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:
A suggested combo regimen of rapamycin and doxy by perplexity:
*** Rapamycin:**
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
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 |
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.
It may be that a low dose has useful hormetic effects, but it does not strike me as a priority as an intervention.
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! 
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.
Can you create a simple lifespan and healthspan data matrix on that compound on multiple species?
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
Exciting new partnership for Rapamycin Longevity Lab!
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
The candidates that beat rapamycin in roundworms:
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.
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.
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.
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.
The remaining outliers target distinct, secondary enzymatic pathways that force cells into a survival/maintenance state rather than a growth state:
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
Other than the very top results there are 3 molecules in this screening that stand out to me as they are naturally derived and potential safe to consume. They’re difficult to find but I’m curious what people here think of them and if they’d be willing to try them?
These are derived, among other sources, from ginkgo biloba leaf, chamomile and garlic skin. All of these are relatively benign. We know that some amount of them are safe and therefore some amount of these molecules are safe. The question lies in how much.
Those 3 molecules are:
Isoginkgetin is a naturally occurring biflavonoid first isolated from Ginkgo biloba leaves.
In conclusion, we showed that IGG effectively triggered apoptotic cell death in OSCC, employing a JNK-dependent pathway of caspase activations. Our findings implicate this natural compound as a tentative therapeutic modality against oral malignancies.
Isoginkgetin Induces Caspase Cascade Activation and Cell Apoptosis via JNK Signaling in Oral Cancer - PMC
Lysosomal dysfunction is a core pathological driver of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Transcription factor EB (TFEB) serves as a master regulator of lysosomal biogenesis, and its pharmacological activation represents a strategy to restore lysosomal function in disease and aging. Here, using a series of artificial intelligence-powered computational virtual screening workflows, we have identified isoginkgetin (ISO), a small-molecule compound, as a potent TFEB activator that promotes mechanistic target of rapamycin complex 1 (mTORC1)–independent TFEB nuclear translocation to enhance lysosomal biogenesis and function. Mechanistically, ISO functions as an ATP-competitive inhibitor that binds to the key Lys85 residue within the ATP-binding pocket of glycogen synthase kinase 3β (GSK-3β), thereby regulating the GSK-3β–TFEB signaling axis to activate TFEB nuclear translocation. Functionally, ISO improves lysosomal function and protects motor neurons differentiated from induced pluripotent stem cells derived from patients with ALS from degeneration. Collectively, these results support the hypothesis that lysosomal dysfunction is a druggable target for ALS.
Isoginkgetin protects against degeneration of ALS motor neurons via regulating the GSK-3β–TFEB signaling axis - PMC
IGK inhibited catabolism and promoted anabolism after stimulating by IL-1β in vitro. Following destabilization of the medial meniscus (DMM) surgery, administration of IGK significantly reduced OARSI scores and attenuated AGGRECAN and COLLAGEN2 loss, overexpression of MMP3 and articular cartilage deterioration. IGK relieved pain of mice after DMM. Besides, PI3K/AKT/NF-κB, P53, Autophagy, Ferroptosis pathway and reactive oxygen species (ROS), senescence of cartilage were changed after IGK treatment.
Isoginkgetin protects chondrocytes and inhibits osteoarthritis through NF-κB and P21 signaling pathway - PMC
In summary, this study provides the first preclinical evidence in support of the lipid-lowering and atheroprotective of ISOGK by targeting ACLY enzyme activity. These findings indicate that the novel ACLY inhibitor ISOGK holds promise for clinical translation and suggest the potential therapeutic value of ISOGK in treating atherosclerotic vascular diseases.
A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY - PMC
In summary, our study illustrated that ISO is a potential novel anticancer agent against HCC that directly binds the N terminus of CDK6 to induce its degradation with fewer side effects. Moreover, our results provide a new molecular mechanism by which ISO treatment or CDK6 deletion promotes autophagy; that is, ISO targeting the N terminus of CDK6 for degradation inhibits the expression of SLC2A1/GLUT1 by decreasing the enhancer activity of SLC2A1/GLUT1 , resulting in decreased glucose and inducing the AMPK-ULK1 pathway.
Isoginkgetin, a potential CDK6 inhibitor, suppresses SLC2A1/GLUT1 enhancer activity to induce AMPK-ULK1-mediated cytotoxic autophagy in hepatocellular carcinoma - PMC
Considering the extreme intra- and intertumoral heterogeneity of glioblastoma and the innate or acquired resistance of high-grade brain tumors to conventional therapy, the present study aimed to evaluate the effect of Iso, a natural substance, as a single inhibitor agent on the growth, clonogenic potential, and migration of U87MG. Furthermore, an attempt was made to identify the main mechanisms underlying the inhibition of growth induced by Iso, highlighting that Iso has effects on the blocking of cell growth through a reactivation of apoptosis and autophagy. The most interesting future research, certainly, could be investigating the ability of Iso to act in synergy with temozolomide-bypassing drug resistance mechanisms, preventing therapy failure and reactivating the homeostatic mechanism in cancer cells.
Isoginkgetin—A Natural Compound to Control U87MG Glioblastoma Cell Growth and Migration Activating Apoptosis and Autophagy - PMC
In conclusion, the present study identifies IGK as a novel naturally-occurring Nrf2 activator from eminent medicinal herb Ginkgo Biloba , and demonstrates its safety and efficacy to ameliorate obesity-induced cardiomyopathy.
Isoginkgetin, a bioactive constituent from Ginkgo Biloba, protects against obesity-induced cardiomyopathy via enhancing Nrf2/ARE signaling - PMC
In summary, the present study demonstrated that isoginkgetin could inhibit the production of peripheral inflammatory cytokines, decrease the neuroinflammation by downregulating p38/NF-κB signaling pathway in microglia, and protect neuronal cells from activated microglia-induced toxicity and apoptosis (Figure 2), which may contribute to it attenuated LPS-induced depression- and anxiety-like behavior and restored neurotransmitter synthesis and metabolism in mice. These data suggest that isoginkgetin may be a potential antidepressant candidate.
Isoginkgetin treatment attenuated lipopolysaccharide-induced monoamine neurotransmitter deficiency and depression-like behaviors through downregulating p38/NF-κB signaling pathway and suppressing microglia-induced apoptosis - PMC
We utilized virtual screening based on the structure of the viral major protease, 3Cpro, to filter potential anti-FMDV inhibitors from phytochemical compound libraries. Among the 5789 tested molecules, two flavonoids, luteolin and isoginkgetin, demonstrated a high potent negative effect on the FMDV life cycle by blocking the 3Cpro activity. The molecular docking revealed a good binding affinity of both compounds and FMDV 3Cpro, which strengthened our findings by the cell-based and FRET-based protease assays. As both phytochemical flavonoids presented negative effects on both DNA and RNA viruses in several studies, they could become promising board-spectrum antiviral agents effective against FMDV and other viruses.
Natural Phytochemicals, Luteolin and Isoginkgetin, Inhibit 3C Protease and Infection of FMDV, In Silico and In Vitro - PMC
Daphnetin is a molecule found in chamomile and plants from the genus Daphne.
Daphnetin has demonstrated the ability to reduce the production of pro-inflammatory cytokines through various mechanisms, including regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and suppressing NF-κB signaling (Zhang et al., 2018). Shen et al. conducted a study revealing that daphnetin effectively mitigated inflammation induced by LPS and decreased the mortality rate associated with endotoxin in mice. Their findings indicated that daphnetin significantly reduced the release of TNF-α, IL-1β, IL-6, NO, and PGE2 in Raw264.7 cells. Furthermore, it downregulated the expression of iNOS and COX-2, as well as the generation of ROS.
Coumarin: A natural solution for alleviating inflammatory disorders - PMC
In conclusion, the administration of daphnetin resulted in a reduction in blood glucose levels in diabetic rats. Furthermore, daphnetin demonstrated a dose-dependent improvement in cardiac function, attenuation of myocardial injury, and a reduction in the inflammatory response, as well as suppression of ER stress-induced apoptosis, through the inactivation of JNK and MAPK in diabetic rats. These findings indicate that daphnetin may be a promising therapeutic agent for the treatment of DCM.
Daphnetin ameliorates diabetic cardiomyopathy by regulating inflammation and endoplasmic reticulum stress-induced apoptosis - PMC
In summary, the present study demonstrated that DAP alleviated cerebral I/R injury by reducing inflammatory cytokines production and neural cells apoptosis in vivo. Furthermore, the potential mechanism responsible for neuroprotective and anti-inflammatory effects of DAP was involved with the inhibition of TLR4/NF-κ B mediated inflammatory signaling pathway. DAP showed a therapeutic potential for the treatment of stroke.
Daphnetin Protects against Cerebral Ischemia/Reperfusion Injury in Mice via Inhibition of TLR4/NF-κB Signaling Pathway - PMC
In conclusion, the present study has demonstrated that daphnetin alleviates HGHF-induced pathological damage in NK-92 cells via upregulating the secretion of inflammatory cytokines, thereby restoring the expression of the intracellular cytotoxic molecules (perforin and granzyme B), and inhibiting cell apoptosis. Taken together, these findings have provided a nove experimental basis for the application of daphnetin in the treatment of T2DM and has been laid a foundation for further exploring the immunomodulatory mechanism of natural coumarin derivatives in metabolic diseases.
Daphnetin Ameliorates Pathological Damage in NK-92 Cells Induced by High-Glucose and High-free Fatty Acids - PMC
Daphnetin attenuates Aβ-associated AD progression via inhibition of AChE activity, scavenging of free radicals, reduction of inflammation, and restoration of neuronal KCC2 channels. Hence, it may be a potential therapeutic agent for the treatment of AD. However, more extensive studies are required to confirm this therapeutic potency in different AD conditions and various animal species.
Daphnetin Ameliorates the Amyloid β-Induced Alzheimer Disease via Restoring Potassium-Chloride Co-Transporter 2 (KCC2) Ion Channel Functions in Mice - PMC
Daphnetin or 7,8 dihydroxycoumarin was found to be a potential salivary and pancreatic α-amylase blocker both in vivo and in vitro . It also inhibited α-glucosidase but to a lesser extent. Application of daphnetin for 7 days had no toxic effect on the organs like liver, kidney, small intestine in mice. Hence, it can be concluded that daphnetin has the potential to act as an α-amylase blocker. Further studies and careful investigations can lead to a more conclusive role of daphnetin in future.
Evaluation of toxicity and anti-amylase activity of 7, 8 dihydroxy coumarin (Daphnetin), a novel α-amylase blocker in vitro and in vivo - PMC
In conclusion, the present research provides evidence supporting the beneficial impacts of DAP in IDD (Intervertebral disc degeneration) treatment. This study demonstrates that DAP has a beneficial effect on oxidative stress, ECM degradation, and NLRP3 inflammasome activation caused by TBHP. This effect is achieved by increasing Nrf2/PINK1-mediated mitophagy in NPCs. Furthermore, the therapeutic efficacy of DAP in delaying IDD in rats was shown via in vivo tests. These results provide novel perspectives for understanding the potential of DAP in the therapeutic management of IDD.
Daphnetin-mediated mitophagy alleviates intervertebral disc degeneration via the Nrf2/PINK1 pathway: Daphnetin enhances mitophagy to alleviate disc degeneration via Nrf2/PINK1 - PMC
N-Feruloyloctopamine is an antioxidant compound isolated from garlic skin. Of the three compounds it is the one with the least amount of scientific data.
We provide evidence that FO can inhibit proliferation and stimulate apoptosis in Huh7 and Hep3B cells. Moreover, the critical pathways and potential target genes modulated by FO were screened. The conceptual diagram of the signal that FO stimulates apoptosis by regulating hub genes is simulated, but the specific mechanism by which FO mediates signal pathway transduction by regulating the expression of candidate genes is still unclear. We also need to reveal this hypothesis in subsequent molecular biology and histopathological experiments. It implies that the reformed FO can inhibit tumors by their effect on genes in critical signals and can be used as a promising antitumor drug.
N-trans-Feruloyloctopamine Wakes Up BBC3, DDIT3, CDKN1A, and NOXA Signals to Accelerate HCC Cell Apoptosis - PMC
Lansoprazole seems pretty significant. I would expect if it worked as well in humans we would be able to see it. Prevacid approved in 1995.
