It's been 4 weeks since my last report, so I'll update. But not much has changed.
I'm 59 yo with early-onset Parkinson's Disease. In addition to longevity, my goal is to see if there is any effect on my PD.
I started this 10 weeks ago. I now take 6mg Sirolimus / week (I had been taking 2mg/wk with grapefruit juice, but changed 4 or 5 weeks ago). Plus, I take all the supplements i listed before (yes, including NR).
Continue to lose weight (about 1 pound/week) 8 pounds so far. I'm able to exercise about 50% longer. For example now up to 35 push ups (from 25).
My glucose levels continue to be well below any warning sign. I feel good. Mouth sores have not returned. I still consider these results to be inconclusive but encouraging.
Thinking about upping my dose to 7 mg / week, or maybe just shortening the period to 6 days.
I have been taking Rapa plus Metformin for 5 weeks now. Started out at 7 mg once per week of Rapa, and 500 mg Metformin daily. I have since changed my dosing schedule to 4 mg x 3 days a week = 12 mg weekly plus 2000 mg Metformin, 1000 mg morning and 1000 mg evening. Plus I take a statin, and low dose aspirin. After reading carefully the dosing schedule of the dogs and human volunteers, I came to the conclusion that I could comfortably increase the Rapa with a low chance of adverse side effects. This schedule is a little less than the low dosage given to the dogs, (.05 mg/kg x 3 days week divided by 1.8) and it is exactly the same schedule of 3 x week. Was also influenced by the 20 mg weekly dosage in the elderly immune trial. Have been on this schedule for 2 weeks with no noticeable side effects. Will be doing a complete blood work up in 6-7 weeks. I expect to stay at this dosage for the remainder of this experiment. I don't think that it is best to use it all your life. Better to use Intermediate Dosing, such as 3 months on 24 months off or something similar to that. Don't know for sure because there are no long term studies with humans. Of course one could stay on specific dosage forever if they were very vigilant about watching for side effects and doing complete blood work ups at least every 3 months. In the mouse studies the positive effects of their treatment lasted for longer than the treatment. I would guess that once you interfere with the Torc 1 signal, it does not easily come back on. It is almost as If the mice and/or dogs were given a much younger body, and they start over from there. This is a work in progress, but more clinical trials, and studies will be coming out in the future.
As for the Metformin increase. I'm pre diabetic with a fasting glucose of 120-130, and a A1c of 6.1-6.8. I need to lose weight, (20-30 lbs) and the Metformin will help do that along with the Rapa. Much easier to say no to extra food. Anyone that is thinking of taking Metformin, I strongly recommend they read the following forum on this site http://www.longecity...-non-diabetics/. After reading this entire post, you will see why I upped my dosage to 2000 mg daily.
And those that want to take it for longevity purposes look at this chart which has already been posted on this forum by someone else. https://static1.squa...3/?format=1500w
I was going to wait until I have taken this combination of Rapa and Metformin for 3 months before reporting. At that time, I will have my blood work done, my weight loss if any, my energy level increase if any, side effects if any, etc. From reading the clinical trials, I believe you have to take it for at least 2 months before you start to get results.
Rapamycin's life extension effect seems to be related to Cancer prevention. 70% of mouse used die from cancer while humans die mostly from age related diseases. So the life extension does not translate into humans.
The gene expressions are also very different from calorie restriction so its ability to prevent aging is questionable and
There are many side effects because many other genes not related to life extension are activated.
Rapamycin's life extension effect seems to be related to Cancer prevention. 70% of mouse used die from cancer while humans die mostly from age related diseases. So the life extension does not translate into humans.
The gene expressions are also very different from calorie restriction so its ability to prevent aging is questionable and
There are many side effects because many other genes not related to life extension are activated.
"...In addition the drug has symptomatic effects on some aging traits, such as age-related cognitive impairments."
and
Rapamycin effects on numerous aging traits have been analyzed to date (as outlined above), mostly employing the original rapamycin administration regimen developed by the ITP that was shown to extend lifespan in mice [10]. Although there were a considerable number of aging traits not modified by treatment, rapamycin afforded improvement of a subset of traits examined [11–14, 18–22]. The aging traits found to be ameliorated by rapamycin were either related to immune system changes (e.g., plasma immunoglobulin concentrations, frequency of specific T cell subsets, cytokine concentrations in blood and heart, response to vaccination), age-related alterations in body mass, organ size and dimensions (body weight, fat mass, lean mass, thyroid follicle size, cardiac dimension, heart weight), tumors and pre-cancerous lesions, as well as neurobehavioral changes (motor activity, learning and memory). Where available [13], the data indicate that similar effects are seen using shorter-term treatments in young adult animals, indicative of aging-independent drug effects. More work is, therefore, needed to determine to what extend these rapamycin effects on the aged organism reflect symptomatic improvements (such as seen on a number of traits in the Neff et al. [13] study) versus a true slowing of aging processes. Although many drug effects are seen with the ITP rapamycin protocol, it will also be important to assess higher doses that may allow for a more complete mTOR inhibition in target tissues.
So it seems that even if rapamycin does not slow the rate of aging, it improves the quality of life in young animals. such that they have improved health even in old age???
. In both studies significant testicular degeneration was observed in rapamycin-treated animals, indicating that this is a robust side effect of rapamycin that is seen at various doses and across different genetic backgrounds.
A common aging-associated pathology affecting the anterior part of the eye is cataract formation [65]. Two studies published to date assessed rapamycin effects on age-related lens density alterations [13, 18] (Table 3). Wilkinson et al. [18] employed investigator-based ratings of lens density during slit lamp examination in UM-HET3 mice. They reported an exacerbation of age-related lens density alterations under rapamycin treatment [18]. Assessing C57BL/6J Rj mice and using computer-assisted automated Scheimpflug imaging, Neff et al. found no clear effects of rapamycin on age-related changes in mean lens density [13]. Neff et al. [13] also used the virtual drum vision test to examine if rapamycin can prevent the aging-associate decline in visual acuity. While aged animals showed significantly reduced visual acuity, rapamycin treatment had no measurable effects on this aging trait. Together, the data available indicate that the lifespan-extending rapamycin treatment regimen pioneered by the ITP does not beneficially influence age-related ophthalmological changes and may even have adverse effects on specific aging traits of the eyes (i.e., changes in lens density).
Rapamycin treatment, however, resulted in a significantly increased prevalence of vacuolization of tubulus epithelial cells [13], indicative of nephrotoxic side effects of rapamycin treatment.
MikeDC and maxwatt bring up some potentially troubling quotes from a paper in 2014 that aggregated studies on Rapamycin.
I've looked into this paper before. While I'm not qualified to give an opinion, here's a link to a video from Dr. Steven Phillips (note: it's not really about Lyme disease):
The video is quite long, but is excellent. He also explores many more studies - not just of Rapamycin and ageing, but also of other mTOR inhibitors and neurodegenerative diseases. He does this to show that the accumulative evidence supports the theory that the common mechanism of inhibiting mTOR1 is in many ways beneficial.
Dr. Phillips addresses the 2014 paper and you can find his comments on it near the end at time-index 51:45. Do yourself a favor though and don't jump straight to it. At least start at 47:09 if not earlier.
To save you time, here are some other time-indexes to help you find interesting points in the video. The really interesting bits of information are in bold.:
1:00: Autophagy - the basics
2:35: Dual edged sword
3:30: Caloric Restriction
3:56: Autophagy and infections
5:02: Rapamycin
6:08: Has "differential" side effects; high doses have side effects, but low doses have the opposite effects (are not simply reduced)
6:34: mTOR basics
7:50: Aging and Neurodegeneration
9:30: Diabetes and Alzheimer's
9:42: Growth gone bad (aging obesity, cancer)
12:08: mTOR1 and mTOR2 - short-term and low-dose vs high dose and chronic use
13:10: Other mTOR Inhibitors - the theory (which he discusses later)
19:00: Alzheimer's
19:47: Parkinson's Disease
20:35: ALS
23:18: Autophagy - the Rosetta Stone (how it all fits together)
23:36: Alzheimer's and Rapamycin - animal studies
24:15: Talks a LOT about curcumin and others to show similarities with Rapamycin results
33:40: More on Parkinson's and Rapamycin
35:20: Talks a LOT again about other things (not directly related to Rapamycin)
45:40: Autophagy can make some diseases worse
46:15: Improved delivery system, like lypisomes
47:09: Rapamycin and "normal" age related cognitive decline
48:07: Rapamycin - Extension of life and health-span in mice
50:00: Everolimus improved immune response in elderly humans (low dose vs high dose)
51:25: Several studies - Rapa prevents and reduces cancers in mice
51:45: Rapamycin - anti-aging or just anti-cancer?
53:22: Tetracyclines, vit D, trehalos, lithium, etc.
it's on the site. It can be bought at 500mg and 1g with $30 off or as the full 5g as priced. With 5g TOTAL commitment we will give $30 off individual orders of the listed 0.5g and 1g price. Plus whatever shipping people wish for, if purchased individually.
The 5g total is mostly just an honor basis situation. As long as intent a total of 5g seems likely.
It's on the site. It can be bought at 500mg and 1g with $30 off or as the full 5g as priced. With 5g TOTAL commitment we will give $30 off individual orders of the listed 0.5g and 1g price. Plus whatever shipping people wish for, if purchased individually.
The 5g total is mostly just an honor basis situation. As long as intent a total of 5g seems likely.
Jaris,
Inhibiting mTORC1 is beneficial except it is bad for intestine.
Rapamycin is not a perfect mTORC1 inhibitor and it is not even close to perfect. So it has many side effects.
NAD+ is a perfect longevity intervention target and Niagen is close to perfect in increasing NAD+.
it's on the site. It can be bought at 500mg and 1g with $30 off or as the full 5g as priced. With 5g TOTAL commitment we will give $30 off individual orders of the listed 0.5g and 1g price. Plus whatever shipping people wish for, if purchased individually.
The 5g total is mostly just an honor basis situation. As long as intent a total of 5g seems likely.
It's on the site. It can be bought at 500mg and 1g with $30 off or as the full 5g as priced. With 5g TOTAL commitment we will give $30 off individual orders of the listed 0.5g and 1g price. Plus whatever shipping people wish for, if purchased individually.
The 5g total is mostly just an honor basis situation. As long as intent a total of 5g seems likely.
MikeDC, for the record, I'm not marking your posts negatively. i believe that, as long as it doesn't get out of hand and swamp the communication between those who are using this topic for its initial purpose (Rapamycin self-experimentation), a counter-view can be helpful.
I believe that most people have their blind spots, and I appreciate fact-based input. Choosing a medication path to follow, whether it be NR, Rapamycin, or tons of others, is a personal one, not unlike a political choice. People can become defensive and dogmatic, ignoring all points someone with a differing viewpoint might make. As with many people here, I have looked at many, many anti-aging supplements and meds. I've tried a few, and still take several that I believe may support Rapamycin. As I've mentioned before, I do take NR, which - yes - should increase NAD+ which is a good thing. I also take liposomal glutathione, QH+ PQQ and others.
Having said that, I will address some of the points you make, since you have referred to a paper that is valid, even though some of its conclusions may not be. If you haven't yet, please watch the video in my last post, just so that we have a place to start.
Those taking Rapamycin should be careful not to slip into taking too much. Unlike almost all other meds, Rapamycin has very different side effects at high-dose chronic use, vs low-dose intermittent use. Many, if not all of the negative results in mice studies are due to high doses and chronic use. A high dose of a rapalog might seem low to those with experience with other meds. 20 mg per week is (I believe) a fairly high dose and I keep my intake below 7 mg/week. Rapalogs have been taken as anti-cancer and immune suppressants for a long time, but at very high doses. Again, taken this way, there are several potentially serious side effects that have yet to be seen in low dose studies (of which there have been very few).
Let me take on your latest claim first:
"Inhibiting mTORC1 is beneficial except it is bad for intestine."
I assume that you mean gut bacteria? You don't refer to a study, so allow me:
OK I watched that video. I see how NAD+ supports the repair of several important elements of cells, including DNA damage. I also see where you're coming from regarding the intestine. Let me first ignore the intestine and look at the general case (other types of cells).
NAD+ can only help with repairs when the cell is in autophagy mode, not in growth mode. As we grow older, our cells spend more and more time in growth mode, but we can turn on autophagy by inhibiting the cell's mTOR1. So, to me, these two seem to work together; rapa switches the cell to autophagy and repair becomes possible, and NAD+ has what it takes to do the repair work. I'm sure it's not that simple, but that's what I can get my head around.
As to your comment about intestine stem cells, the video you suggested looks at the (apparently) special case of intestinal stem cells (ISCs). Much of that video covers the work of uncovering what's happening, but the conclusion is that inhibiting mTOR1 reduces the number of ISCs. To fight aging, their theory goes, you want ISCs to remain at the high levels seen in youth. This runs counter to the belief that inhibiting mTOR1 (including via CR) counters aging in all cells.
Meanwhile, the study I referred to mentions that "rapamycin can slow down the proliferation rate of intestinal stem cells (ISCs) in the aging guts and induce autophagy in the intestinal epithelium". This supports the results in "your" video. However, in "my" study, they believe that's a good thing: "Collectively, these findings reveal that rapamycin can delay the intestinal aging by inhibiting mTOR and thus keeping stem cell proliferation in check. These results will further explain the mechanism of healthspan and lifespan extension by rapamycin in Drosophila."
So who's right? That's "above my pay grade". Stay tuned. We may have to find a way around this if it is a problem. Off the top of my head, I would say that this adds merit to the idea of taking some time off of Rapamycin. That may "salvage" the intestine and increase the number of ISCs (the video says that NAD+ can do that if Rapamycin - or CR - doesn't block it.) So I think the first question to answer is: are more ISCs good or bad for fighting aging?
Just one last point. I take both NR and Rapamycin, because I think they might work well together. It's possible that Rapamycin keeps the NAD levels from dropping as we get older, but I don't think I've seen any study that's tested that. So I take both.
You need to learn more about how longevity is achieved through fasting and exercise. Increasing NAD* activates the same genes as fasting and exercise including autophagy. Inhibiting mTORC1 is not as good as increasing NAD+. There is no need to experiment with Rapamycin when Niagen is available. Niagen helps more and without all the side effects Rapamycin has.
I'm not knocking NAD+ enhancement, but I didn't notice nearly as strong youth inducing effects from Nicotinamide Riboside as those derived from Dasatinib with Quercetin or from injecting the peptides Epitalon with TB500. Maybe I didn't take it long enough? Only for a couple of months at 375mg/day along with MitoQ at 10mg/day. Possibly it takes several years of continued use for the positive effects of NR supplementation to show their effect? However, I stopped NR for now due to it affecting my digestive track unmentionably. Please note that I have not taken any Rapamycin yet, but do want to try it out combined with Metformin with which it has been proven to have synergetic effects.
short term boost in energy or some aspect of health don't necessarily extend life span.
"Quercetin is a common flavonoid, polycyclic, found in black currents, cilanthro, red onion, watercress, cranberries, and smaller amounts in many fruits and herbs. It is an anti-oxidant, but you know I’m not much impressed by that. Though it is natural, it is a mutagen, which means it breaks DNA. Substances like this would never be approved by the FDA, if they had to be approved by the FDA, but they don’t because they escape regulation as GRAS — “generally recognized as safe”. This is not to damn the stuff–many toxins have a beneficial effect in small doses. This is hormesis, a paradoxical but common and well-documented fact of longevity science.
But in the case of quercetin, it has been tried in longevity tests with mammals, and the results are not promising. In 1982, the first published study showed no life extension, and perhaps a slight shortening of life span in male mice. Stephen Spindler, our reality check for life extension claims, found that quercetin had zero effect on mouse life span in a 2013 study."
You need to learn more about how longevity is achieved through fasting and exercise. Increasing NAD* activates the same genes as fasting and exercise including autophagy. Inhibiting mTORC1 is not as good as increasing NAD+. There is no need to experiment with Rapamycin when Niagen is available. Niagen helps more and without all the side effects Rapamycin has.
Yes maybe, fast then refeed; fast then refeed; fast then refeed; over and over; net calorie restriction alone or through fasting may be triggering all sorts of metabolic chemistry experiments no one is close to understanding. NR? Pfftt... Ain't no metabolic silver bullet pill, folks...
Like Dare Devil is suggesting, I am, too, first aiming at killing senescent cells since this seems closest to actual clinical trial evidence (not here yet of course for LS extension) thus far in our little pre-science gaming (possibly completely loony...)
Also, isn't this a thread about rapamycin? Why do the virtues of NR keep popping up here and there and elsewhere unrelated? If you're a big fan of the stuff, beautiful, we're happy and proud for you. But to me, if you repeatedly post about NR in non-NR threads this may be some sorta mental indication that the stuff ain't working so well for ya... If NR is slowing human aging, gonna make us all healthier and live longer, it's gonna sell itself. So trying to prop it up short term just makes it look fraudulent like all the rest of the useless garbage that's been pitched at us for years & yrs
I think the NR excitement just bleeds over into other topics unintentionally. Are we lunatics? Maybe. We are also living on the cutting edge of anti aging research. If we are correct, we will see the benefits years in advance of anyone else. We will also enjoy it at dramatically reduced prices thanks to group buys.
You need to learn more about how longevity is achieved through fasting and exercise. Increasing NAD* activates the same genes as fasting and exercise including autophagy. Inhibiting mTORC1 is not as good as increasing NAD+. There is no need to experiment with Rapamycin when Niagen is available. Niagen helps more and without all the side effects Rapamycin has.
You really need to provide references. These general comments without papers and studies to back them up aren't helpful. For example, I know there's some evidence that it restores mitochondria function, but at what dose? In mice or humans? And, for humans, what are the side effects at that dose? To say it helps more with fewer or less severe side effects, implies that studies have been carried out to compare both benefits and side effects of rapamycin and niagen. What side effects do you think low-dose rapamycin has? What dose do you take of niagen? How sure are you that you will see benefits at that dose? Let's see if we have enough real data yet to compare. I'm guessing we don't.
I'm not saying that NR is useless. It might even end up being safer and/or more helpful than rapamycin. Until we have studies that show that, I'll stick to my dual approach.
If you are really interested in Niagen. Read the Nicotinamide Riboside threads.
Mouse studies say Niagen is a miracle drug that turned old mouse muscles into
Young ones. Cured fatty liver diseases, prevented Cancer and cured cancer.
Human studies show 250 mg increased NAD+ by 40% and 500 mg much higher.
Two IND will be submitted soon. One for Cockayne Syndrom, the other one for nerve
Pain due to Cancer treatment. I will not be surprised if 10 more New drug application get
Submitted and clinical trials started.
Now you have me confused. Why in the world would a supplement like NR need an IND, much less 2? And why would there need to be any drug applications? Anyone can buy NR. Pricey but available w/o a prescription. And if I can increase my NAD+ levels so much, why would i need some other drug?
The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines (usually to clinical investigators) before a marketing application for the drug has been approved.
It appears (if I am interpreting the study correctly) that supplemental glutamine may alleviate the intestinal mtor downregulation of ampk promoting substances
I would not be surprised if this was one of those biochemical individuality things, where some people are more sensitive in the digestive area and would have issues with ampk (yin) intestinally while others would have the opposite (yang)
Now you have me confused. Why in the world would a supplement like NR need an IND, much less 2? And why would there need to be any drug applications? Anyone can buy NR. Pricey but available w/o a prescription. And if I can increase my NAD+ levels so much, why would i need some other drug?
The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines (usually to clinical investigators) before a marketing application for the drug has been approved.
In order to do clinical trials, you need to file IND so you can experiment on humans.
It appears (if I am interpreting the study correctly) that supplemental glutamine may alleviate the intestinal mtor downregulation of ampk promoting substances
I would not be surprised if this was one of those biochemical individuality things, where some people are more sensitive in the digestive area and would have issues with ampk (yin) intestinally while others would have the opposite (yang)
If L-glutamine negates the effect of Rapamycin, why take Rapamycin. L-glutamine's effect is not limited to intestine cells. Also the negative effect of Rapamycin is on intestine stem cells.
It appears (if I am interpreting the study correctly) that supplemental glutamine may alleviate the intestinal mtor downregulation of ampk promoting substances
L-Glutamine enhances enterocyte growth via activation of the mTOR signaling pathway independently of AMPKhttps://www.ncbi.nlm...pubmed/25280462
I would not be surprised if this was one of those biochemical individuality things, where some people are more sensitive in the digestive area and would have issues with ampk (yin) intestinally while others would have the opposite (yang)
If L-glutamine negates the effect of Rapamycin, why take Rapamycin. L-glutamine's effect is not limited to intestine cells. Also the negative effect of Rapamycin is on intestine stem cells.
Glutamine is usually quickly taken up by just intestinal cells, so there shouldn't be any systemic blocking of rapamycin' s effects. Mitigating a side effect of an otherwise useful drug or supplement is useful -- you might want to look into that since your product is starting to produce anecdotal reports of joint pain and neuropathies in under methylators...
The funny thing is that NR is a good idea, and I actually take it. But it's over-hyped and over-priced IMO. Now I find myself LESS inclined to defend. But back to Rapamycin.
Anyone have any good feedback? I'm not expecting much yet of course. If I continue seeing small improvements and no negative side effects, I'll be happy.
Thanks for wishing us luck testing Rapamycin.
Likewise we wish you luck marketing NR.
DD
The funny thing is that NR is a good idea, and I actually take it. But it's over-hyped and over-priced IMO. Now I find myself LESS inclined to defend. But back to Rapamycin.
Anyone have any good feedback? I'm not expecting much yet of course. If I continue seeing small improvements and no negative side effects, I'll be happy.
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