Anything is conceivable, but I’m more concerned about the pro coagulant effects.
I mean what could be the mechanism for increased coagulation factors, and several of them at that?
Is this isolated to this group of renal transplant patients? Why?
As you know, we’re at risk just by aging . Is this something that’s happening, like DVT’s , and we’re not seeing it?
Any ideas?
Maybe Matt’s study will shed some light on it.
Regarding your posted paper: Treatment with everolimus is associated with a procoagulant state - PubMed (Treatment with everolimus is associated with a procoagulant state)
RESULTS: The use of an mTORi was associated with significantly higher levels of von Willebrand factor, prothrombin fragment 1+2, thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 as compared to a non-mTORi based immunosuppressive regimen.
This sure sounds more fundamental causation than simply an association in renal transplant patients? Those are a lot of critical endothelial/hematological type markers?
I get the statement “Renal transplant recipients are at increased risk of venous thromboembolic events, which is in part caused by their treatment with maintenance immunosuppressive drugs”
But it’s the “IN PART caused BY their treatment with maintenance immunosupressive drugs”
That sounds unmistakably directly attributable to mTOR.
And does pharmacological treatment of elevated lipids on Rapamycin address these pathways?
Put me down for “worried” if my lipids major dysregulate.
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What was the reason that this pro coagulant effect is being ascribed to mTORC1 rather than mTORC2?
Is it a TOR1 or 2 issue? And what’s the mechanism?
I’m not aware that treating lipids has any bearing on coagulation pathways.
Here’s a summary of things leading to hyper coagulation
I’ll look to see why other meds cause it.
I would say that right now we don’t know.
I see. So we cant dismiss the coagulation danger as simply one of those side effects of prolonged TOR2 inhibition since we don’t know the mechanism and therefore don’t have a rationale for ascribing it to TOR2
This study shows that low mTOR in platelets Reduces the risk of thrombosis
Cardiologists often use drug eluding stents to open up occluded coronary arteries. One of these drugs is rapamycin and is very effective but does it increase clotting/ thrombus formation compared with other stents?
This overview states on pp. 16-17 that rapamycin stents Do Not increase thrombus/ clot formation
Many of us have been on Rapamycin for 5 years or so . Are we having clotting issues? Are Alan Green’s patients?
Maybe it’s specific for some reason in the renal transplant patients. Some kind of interaction?
Web MD describes blood clotting as a possible rapamycin side effect . But also lists it as Rare.
I would say that that’s true, yes.
We’ve discussed grape seed extract. It may be very important in the context of rapamycin and clotting. Seems to have fairly potent anticoagulant effects.
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This question is complex, but our weekly dosing protocols would seem to suggest we are mainly TOR1 inhibition. But in the renal transplant cohorts with reported lipids/CAD risk, they are under chronic dosing. Does this chronic dosing cross the mTOR2 threshold, or is still all TOR1?
From this mice study of chronic 2.24 mg/day (equivalent to 13 mg/day humans) they found 30% mTOR1 reduction, and NO mTOR2 reduction.
“Chronic rapamycin treatment inhibits mTORC1 but not mTORC2 in brains of C57BL/6J mice. Phosphorylation of Akt/PKB at Ser473, a target of mTORC2, was unaffected both in
whole brain lysates as well as in hippocampi. Taken together, these data indicate that
long-term oral treatment with rapamycin significantly inhibits mTORC1 but does not reduce mTORC2 activity in brain.”
So it seems it might take some massive doses to dysregulate mTOR2.
Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins (2015)
"Ten-week-old C57BL/6J mice were given intraperitoneal injections of 8 mg/kg (47 mg/day human equivalent) rapamycin every other day for 10 days. While rapamycin acutely and directly inhibits mTORC1, only chronic administration of rapamycin can inhibit mTORC2 in some, but not all, cell lines or tissues. The mechanism leading to cell specificity of mTORC2 inhibition by rapamycin is not understood and is especially important because many of the negative metabolic side effects of rapamycin, reported in mouse studies and human clinical trials, have been "attributed" recently to mTORC2 inhibition.
Role of mTOR in Glucose and Lipid Metabolism
“Relative to mTORC1, the upstream signals and downstream substrates of mTORC2 are less known. mTORC2 can be activated by the growth factors such as insulin and IGF, but insensitive to the nutrients. Activated mTORC2 phosphorylates AGC kinase family, including AKT, SGK, and PKCα, to regulate cellular survival and metabolism, as well as cytoskeletal remodeling. The most well characterized substrate of mTORC2 is AKT which is phosphorylated at the serine 473. AKT could further phosphorylate TSC2, the upstream inhibitor of mTORC1. Therefore, activation of mTORC2 inactivates mTORC1. Vice versa, mTORC1-S6K axis could also directly phosphorylate mSIN1, the core component of mTORC2 and inactivate it. Therefore, mTORC1 and mTORC2 form a feedback loop regulating the complex activity”
It appears mTOR2 is more acting on glucose pathways.
“Hepatic mTORC2 regulates glucose and lipid metabolism via AKT signaling. The role of hepatic mTORC2 has been examined in vivo using the mice lacking Rictor in liver. Deficient expression of mTORC2 in liver leads to defective insulin-stimulated AKT phosphorylation, resulting in constitutive gluconeogenesis”
So does elevated glucose signal mTOR2 dysregulation or still related to mTOR1?
For practical purposes, we can assume these two pathways are in play, but not sure how knowing is going to resolve clinically our concerns of elevation in lipids/glucose and CAD risk.
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Well, that’s more unknowns re using standard playbook statins to address elevated lipids. We might indeed a cocktail of pharma, but which meds??
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Some more on the possible iron/anemia connection associated with Rapamycin.
We know Rapamycin can induce RBC microcytosis and iron dysregulation.
Anaemia, microcytosis and sirolimus--is iron the missing link? - PubMed (btw, this study showed it is liver mediated, and ONLY IV iron rectified…not oral)
We know hepcidin is associated with VTE:
Plasma hepcidin is associated with future risk of venous thromboembolism
“RDW was inversely associated with hepcidin, FtL, and hemoglobin. The risk of VTE increased linearly across categories of higher plasma hepcidin levels. Participants with hepcidin in the highest quartile had an OR for VTE of 1.32 (95% CI, 1.00-2.42), and those in the .90% percentile had an OR for VTE of 1.66 (95% CI, 1.14-2.42) compared with the reference group (quartiles 2 and 3).”
Iron Metabolism, Hepcidin, and Anemia in Orthotopic Heart Transplantation Recipients Treated with Mammalian Target of Rapamycin
https://sci-hub.se/https://pubmed.ncbi.nlm.nih.gov/23375326/
“The study included 169 patients including 35 females who underwent their first OHT. In this study we focused on the prevalence of functional iron deficiency among mTOR antagonist-treated patients, observing 80% of them to exhibit functional iron deficiency. In addition, they also
showed increased serum hepcidin and markers of inflammation, suggesting that this drug could be responsible for an anemia resembling that associated with chronic inflammation”
Hepcidin in the diagnosis of iron disorders
So is hepcidin yet another risk for clotting secondary to rapamycin?
It looks like grape seed extract can really help with this issue of clotting in a very safe manner.
It required a blood level of 15 ug/ ml and I have no idea what dose would be necessary to achieve that level.
I asked Alan if he’s seeing any clotting issues in his patients and am waiting for a reply.
This is interesting if you have a spare hour or so. They looked at centenarians and all things longevity related.
No particular common denominators with diet as far as I can see. Or even BMI.
At one point they said that glucose and insulin sensitivity have Not been shown related to longevity.
I went away thinking that there’s so much we don’t know.
I just took the test and it says 97.
like “but he doesn’t know I take rapamycin”
Appears so, but I am also trying to make the Rapamycin side effect connection.
Relation between high serum hepcidin-25 level and subclinical atherosclerosis and cardiovascular mortality in hemodialysis patients
"In hemodialysis (HD) patients, cardiovascular disease (CVD) is the major cause of mortality and morbidity. In atherosclerotic diseases, iron gets accumulated in the arterial wall. Hepcidin is an important hormone in iron metabolism. Furthermore, hepcidin is associated with atherosclerotic disease. Therefore, this study aims to investigate the relation of serum hepcidin-25 (SH-25) and sub-clinic atherosclerosis measured by carotid intima-media thickness (CIMT) and mortality in HD patients.
Methods: We enrolled 82 HD patients in a cross-control study. We measured SH-25 using ELISA kit and CIMT using high-resolution real-time ultrasonography. After 4 years of first assessment, we investigated the relation between all-cause and cardiovascular mortality and SH-25 and CIMT.
Results: The SH-25 levels were statistically significantly higher in patients who died of CVD (40.3±25 vs. 29.1±13; p<0.05). Linear regression analysis showed a positive correlation between CIMT and SH-25 in the study population and in those who died from CVD (r=0.41; p<0.05 and
r=0.606; p<0.05, respectively).
Conclusion: This study suggests that hepcidin is effective in cardiovascular mortality and pathophysiology of subclinical atherosclerosis in HD patients.
Relationship between serum hepcidin levels and cardiovascular disease in patients with maintenance hemodialysis
Conclusions : Serum hepcidin level is associated with CVD in MHD patients, indicating that hepcidin may be a novel biomarker and therapeutic target for CVD.
In‑depth review: is hepcidin a marker for the heart and the kidney?
“Hepcidin induces iron trapping within macrophages. This iron trapping within the macrophages of an atherosclerotic plaque may enhance iron-mediated oxidative stress and lipid peroxidation. Thus, hepcidin increases foam cell formation and induces plaque instability. Furthermore, hepcidin also inhibits cholesterol efux in macrophages. Therefore, iron trapping within plaque macrophages promotes atherogenesis in these cells. The “iron hypothesis” [25] suggests that iron defciency may be protective against ischemic heart disease. Hepcidin, the major regulatory hormone of systemic iron homeostasis, may promote atherosclerosis .Haase-Fielitz et al. [28] showed that among survivors after cardiac surgery, preoperative urine and plasma hepcidin levels were increased by 20-fold and 2-fold, respectively, compared to non-survivors. Authors concluded that hepcidin measured in plasma predicted mortality after cardiac surgery”
They looked at centenarians and all things longevity related.
One thing I’ve wondered about is – when old people die, what is the cause? Generally, it is aging, of course, though I believe that isn’t a diagnosis that can be put on a death certificate (& I suspect what is often put down is heart attack, causing people to believe that heart problems are the main cause of death in the elderly).
However, it seems to me that IRL, we don’t necessarily know what the proximate cause of death is for any given person that wakes up dead (i.e. goes to sleep & dies) unless there is some particular disease they are being treated for. With the elderly there isn’t generally an autopsy, but even if there is, I don’t see any reason to expect the cause to leave a signal that can be determined after the fact.
It seems like an interesting & challenging research topic, even in mice, much less people.
Does anyone have any thoughts about this to share?
Beth
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Just an observation from someone who is 81 years old.
At 81 I have seen many of my friends and relatives die. The most common diagnoses reported was “heart failure” followed by death due to various cancers.
I had a sister die in her sleep. She reportedly said, " I feel tired, I think I will go to bed early". She just died peacefully in her sleep.
She may have had undiagnosed heart problems from an unhealthy lifestyle.
Older people who die of “natural causes” are seldom autopsied so we don’t know the actual cause of death.