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mTOR pulse + NAD+ substrate + senolytic layer

Longevity

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Longevity is the most-claimed and least-evidenced goal in the peptide community. Be honest with yourself before starting this protocol: nothing here is a guarantee of a longer life. The closest thing we have to modern human evidence for any of these interventions is the PEARL Phase 2 trial (2024) for off-label rapamycin in healthy adults — and the results were equivocal. The mechanistic stories for rapamycin (mTOR inhibition), NAD+ precursors (cellular redox), and pineal peptides (telomerase, melatonin signaling) are real. The translation from "raises blood marker X" to "actually lives longer" is not.

This protocol is built on the principle that if you're going to chase longevity peptides anyway — and many users will — the editorially-honest path is to sequence them in a way that maximizes safety oversight, builds in cycling discipline, and keeps the user grounded in what the evidence actually says.

If you have an active health condition, take this conversation to a clinician familiar with off-label rapamycin use rather than self-experimenting. There are physicians who specialize in this; they're not common but they exist. If you're a healthy adult and you want to run this carefully, the phases below are the editorially-defensible sequence.

Phases

  1. Phase 1 — Substrate (NAD+ precursor)

    weeks 1-8

    Nicotinamide riboside (NR) at 300mg daily, oral. Substrate restoration phase — establish a baseline NAD+ elevation before adding interventions that depend on it. NR has Tier 2 evidence for reliably raising blood NAD+ in humans; the translation to clinical longevity outcomes is Tier 3 at best. NMN is interchangeable at the substrate level if NR sourcing is a problem; NAD+ infusions are an alternative but produce transient BP swings and require IV access.

    • Nicotinamide Riboside (NR)300 mg · daily · morning

      300mg oral daily with breakfast. Middle of the studied range (100-1000mg); the dose-response for blood NAD+ is shallow above 300mg.

    What “working” looks like

    There is no reliable subjective signal at 300mg/day NR. Some users report energy or sleep improvement; most do not. The phase is primarily substrate restoration in preparation for Phase 2. Trust the lab data more than subjective response — if you can measure blood NAD+ before and after 8 weeks, that's the cleanest signal.

    Decision criteria

    At week 8: regardless of subjective response, advance to Phase 2 if your baseline labs (Phase 2 prep) are clean. NR is generally well-tolerated; the substrate phase is more about preparation than confirming benefit.

    Labs to pull

    • Lipid panel — establish baseline before Phase 2 (rapamycin can elevate LDL + triglycerides)
    • Fasting glucose + HbA1c (rapamycin can transiently worsen glycemic control)
    • CMP including liver and kidney function
    • CBC + differential (rapamycin is an immunosuppressant; baseline matters)
    • If available: blood NAD+ assay (specialty labs only; not standard)

  2. Phase 2 — mTOR pulse (rapamycin weekly)

    weeks 8+

    Rapamycin 5mg orally once weekly, taken with a small fat-containing meal for absorption. Continue NR substrate from Phase 1 throughout. Mechanism: pulsatile mTOR inhibition — the once-weekly schedule (vs daily organ-transplant dosing) is the community-standard hypothesis for capturing autophagy + senescence-clearance benefit while avoiding the chronic-immunosuppression side-effect profile. This is the editorially-defensible off-label dose; some practitioners go to 6-8mg weekly, a few experiment with 2-week cycling. Stay at 5mg weekly unless you have clinician oversight to go higher.

    • Nicotinamide Riboside (NR)300 mg · daily · morning

      Continue Phase 1 dose. The substrate layer is maintenance throughout the protocol.

    • Rapamycin5 mg · weekly · morning

      5mg oral once weekly, with a small fat-containing meal (improves absorption). Pick a consistent day; record the exact day of the week in your stack notes. Do NOT take on a day you've had a vaccine or expect to receive one.

    What “working” looks like

    Most users report no acute subjective change on weekly rapamycin pulses. The signal is in labs: stable or improving HbA1c, manageable LDL elevation (or none), CBC unchanged, no opportunistic infections. The intended benefit is on a multi-year timescale; you cannot self-evaluate longevity benefit in 8 weeks.

    Decision criteria

    At week 12 of Phase 2: repeat lab panel. If LDL has risen >20% or HbA1c >5.7% or any infection-related concern: discuss with clinician — pause or reduce dose may be warranted. If labs are stable: continue indefinitely with quarterly re-checks. If considering Phase 3: confirm 12+ weeks of stable Phase 2 labs first.

    Labs to pull

    • Repeat lipid panel (compare to Phase 1 baseline — flag if LDL up >20%)
    • Repeat HbA1c + fasting glucose (rapamycin can transiently worsen glycemic control)
    • Repeat CBC + differential (any opportunistic-infection pattern is a flag)
    • ALT + AST (rapamycin is hepatically metabolized)

  3. Phase 3 — Senolytic + pineal layer (cyclical, optional)

    1-2 cycles per year

    Layer in an epithalon cycle (Khavinson-style pineal peptide for telomerase signaling + circadian restoration) for 30-60 days at a time, 1-2× per year, with 4-6 month off-periods. Optionally, an experimental FOXO4-DRI senolytic course can be considered by users with high tolerance for early-stage evidence — heavy "this is preclinical" framing applies. Continue Phase 1 NR and Phase 2 rapamycin throughout; the senolytic layer is additive, not replacement.

    • Nicotinamide Riboside (NR)300 mg · daily · morning

      Continue substrate layer throughout.

    • Rapamycin5 mg · weekly · morning

      Continue weekly pulse. Some practitioners skip rapamycin during the epithalon on-cycle to reduce intervention density; community-level evidence either way is thin.

    • Epithalon5 mg · daily · evening

      5mg SubQ nightly during the 30-60 day on-cycle, then OFF for 4-6 months. See the epithalon peptide page for the full cycle metadata — same cycling discipline as the Sleep protocol.

    • FOXO4-DRI5 mg · weekly · morning

      EXPERIMENTAL — no human safety or efficacy data. 5mg SubQ once weekly for 2-3 doses as a 'senolytic pulse' is community-level practice for users who choose this layer. Skip this peptide if you have any concern about preclinical-only interventions. See Caution #6.

    What “working” looks like

    During an epithalon cycle: sleep-quality improvements often emerge by week 2-3 (matches Sleep protocol Phase 1 signal). Senolytic-targeted improvements (joint stiffness, skin elasticity, recovery quality) are theoretical and difficult to subjectively detect on a 30-60 day timeframe. Trust the labs + multi-cycle trajectory over single-cycle subjective response.

    Decision criteria

    After first full Phase 3 cycle (30-60 days on + 4-month off): assess whether the added intervention burden is justified by perceived benefit. Many users find Phases 1+2 alone are the maintainable longevity stack; Phase 3 is genuinely optional. If continuing: schedule 1-2 cycles per year, never continuous. If discontinuing Phase 3: return to Phases 1+2 maintenance, which is the editorially-recommended baseline.

    Labs to pull

    • Pre-cycle: repeat full Phase 2 lab panel + add IGF-1 (epithalon affects pineal signaling that can modulate the GH axis)
    • Post-cycle: same panel, compare deltas

Cautions

  • This protocol is NOT a guarantee of a longer life. The mechanistic stories are real; the human-outcome evidence is thin. The PEARL Phase 2 trial (2024) — the most rigorous modern healthy-adult rapamycin RCT — was equivocal for the longevity-related endpoints it measured. Run this with eyes open about what the evidence does and does not support.
  • Rapamycin is an FDA-approved immunosuppressant. Even at the pulsatile weekly dose used here, you are modulating immune function. If you are in a high-infection-exposure environment (healthcare worker, recent travel to endemic areas, immunocompromised household contacts), think hard about whether this is the right time. Stop the pulse if you develop any signs of infection that don't resolve quickly.
  • Vaccine timing matters. Do NOT take rapamycin in the same week as a vaccination, or the following week. The mTOR inhibition can blunt the antibody response — there's both observational data and the underlying mechanism supports this. Skip a week (or schedule your weekly pulse accordingly) when you're due for a vaccine.
  • Lipid panel monitoring is non-negotiable. Rapamycin can elevate LDL cholesterol and triglycerides — sometimes meaningfully. Pull labs every 12 weeks for the first year of Phase 2. If LDL rises >20% above your baseline, discuss with your clinician — dose reduction or pause may be appropriate. Some users add a statin specifically for the rapamycin window.
  • mTOR + intermittent fasting interaction is uncharacterized. Both inhibit mTOR. If you are doing prolonged fasts (>24 hours) and weekly rapamycin pulses, you are stacking mechanism in a way the trials did not study. Community practice varies; the editorially-conservative position is to fast OR pulse rapamycin on a given week, not both.
  • Senolytic claims (Phase 3 FOXO4-DRI specifically) are preclinical. The 'clear zombie cells' marketing is ahead of the human evidence by years. FOXO4-DRI has rodent + cell-culture data; no human safety or efficacy trials. If you choose to include it, do so with the understanding that you are participating in informal n=1 experimentation, not following established practice.
  • Pregnancy is a hard refusal. Rapamycin is teratogenic (Category C); washout periods are months. If there is any possibility of pregnancy, do not start this protocol. Discuss conception plans with a reproductive specialist before considering rapamycin.
  • Wound healing is impaired on rapamycin. If you have planned surgery (including dental procedures), pause rapamycin for at least 2 weeks before and 4 weeks after. Discuss timing with your surgeon — rapamycin is well-known to surgeons specifically because it complicates post-operative healing in transplant patients.

Discuss with your clinician

  • Find a clinician familiar with off-label rapamycin use BEFORE starting Phase 2. Most PCPs are not — they're not wrong to be cautious. There are physicians who specialize in healthspan/longevity medicine and have experience with weekly-pulse dosing. Search engines + the AgelessRx/Healthspan Society directories are starting points.
  • Bring the full Phase 1 baseline lab panel to the first Phase-2 visit: lipid panel, HbA1c + fasting glucose, CMP, CBC + differential. The clinician needs the baseline to monitor against.
  • Discuss your vaccine schedule explicitly — which vaccines you're due for in the next year, how to time them around rapamycin. Get this written down rather than left to your weekly memory.
  • Lipid management plan: ask the clinician whether they monitor every 8 vs 12 weeks for the first year, and what the threshold for intervention is (dose reduction vs adding a statin vs pausing rapamycin).
  • If you are planning any surgery or dental procedure in the next 6 months, raise this with both the surgeon AND the rapamycin-prescribing clinician — wound-healing pause timing matters.
  • If you are pursuing the Body Composition protocol concurrently, raise this explicitly — the GH-axis stimulation in Body Composition Phase 2 (CJC-1295 + Ipamorelin) increases IGF-1 signaling, which works in mechanism-opposition to rapamycin's mTOR inhibition. There is no clean answer; your clinician should help you decide whether to run one or the other but not both simultaneously.
Evidence summary

Tier 4 protocol overall — the most-disclaimed of any V1 Juno protocol. Rapamycin (Phase 2) has Tier 1 evidence for FDA-approved organ-transplant immunosuppression, but for off-label longevity use in healthy adults the tier drops to Tier 3 (Rule 6) — the PEARL Phase 2 trial (2024) is the largest modern healthy-adult RCT and was equivocal for longevity-related endpoints. NR (Phase 1) is Tier 2 for raising blood NAD+ in humans but Tier 3 for translating that into clinical longevity outcomes. Epithalon (Phase 3) is Tier 4; FOXO4-DRI is Tier 4 with no human safety or efficacy data. The mechanistic case across the stack is coherent; the human-outcome evidence gap is the largest of any V1 protocol.

Components (4)

Often combined with

  • Body Composition

    REAL TENSION. Body Composition Phase 2 (CJC-1295 + Ipamorelin) stimulates GH and IGF-1 — pro-anabolic, pro-mTOR signaling. Longevity Phase 2 (rapamycin) inhibits mTOR. The two protocols work against each other on this central axis. There is no clean answer; pick one direction at a time and stick with it. If you cycle between them, discuss the timing explicitly with your clinician.

  • Recovery from Injury

    Rapamycin impairs wound healing. If you are actively recovering from injury (especially post-surgical recovery), pause Phase 2 rapamycin until healing is complete — the recovery protocol's tissue-repair work is directly antagonized by mTOR inhibition.

  • Sleep Optimization

    Phase 3 epithalon overlaps with the Sleep protocol's Phase 1 epithalon cycle. If you are running both, do NOT double-dose — your epithalon cycle counts toward both protocols. The Sleep protocol's cycling discipline (30-60 day on / 4-6 month off) is the load-bearing rule; follow it.

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