Longevity Series Index A map of the split stack — not a deep combination monograph
Earlier filings treated “longevity stack” as a class shelf. That metaphor overstated combinatorial evidence. After the 8 August 2026 deep harvest (~1,039 discovery hits), the series splits into per-compound monographs: rapamycin and metformin as the strongest scientific brands; NMN/NR/NAD as the Sinclair-adjacent NAD lane; everolimus as the human mTOR immune comparator; AICAR, urolithin A, and spermidine as distinct mechanism stories. This index is intentionally short. Depth lives in the siblings. Combinatorial stacks remain unsupported without factorial trials. No human use is recommended.
01 Why the stack was split
A single class document cannot carry Easter Island / TOR history, Galega / TAME unfinished business, NAD salvage biochemistry, Mannick everolimus immune trials, Narkar AMPK exercise-mimetic lore, urolithin mitophagy RCTs, and spermidine autophagy pilots without becoming a shallow catalogue. The 8 August 2026 commission therefore keeps No. 95 as an index and moves depth into Nos. 96–97 and 99–105.
02 Ranking without a leaderboard fantasy
Rapamycin holds the strongest genetically heterogeneous mouse lifespan package (Harrison ITP, PMID 19587680) and a growing but still thin human healthy-aging dossier (Mannick; PEARL PMID 40188830). Metformin holds the strongest named human aging-trial brand (TAME) without admitted efficacy results at harvest. NAD precursors hold the strongest consumer brand and the clearest blood-biomarker pharmacology, with limited broad clinical aging efficacy per 2025 reviewing. Everything else on this shelf answers a different question.
03 Pointers
96 Rapamycin — Rapa Nui / Sehgal / TOR / ITP / PEARL.
97 Metformin — Galega / Glucophage / AMPK / TAME pending.
99 NMN — Yoshino / Yi / limited human efficacy synthesis.
100 NR — Brenner / Trammell PK lane.
101 NAD+ — cofactor biology; IV wellness caveats.
102 Everolimus — Mannick immune aging comparator.
103 AICAR — AMPK tool; not Cardarine.
104 Urolithin A — mitophagy; muscle RCTs with primary misses labelled.
105 Spermidine — autophagy pilots.
Cardarine — LIBRARY stem 90 (PPAR-δ; not a SARM).
04 Stacks remain unsupported
Animal cocktails and podcast protocols do not licence human multi-drug longevity regimens. Without factorial or pre-specified combination RCTs, stack claims default to unsupported bundling in this series.
How this document was assembled
Commissioned and deep-rewritten 8 August 2026 after the longevity
stack was split into per-compound monographs. Discovery harvest:
projects/adjacent_compounds_research_2026/deep_harvest/longevity_v2/
(~1,039 Tavily/Exa/PubMed rows; Sinclair cross-cut included). Additional
full-text pulls covered Nature Metabolism NAD precursor reviews, metformin
history (Bailey), rapamycin Easter Island / Sehgal origin literature, urolithin A
RCTs, and spermidine autophagy reviews. HOUSE_STYLE governs presentation.
PubMed-indexed references are NCBI-resolved in
manifest/05_references.json.
Evidence handling
Study type is named in the reporting sentence. Mouse ITP and invertebrate lifespan results are not phrased as human outcomes. Sinclair-linked popular claims, OSK reprogramming narratives, and consumer NAD IV wellness marketing are secondary unless a peer-reviewed citation is admitted. Combinatorial “stack” claims default to unsupported without factorial or pre-specified combination trials. TAME and other unpublished efficacy programmes are labelled pending and must be re-verified against AFAR and registry records at each reissue.
References
- Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566-1576.
PMID 28776081 · doi:10.1007/s00125-017-4318-z - Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al.. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392-5.
PMID 19587680 · doi:10.1038/nature08221 · PMC2786175 - Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, et al.. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):268ra179.
PMID 25540326 · doi:10.1126/scitranslmed.3009892 - Moel M, Harinath G, Lee V, Nyquist A, Morgan SL, Isman A, et al.. Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results. Aging (Albany NY). 2025;17(4):908-936.
PMID 40188830 · doi:10.18632/aging.206235 · PMC12074816 - Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, et al.. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016;22(8):879-88.
PMID 27400265 · doi:10.1038/nm.4132 - Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, et al.. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224-1229.
PMID 33888596 · doi:10.1126/science.abe9985 · PMC8550608 - American Federation for Aging Research. TAME Trial programme page (verify).
https://www.afar.org/tame-trial - NIA Interventions Testing Program publications index.
https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/publications - ClinicalTrials.gov. Protocol inventory via API v2; not peer-reviewed results.
https://clinicaltrials.gov/ - U.S. Food and Drug Administration. Approved labeling context for primary indications — not aging approvals.
https://www.fda.gov/ - American Federation for Aging Research. TAME Trial programme page (secondary status communications; verify before reissue).
https://www.afar.org/tame-trial - NIA Interventions Testing Program publications index.
https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/publications - PubChem compound summary pages used for identity cross-checks.
https://pubchem.ncbi.nlm.nih.gov/
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