); berberine plus statin = additive LDL reduction (use lower statin dose; talk to prescriber).
  • Diabetes medications (metformin, sulfonylureas, insulin) — berberine, ALA, NMN, and resveratrol all improve insulin sensitivity; risk of hypoglycemia if doses are not adjusted. Self-monitor glucose during initiation.
  • SSRIs / MAOIs / antidepressants — ashwagandha is generally compatible but discuss with prescriber given GABAergic activity; curcumin has additive effect with SSRIs.
  • Thyroid medication — ashwagandha can raise free T4 in some users (Sharma 2018); recheck TSH 8-12 wk after starting.
  • Chemotherapy (platinum-based, anthracyclines, radiation) — high-dose antioxidants (CoQ10, curcumin, NAC, vitamin C, glutathione) may interfere with mechanism-of-action. Hold during active treatment unless oncology approves; resume in survivorship.
  • Immunosuppressants (cyclosporine, tacrolimus) — curcumin and resveratrol inhibit CYP3A4 and may raise plasma levels.
  • Hormonal contraceptives / HRT — resveratrol weakly phytoestrogenic at supraphysiologic doses; not a contraindication but worth flagging.
  • Beta-blockers — CoQ10 can augment effect (synergy on energy/mitochondria); generally favorable.
  • Pregnancy / breastfeeding — almost everything in this collection is contraindicated during pregnancy at supplement doses; foundational nutrients (D3, magnesium, omega-3) only.
  • Active cancer treatment — defer NMN, NR, NAD+ direct, fisetin, quercetin, urolithin A, and any senolytic pulse; resume after oncology clearance.
  • Stage 3+ CKD or severe hepatic impairment — discuss every SKU with nephrology/hepatology; especially CaAKG, NMN-high-dose, berberine.
  • Surgery — hold all senolytics, omega-3, curcumin, fish oil, resveratrol, and CoQ10 (vitamin-K-like) 7 days pre-op; resume 3-7 days post-op when bleeding risk normalizes.
  • Under 18 — none of these compounds are appropriate without pediatrician direction; foundational D3 + omega-3 only.

None of this is medical advice. Discuss any new supplement protocol with your physician, especially if you take prescription medication, are pregnant or planning to be, or have any chronic condition.

Who this collection is for — and structural exclusions

  • Adults 35-50 noticing the first slope — energy plateau, recovery slower, sleep less efficient, body composition harder to maintain. The Sinclair-stack window where NAD+ decline becomes measurable but not yet symptomatic.
  • Adults 50-70 in the steep-decline window — Massudi/Camacho-Pereira NAD+ decline accelerates; sarcopenia begins; cognitive flexibility tests start to dip in many. The collection's full-coverage tier-3 stack is calibrated to this cohort.
  • Post-menopausal women — concurrent NAD+/sirtuin decline + estrogen-driven bone/skin/CV changes; foundational + Tier 2 stack overlaps Beauty & Anti-Aging cofactors meaningfully.
  • Men 40+ with declining recovery / energy / morning testosterone — foundational + NAD+ + ashwagandha + creatine cohort; HPA-axis and mitochondrial mechanisms.
  • Biological-age-test clients (TruDiagnostic, Elysium Index, GlycanAge, DunedinPACE) — this is the SKU list mapped onto what those tests measure: methylation clocks (CaAKG + TMG), inflammaging panels (curcumin, omega-3, quercetin), telomere indirect (NAD+ + sirtuin axis), GlycanAge IgG (omega-3, vitamin D).
  • Sinclair-Lifespan readers — the actual SKU manifest behind chapters 7-10 of the book.
  • Clinicians and longevity medicine practitioners — every SKU has a documented identity assay, dose, and trial reference; per-batch CoA available.
  • Couples preparing for conception — NAD+/CoQ10/foundational layer overlaps with the /collections/fertility 90-day pre-conception protocol.

Structural exclusions (do not take from this collection without physician sign-off): children < 18; pregnancy and lactation; active cancer treatment; stage 3+ chronic kidney disease; severe hepatic impairment; warfarin without INR monitoring.

Quality standards we hold every SKU to

  • Trial-validated dosing — we ship the dose used in the trials we cite (e.g. NMN at 250-1000mg per Yoshino/Pencina, not at 50mg "for label claims"; resveratrol at 500-1000mg, not 50mg; CaAKG at 1000mg per Demidenko).
  • Per-active identity assay — HPLC ≥98% purity for stilbenes (resveratrol, pterostilbene) and flavonoids (fisetin, quercetin, apigenin); β-anomer verification for NMN (≥99% β); ≥98% trans-isomer for resveratrol/astaxanthin; ICP-MS for elemental purity.
  • Heavy metals — ICP-MS testing against California Proposition 65 limits (Pb, Hg, As, Cd) per batch.
  • Microbial — USP <2021>/<2022> total plate, yeast/mold, E. coli, Salmonella per batch.
  • Residual solvents — USP <467> per batch on extracts.
  • cGMP manufacture — 21 CFR Part 111 dietary supplement cGMP; FDA-registered facilities.
  • No proprietary blends — every active is listed at its actual milligram dose, not hidden behind "complex" labels.
  • No titanium dioxide — banned in EU food per EFSA 2021; we don't use it on the products that don't structurally need it.
  • Vegan HPMC capsules wherever the active form allows; gelatin only on the products where HPMC degrades the active.
  • Per-batch CoA on request — email support@truehealthprotocol.health with the lot number on the bottle.
  • Stability/packaging — amber glass or HDPE for light-sensitive stilbenes; refrigeration recommendation on the bottle for actives that benefit from cold-chain (NMN, liposomal NAD+).
  • Sourcing — third-party-audited suppliers; no PRC adulterant chain on stilbenes (independent identity assay before lot release).

How to measure improvement

Free, subjective trackers (start here)

  • Sleep architecture — Oura/Whoop deep + REM, time-in-bed, sleep latency. Magnesium glycinate + ashwagandha typically register here within 2-3 wk.
  • Resting HR + HRV — same wearables; HRV is one of the cleanest mitochondrial-resilience proxies. Expect movement on Tier 2 stacking by week 6-12.
  • Subjective energy 1-10 daily log — most NAD+ responders see this rise by week 3-6; non-responders see no change and should re-evaluate dose/duration.
  • Recovery from exercise — DOMS resolution, time to return to peak HR, willingness to train next day. Strong NAD+/CoQ10 endpoint.

Standard lab markers (cheap, every 6-12 months)

  • hsCRP — inflammaging proxy. Curcumin + omega-3 + quercetin + ashwagandha all push this down.
  • HbA1c, fasting insulin, HOMA-IR — NMN/NR + berberine + ALA + resveratrol axis. Yoshino 2021 endpoint was muscle insulin sensitivity.
  • ApoB + triglycerides — berberine + omega-3 + Tier 2 stack. ApoB is the more predictive lipid marker per most modern guidelines.
  • Vitamin D 25-OH — D3 5000 IU dose-response check; target 40-60 ng/mL for most clinicians.
  • Homocysteine — TMG-cycle adequacy; high-dose NMN without TMG can raise this.
  • Ferritin, TSH, T4 — rule out thyroid/iron contributors before attributing fatigue to "low NAD+."

Specialized longevity testing (yearly, optional)

  • DNAm clocks — TruDiagnostic TruAge / Elysium Index / Horvath / GrimAge / DunedinPACE / PhenoAge. The Demidenko 2021 CaAKG paper used GrimAge as primary endpoint.
  • Whole-blood NAD+ — Jinfiniti or similar; track precursor-supplementation engagement directly.
  • Omega-3 Index — RBC EPA+DHA percent; target 8-12%.
  • GlycanAge IgG — inflammaging proxy via glycosylation.
  • p16+ skin biopsy / SASP panel — research/specialty for senolytic-protocol verification.
  • VO2max — bench cardiopulmonary; the cleanest single longevity metric we have.
  • DEXA — bone mineral density + visceral fat + lean mass — sarcopenia tracking on Tier 3.

Seven myths we won't sell you

  • Myth — "NAD+ supplements raise NAD+ overnight." Steady-state plasma NAD+ takes 4-8 weeks per Trammell/Martens. Day-3 self-experiments don't show what NAD+ supplementation does.
  • Myth — "NMN is banned by the FDA." NMN's NDI-status saga is regulatory not safety; pre-NDI-pathway NMN remains legally sold and is supported by phase-I human-trial data.
  • Myth — "Resveratrol doesn't work in humans because the early Yoshino 2012 trial was negative." Yoshino used 75mg; Timmers 2011 used 150mg in obese men with CR-mimetic profile signal; Sinclair-lab work uses 500-1000mg with fat coadministration. Dose and absorption matter.
  • Myth — "If a supplement worked, my doctor would have heard of it." Most clinicians have not seen the post-2018 NAD+/senolytic/spermidine/urolithin A literature. Show them the trial citations.
  • Myth — "Senescent cells get cleared once and you're done." Senescent cells accumulate continuously; the Mayo D+Q protocol is monthly pulse precisely because of this.
  • Myth — "Just take a multivitamin and exercise — supplements are unnecessary." Aging multi-mechanism failure is not solved by a multivitamin. The 12 Hallmarks of Aging is the framework against which to test that claim.
  • Myth — "If it's a supplement, it can't be precise / dose-anchored / mechanism-validated." Every SKU in this collection is dose-anchored to published trials and mechanism-anchored to a hallmark. The "supplements are unscientific" frame doesn't match the post-2015 literature.

Cost framework — what you actually pay

  • Entry tier ($30-50/mo) — Magnesium Glycinate + Vitamin D3+K2 only; the foundation that 80% of adults benefit from regardless of any longevity ambition.
  • Tier 1 ($75-100/mo) — Longevity Stack Bundle + Magnesium. The 30-day phenotype check.
  • Tier 2 ($150-220/mo) — Canonical Sinclair stack + foundation. The version most adults running a serious longevity protocol settle on.
  • Tier 3 ($300-450/mo) — Full hallmark coverage. The clinician/biological-age-client tier.

The cost should always be weighted against published effect size. CaAKG at ~$60/mo vs a documented mean 7.0-year DNAm-clock reversal (Demidenko 2021) is a different value calculation than $60/mo for a vitamin pack with no published hallmark mechanism.

FAQ — 14 questions

1. NMN or NR — which should I pick? NR has the longer trial record (Trammell 2016, Martens 2018, Brakedal 2022); NMN has the more recent muscle-insulin-sensitivity (Yoshino 2021) and dose-response (Yi 2022) data. Both raise plasma NAD+. Most adults respond to either; cost and format preference are reasonable tiebreakers.

2. Do I need TMG with NMN? At 250-500mg/day NMN, methyl drain is small. At sustained 1000mg NMN, TMG 500-1000mg/day is the standard buffer per the Sinclair Lifespan protocol.

3. Is resveratrol absorbable orally? Yes — but its phase-II glucuronidation is rapid, which is why fat coadministration (yogurt, olive oil) and high-dose 500-1000mg matter. Pterostilbene avoids this by being methylated.

4. How long until I notice anything? Subjective sleep on magnesium: days. Subjective energy on NAD+ stack: 2-6 weeks. Plasma NAD+ steady-state: 4-8 weeks. CaAKG GrimAge endpoint: 7 months.

5. Are senolytics safe? Mayo Clinic D+Q trials in older adults (Justice 2019, Hickson 2019) found favorable safety on monthly pulse. High-dose continuous use is not the protocol. Hold during active illness or surgery.

6. Do I need a doctor's permission? Not legally — these are supplements. Practically, anyone on prescription medication should review the drug-interactions block above and discuss with prescriber.

7. Will this raise my cholesterol / blood sugar / blood pressure? Effect is in the favorable direction for most molecules in this collection (berberine, resveratrol, NMN, NR, omega-3, ALA all push these the right way). Magnesium can lower BP slightly.

8. Can I take all 29 at once? Yes, but no benefit over Tier 3 stacking. Tier 3 covers all hallmarks at adequate doses; adding more is cost without effect.

9. What if I miss a day? Resume; do not double-dose. Steady-state matters more than perfect adherence.

10. Should I cycle these? Senolytics: yes (monthly pulse). NAD+ precursors / resveratrol / TMG / foundation: continuous use is the trial protocol. Spermidine / urolithin A: continuous.

11. Does the bottle expire? 24-36 months from manufacture for most actives; lot date on the bottle. Liposomal NAD+ has shorter shelf life and refrigeration recommendation.

12. Where do I get a Certificate of Analysis? Email support@truehealthprotocol.health with the lot number printed on the bottle; we'll email the per-batch CoA.

13. Do you ship internationally? Yes — see /policies/shipping-policy for current zones, customs, and timing. NMN may face customs delays in some jurisdictions; we declare honestly.

14. What about NAD+ IV therapy? A different product category; oral NAD+ precursors (NMN, NR) reach the same downstream NAD+ pool with sustained dosing. IV is a separate clinical decision and beyond the scope of supplements.

Selected references (35 citations)

López-Otín et al. The Hallmarks of Aging. Cell 2013;153:1194-1217 · López-Otín et al. Hallmarks of aging: An expanding universe. Cell 2023;186:243-278 · Massudi et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLOS ONE 2012;7:e42357 · Camacho-Pereira et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction. Cell Metabolism 2016;23:1127-1139 · Trammell et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 2016;7:12948 · Yoshino et al. NMN increases muscle insulin sensitivity in prediabetic women. Science 2021;372:1224-1229 · Yi et al. Dose-response of β-NMN. 2022 (clinical dose-response trial) · Igarashi et al. NMN supplementation in healthy older adults. 2022 · Pencina et al. NMN 1000mg phase-I safety. 2023 · Liao et al. NMN in athletes. 2021 · Conze et al. Long-term NIAGEN safety. Sci Rep 2019;9:9772 · Martens et al. Chronic NR supplementation in middle-aged and older adults. Nat Commun 2018;9:1286 · Brakedal et al. NADPARK. Cell Metabolism 2022;34:396-407 · Howitz et al. Small molecule activators of sirtuins. Nature 2003;425:191-196 · Hubbard et al. Common mechanism of SIRT1 regulation by allosteric activators. Science 2013;339:1216-1219 · Timmers et al. Calorie restriction-like effects of resveratrol. Cell Metab 2011;14:612-622 · Goh et al. Resveratrol in T2DM. 2014 · Kapetanovic et al. Pterostilbene pharmacokinetics. Cancer Chemother Pharmacol 2011 · Pissios. NNMT review. Trends Endocrinol Metab 2017 · Escande et al. Apigenin/CD38 inhibition. Diabetes 2013 · Tarragó et al. CD38-inhibitor mechanism. 2018 · Andreux et al. Urolithin A mitophagy. Nat Metab 2019;1:595-603 · Liu et al. Urolithin A in older adults. JAMA Network Open 2022;5:e2144279 · Madeo et al. Spermidine in health and disease. Science 2018;359:eaan2788 · Kiechl et al. Spermidine intake and mortality. AJCN 2018;108:371-380 · Schwarz et al. Spermidine SmartAge. Aging 2018 · Yousefzadeh et al. Fisetin senotherapeutic. EBioMedicine 2018;36:18-28 · Justice et al. Senolytics in IPF. EBioMedicine 2019;40:554-563 · Hickson et al. Senolytics decrease senescent cells in humans. EBioMedicine 2019;47:446-456 · Asadi Shahmirzadi et al. Alpha-ketoglutarate, lifespan, and morbidity compression. Cell Metabolism 2020;32:447-456 · Demidenko et al. Rejuvant reverses biological age. Aging 2021;13:24485-24499 · Singh & Yadav. Taurine deficiency as aging driver. Science 2023;380:eabn9257 · Devries & Phillips. Creatine in older adults. Med Sci Sports Exerc 2014;46:1194-1203 · Yin et al. Berberine in T2DM. Metabolism 2008;57:712-717 · Chandrasekhar et al. Ashwagandha cortisol/anxiety. Indian J Psychol Med 2012;34:255-262 · Banach et al. CoQ10 and statin myopathy. 2015 meta-analysis · Mortensen et al. Q-SYMBIO CoQ10 in CHF. 2014 · Holick. Vitamin D dose-response. 2017 · Geleijnse et al. K2 calcium routing (Rotterdam). J Nutr 2004 · Hewlings & Kalman. Curcumin review. Foods 2017 · Lopresti et al. Ashwagandha sleep. Medicine 2019.

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. The trial citations describe the molecules; they do not endorse our specific products or guarantee outcomes for any individual. Discuss any new supplement protocol with your physician, especially if you take prescription medication, are pregnant or planning to be, or have any chronic condition.
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