All but one of your studies here involve an acute inflammatory insult such as LPS, which tends to cause BBB leakiness, which might explain why rapa gets in under these circumstances and not under physiological conditions. Also, most involve repair of the brain vasculature itself, which does not require BBB transit.
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Macrophages move around and distribute mitochondria. EVs move around containing mitochondria.
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Oh yeah, Spindler is a legendary name in CR and generally longevity field, I’ve been following him for decades. Extremely competent and very credible. His word counts for a lot with me, which is saying something, as I tend to be very resistant to personality driven authority. Spindler studies were always of the highest standards.
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Are you referencing this paper, or is there another? In addition to being a Chinese group, the control animals were miserably short-lived (median survival 690 days) and survival was only improved 5.9% (to a still-abominable 730.8 days in Empa) in the male mice; that’s pretty much meaningless.
Very good point on the MR, though.
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Median survival:
- Control: 983 days
- Everolimus 4.7 mg: 954 days (-3%, p=0.35)
- Everolimus 28.3 mg: 1040 (+6%, p=0.01)
How do these doses convert to human doses?
Comparison to sirolimus (DrugAge):
So clearly inferior?
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Looks like a really high dose if that is per mouse rather than per kilogram of mouse.
I don’t think you can read much into this.
I would assume that beyond the issue of short life and dosing the effect of inhibiting mTOR is much the same.
I am personally sticking with Rapamycin because it does what I want it to do, but at the moment I don’t want to take it until I have resolved the issue with my low WBC. I think I have resolved the issue, but I don’t have test results to prove this.
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Wow! That’s a pathetically small effect! I had never gotten a clear shot of the numbers. I had assumed that the effects of rapa and everolimus would be quite similar; this is effectively a null result 
.
Good question. It seems unlikely it means mg/kg mouse (why would they start with double the rapa dose and then go to 10x of it?), but the other alternatives also seem unlikely (28.3 mg per mouse (definitely not), or 28.3 mg/kg food).
I’d have to say so!
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OK so from a lifespan point of view, everolimus seems useless (vs sirolimus).
The question of the potentially better BBB crossing remains. However, sirolimus seems beneficial according to this trial: Rapamycin as a preventive intervention for Alzheimer’s disease in APOE4 carriers: targeting brain metabolic and vascular restoration
I am not myself sure that everolimus would be necessarily worse than sirolimus. My reason for concentrating on Rapamycin is that we have more knowledge about its potential risks and hence if I take a high dose I am more likely to be aware of any negative consequences and how to handle them.
Also there is only so much experimentation that can be done. My experiments take multiple weeks at times and I really cannot slot in an alternative to rapamycin that has much the same mechanism.
I am also not persuaded of the argument that rapamycin does not cross the BBB. It probably crosses at a lower rate.
I don’t think that any one molecule (citrate, rapamycin, menaquinone-7, melatonin) is the solution to repairing the mitochondrial dna. I think a combination in a cyclical manner is going to produce the optimal results.
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To revive this thread, wanted to check if there is any new evidence to say that Everolimus is a viable option for longevity gains. Am seeing more comments about its usage in some biohacking circles due to shorter half life and lower AE profile, but the last discussion on this thread seems to indicate it is a dud for longevity.
I wouldn’t say it’s a dud at all. I would disagree with @adssx on his assessment above.
I still expect the effect is likely very similar to rapamycin. The key unresolved issue is the exact dosing requirement to get similar results. That one datapoint that was posted a few posts back is only one study. Everolimus has rarely been studied for longevity… because it’s so similar to rapamycin (so most scientists expect it to have very similar lifespan enhancing results).
I have a good stash of Everolimus because of this. Given that it comes in 10mg tablets, it’s a little easier to order larger quantities from India or other locales.
But I tend to default to rapamycin use because it’s the compound that has the most research behind it, and is easy to get, and I started on it 6 years ago. And, I wouldn’t say I’m so confident in the everlimus effectiveness that I’d give up Rapamycin for it. There is no obvious reason to move to Everolimus really, at this point. Rapamycin is well validated, inexpensive and easy to get. Everolimus probably works equally well at some dosing, but why risk it?
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Various doses of sirolimus extended lifespan. Various doses of everolimus did not. And no one seems to study everolimus anymore. So clearly everolimus is shit (until proven otherwise!).
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Its shorter half life may actually be an issue. What we don’t know is how long mTOR needs to be inhibited in order to kick things off. It could be something like a few hours. I am sticking with SIro.
chatGPT says:
Here’s a compact set of tables for the key everolimus / lifespan or survival experiments by species.
1. C. elegans (worms)
| Species / strain | Health context | Study (year) | Everolimus regimen | Lifespan effect | Notes |
|---|---|---|---|---|---|
| C. elegans N2 (wild-type) | Normal aging | Demirel et al., 2024, Russian J. Nematology (russjnematology.com) | 0.01–10 nM in agar throughout life | Mean lifespan ↑ ~40–53% across 0.01–5 nM; slightly less at 10 nM | Very large extension; non-monotonic dose–response; also tested rapamycin & temsirolimus. |
| C. elegans lin-35 mutant | Tumour-suppressor mutant (Rb ortholog) | Demirel et al., 2024 (russjnematology.com) | Same doses as above | Mean lifespan ↑ ~2–31% depending on dose | Effect smaller and more variable than in N2; still generally positive. |
| C. elegans N2 | Normal aging | Zhang et al., 2024, J Gerontol A (PubMed) | Liposome-delivered everolimus at several doses during adulthood | Pooled data: ~+6.8% mean lifespan, not statistically significant (p ≈ 0.075) | In same study, rapamycin & temsirolimus showed clearer, significant lifespan extension; everolimus weaker. |
2. Drosophila melanogaster (flies)
| Species / strain | Health context | Study (year) | Everolimus regimen | Lifespan / survival effect | Notes |
|---|---|---|---|---|---|
| Male D. melanogaster | Normal aging | Spindler et al., 2012, PLoS ONE (PMC) | Food containing 3 mM everolimus (library screen) | Male lifespan ↑ ~17% | Identified everolimus as a positive hit in a kinase-inhibitor screen; baseline lifespan short (screen conditions). |
| Male D. melanogaster (reviewed) | Normal aging | dos Santos et al., 2024 review on pharmacology of aging in flies (PMC) | Various (summarising prior work) | Confirms everolimus extends fly lifespan in at least some conditions | Review categorises everolimus among clinically used drugs that extend fly lifespan; detailed dose data from Spindler. |
3. Mice – survival / “lifespan” in disease models
(There is still no classic “healthy mouse lifespan” everolimus study analogous to Harrison 2009 for rapamycin.)
| Model / genotype | Health context | Study (year) | Everolimus regimen | Survival / lifespan effect | Notes |
|---|---|---|---|---|---|
| EGFR-mutant transgenic mice (lung tumours) | Oncogene-driven lung cancer | Yasugi et al., 2014 (PubMed) | Everolimus (RAD001) given chronically after tumour induction | Median survival: 31.2 → 58.0 weeks (~+86%, p < 0.001) | Strong prolongation of survival; pS6 down, angiogenesis suppressed; little evidence of apoptosis/autophagy change. |
| TgMISIIR-TAg ovarian cancer mice | Transgenic ovarian carcinoma | Mabuchi et al., 2007, Cancer Res (PubMed) | RAD001 treatment in transgenic females | Markedly delayed tumour onset; tumour burden ↓ ~84%; improved tumour-free survival | Ascites & peritoneal dissemination in 21% of treated vs 74% controls; survival benefit via delayed aggressive disease. |
| Eµ-Myc transgenic mice | B-cell lymphoma / leukemia model | Wall et al., 2013, Cancer Discov (PMC) | Everolimus as prevention and therapy | Strongly prolonged overall survival; in one cohort median survival 73 days (placebo) vs not reached (everolimus) | Everolimus clears premalignant B cells, restores normal B-cell differentiation, induces p53-linked senescence; robust delay of lymphoma onset. |
| Lmna H222P/H222P mice | Cardiomyopathy (cardiolaminopathy) | Wu et al., 2024, Circ: Heart Failure (PubMed) | Everolimus started after onset of heart failure | Median survival ↑ 9% vs placebo (p ≈ 0.035) | Also improved cardiac structure/function; reactivated autophagy; modest glucose intolerance as side effect. |
| Ovarian cancer xenografts & related models | Advanced ovarian cancer | Mabuchi et al. plus later summaries (e.g. Guo 2016; Blagosklonny 2023 review) (PubMed) | Everolimus alone or with other therapy | Delayed tumour onset, reduced tumour burden and intra-abdominal spread; prolonged survival in several models | Used more as an anti-cancer drug; survival benefits are disease-specific, not general aging models. |
4. Humans – aging-related endpoints (no lifespan data)
| Population | Health context | Study (year) | Everolimus regimen | “Lifespan-adjacent” outcome | Notes |
|---|---|---|---|---|---|
| Adults ≥65 yrs (healthy) | Immunosenescence | Mannick et al., 2014, Sci. Transl. Med. (PubMed) | RAD001 0.5 mg/day or 5 mg/week for 6 weeks vs placebo | ~20% improvement in influenza vaccine response; ↓ PD-1⁺ T-cells; no lifespan follow-up | First “aging” oriented RAD001 trial in humans; short-term immune functional data only. |
| Adults ≥65 yrs (ongoing / planned trials) | Aging biomarkers, function | Mannick et al., various; summarized in 2021 & 2024 reviews (PMC) | Low-dose everolimus alone or in combination with other mTOR inhibitors | Endpoints: immune, inflammatory, functional; no mortality endpoints | Designed to explore safety, dosing and biomarker changes rather than hard survival. |
| Patients with cancers, TSC, etc. | Disease treatment | Multiple RCTs across indications (neuroendocrine tumours, renal cell cancer, TSC, etc.) (MD Anderson Cancer Center) | Therapeutic doses (e.g. 5–10 mg/day) | Improved progression-free survival / disease outcomes in specific diseases | These are oncology / transplant trials; they don’t speak to “normal aging lifespan” in otherwise healthy humans. |
Quick overall read
- Invertebrates: Clear evidence that everolimus can extend lifespan, with effect sizes ranging from non-significant ~7% up to ~50% depending on strain, dosing, and protocol.(russjnematology.com)
- Mice: Strong survival extension in multiple disease-prone models (cancers, cardiomyopathy), but no clean “healthy mouse lifespan” study yet.(PubMed)
- Humans: Only short-term functional improvements (especially immune function in older adults); no direct lifespan/healthspan endpoints yet.(PubMed)
If you’d like, I can next add a second table comparing everolimus vs rapamycin vs temsirolimus in the same experiments (e.g. Demirel & Zhang, worm and fly data) to get a clearer sense of relative potency.
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These are cancer models: irrelevant.
Longevity studies for everolimus are here:
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I took rapamycin for over 2 years and didn’t see any results. I saw a recent study that said it only worked for 75% of people, so I just switched to everolimus, because it is supposed to cross the blood/brain barrier better. It is much more expensive and harder to get, but my doctor found it from Mark Cuban’s pharmacy for about $60 for 30. It was $2,500 from Walgreens! Today was day 6. I’m also taking Lithium and b vitamins but eliminated most of the other supplements I had been taking in case they interfered with the everolimus. I will add them back one at a time eventually. I don’t know if I will live longer, but I really need to feel better–I have adrenal POTS among other things.
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Thank you for your report. Keep us posted on any benefits (or not) of your new regiment. Best of luck!
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In the 2014 trials where everolimus increased immune function they found 5mg weekly worked but 20mg did not if I remember correctly. From everything I read so far a dosing conversion factor of around 1.3-1.5x seems to be ideal to account for everolimus’ higher bioavailability.
So 5mg everolimus should be similar to 7-8mg rapamycin but everolimus will always achieve a lower trough by the end of the week but some rapamycin will still remain at day 7 so its hard to find a true equivalent dose