djmichel I'm recently in the higher numerical half of his 60s, male, fair skinned, 99.7% norther eurpean decent. And actually have seen studies showing that Rapamycin (taken intermittently) will boost your immune system. https://www.ncbi.nlm.nih.gov/pubmed/25540326 as this study shows.
And it is being considered as a supplement to the flu vaccine as it enhances the immune system response.  I'm just at my third year of rapamycin use and 18 mos into using it with metformin etc.  mtor1 pathways are 'exquisitely' sensitive to rapamycin and mtor2 (primary immune response pathway) is not.  Only by daily dosing of rapamycin, which builds the rapamycin up high enough to surpress mtor2 (primary immune pathways) does it lower overall immune systems....and it is used this way (daily) to avoid transplant rejection.  Surprisingly, the experience of transplant patients using cyclosporine to suppress the immune system for transplant anti-rejection purposes sees about 50% of patients developing skin cancer..... BUT when using rapamycin in higher doses this for this same purpose.....lower than normal rates of skin cancer are seen.  Now rapamycin is being tested for its anticancer properties.  As someone (fair skinned and abused the sun) with a close personal relationship with my dermatologists liquid nitrogen for may years before I started rapamycin and having a melanoma (in-situ) recently removed I am acutely aware of the risks.  So three years in, I've read on this obsessively and I am very comfortable with rapamycin and consider it to strongly (or even mildly) reduce my cancer risk profile.  

djmichel Two related papers:

http://ar.iiarjournals.org/content/29/6/1927.full

https://www.ncbi.nlm.nih.gov/pubmed/26138646

"488 were exposed to sirolimus and 47 developed an incident SCC."

SCC risk with Rapamycin sounds fairly real... even with weekly intermittent use based on your experience. (we have to go with N=1, as majority of things we're doing here is an extrapolation from basic science + N=1).

djmichel Hope you're doing well. Sorry to hear about the SCC. Given everything you've shared on this forum, I see you as a pioneer. Thank you so much! Have you stopped using Rapa? I was just about to start it :/ SCC risk, with prolonged use, seems real.

 Gokhan The papers you cite, and the general knowledge regarding immunosuppression in solid organ transplant recipients indicates very strongly that Cyclosporin (Sandimmune) is responsible with up to 16% of transplant patients treated with this drug getting SCC, many with catastrophic SCC. That is, multiple lesions with high grade of metastisis. The use of sirolimus as an adjunct to cyclosporin does not increase this incidence. Rather, when comparing tacrolimus (calcineurin inhibitor) to sirolimus adjunctive therapy in organ transplant patients on cyclosporin, the SCC's in sirolimus are less thick, less vascular, and less aggressive. The 47 patients out of 488 transplant patients in the Kaiser Permanente retrospective study is consistant with SCC incidence in solid tumor transplants treated with cyclosporin (the mainstay of transplant immunosuppression). Please read the following two statements carefully as it comes right out of the study you cited "SCC risk was not associated with ever use of sirolimus (adjusted hazard ratio 1.18, 95% confidence interval 0.84-1.16) or cumulative duration of sirolimus exposure (adjusted hazard ratio 2.75, 95% confidence interval 0.84-9.04, comparing long-term users with nonusers). "Among a large cohort of SOTRs, sirolimus exposure was not associated with a reduction in incident posttransplantation SCC risk."

This study simply states that sirolimus does not reduce the high incidence of SCC in transplant patients, nor does it increase it. Other studies, such as your first citation above indicate that SCC in organ transplant patients treated with sirolimus versus tacrolimus show less vascularity and thickness of SCC. Less vascularity would be consistant with sirolimus known inhibition of angiogenesis and a less vascular tumor is generally smaller and less prone to metastasize

Extrapolating broad conclusions such as "rapamycin causes SCC" from reading studies of transplant patients recieving immunosuppressive therapies which include rapamycin is what happens when the reader does not possess a broad clinical/scientific background. In order prove the hypothesis that rapamycin causes SCC, long term studies of otherwise normal people, with a cohort in the many thousands taking rapamycin, versus a cohort not taking rapamycin, and controlling for relative sun exposure and fairness of skin (among other things) would have to be performed. This study will never be done. As it stands, the way I read the literature is that in patients with the highest risk of SCC (transplant patients treated with cyclosporin), sirolimus does not increase incidence of SCC but may reduce severity via decreased vascular supply, thickness, and aggression. I can't see how any other conclusions are possible. 

Mark Thimineur Thanks for posting. I was gathering the same thing and wondering why the OP posted as he did. 

uzoma iwuagwu 4 million basal cell carcinomas, 1 million squamous cell carcinomas, and 200 thousand melanomas are diagnosed yearly in the U.S. Over 90% of these are due to exposure to non-ionizing radiation (sun). Having 5 sunburns doubles the risk of melanoma, just one sunburn in childhood doubles the risk later in adulthood. SCC is 100 times more prevalent in transplant patients.

The sun exposure issue is one of concern as most of us baby boom generation have had multiple burns in childhood and many of us have spent long hours in the sun through adulthood. My view on sirolimus use currently is that there are thousands of experiments indicating a general antineoplastic effect, which includes skin cancer. I have posted previously that in vitro studies of skin exposed to non-ionizing radiation indicates (at least in vitro) a protective effect of rapamycin on the many damaging effects of sunlight on skin. I noticed last summer and through the caribbean yachting season this year (cut short by pandemic) that I was more resistant to sunburn and needed less sunblock. That is why I began looking into possible protective effects of sirolimus from solar radiation and discovered that study.

I actually feel pretty positive on my use of sirolimus as it relates to antineoplastic effects including that caused by far to much sunlight exposure over my lifetime.

Gokhan Doing well, thank you for asking.  I am still on all of the life extension protocols and take 3.5 mg Rapamycin once a week and am getting ready to do another D+Q round shortly.  I think it is important at this time to take additional Vit. D3, of which I am taking 5K a day, in-addition to my regular regimen of supplements. So far OK, which reminds me of the guy who jumped off the Empire State Bldg. and as he passed the 60th floor he saw someone at a window and yelled, "So far OK"

Mark Thimineur Thanks for the more careful analysis. I feel this is definitely worth the discussion. I'm glad you took the time to post a detailed response. Thanks!

A response to the 2nd study I shared: 

https://www.jaad.org/article/S0190-9622(16)00067-0/fulltext

It basically says that this analysis isn't quite meaningful due to very powerful confounders such as other immunosuppressant use. 

djmichel I wonder if this discussion has reviewed the differences in the innate vs the adaptive immune response and exactly what the sirolimus affects?  And consider that affect in light of the Mannix study showing flu shot response is enhanced ~20% in seniors that had sirolimus dosing prior to the vaccination.  Also I have seen papers showing the vast reduction in skin cancer issues for transplant patients on sirolimus vs traditional immune suppressors.....  Lastly, I would remind some that sirolimus is being used as an anticancer drug in high doses and I take it with grapefruit juice weekly using caution that any other meds I've ingested were taken ~4 hours prior to the GF juice.........this approach makes my 2 mg dose weekly worth more for less $ which is an issue for me....  https://www.oncologynurseadvisor.com/home/headlines/web-exclusives/grapefruit-juice-harnesses-power-of-sirolimus/

This was discussed more thoroughly in the Smithsonian and a better discussion might be found there.