Longevity Technology article on Rapamycin Longevity Lab:
The 301 mTOR modulator compounds tested in the first half of the mTOR modulator lifespan study have been added to the Rapamycin Longevity Lab Longevity Intervention Database (LID): Rapamycin Longevity Lab - It's time to speed things up!
To see them, enter “RLL” into the ‘Tags’ field.
Read this X post for more information from Krister:
https://x.com/KristerKauppi/status/1972964640482279706
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Thanks for sharing, @AustraliaLongevity! And big thanks for all the great support in the project. Now the next goal is to get the last remaining 300 compounds screened as well in phase 2 of the project. Please reach out if you want to support or if you know someone who may be interested in doing so. Just to give a thumbs up or share the social media post is also a great way to support the project if you are not able to financially help out 
Here is also the LinkedIn post:
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A suggested combo regimen of rapamycin and doxy by perplexity:
*** Rapamycin:**
- Role: Inhibits mTOR, inducing autophagy and metabolic stress.
- Suggested Use: 1–2 mg daily or 5–10 mg weekly (common in research for mTOR inhibition). Low, intermittent doses may reduce side effects while maintaining efficacy.
- Timing: Once weekly (e.g., Monday) to sustain mTOR suppression, as effects were reversible after short-term treatment in the study.
*** Doxycycline:** - Role: Disrupts mitochondrial function, enhances mitophagy, amplifies metabolic stress.
- Suggested Use: 100 mg daily (standard antimicrobial dose, often used in cancer studies for mitochondrial targeting). Continuous low-dose may align with study’s long-term treatment efficacy.
- Timing: Daily, morning or evening, to maintain mitochondrial disruption and synergize with rapamycin’s autophagy induction.
*** Weekly Stack Example:** - Monday: Rapamycin (5–10 mg, single dose) + Doxycycline (100 mg daily, continue through week).
- Tuesday–Sunday: Doxycycline (100 mg daily).
- Rationale: Rapamycin’s weekly pulse sustains mTOR inhibition; daily Doxy maintains mitochondrial stress and mitophagy, as seen in ~2/3 cell line efficacy.
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Yes, we are exploring this combo at the Rapamycin Longevity Lab. Here is the current monthly update of the pipeline.
X post
https://x.com/KristerKauppi/status/1975501359974629770
LinkedIn post
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I don’t myself like the effect doxy has on mitochondria
Summary
| Category | Effect |
|---|---|
| Target | Mitochondrial 30S ribosome |
| Primary effect | Blocks mitochondrial protein synthesis |
| Secondary effects | ↓ ETC complexes I–V, ↓ ATP, ↑ glycolysis |
| Stress response | Activates UPRmt and mitonuclear signaling |
| Morphology | Fragmentation, loss of cristae |
| Reversibility | Yes, after withdrawal |
| Research caution | Confounds metabolic/aging experiments |
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Lets see if different doses protocols result in the same effect. My guess is that this is not the case. Like with many things in life. Too much water can cause really bad effects and even result in death but the right amount of water has great effects.
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It may be that a low dose has useful hormetic effects, but it does not strike me as a priority as an intervention.
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Do you have any suggestion on a combo that may perform better than Omipalisib + Doxycycline in multiple species? Rapamycin Longevity Lab’s goal is to explore and accelarate research around mTOR inhibitor based combinational therapies so we start to push the boundaries of human longevity. So just reach out if there are some things that should be looked at. We are going to do some big things this year so exciting things are coming! 
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I am currently wondering about proline
As interesting as mechanistic theories are, lifespan data is a much better metric to go by. Impressive lifespan data can unlock new mechanistic insights.
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Can you create a simple lifespan and healthspan data matrix on that compound on multiple species?
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2nd half of the mTOR inhibitor/modulator project has been fully funded! .
"We have officially reached our funding goal for the largest-ever lifespan analysis of 601 mTOR modulators! This project is driven by Rapamycin Longevity Lab (@omipalRLL) in partnership with
@OraBiomedical
(CEO @benblueAK). The mission is to identify compounds even more potent than Rapamycin in extending lifespan in worms.
I am deeply grateful for the community’s support for this historic project. A special thank you to our latest anonymous donor whose generous contribution pushed us over the finish line. This support allows us now to accelerate our understanding of the promising mTOR pathway.
A big thank you to all our sponsors who made this possible!
Our gold sponsors
Anonymous: Three anonymous contributions to the project and one by Anonymouse.
Antoine Dusséaux: a London-based entrepreneur.
Dmitry Sadovnikov: Connect with him on LinkedIn or X via
Ciarán Murray: a longevity enthusiast and tech founder of
Other sponsors of the project
: A cutting-edge telemedicine platform that specializes in making various longevity interventions accessible for people. The company is also actively involved in research and clinical trials around longevity interventions.
Winslow Strong: Dedicated to advancing human health and wellbeing.
Dr. Grant Fraser: Specializes in longevity medicine. The clinic uses a holistic approach, integrating lifestyle interventions with personalized medical treatments to enhance health and longevity.
: A unique online platform that empowers individuals, health professionals, laboratories and researchers with the purpose to accelerate the development of longevity interventions.
Revi Health (): Modern clinic in Sweden which combines regenerative medicine, performance health and longevity protocols for measurable results.
: The first-ever digital medical clinic to help patients fight cellular senescence and regain control over the levers of aging that are at the foundation of most age-related chronic diseases.
Rapamycin Longevity Lab (): Our mission is to become the leading expert around mTOR inhibitor based combinational therapies for longevity.
People in the longevity: Thank you for every donation, like and share. Your support has fueled this project!
PS 1. Big thanks also to Victor Björk for the help with the fundraising!
PS 2. All lifespan data from this project will be released to a public online database this May. I will announce the launch when the time comes."
Note: had to remove the X @'s from this post because rapamycin.news thought I was trying to tag a bunch of people. You can see the full post by going to the link: https://x.com/KristerKauppi/status/2016103901251174623
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Exciting new partnership for Rapamycin Longevity Lab!
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2nd half of the mTOR screening is about to be released. Like and share Krister’s X post to learn more and support!
x.com/KristerKauppi/status/2059212951806996986
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The candidates that beat rapamycin in roundworms:
1. Ceftriaxone / Ceftriaxone Sodium Trihydrate
- Summary: Ceftriaxone is a widely used, FDA-approved third-generation beta-lactam antibiotic. Beyond its standard antibacterial use, it has been heavily researched in longevity and neurology because it upregulates GLT-1 (glutamate transporter 1), protecting brains from neurotoxicity and inflammation. In this screen, it achieved the highest lifespan extension (>65% and 31% respectively).
- Availability: Highly Available. As a standard prescription antibiotic, it is globally manufactured and accessible via regular medical channels, though it requires a prescription. It is also cheap and readily available as a high-purity chemical from standard chemical suppliers for laboratory use.
2. Omipalisib (GSK2126458)
- Summary: Omipalisib is an extremely potent, orally bioavailable dual inhibitor of PI3K (all isoforms) and mTOR (both mTORC1 and mTORC2). It was primarily developed as an anti-cancer therapeutic to halt tumor cell proliferation and strongly induce autophagy.
- Availability: Restricted / Lab-Only. It reached Phase I clinical trials but is not an approved medical drug. It is actively manufactured and easily purchased from global life-science chemical suppliers (like Sigma-Aldrich or Cayman Chemical) strictly for in vitro or animal research purposes.
3. D-alpha-Hydroxyglutaric acid disodium
- Summary: This is a disodium salt form of D-2-hydroxyglutarate (D-2-HG). In human biology, it is normally classified as an endogenous “oncometabolite” because excessive accumulation (due to IDH1/2 genetic mutations) is associated with certain cancers. However, at modulated physiological levels in non-mutant settings, its structural impacts on cellular metabolism interact directly with alpha-ketoglutarate pathways to alter lifespan.
- Availability: Restricted / Lab-Only. It is not an approved pharmaceutical and cannot be prescribed. It is exclusively available through specialized biological research vendors as a laboratory reagent.
4. N-Feruloyloctopamine
- Summary: A naturally occurring antioxidant alkaloid and phenol compound that can be isolated from garlic skins or specific herbs (like Datura arborea). It acts as a signaling inhibitor—specifically dampening the PI3K/Akt and MAPK pathways—which accounts for its experimental anti-tumor and lifespan-modulating traits.
- Availability: Scarce / Lab-Only. It is completely absent from the consumer supplement or medical market. It can be custom-ordered or purchased in minute milligram quantities from specialized phytochemical reference standard companies (like ChemFaces or MedChemExpress) for laboratory assays.
5. WP1066
- Summary: WP1066 is an experimental small-molecule inhibitor primarily known for targeting the STAT3 pathway, but it secondary-modulates downstream PI3K/Akt/mTOR pathways. It induces apoptosis (cell death) in malignant cells and has been studied for treating aggressive brain tumors (gliomas).
- Availability: Restricted / Lab-Only. It is an unapproved investigational drug. It is widely accessible to the scientific community through chemical research catalogs but cannot be obtained for human use.
6. GDC-0032 (Taselisib)
- Summary: Taselisib is an experimental, potent, and selective beta-sparing PI3K inhibitor. By choking off PI3K, it effectively cuts off upstream activation of the mTOR pathway. It was heavily trialed for advanced breast cancers.
- Availability: Restricted / Lab-Only. While it advanced quite far in clinical oncology trials, its development was largely halted due to side-effect profiles. It is readily available from pharmaceutical chemical suppliers solely for laboratory research.
7. Lansoprazole
- Summary: Lansoprazole is a very well-known, FDA-approved Proton Pump Inhibitor (PPI) used globally to treat acid reflux, GERD, and stomach ulcers. Interestingly, PPIs have been found in various automated drug-screening models to possess off-target effects on lysosomal function and autophagy pathways, which likely explains its inclusion in an mTOR/longevity screen.
- Availability: Highly Available. It is incredibly accessible worldwide over-the-counter (OTC) or via generic prescription at any pharmacy.
8. IPI-145 (Duvelisib / INK1197)
- Summary: Duvelisib is a small-molecule dual inhibitor of the PI3K-delta and PI3K-gamma isoforms. Like other PI3K inhibitors, it acts to downregulate downstream mTOR signaling, particularly within immune cells.
- Availability: Prescription / Restricted. Unlike the others on this list, this is an FDA-approved medication (sold under the brand name Copiktra) specifically indicated for certain types of leukemia and lymphoma. It is tightly regulated, expensive, and only accessible via oncology prescriptions, or as a raw compound from lab suppliers.
9. AMPK-IN-1
- Summary: As the name implies, AMPK-IN-1 is an experimental chemical compound designed specifically to act as an AMPK inhibitor (IN stands for inhibitor). Because AMPK is the primary upstream energy sensor that suppresses mTORC1 when energy is low, inhibiting it interacts significantly with nutrient-sensing longevity pathways.
- Availability: Restricted / Lab-Only. This is a tool compound used purely in biochemistry labs to map cell signaling. It has no medical approval and is only found in scientific chemical inventories.
10. Serabelisib (INK1117 / MLN1117)
- Summary: Serabelisib is a highly selective, small-molecule inhibitor of the PI3K-alpha isoform. It was engineered to block the hyperactive PI3K pathway seen in a variety of human cancers without causing the pan-PI3K toxicities of older generation drugs.
- Availability: Restricted / Lab-Only. It has been evaluated in early-phase oncology clinical trials but has not received FDA approval. It can only be sourced by research entities from clinical chemical repositories.
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I asked AI to analyze what common pathways these compounds modulate, in addition to mtor.
The common denominator tying all these compounds together is their interaction with the PI3K / Akt / mTOR signaling axis, an evolutionarily conserved master regulator of cellular growth, metabolism, and nutrient sensing.
Rapamycin works by selectively inhibiting mTORC1 downstream. However, many of the compounds that outperformed Rapamycin in this Ora Biomedical screen do not just hit mTOR; they strike upstream or parallel nodes in this exact cascade, or bypass it entirely to manipulate downstream targets like translation and cellular stress.
Here is a breakdown of the specific additional pathways these top-tier compounds inhibit or activate, along with examples and their exact median lifespan extension numbers from the data.
1. Upstream PI3K / Akt Pathway Inhibition
The most prominent additional path manipulated by these top performers is the inhibition of Phosphoinositide 3-kinase (PI3K) and Akt (Protein Kinase B).
Normally, when growth factors or insulin bind to a cell, they activate PI3K, which activates Akt, which subsequently turns on mTORC1 to promote growth and suppress cellular cleanup. By shutting down PI3K/Akt upstream, these compounds completely freeze the pathway, powerfully inducing autophagy (the recycling of cellular waste) and improving metabolic proteostasis.
- Omipalisib (GSK2126458): Dual PI3K and mTOR inhibitor 63% lifespan extension
- GDC-0032 (Taselisib): Selective alpha/beta/gamma-sparing PI3K inhibitor 31% lifespan extension
- IPI-145 (Duvelisib): Dual PI3K-delta and PI3K-gamma inhibitor 30% lifespan extension
- Serabelisib: Highly selective PI3K-alpha inhibitor 29% lifespan extension
2. Upstream AMPK Pathway Inhibition (Alternative Energy Sensing)
AMPK (AMP-activated protein kinase) is the cell’s low-energy gauge. Normally, activating AMPK inhibits mTORC1 (which is why caloric restriction works). However, manipulating this pathway from the opposite direction with specific temporal dynamics or in specific tissue contexts can dramatically alter systemic nutrient signaling, forcing cells to reorganize how they allocate energy reserves over a lifetime.
- AMPK-IN-1: A highly specific AMPK inhibitor 30% lifespan extension
3. Neuro-Glutamate and Proteostasis Activation
Instead of interfering directly with the standard insulin/mTOR signaling cascade, this pathway involves upregulating Glutamate Transporter 1 (GLT-1 / EAAT2). Doing so clears excess extracellular glutamate—the primary excitatory neurotransmitter. This prevents excitotoxicity, halts chronic neuro-inflammation, and mitigates the proteostatic stress (misfolded protein accumulation) that typically accelerates aging.
- Ceftriaxone: Beta-lactam antibiotic that acts as a potent GLT-1 activator >65% lifespan extension
- Ceftriaxone Sodium Trihydrate: Same molecular mechanism 31% lifespan extension
4. Epigenetic, Metabolic, & Cellular Stress Re-programming
The remaining outliers target distinct, secondary enzymatic pathways that force cells into a survival/maintenance state rather than a growth state:
- D-alpha-Hydroxyglutaric acid disodium: Interacts with alpha-ketoglutarate-dependent dioxygenases. It essentially acts as a metabolic signal that reprograms chromatin methylation and cellular respiration 60% lifespan extension
- N-Feruloyloctopamine: A polyphenolic compound that actively dampens both the PI3K/Akt pathway and the parallel MAPK (Mitogen-Activated Protein Kinase) pathway, providing powerful antioxidant and anti-proliferative cellular defense 35% lifespan extension
- WP1066: A small molecule that blocks the STAT3 (Signal Transducer and Activator of Transcription 3) pathway. Suppressing STAT3 downregulates chronic systemic inflammation and halts the translation of pro-inflammatory aging factors (SASP) 34% lifespan extension
- Lansoprazole: A proton pump inhibitor that alters lysosomal pH. Because lysosomes are the physical recycling centers where mTORC1 resides and operates, altering lysosomal acidification directly modifies how autophagic cleanup is performed 30% lifespan extension
Seeing as pi3k and akt inhibition seems prominent I’ll note that both quercetin and fisetin provide decent inhibition of those pathways, but only the lyposomal versions. Since some of these compounds on the list have spotty availability, the next best thing might be to mimic the pathways they hit through multiple drug combinations. An easy example is that since Omipalisib inhibits both pi3k and mtor, a combination of rapamycin + quercetin could do the same.
Obviously this is the most interesting result. This is the first I’ve heard of this pathway. I suspect drugs affecting GLT-1 to be promising Parkinson’s, dementia and Alzheimer’s interventions and may play a role in slowing down brain aging.
From Claude:
Drugs that upregulate or enhance GLT-1:
Beta-lactam antibiotics
Ceftriaxone — the most studied; induces GLT-1 expression via NF-κB pathway. Has shown efficacy in preclinical ALS, addiction, and pain models. One large ALS trial (Cudkowicz et al.) failed on survival endpoint but there’s ongoing interest in other indications.
Xanthine derivatives
Propentofylline — modest GLT-1 upregulator, also reduces neuroinflammation; studied in vascular dementia and neuropathic pain
MS-153
Experimental compound, directly stimulates glutamate uptake via GLT-1; used in animal addiction models
N-acetylcysteine (NAC)
Indirectly increases GLT-1 expression in nucleus accumbens via cystine-glutamate exchanger (xCT) normalization; this is actually the main mechanism behind its use in addiction and OCD research
Riluzole
FDA-approved for ALS; partly works by enhancing glutamate reuptake, though its primary mechanism is sodium channel blockade
GPI-1046 / other compounds
Various FKBP12 ligands have shown GLT-1 upregulation in research contexts