Aging is convergent, not singular.
Aging is not one disease — it is the convergence of twelve biological hallmarks. No single compound resolves it. Therefore the unit of intervention is the rationally combined, mechanism-orthogonal stack, and the unit of evidence is the validated biomarker class. A stack of four senolytics is one bet. A stack covering senescence + mitophagy + autophagy + glycation is four. The Longevity Program is built on the latter.
The mission is explicit: within seven years, deliver the first multi-target plant-based therapeutic protocol that demonstrably decelerates human biological aging by ≥20% across at least three independent validated biomarker classes — with the scientific rigor required to make the result undeniable to the FDA, NIA, the López-Otín group, the ITP, and an adversarial peer reviewer.
Twelve hallmarks → six mechanism-orthogonal studies.
| Study | Hallmarks | Lead axis | Status |
|---|---|---|---|
| LON-S1 | Cellular senescence · Altered intercellular comm | Senolytic / SASP modulation | Phase 1/2 designed |
| LON-S2 | Mitochondrial dysfunction · Deregulated nutrient sensing | Mitophagy / NAD+ salvage | Phase 1/2 designed |
| LON-S3 | Loss of proteostasis · Disabled macroautophagy | Autophagy induction | Pre-clinical |
| LON-S4 | Nutrient sensing · Epigenetic alterations (partial) | Sirtuin / AMPK coupling | Pre-clinical |
| LON-S5 | Telomere attrition · Genomic instability · Epigenetic alterations | Genomic stability | Pre-clinical |
| LON-S6 | Chronic inflammation · Dysbiosis · Intercellular comm | Glycation / inflammaging | Phase 1/2 designed |
Each study's compound list, dose escalation, blend logic, and clinical-trial design are gated. Gated
Three tiers, one program.
The six studies converge on three outcome tiers, each with its own go/no-go gate. The lead scientist enforces kill criteria at every transition.
Biomarker deceleration
Pre-registered biomarker class movement with effect size > 0.3 Cohen's d in at least three orthogonal classes. Go/no-go gate before functional studies.
Functional healthspan
Frailty, cognition, VO₂max, body composition, gait speed, grip strength. Functional primary endpoints in defined disease subpopulations.
Composite age-related
TAME-style composite endpoint targeting mortality, hospitalisation, and incident age-related disease. IND-grade trial with full regulatory engagement.
Orthogonality is the discipline.
A successful stack must move at least three of the eight biomarker classes in the predicted direction with effect size > 0.3 Cohen's d. One class moving alone is artifact until proven otherwise; three independent classes moving together is signal.
- Cellular senescence load — p16INK4a, p21, SA-β-gal, T-cell senescence flow
- SASP / inflammaging cytokines — IL-6, MCP-1, IL-8, GDF15, hsCRP
- Mitochondrial bioenergetics — NAD⁺/NADH, lactate, ATP, ETC, FDG-PET
- Autophagy flux — LC3-II/I, p62, Beclin-1, mTOR-pS2448
- Hormesis / stress response — Nrf2 targets, AMPK, FOXO
- Epigenetic age — Horvath, GrimAge, PhenoAge, DunedinPACE (exploratory only)
- Telomere & DNA damage — telomere length, γH2AX, 8-OHdG
- Glycation & metabolic stress — HbA1c, fructosamine, AGEs, CML, MGO
Pre-registered, responder-enriched, kill-criterion-bound.
Every Stage 6 in vivo and Stage 8 clinical study is pre-registered before data collection. Hypotheses, primary endpoints, statistical analysis plan, and kill criteria are time-stamped. HARKing — hypothesising after results are known — is treated as scientific misconduct.
The 2024 Mayo Kogod D+Q osteoporosis readout (Farr et al., Nature Medicine) established that whole-cohort senolytic effects are not significant — bone-formation benefit was concentrated in patients with high baseline senescent burden. Effective immediately for this program:
- Every senolytic Phase 1/2 trial stratifies by baseline senescent burden (p16INK4a tissue or T-cell flow, plus SASP cytokine panel).
- Every inflammaging trial stratifies by hsCRP, IL-6, GDF15 before randomisation.
- Every blend trial pre-specifies a high-burden subgroup analysis in the SAP — not as post-hoc rescue.
- TROFFi (NCT05595499 — fisetin in frail breast-cancer survivors) is the explicit Phase 1/2 design template: frailty endpoints in a defined disease subpopulation, not healthy aging.
What this program will not pursue.
The lead scientist has reviewed the 2024–2026 evidence base and formally closed five theses. These are not embargoed — they are judged unlikely to deliver the program mission. Reopening requires new L2-or-better data.
CF-2 · NMN/NR functional translation as marketed — closed for healthspan endpoints. Plant-based NAD⁺ work routes through CD38 inhibition (apigenin) and downstream sirtuin-AMPK coupling, not precursor monotherapy.
CF-3 · Trehalose as standalone autophagy inducer in CNS — closed after HEALEY ALS Platform negative readout (March 2024). Autophagy work concentrates on spermidine and rapamycin-parallel benchmarking.
CF-4 · Healthy-aging FDA indication — closed for the program's first decade. All Phase 1/2 trials target a defined disease subpopulation (frailty in cancer survivors, sarcopenia in cirrhosis, MCI in early cognitive decline).
CF-5 · Epigenetic clocks as primary endpoints — closed; clocks remain exploratory secondary. Primary endpoints must be functional (SPPB, gait, grip, VO₂max) or hard (mortality, hospitalisation).
Same stack, every indication.
- M2 · Pre-Registration — SHA-256 locking of hypotheses, endpoints, SAP, and kill criteria before data collection.
- M1 · IBC Reasoning — 19-agent audit (8 reasoning nodes + 11 core agents) of every prediction and kill decision.
- M3 · Cross-Trial Validation — NIA-ITP-style external replication, dose-response, and cross-species reproducibility requirements.
- M4 · RWE Pipelines — ClinicalTrials.gov, PubMed, FDA, EDGAR, and patient-reported feeds, including TROFFi and PEARL surveillance.
Want the full Longevity protocol?
The abstract above is open. The compound universe (Tier 1 / 2 / 3 plant-compound list), per-study blend formulations, biomarker-class stratification rules, SHA-256-locked Phase 1/2 trial designs, responder-enrichment SAP details, and agent-network reasoning chains are available to verified clinicians, geroscientists, and sponsors under MNDA. Contact management to begin the access request.
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