AMPK activation
AMPK is the cellular energy sensor. Activation mimics caloric restriction signaling, promotes mitochondrial biogenesis, and inhibits anabolic pathways tied to aging.
Compounds at this target
- MOTS-c
- 5-Amino-1MQ
- SLU-PP-332
Multi-step research synthesis · Longevity
Longevity & Healthspan
Extend healthspan via AMPK / SIRT1 / NAD+ axis activation, mitochondrial support, and senescent cell clearance
⚠ Research synthesis · NOT medical adviceFind a qualified physician to supervise. See referral panel below.
§ Abstract
This protocol synthesizes peer-reviewed evidence across six biological pathways implicated in healthspan extension: AMPK activation, NAD⁺ coenzyme availability, SIRT1 deacetylase activity, mitochondrial function, telomere maintenance, and senescent cell clearance. None of these compounds is FDA-approved for life extension; the evidence base for the OUTCOME (extended healthspan in humans) remains immature, even where individual compound mechanisms are well-characterized in animal models. The protocol is offered as a research synthesis to be implemented under qualified clinical supervision — not as a self-administered regimen. The honest read: the mechanistic rationale is strong, the human-outcome data is thin, and the right way to engage with it is with a physician who can baseline-test, monitor for harms, and adjust based on individual response.
§ Pathways targeted
Six biological
pathways.
Each compound in the protocol acts on one or more biological pathways implicated in aging biology. The combined intent: hit multiple complementary pathways rather than overfit a single target.
NAD⁺ optimization
NAD⁺ is the essential coenzyme for sirtuin activity and DNA repair. Tissue NAD⁺ declines ~50% by age 60. Direct supplementation and precursor strategies both pursued.
Compounds at this target
- NAD⁺ injectable
- NMN (ref)
- NR (ref)
- 5-Amino-1MQ
SIRT1 / sirtuin activity
Sirtuins are NAD⁺-dependent deacetylases that regulate metabolism, stress response, and longevity pathways. Activation requires both adequate NAD⁺ and direct SIRT1 stimulation.
Compounds at this target
- Resveratrol (ref)
- Pterostilbene (ref)
Mitochondrial function
Mitochondrial decline is a hallmark of aging. Targets include cardiolipin protection (SS-31), uncoupling-mediated efficiency (BAM15), and electron transport support (Methylene Blue).
Compounds at this target
- SS-31 (Elamipretide)
- BAM15
- Methylene Blue
Telomere maintenance
Telomere shortening contributes to replicative senescence. Epitalon has been studied for telomerase activation; human outcome data is limited.
Compounds at this target
- Epitalon
Senescent cell clearance
Senescent cells (zombie cells) accumulate with age and secrete pro-inflammatory cytokines (SASP). Pulse-dosed senolytic compounds aim to selectively clear them.
Compounds at this target
- Fisetin (ref)
- Quercetin (ref)
- Dasatinib + Quercetin (ref, clinical Rx)
→ Outcome targetExtended healthspan
§ The protocol
Five phases,
sequenced.
Sequencing is informed reasoning, not RCT data. Foundation first; layer pathway-active compounds in over time. Each phase assumes the previous is in place.
- 01
Foundation
Weeks 0–4
Establish baseline labs, build redox and coenzyme reserves before adding pathway-active compounds.
Glutathione
Role
Antioxidant / redox baseline
Dose range
200–600 mg
Frequency
3× weekly subQ or IV under clinical supervision
Note · Reduced (GSH) form preferred. IV access typically via clinical infusion.
NAD⁺ injectable
Role
Coenzyme baseline restoration
Dose range
100–500 mg
Frequency
Weekly subQ, or IV loading 100–500 mg over 2–4 hr
Note · IV loading is uncomfortable and clinic-supervised. SubQ at lower doses is the typical at-home route.
- 02
AMPK activation
Weeks 4–12
Engage the energy-sensing arm of the longevity axis with a peptide-based AMPK activator.
- See full grade →
MOTS-c
Role
Mitochondrial-derived peptide; activates AMPK via AICAR accumulation
Dose range
5–10 mg
Frequency
Daily subQ for 5 days, then 2 days off (5/2 cycle)
Note · WADA-prohibited. Cycle to limit potential AMPK adaptation.
5-Amino-1MQ
Role
NNMT inhibitor; indirectly preserves NAD⁺ pool and supports AMPK signaling
Dose range
50–150 mg
Frequency
Daily oral, 4–8 weeks then reassess
Note · Oral capsule. Limited human data; clinician should monitor liver enzymes.
- 03
Mitochondrial support
Weeks 8–24 (overlaps phase 02)
Protect mitochondrial cardiolipin and improve electron transport efficiency.
SS-31 (Elamipretide)
Role
Cardiolipin-binding tetrapeptide; restores mitochondrial structure and ATP production
Dose range
10–40 mg
Frequency
Daily subQ for 8–12 week cycles
Note · Phase 2 trials in mitochondrial myopathy and primary mitochondrial disease have shown signal.
Methylene Blue
Role
Alternative electron carrier; supports mitochondrial respiration at low doses
Dose range
0.5–4 mg
Frequency
Daily oral, in the morning
Note · Pharmaceutical-grade only. Avoid combining with serotonergic drugs (serotonin syndrome risk).
- 04
Telomere & senescent cell phase
Weeks 12–52
Add telomere-targeted peptide and pulse-dose senolytic clearance under physician supervision.
- See full grade →
Epitalon
Role
Tetrapeptide studied for telomerase activation
Dose range
5–10 mg per cycle
Frequency
10–20 day course, repeated quarterly
Note · Human outcome data is limited; mechanism is established in cell culture.
Fisetin (reference)
External reference (not on Peptigrade)
Role
Senolytic flavonoid; pulse-dose protocols studied (Mayo Clinic)
Dose range
20 mg/kg/day
Frequency
2-day pulse, repeated monthly
Note · Not a peptide; included for protocol completeness. Discuss timing with physician.
Quercetin (reference)
External reference (not on Peptigrade)
Role
Senolytic flavonoid; combined with dasatinib in early human trials
Dose range
Per physician guidance
Frequency
Pulse only, not chronic
Note · Drug-interaction risk with several common medications. Physician supervision required.
- 05
Reassessment & adjustment
Week 26 and ongoing
Re-baseline biomarkers, evaluate response, decide on continuation, modification, or discontinuation.
Repeat full lab panel
Role
Decision point for the next 6-month block
Dose range
—
Frequency
Every 6 months
Note · Compare against baseline and 3-month interim labs. Discontinue or modify any compound with a negative trend.
§ Clinician monitoring
What gets
measured.
If you cannot get these labs done by a qualified physician on this cadence, this protocol is not appropriate for you. You cannot run an unmonitored experiment on yourself.
Baseline (week 0)
Establishes the personal baseline against which all protocol effects are measured. Without this, you have no way to know if the protocol is helping, neutral, or harming.
- CBC with differential
- Comprehensive metabolic panel (CMP)
- Fasting glucose, insulin, HOMA-IR
- Hemoglobin A1c
- Lipid panel + ApoB + Lp(a)
- hsCRP
- Vitamin D, B12, ferritin
- TSH + free T4
- Total + free testosterone, SHBG, estradiol
- IGF-1
- NAD⁺ level (if assay available)
- Epigenetic age clock (GlycanAge, DunedinPACE, or similar)
Every 3 months
Catches early signals — liver/kidney stress (CMP), inflammatory shift (hsCRP), insulin resistance (HOMA-IR delta), or unintended IGF-1 elevation that could promote tumor growth.
- CMP
- Fasting insulin
- hsCRP
- ApoB
- IGF-1
Every 6 months
Evaluates trajectory on the outcome metrics that matter (epigenetic age, body composition, full metabolic picture). Decision point for continuation.
- Full baseline panel
- Epigenetic age clock
- Body composition (DEXA preferred)
Annual
Standard preventive medicine alongside any longevity protocol. Worth doing whether or not you pursue this protocol.
- Cardiac calcium score (age 40+)
- Age-appropriate cancer screening (colonoscopy, mammography, prostate, skin)
- Cognitive assessment baseline (e.g., MoCA)
§ When NOT to attempt this
Contra-
indications.
These are absolute or strong relative contraindications. None of them is exhaustive — a qualified physician will identify additional individual factors.
- ✕
Active malignancy or recent cancer history — many compounds in this protocol have angiogenic or growth-signaling activity that is theoretically problematic with active disease.
- ✕
Pregnancy or breastfeeding — none of these compounds has been adequately studied in pregnancy.
- ✕
Significant renal or hepatic dysfunction — clearance is impaired; dose adjustments and additional monitoring required, ideally avoid.
- ✕
Bleeding disorders or active anticoagulation — discuss timing with prescribing physician.
- ✕
Concurrent serotonergic medications + Methylene Blue — serotonin syndrome risk; do not combine.
- ✕
Known peptide hypersensitivity — test dose and supervision required.
- ✕
Children and adolescents — none of this is appropriate for developing physiology.
§ Honest gaps
What we don’t
know yet.
- !
Whether a multi-compound longevity protocol produces measurably greater healthspan extension in humans than any single compound — almost no head-to-head or factorial human trial data exists.
- !
Whether the surrogate endpoints we monitor (epigenetic age, IGF-1, hsCRP) actually predict mortality or healthspan in individuals — population-level associations exist; individual prediction is uncertain.
- !
Optimal sequencing and cycling of AMPK / NAD⁺ / mitochondrial / senolytic interventions — current sequencing is informed reasoning, not trial data.
- !
Long-term safety of chronic NAD⁺ pool elevation in adults — most NAD⁺ longevity data is in animals or short-term humans.
- !
Whether the angiogenic and growth-supportive effects of several included compounds are net-positive or could accelerate occult tumor growth in some patients.
- !
Drug-drug interactions across this many simultaneously-administered compounds are largely uncharacterized.
§ Required clinical handoff
Find a qualified
physician.
This protocol is research synthesis, not a prescription. Before initiating any compound: identify a physician with relevant subspecialty expertise who will baseline you, supervise initiation, monitor for harms, and adjust based on individual response. The compounds in this protocol are not FDA-approved for healthspan extension; legitimate clinical use is necessarily off-label and must be physician-directed.
Specialties that typically supervise this protocol
Functional medicine physician (IFM-trained)
Where to find: Institute for Functional Medicine practitioner directory
Internal medicine — longevity / preventive focus
Where to find: American Academy of Anti-Aging Medicine (A4M) directory; Peter Attia network practitioners
Endocrinology
Where to find: If hormone-axis optimization is part of your stack — board-certified endocrinologist with metabolic medicine focus
Mitochondrial medicine specialist
Where to find: United Mitochondrial Disease Foundation directory; major academic medical centers
⚠ Important
Peptigrade does not refer to specific physicians and does not maintain a paid practitioner directory. The directories above are not endorsed by Peptigrade — they are starting points for your own due diligence. Verify licensure, specialty board certification, and any disciplinary history before establishing care.
§ Citations
Source
papers.
Protocol-level citations. Compound-specific citations are on each compound’s peptide page.
- [01]
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
Lee C, Zeng J, Drew BG, et al. · Cell Metab · 2015
- [02]
Inhibition of nicotinamide N-methyltransferase enhances energy expenditure
Kraus D, Yang Q, Kong D, et al. · Nature · 2014
- [03]
Elamipretide for primary mitochondrial myopathy: a randomized, double-blind, placebo-controlled crossover trial (MMPOWER-3)
Karaa A, Haas R, Goldstein A, et al. · Neurology · 2020
- [04]
Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib + quercetin in individuals with diabetic kidney disease
Hickson LJ, Langhi Prata LGP, Bobart SA, et al. · EBioMedicine · 2019
- [05]
Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. · EBioMedicine · 2018
- [06]
Effect of peptides on telomere length and lifespan in mammalian somatic cells (Epitalon)
Khavinson VK, Bondarev IE, Butyugov AA · Bull Exp Biol Med · 2003
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alongside this.
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Protocol
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Metabolic dysfunction is a major aging driver; the GLP-1 protocol is FDA-approved territory and pairs naturally with longevity work.