I clearly remember that exchange. At that time I was very swayed by the M Kaeberlein mouse study demonstrating rather extreme life extension using high rapamycin doses, especially in males. I remember emailing Blagosklonny and expressing my concern that we were under dosing the drug in humans. He was in agreement.
But , of course, mice aren’t men and estimates of human translation are from 37-50%. There are multiple reasons for this .
Since then I’ve been wavering in my opinion on dosing based on the low weekly dose of Mannick, and the very low dosing in the prostate prevention trial. In the Mannick study, high doses weren’t superior to low doses.In each case there was evidence of a reversal of immunosenescence, less T cell exhaustion, and improved immunity in actual human trials. Humans trump mice every time and I consider the loss of immune function to be one of the biggest detrimental factors in aging.
So if low dosing is positively impacting one organ system in humans, it’s likely that that’s not an isolated phenomenon, and it’s probably having multiple positive effects. These will most likely lead to a delay in age related diseases and prolong lifespan.
So yeah, I’m changing my mind for the millionth time on dosing and will probably change it again.
I have my hands full managing an entirely new protocol of drug delivery to think about hopping off the train. Besides, for mass uptake and low cost, I’d like to see rapamycin prevail. We are still in the infancy stage of harnessing sirolimus for human lifespan extension.
Took a brief look at Temosirolimus. It’s basically a prodrug of sirolimus…the active metabolite appears to be really sirolimus, but there may be a hybrid mTOR effect at play.
“Our results demonstrate that rapamycin and temsirolimus exert similar in vitro and in vivo anti-proliferative effects against prostate cancer cells. Our results demonstrate that both compounds possess a superimposable pharmacological profile on these prostate cell lines.”
There does not appear to be any “compelling” pharmacological reason to consider it.
It’s FDA approved as an IV delivery (30-60 minutes) version (Torisel, Pfizer) and has some nasty side effects in clinical trials. I don’t read same with sirolimus, so not sure how and why the ADE translation is different between rapalogs.
“An H1 antihistamine should be administered to patients before the start of the intravenous
temsirolimus infusion”
“Pneumocystis jiroveci pneumonia (PJP), including fatalities, has been reported in patients who received temsirolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Cases of fatal bowel perforation occurred in patients who received TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Patients should be advised to report promptly any new or worsening abdominal pain or blood in their stools. Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. Some of these cases were not responsive to dialysis. Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding including fatal outcomes) while receiving TORISEL.”
A lot of “fatal” outcomes associated with this rapalog and IV delivery. Not sure I want to take this on right now.
So I’ve got massive Sirolimus, my lipids and glucose are CLASSIC mTOR markers, gut microbiome alteration, anemic, but yet I’ve got no MTOR inhibition? I don’t believe it.
“Rapamycin was obtained from LC Laboratories (Woburn, Massachusetts, USA), dissolved in dimethyl sulphoxide (DMSO) at 25 mg/ml and stored at −20°C. For injection, the stock solution was diluted in phosphate buffered saline (PBS). Mice received daily intraperitoneal injections of rapamycin at 1 mg/kg body weight/dose in a total injection volume of 0.3 ml for 10 weeks and control animals received the DMSO vehicle at 0.4% in a total injection volume of 0.3 ml”
Some additional interesting properties of DSMO as my carrier.
And here’s another magical property of DSMO…perhaps of huge benefit getting Rapamycin thoroughly inside body tissue, something far more difficult with plain oral delivery?
“In the body, DMSO can pass through cell membranes as readily as water does without damaging the tissues, and it can replace water molecules within many bodily fluids. And, because DMSO so readily dissolves other molecules, it can also carry them through the cell membranes with it. “DMSO alters cell membrane permeability,” says Jacob. “It moves through membranes and substitutes for water so that it pulls substances through cells that ordinarily would not move through them. This is its basic mechanism of action.”
“Dimethyl Sulfoxide (DMSO) in Trauma and Disease” by Stanley W. Jacob and
Jack C. de la Torre
The book on DMSO
Selected Contents
Chemistry of DMSO. DMSO in Basic Pharmacology. DMSO Clinical Pharmacology.
DMSO in Genetics. DMSO in Basic Microbiology. DMSO in Clinical Microbiology.
DMSO in Malignancy. DMSO in Basic Neuroprotection. DMSO in Clinical
Neuroprotection
You know - I might give Fabio a run for his money on this hair thing. My hair is getting real “purty”, soft and silky. Amazingly rich in color and shine. LOL.
So I had my first post IM+IN rapamycin doc consult yesterday.
On lipids, of course, some concern…but he’s deferring to my upcoming cardiologist consult.
On the anemia, surprisingly sanguine. He figures with my chronic blood donations, my body has adapted to the low iron now (re not being symptomatic or athletic diminution). He use to consternate before I blew by his red line “not < 80 ferritin” a long time ago. TRT also stimulates red blood cell production, so perhaps an underlying resiliency buffer. Could also be partly my iron genes.
On the rapamycin, I had to explain the markers rise was entirely from the recent intervention, including the PSA (he didn’t know what to make of the blip either). Also deferring to my urologist, once I have more duration/transiency data. He knew I started experimenting with rapamycin last year. He knows a little about rapamycin (thank god for Attia…doc says if Attia’s taking it, it must be ok!). His biggest concern is immunosuppression, so he’s adding a deep biomarker panel to capture. As well, more short term markers followup tracking testing (1 month, 3 month) including more sirolimus levels. He didn’t even chastise me for the IM+IN vs oral.
With all the junk he’s had slathered in that voluminous hair (and absorbed systemically) over the decades…no way his biological age is lower than yours.
I am impressed with your physician’s support.
Sounds rare from the members on this site.
Glad my Physician sees his role is to guide… not dictate… and try reasonable treatments and supplements. Rapamycin, TRT, oral Minoxidol, Metformin. All reasonable.
My transformation can’t be denied…so he is more flexible than ever.
“The speed of absorption is faster for intramuscular injection compared to subcutaneous injection. This is because the muscle tissue has a greater blood supply than the area just under the skin. Muscle tissue may also hold a larger volume of medication than subcutaneous tissue.”
“Sirolimus is a highly lipophilic compound with a high blood to plasma ratio and small free fraction in plasma. In general, the adipose tissue is a storage compartment for lipophilic compounds with slow release from this storage site resulting in long elimination half-lives.”
So I didn’t want rapamycin lingering in fat tissue, and thus bioavailability and AUC is generally lower for SC vs IM.
“These results demonstrate the ability of engineered nanocarriers to repurpose drugs (rapamycin) for alternate routes of administration by rationally controlling cellular biodistribution”
The above SC delivery route paper showed that SC was a more targeted approach whereas I wanted wide pan tissue volume of distribution.
The same paper also showed quite fundamentally the huge benefits (reduced side effects) of bypassing oral delivery:
“These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug (rapamycin) by controlling cellular biodistribution”
Plus I am very comfortable doing TRT via IM. But biology trumped practical issues.
@MAC - All well thought out. I knew you had your reasons and that they were probably backed up by data. Many physicians are starting to use TRT in SQ dosing and getting great responses much of which you have already covered, but trying to avoid the peaks and troughs that may be more valuable in Rapa longevity dosing to avoid immunosuppression. Keep us posted and good luck!
