#284

Recall the oncologist in the Rapamycin/cancer/GFJ study said in his patients, anemia and ILD were common side effects?

Well turns out getting ILD may greatly increase your risk for…lung cancer. Yes, stopping Rapamycin generally ameliorates symptoms…but has the seed been planted? And then you’re done with Rapamycin and longevity?

Lung cancer and interstitial lung disease: a literature review

“The association between lung cancer (LC) and interstitial lung disease (ILD) can be explained by the shared risk factors like smoking and physiopathology of fibrogenesis and cancerogenesis. The relative LC risk is shown to be 3.5- to 7.3-times higher in ILD, with LC occurrence estimated at 10 20% in ILD, with >15% of ILD patients likely to die from LC”

These are not inconsequential human risks.

#285

The cause of death is the same, rapamycin just delays aged related diseases.

But yet, as you say, Blagolsklonny only cites “cancer” (that’s mice talk)…what about human CAD??

#286

I took another look at the ITP study that you’re referencing. Yes there were some increase in certain cancers in the rapamycin group but they state that they didn’t change the distribution of presumptive causes of death. I’m assuming they mean that they didn’t reach statistical significance c/ w controls.

#287

Regarding rapamycin and lymphoma, here’s a study just published last year on the benefits of mTOR inhibition in All forms of hematologic malignancies including lymphoma, both Hodgkins and non Hodgkins. And this in humans.

#288

On another note, looks like you can Double your life span if:
You take rapamycin,berberine,and fucoxanthin
Live in a cold and dark room for the rest of your life
And you’re a fly

https://www.nature.com/articles/s42003-022-03524-4

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#289

Very good reference, but sparse benefits administered alone, and only in subset of hematologic cancers. But likely of some net benefit wrt to cancer, as in mice, generally agree.

Highlights

Results of clinical trials using Rapalogs as a single agent have shown very limited response in Acute myeloid leukemia (AML) patients, such as sirolimus, deforolimus, or everolimus.

Myelodysplastic syndrome (MDS) is a group of hematopoietic stem cell disorders, characterized by ineffective clonal hematopoiesis leading to blood cytopenias. Platzbecker et al. treated 19 MDS patients with SRL as a single agent, and demonstrated that SRL might have some activity in patients with more advanced MDS but lacked efficacy in low-risk MDS patients. Martin et al. treated 20 MDS patients with temsirolimus at a weekly dose of 25 mg; however, only four (20%) reached the response assessment after 4 months without hematological improvement. Based on these this response assessment, they concluded that Temsirolimus has no beneficial effects in elderly MDS patients."

Chronic Myeloid Leukemia (CML) Whether Rapalogs represent a new treatment opportunity for TKI resistant CML remains to be investigated in the clinic.

Myeloproliferative Neoplasms Guglielmelli et al. carried out treatment of patients with myelofibrosis with everolimus, resulting in 20% of patients’ spleens shrinking > 50%, 40% of patients’ spleens shrinking > 30%, and 15%–25% of patients with hematological reaction

Hodgkin Lymphoma Everolimus has significant activity in relapsed/refractory (R/R) HL and is currently listed as a treatment option for HL in the National Comprehensive Cancer Network (NCCN) guidelines. Everolimus demonstrates single-agent activity in treating Hodgkin and non-Hodgkin lymphoma with responses ranging from 20% to 47%. The emergence of effective new drugs in the treatment HL, including CD30 mAbs and checkpoint inhibitors, such as PD-(L)1 mAbs, may limit the broad application of mTORi in this setting. However, mTORi may be useful in later lines of therapy for difficult-to-treat, multidrug-exposed patients with R/R HL.

Non-Hodgkin Lymphomas. There are also clinical trials using Rapalogs to treat NHL, for example, temsirolimus is used for relapsed MCL with an ORR 38-47%. Temsirolimus and everolimus are not very effective in lymphoma, which may be due to inhibition of mTORC1 but not mTORC2, resulting in feedback activation of PI3K/Akt. Taken together, subtypes of lymphoma may respond differently to mTORi

Conclusions and Future Directions

Rapalogs, as inhibitors of mTOR, have demonstrated clinical value, not only in the regulation of abnormal immune responses found in benign hematologic diseases, but also for the treatment of hematological malignancies. However, there are still some challenges in the application of Rapalogs. First, at present, most of the studies of Rapalogs are case reports of three-line or further line drugs, which are not widely used in large-scale populations, so there remains a lack of evidence—effectiveness and long-term safety of Rapalogs need to be further studied

#290

@rivasp12

What a witches brew of interventions. The dark and cold is a non-starter, sorry. Leave that for the long lived naked mole rats!

Missed an additional intervention: “…combined influence of dietary restriction”

“Predictably, our results revealed that geroprotective interventions affect the evolutionarily conserved molecular pathways associated with longevity. We found that a combination of interventions modulated the activity of the mTOR signaling pathway”

#291

You know , even though it’s a crazy brew , it’s nevertheless interesting that mixing rapamycin with other interventions can give a pretty amazing lifespan extension. I’ve never seen anything like it.
So maybe we should be focusing more on rapamycin as a baseline and looking for synergies.
If you eliminate the darkness part, it’s not difficult to mix rapamycin, fucoidin, and berberine while getting some cold exposure. Win Hof is the guru of cold exposure and the way that he can voluntarily control his immune response is remarkable.

#292

Don’t forget CR.

From what we already know about CR and Rapamycin, this mega-mix should boost lifespan Immensely in mice too! Mice are nocturnal, they may be ok with complete darkness like their long lived cousins, naked mole rats.

I haven’t yet run out of my Berberine, maybe reconsider dumping.

Many large, long lived mammals like whales, turtles…are cold species. They have very low somatic mutation rates, major reason for their longevity. Does the cold “slow” things down?

#293

I never think about CR actually but you’re right.

The cold would slow things down and also a very significant hormesis effect. Read that book about Win Huf if you get a chance. It’s fascinating.

The naked mole rat has enormous DNA damage but also remarkable repair capabilities. It also has a sort of intrinsic ability to inhibit mTOR. A very strange animal. It never gets cancer and doesn’t actually age.

I’m not sure that I understand the perpetual darkness part.

#294

After many years of flirting with pre-diabetes (A1c ~ 5.6-5.7), it only took a couple of months of empagliflozin (10mg) and acarbose (50mg) added to my regimen to bring it down to 5.1. Although I have been found to not have insulin resistance, I have no doubt there is sub-clinical insulin resistance and accumulated vascular damage. I expect some geroprotection from my rapa and senolytics but would like to do more. To try to reverse some of the damage and improve arterial elasticity, a nutraceutical product called Arterosil is claimed to repair and restore the endothelial glycocalyx.

Does anyone have familiarity with this product?

Regeneration and Assessment of the Endothelial Glycocalyx To Address Cardiovascular Disease https://pubs.acs.org/doi/full/10.1021/acs.iecr.1c03074

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#295

That’s great!

“A state of continuous hyperglycemia induces endothelial glycocalyx damage” This is root cause damage caused by elevated glucose, and why CVD is so highly correlated with diabetic like metabolic profile. I would argue one dosen’t have to be hyperglycemic to induce damage to this fundamental layer.

Never heard of this Arterosil product, here’s a company sponsored summary of some of their therapeutic findings.

Interestingly, no CT cardio (CAC) study/scans referenced, fundamental to whether this reduces CVD risk.

Have you ever had any CIMT, CAC, or pulse wave velocity scans?

Clinical trial evaluating an intervention:

#296

I had Cardiac calcium around 18 years ago, score was 278 as I recall. Pretty bad. I’m assuming that it hasnt regressed and there is not much I could do to reverse it. Maybe its the soft placque that I might more likely be able to improve. No CIMT or PWV. Testing with a Cardiovascular Profiler device (CAPWA) noted a loss of elasticity in the small arteries, though scoring in normal range, 7.1.

I’ve recently introduced Gotu Kola and Pine Bark Extract. A fairly inexpensive nutraceutical like Arterosil, if it works as claimed, might be what I need to increase my CAPWA score at a 6 month follow up.

#297

How old are you if I may ask?

Have you changed your lifestyle much in the 18yr since last CAC, re diet/lifestyle/BMI?

How are your lipids?

Reducing/halting the rate of progression and improving your entire vascular is focus.

Suggest you get another one to see where you are re risk “runway”.

#298

I’m 82. Despite what should have been a warning with that cardiac calcium, I didn’t change any of my habits. I continued with supervised HgH for too many years. Did nothing different other than taking metformin and statins and an ever increasing bundle of supplements… which were probably helpful.
Since I can eat anything and never put on weight I figured it must be okay to continue to eat whatever I wanted, much of it heavy with carbs. Until I recently tried a CGM and was horrified to see what my glucose was doing, I didn’t see any reason to change my dietary habits. I am now enlightened! I do work out daily, very little fat, good muscle development and continue to be able to add muscle with exercise.
Total cholesterol 189, LDL 113, triglycerides 50, HDL 66. APO B was 78, Lipoprotein A was 10.

#299

Excellent videos of aging bio-markers
They are not always what one would expect.

by Michael Lustgarten, PhD
Conquer Aging Or Die Trying!

His series of videos examine most blood test biomarkers and all-cause mortality risk.
The two videos on centenarians provide a relatively quick summary of the most common biomarkers and aging all-cause mortality risk.

His videos definitely will let you know which ones of your blood biomarkers you need to work on to reduce your all-cause mortality risk

Rapamycin definitely seems to be screwing with my lipids. My lipids were much lower before I started taking rapamycin.

Centenarian Blood Test Analysis Pt I

Centenarian Blood Test Analysis Pt II

2 Likes
#300

Very good lipids, TG/HDL, TG, remnant cholesterol and apoB. One can be skinny fat…insulin resistant on the inside, building fat around the liver, NAFLD.

If you’re “really” concerned about CVD, consider getting another CAC snapshot to look inside.

1 Like
#301

Thanks for your comments and insights, MAC.

I think I will try the Arterosil. If follow up testing shows improvement in my small artery elasticity, I’ll pass on that valuable information. Also any changes if I get another CAC test.

#302

Rapamycin and Risk of Cardiovascular Disease. Part 2.

I thought I’d take an even deeper look into this issue and found studies that did just that. For those of you who don’t have the luxury of reading the studies, here’s the gist:

mTOR 1, left uninhibited, does the
following:

  1. Increases lipogenesis , or the creation of lipids
  2. Increases adipogenesis or the creation of fat cells
  3. Decreases cholesterol efflux from cells

But, it has a negative feedback loop where these processes are stopped when they start to get out of hand! So basically things are maintained in a steady state.

When we introduce rapamycin into the equation and inhibit TOR 1, some good things happen

  1. Decrease adipogenesis and fat cells
  2. Inhibit PPAR gamma leading to further decrease in fat cells
  3. Increase of cholesterol efflux out of cells
  4. Decrease in lipogenesis

However rapamycin also

  1. Downregulates liber LDL receptors causing an increase in blood levels.
  2. Stimulates lipophagy causing a breakdown of lipids that are stored which also elevates blood lipids.

This is all independent of TOR 2 effects.

What about rapamycin and atherosclerosis. The authors note that numerous studies have shown that rapamycin Limits the progression of atherosclerosis Despite dyslipidemia.

But what about cardiovascular events in renal transplant patients getting rapamycin

The authors conclude that the events don’t reach significance and therefore no correlation.
But this study concerns me even though I drink the rapamycin Kool Aid.
26/115 people in the rapamycin arm had CVD as defined by MI, stroke, and also pulmonary embolism and per cutaneous coronary interventions c/ w 4/58 in the control group.
Could this be something other than lipids/ atherosclerosis? Pulmonary embolism?
Could this represent an increased clotting issue in the rapamycin arm? We’ll, yes, it might.

Is this worrisome for us? We need to look at that next.

2 Likes
#303

@rivasp12 Great finds, and high level summary.

First glance, still major questions unanswered, tread carefully. Need to review the papers as I haven’t yet accepted the thesis mTOR inhibitors are anti-atherogenic and do not elevate CAD risk in humans. I noted the concomitant use of statins/metformin was regularly associated with mTOR therapy as default “standard of care”, but the net CAD benefit in healthy human trials does not exist (other than the 2 “unhealthy” cohort renal transplant papers you referenced, the latter of which reported major red flags)