Larry My wife saw my good results with rapamycin and metformin so she saw Dr Green with me. (I had been self experimenting before that) She is on 3 mg a week since last April with no metformin. I'm not sure why Dr Green did not put her on metformin but her blood work was excellent when he saw her.  She is suffering from a bad case of cervicogenic headaches due to occupational damage to her neck. 

The reduction in pain was dramatic. She was able to reduce her use of NSID's from 8-10 a day to maybe 5-10 a week. She is not cured but much better, maybe about 75% better.  She also had a similar reduction in her weight setpoint. She just did a dose of D&Q last week and still waiting for results and I'm hopeful we can get her pain under control. 

Tam  Thanks for the info. Definitely a minority view. How do they explain the D&Q results (significant age extension given at old age) with mice? He has a company that is trying telomerase to cure Alzheimer's. De Grey and SENS do not agree and are not optimistic about this therapy. SASP make up such a small percent of your total cells that it makes no sense to worry about their loss. Trying to save them also risks cancer IMHO. Anyway, there are now at least 12 human studies underway and one completed, so we will get more answers in the future. I do not recommend D&Q unless you are in your 50's and your risk tolerance is high. 

Larry I agree with this view of telomerase. https://www.fightaging.org/archives/2015/04/telomere-erosion-is-complex-but-looks-more-like-a-measure-of-damage-than-a-source-of-damage/

Larry  A gentleman, Robert H Olander, posted on Josh Mittledorf's site that he has been taking 100mg Dasatinib/1000 mg Quercitin monthly since the winter of 2015. He seems very healthy and still plays tennis 3 times a week at age 83. He has details of his blood, telomere and Horvath test results in the comments. He has taken everything since the '80s related to anti-ageing and the only things he noted an immediate change for the better was Rapamycin and D&Q. Four years and no problems is a good sign. https://joshmitteldorf.scienceblog.com/2018/08/01/the-most-effective-personal-anti-aging-program/

Tam From the article you posted with a neat graph: 

"Repetitive injury (e.g., repetitive trauma to a knee joint in the case of a basketball player, hypertension with accelerated rheological trauma in the aorta, or traumatic brain injury in the case of the CNS) can be represented as “Repetitive Injury” (in yellow)"

"Senolytic intervention should cause an initial improvement in clinical status followed by an accelerated clinical failure with the steepening curve, represented here as “Delete Senescent Cells” (in red). This is precisely what we see in the published senolytic data [27]. Finally, telomerase therapy should cause improvement at both the cell [8] and the tissue levels (as it does at organ and biomarker level [18,19]) represented here as “Reset Senescent Cells” (in green)".

They are mistaking acute senescence with chronic senescence. Acute is good for wound and tissue healing at the site of an injury. Chronic senescence is always bad and increases with age. This is what synolytics clear out. You would not want to take synolytics just before surgery for instance. 

Larry Robert Olander is my Dad! He is 84 years old and he has more energy than I do at age 58! He’s a brilliant guy with an IQ in the 140s and no indication of having experienced a decline in cognition. (Except he has trouble multitasking nowadays). He plays tennis with his 84 year old wife daily, and does some strength training, though I couldn’t say how much or what type. Yay, Dad! 

He takes Rapamycin and DandQ but recently has been experiencing some neuropathy in his lower legs, which he attributes to the 100 mg of Dasatinib. He has temporarily discontinued Dasatinib pending medical testing. 

Karl Olander Thanks for the update and wish I your dad well. 100mg a month seems very high. I would only do a few times a year at most but it's all a guess now.

Tam the question to ask might be does D&Q tend to clear chronic (persistent) or acute (short term) senescent cells.  If it affects those persistently senescent cells then periodic dosing of some kind (monthly/quarterly) would be of great benefit.

Larry What were the non-subtle positive effects if you don't mind listing?

Charles Richardson Best cycle power levels I've seen in 7 years I have been tracking. Improved energy and mood. I can last 5-10 times longer on a yes4all balance board. No lab work yet. 

Larry Thanks, Larry. I'm just about to try it.

Charles Richardson test your balance before and after.

Larry That's interesting. Unfortunately I was just at a company I'm working with that has a specific and objective testing procedure for that...

Larry Shortening telomeres do affect gene expression as Steve Horvath pointed out as counterpoint in the  article’s comments section. Hence telomeres are not just an odometer of our cellular aging.

Sam Biller did Dr Green explain what each you meds are for?

Karl Yes. He went over them in detail. There is a paper online that discusses each of them. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482593/

They all have, at a minimum, animal studies that show an anti-aging effect. I believe Dr. Green himself is on most of them. 

I’ve had to stop taking the Doxy daily. It was causing incredible reflux so I discontinued. The Doxy was primarily a prophylactic anti-biotic because I have a slight tendency for bacterial infections. I do have a script for a Z-Pak from Dr. Green which he insists on using whenever a patient has a fever over a certain threshold. 

You’ll see from the paper linked above that there is significant evidence that, in addition to Rapa, Tadalafil and ARBs have an anti-aging effect with very few side effects. 

Prior to the ARB, my BP was running 135/85 and now it’s running 120/75. 

Hope this helps. 

Sam Biller thanks. I coincidentally found that article last night. Great info. Seems some drugs like Rapamycin clearly work, but others have minimal evidence, or only alleviate symptoms of old age, or alleviate side effects of other drugs.

Sam Biller I second Karl's thanks Sam. Great article! I've been wondering how all the lowering mTOR meds/lifestyle mods compare in their effects on mTOR so the diagram with the different font sizes reflecting the amount of inhibition was just what I've been wondering. I'll be trying the Lisinopril I got over a year ago again since it appears to have a reasonable amount of mTOR inhibition which I did not recall (75 yr. old on Met for over a year, ran out of rapamycin a year ago and have not repurchased since we have cal. rest./protein rest. etc. and I'm trying some herbal rapalogs also).

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.

djmichel I think that place turned out to be selling sugar. 
I've been on Rapa over a year. Started at 2mg and I'm up to 12mg/wk. I didn't notice a change in white blood cells til 8-10. I'm still in range but lower than I was. Anecdotally I get sick a lot less so IDK. I lower weekly dose when traveling.

Hi Patrick Stanley mTOR1 and 2 respond completely differently. mTOR is responsive (exquisitely it is said) and can be suppressed with only intermittent dosing whereas mTOR2 requires high stable blood levels of an mTOR suppressant to respond and be effected... Eg daily dosing.

Patrick Stanley If you google search for mTORC2 and Rapamycin you will find links to many research papers which to me are hard to understand. But you might want to read this post on fightingaging plus the comments. https://www.fightaging.org/archives/2019/08/a-caution-on-mtor-inhibitors-loss-of-mtorc2-in-the-hypothalamus-harms-mice/

Mark Thimineur 

1.  I’m having trouble coming up with a mechanism by which rapamycin would treat psychiatric illness. Any ideas?
2.  How much concern do you have about malpractice using a powerful drug for a non approved reason?

Karl

As to the psychiatric effects: there are pretty profound effects on neurotransmitter concentrations and behavior observed in rodents Neuroscience. 2012 Oct 25; 223: 102–113.   "Our studies show that rapamycin enhances cognitive function in young adult mice and blocks age-associated cognitive decline in older animals. In addition, mice fed with rapamycin-supplemented chow showed decreased anxiety and depressive-like behavior at all ages tested. Levels of three major monoamines (norepinephrine, dopamine and 5-hydroxytryptamine) and their metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid) were significantly augmented in midbrain of rapamycin-treated mice compared to controls. Our results suggest that chronic, partial inhibition of mTOR by oral rapamycin enhances learning and memory in young adults, maintains memory in old C57BL/6J mice, and has concomitant anxiolytic and antidepressant-like effects, possibly by stimulating major monoamine pathways in brain. "

As for malpractice concerns I always am congizant of risks but often make use of off-label treatments for some pain management issues: Example: Ketamine infusions. Having observed rapamycin effects in myself and some family members, I have some confidence in the relative safety of well monitored use. Animal studies on neuropathic pain (neuropathy and sciatic ligature models of peripheral neuropathic pain, spinal cord injury models of central pain) show rapamycin has consistent and significant pain reducing effects. Rapamycin studies on rodents made opioid tolerant indicate mtor inhibition affected both the tolerance and the hyperalgesia. There are also scholarly articles describing benefits in crohns, RA, and multiple sclerosis. There is enough here to justify using this drug to treat patients who are doing poorly despite all possible on-label treatments (opioids, anti-depressants, anti-convulsants, spinal cord stimulation, intrathecal opioid pumps, behavioral treatment, spinal injections, nerve blocks etc). 

Observations of benefits in humans with severe disease and disabilities seems to fit the biology of mtor inhibition seen in the experiments using rodents. It is quite interesting to me.

Mark Thimineur Thanks for all the info, and thanks for what you do.  Pain management must be one of the most challenging specialties in medicine.

Mark Thimineur Amazing, thank you for your work and posting. 

Karl   Rapamycin has a profound effect on monoamine neurotransmitters.  Odds are this is related to its affect on pain, anxiety and mood. 

https://www.ncbi.nlm.nih.gov/pubmed/22750207

Mark Thimineur A recent paper on Rapamycin and telomeres

Rapamycin worsens diseases and premature aging in mice with short telomeres

https://www.news-medical.net/news/20200303/Rapamycin-worsens-diseases-and-premature-aging-in-mice-with-short-telomeres.aspx

MAC It's too bad the study doesn't go into better detail. I'd be curious as to how they dosed the subjects. MTOR1 and MTOR2 could each have a varied affect but as we take it, we don't inhibit 2

uzoma iwuagwu It's in the METHODS section:

"At 3 months of age, mice were divided in two groups, one of them continued with control chow and the other were changed to chow-containing encapsulated rapamycin at 42 ppm (mg of drug per kg of food). Food and water were provided ad libitum and measurements"

Clearly, chronic rapamycin intake vs intermittent. Cannot tease out absolute rapamycin intake without knowing daily food intake. Anyone know what a mouse eats ad libitum?! So there's a dose/frequency disconnect to typical anti-aging human rapa usage.

Henry walker Blagosklonny commented on this on Twitter. Basic is that mammals need mTor for growth early in life. Rapamycin limits this so would shorten life if given too early. He thinks this supports his hyperfunction theory of aging. 

MAC There is now a singular exception to the longevity effect of rapamycin in all life forms, some of which were bred specifically to represent a condition or disease seen in humans. This one exception is short telomere disease. In humans, this is a rare inherited chromosomal mutation manifesting early in life with organ disease and failure. There are no disease modifying agents and only drugs to manage the organ damage. So, this is one rare condition in which rapamycin needs to be avoided. BTW, these people don't live long and they are sick (and rare).

On a more general or macro view, humans in the "wild" are not like lab experiments with specially bred rodents living in perfect enviroments fed the correct foods etc. Individual variability in the genome, environment, behaviors, injury, etc are massive in the human population. It is amazing how individual we all are. Although mtor can be inhibited in us all, there is little doubt that the overall benefits or detriments will vary by individual.

Unless a person has the rare short telomere mutation (and suffers the severe organ damage at a young age), there should be little concern in regards to mtor inhibition in the case of "normal" aging. Perhaps we all exist along a normal distribution curve with most of us having average telomere length, and a few of us shorter and a few longer telomeres. In this normal distribution we don't have the "disease" of short telomere represented in the rodent study. Perhaps those with the slightly shorter telomeres benefit somewhat less and the longer somewhat more. We won't know this for a long time, if ever.

I've used the gambling metophor before. Using intermittant rapamycin for longevity is playing a pretty good hand with what we know. This study on telomere deficient rodents does not appear to change that, at least in my humble opinion. 

Paul Beauchemin  One item that stands out to me is the small N of only 14 mice in the -/- group that shows only a small difference between the control and the rapamycin fed mice.  

I cannot explain their results.  My only guess is feeding rapamycin when the-/- mice are too young.  But they die young.  So how to redesign this experiment?   

Sam Biller Predictable drug effects: minor dyslipidemia, borderline Hct. I see nothing to be concerned with - these minor blips are common among the patients on longevity rapa dosing. The macroscopic view is that prevention of all age related disease in every organ system and prevention of malignancy dwarfs these minor lab deviations. Small dose of a statin corrects the dyslipidemia and the HCT may be self correcting but it is nothing to worry about at this time. I would suggest waiting 6 months to check again unless you just want more data to trend.

Mark Thimineur Thank you for the quick response! I’m visiting my primary care physician the week after next to discuss. I’m not too concerned and will likely follow-up with additional testing later this year as you suggest. 

Sam Biller looks like all the biomarkers going in the right direction per the Levine spreadsheet 

Sam Biller looks like you have a 15 year predicted improvement in DNAm Age from the spreadsheet posted on this website! I started rapa Dec 1 and also did a dasatanib/quercetin one time treatment. Also take metformin. What else are you doing to achieve this? diet/fasting/exercise other supplements/drugs?

Paul Beauchemin Hi Paul, thanks for the feedback. I didn’t even know about the Levine spreadsheet. Very interesting. I downloaded the spreadsheet and ran the age factors at the linked web site as well. It looks like my predicted age is in the mid 30’s. 

Sam Biller regarding protocol...  I’m a patient of Dr. Green.

Meds: 
Rapamycin 6mg weekly

Candasartan 26mg daily 

Tadalafil 5mg daily 

melatonin 3mg nightly

D&Q - 1 treatment 

Current diet:

Ketogenic with lower fat to accelerate weight loss. I’m currently 6’1”, 170 lbs. Lean body mass is around 135 lbs. I want to get my fat down another 10 lbs. 

Sam Biller Why do you suppose that the BUN deteriorated over 3 years?  The Creatinine improved slightly so we should not blame the kidneys. Perhaps you were a little dehydrated when you took the test? It is well known that there is an increase in cholesterol and your tests seem to confirm this. Despite a very impressive HDL result would you consider a statin? Your diet probably added to the the mild anemia so obviously a minimal change should improve the results.  Otherwise, very impressive.

Jonathan Horwitz Hi Jonathon, I think the change in BUN is almost completely attributable to my change of diet — I went from a primarily plant-based diet for 3.5 years to a ketogenic diet (low carb, moderate fat, protein at 0.8-1.0g per pound of lean body mass). I seem to recall that a plant-based diet has a dramatic impact on BUN but would need to look up the source. The change was precipitated by my desire to lose some body fat. I was putting some weight back on with the plant-based diet. In hindsight, I think the weight gain was mostly attributable to fats sneaking into my plant-based diet. I find it a lot easier to maintain the low carb diet versus the low fat diet although the impact on longevity is not clear. 

Regarding a statin, prior to going plant-based, I was taking a small dose of Crestor but stopped due to definite muscle pain. I don’t plan on going on a statin anytime soon. Since I’m losing some weight right now, my physician and I have discussed retesting in 6 months with some more sensitive lipid testing to determine particle counts, etc. 

Sam Biller I take 1.25mg daily crestor. my gf takes 5mg. we supplement CoQ10. No muscle pain. What dose were you taking?

Sam Biller Here is a video, I would encourage everyone to watch.  It is done by Edward Omron, MD.  He has also made 2 other videos on the update of his self experimentation using B3, Metformin, and Statin.    https://www.youtube.com/watch?v=nq-s7rDuLnc  I feel that a statin is important and there is no reason to stop taking one because of muscle pain.  I have been taking 500-1000 mg  Acetyl L-Carnitine daily and you will no longer have any muscle problems.  This has been used for years for this purpose.

Van thanks for the video. how much statin do you take? Never heard of Acetyl L for the muscle pain. any study links?

uzoma iwuagwu I take 5 mg Crestor.  This gets my LDL to 70.

Just google the L Cartine for statin induced muscle pain.  I use to get bad cramps in my legs.  No more

Van Thanks I will My LDL is 73 @1.25mg triglycerides at 49 so that's what I run. 

I googled exactly as you listed but all the links talk about CoQ10 https://www.ncbi.nlm.nih.gov/pubmed/23190071

GEdwards Thanks for the Grapefruit juice tip!!! I looked it up and this is an interesting article regarding the combo;

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410974/