The Most Promising Way Forward for Anti-Aging Science Today
We now have many effective interventions (mostly of small effect) for longevity and preventive care. Most readers of this blog take more than one supplement each day; some of us (I confess) take very many. We make an unthinking assumption that “more is better”, or rather that if A is beneficial and B is beneficial then if we take A and B we can get the benefits of both. We don’t think to question or deconstruct this reasoning. It is rooted in a reductionism that works pretty well in the physical sciences, much less well in biology.
We know that the benefits of all these interventions don’t just add up like numbers in a spreadsheet, but we continue to act as though this were our reality.
The truth is that we know almost nothing about the cross-talk among different health interventions. The reasons so few experiments have been done are plain enough, but the situation has become untenable. There is an urgent need to understand the interactions among treatments. We might begin with those that are individually most promising, but expect surprises. The combinations that offer the greatest longevity benefits may turn out to be pieced together from components that individually have little or no effect.
I might have said ‘the most promising way forward for medical research today, because I believe that anti-aging science is the most productive area of medical research. If you are reading this page, you probably know this already, but we all take comfort in confirmation of what we already know. So:
Prevention is more cost-effective than treatment. The root cause of most disease in the developed world is aging. This point has been made decisively [for example], most eloquently by Aubrey de Grey. (The root cause of most disease in the third world is poverty, and ending poverty is also an essential imperative, but it is not a subject for medical research.)
The problem of interactions has been neglected for a number of reasons:
- Unconscious linear thinking
- The dizzying number of combinations that need to be studied
- The want of a guiding paradigm that would provide context for individual studies
- Scientific inertia: researchers are more likely to study (and funders are more likely to support) research programs that are established and proven
But the problem is potentially of great import. We expect a great deal of redundancy among the mechanisms of action of various interventions we know about. Taking two or three or four drugs that address the same biological pathway is likely to be a costly waste. More rarely, longevity drugs may interact in ways that actually interfere and reduce overall effectiveness.
But we have good reason to hope that in rare cases there are combinations that are more than the sum of their parts. These fortuitous combinations synergize to offer greater benefits than they provide separately. Finding a few such combinations would be a jackpot that justifies many, many expected null results.
The huge number of possibilities to be covered
If we begin with 30 individual interventions, there are 435 pairs of interactions and 4060 combinations of three and 27,405 combinations of four. If we think traditionally, each one of these combinations is a research program in itself, requiring at least several person-years of professional effort plus overhead. This is the daunting reality that confronts anyone who is intent on beginning to address the problem of interactions. 27,405 experiments of any kind is a labor of Hercules, even for a well-funded, fully roboticized biomedical lab.
There is a hierarchy of experimental models for studying anti-aging interventions:
- Human cell cultures are the cheapest and fastest, but we learn the least
- Complementing human cells are yeast cells, which actually have a life expectancy and some biology that overlaps our own
- Studies of thousands of C. elegans worms can be done efficiently with robotic controls and worm counters.
- Fruitflies are a great deal “more like us” than worms and they can be raised in large numbers, live just a few weeks.
- Lab rats and mice are expensive, but they are mammals with biology that is much like our own. Experiments in rodent longevity last 2 to 3 years.
- Human trials require extensive safety measures and typically take decades to see subtle changes in health and mortality statistics; but this is the most direct indication of what we want to know.
So, how might we begin?
We have no idea what we will find. Maybe there will be a few spectacular combinations. Maybe the interactions will turn out to be small, mostly negative, and boringly expected. (My guess is that both of these will turn out to be true.) We should not try to define the second stage of the program until we have results from the first.
The first step is to choose the most promising interventions to combine. A great number of drugs and supplements are known that extend lifespan in rodents and/or lower mortality in human epidemiology. Magalhaes and Kaeberlein have put together a large database of animal studies that seems to be off-line at present. Another version is live at this address. Here is a list I proposed in this column two years ago:
- Rapamycin
- Aspirin
- Metformin
- Melatonin
- Deprenyl
- ALK5 inhibitors
- Epitalon/Epithalamin
- MitoQ/SkQ
- Beta Lapachone (Pao d’Arco)
- Spermidine
- Berberine
- Dinh lang (Policias fruticosum)
- Pterostilbene/Resveratrol
- Gynostemma pentaphyllum (jiao-gu-lan)
- N-Acetyl Cysteine (NAC) / Glutathione and precursors
- Ashwagandha
- Turmeric/curcumin
- C60
- Oxytocin (not oral)
- J147 (a promising new Alzheimer’s drug)
- NR, NMN and NAD precursors
We might add
- Polyphenols from tea
- Flavinoids from blueberries
- Angiotensin inhibitors
- NLRP3 antibodies
- Acetyl L-Carnitine
- Piracetam
- DHEA
- Statin drugs
- Cardarine / GW501516 / PPAR agonists
- Dasatinib / Quercetin
- FOXO4-DRI
- Astaxanthin
- Momordica charantia (bitter melon)
- Gotu kola / Bacopa
- Reishi mushroom
- Astragalus extracts
- Pine bark extract
- Ginseng
- Acarbose
- BHT
Interventions not in pill form include
- Exercise
- Caloric restriction
- Intermittent fasting (various schedules)
- Plasma transfusions from younger individuals
- Platelet-rich plasma
- Transplanted young thymus
- Transplanted young suprachiasmatic nucleus
How to prioritize and explore the huge number of combinations? Here are four ways we might begin to sort through the possibilities:
- Use theory: Look for biochemical mechanisms that seem complementary
- Traditional Chinese Medicine, Ayurvedic medicine and other ancient traditions suggest combinations of herbs that long experience says function together.
- Broad screens for especially potent combinations
- Statistical mining of an on-line registry of what people are taking presently
Let’s look at these one at a time.
1. Biochemical Theory
We know a few biochemical pathways that are linked to longevity. They all overlap and talk to each other. Nevertheless, we expect that treatments that address the same pathway are likely to be redundant, whereas treatments that address distinctive pathways have a better chance of synergizing. For example, insulin resistance is a robust hallmark of aging. The insulin pathway is most plastic and most accessible to intervention. Fasting and caloric restriction address the insulin pathway, as do metformin berberine, jiaogulan and bitter melon. Exercise has many benefits, some of which work through the insulin pathway.
We might continue classifying interventions that address other pathways. Here are some longevity pathways of which I am aware:
- Insulin
- mTOR
- Inflammation
- Immune senescence / thymic involution
- Epigenetic reprogramming / transcription factors
- Mitochondrial senescence
- Autophagy
- Anabolism / Catabolism imbalance
- Telomere attrition
- P53 / Apoptosis
Someone who knows more biochemistry than I do might be willing to classify the interventions I list (and others) according to these 10 pathways (and others). Here is a template in Google Sheets, which I establish as an open Wiki. http://tinyurl.com/longevity-pathways
2. Eastern and Indigenous Medical Traditions
Many useful modern medicines are derived from ancient folk wisdom. But this work has proceeded with a deductive logic, isolating active chemicals from whole plants (as aspirin from willow bark, cycloastragenol from astragalus, and curcumin from turmeric). Many folk traditions, especially Traditional Chinese Medicine, are based on not just whole herbs but combinations of herbs that have been found over the ages to work together. Ideas may be taken from these traditions to prioritize combinations for testing. For example, the best known Chinese longevity formula is Shou-wu-chi (首乌汁;), which is compounded of (list from Wikipedia):
- Root of Polygonum multiflorum (Radix Polygoni multiflori, also called fo-ti or ho shou wu) – 25%
- Root of Angelica sinensis (Chinese angelica, also called dong quai or danggui) – 25%
- Rhizome of Polygonatum sibiricum (Solomon’s Seal) – 20%
- Rhizome of Rehmannia glutinosa – 10%
- Rhizome of Ligusticum wallichii (Chinese lovage, also called Ligusticum chuanxiong) – 10%
- Root of Angelica dahurica (Dahurian Angelica, also called Angelica glabra Makino) – 7%
- Fruit of Amomum villosum (Villous Amomum, a type of cardamom) – 2%
- Clove – 1%
Other ingredients may also include: Hedychium coronarium (white ginger), Jambosa caryophy Llus Ndz, Citron (Citrus medica), and Conioselinum univittatum Turcz
The Ayurvedic tradition is less contains fewer formulas, but combinations that are said to contribute to longevity include these (which I found, just for illustration, at Banyan Botanicals)
- Haritaki (Terminalia chebula)
- Guduchi (Tinospora cordifolia)
- Amalaki (Embelica officinalis)
- Kumari (Aloe barbadensis, or aloe vera)
- Guggulu (Commiphora mukul)
- Brahmi or gotu Kola (Centella asiatia) or closely-related Bacopa
- Ashwagandha (Withania somnifera)
3. Broad screens for particularly effective combinations
Two years ago in this space, I proposed a screening protocol in which all combinations of 3 interventions from a universe of 15 would be tried on just 3 mice each. I showed with a computational model that if these included at least one lucky combination that increased longevity by more than 50%, then, despite the small number of mice, it would be identified with at least 80% confidence. Combinations of three from a universe of fifteen is a kind of sweet spot for this particular experimental design, and much less is learned if the numbers are scaled back. This means it is not feasible to test the concept on a small scale. The full proposal requires 1365 mice in cages of three, followed for at least two years. Cost estimate is about $2 million in the US or Europe, perhaps as low as $500,000 to do the same experiment in China. I would be eager to work with any lab that has the expertise and the facilities to implement this protocol. The experimental design and simulated analysis was recently published in English in a Russian journal.
4. Data-mining of an online registry where people record what supplements they are taking and commit to reporting their health history
It would be a great public service if someone were to establish a web-based registry where individuals could share information about what supplements they are taking and what results they are getting. Over years, this could turn into a data miner’s heaven for information about individual drugs and lifestyles and their interactions. The subject is too big for a controlled experiment, but enlisting the public would be a great and greatly-rewarding project.
I know there are web sites such as Longecity that are excellent resources for anecdotal accounts of others’ experiences. But the data is not in a format that lends to statistical summaries. If you know of an existing online database of this sort, please reach out and share the web address with me.
I have preliminary plans to create such a web site in conjunction with a forthcoming book project.
The Challenge
There may already be a viable plan for major life extension hiding in plain sight. There is no extant research program to explore the relationships and interactions among life extension measures. Eventually, some large, well-funded agency (perhaps NEA or the Buck Institute) will take on this project in a systematic way. But the large organizations are conservative, and are unlikely to begin until the ice is broken. Thus, even the first shards of information in this area are likely to be valuable indications of a new research direction.
If you have a research lab, or if you know are connected to someone who might be interested in this project, or if you have a funding source, please let us work together.
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Insilco is applying “artificial intellieence” to this kind of examination!! two compounds have been pointed out as mimics of metformin and rapimycin. LIFE Extension Foundation is selling a product which combines the two!!
The average lifespan of mice was increased 24% with BHT supplementation. Why is this ignored?
Hi.
Very excellent list.
Looking at two things not on list.
Rifampicin, rapamycin and allantoin was combinaton showed longest life extension C.elegans.
Rifampicin is antibiotic that used against tuberculosis.
Life-extension is prevents non-enzymatic glycation
Would be great if we could benefit from Rifampicin. But I suspect humans, being so much longer lived than mice, suffer from completely different glycation products.
How is your Rapamycin treatment going Alan, are you still on 6mg/week?
Hi Mark,
Thanks for question.
Still on 6mg rapa and no problems.
Please take look at my new website about prevention AD with rapa.
Blocked from posting name but if go to PD Mangan Rogue Health can find link
Very much like your analysis of basic science and Mouse studies.
I’ve had a look at the new website Alan, very interesting. There is a lot of information in the science section, so it will take me time to read it all.
I am fascinated to discover the underlying reasons for why MTOR rises so much with age. For example much more than 2mg per week does not agree with me, yet you are doing well with 6mg. And actually when you look at the min and max values during the week, your dose is much, much higher.
My personnel theory is that the body sets a rate of inflammation required to spur required regeneration in tissues. And the older you are, the more you suffer from stem cell depletion and telomere loss, so the higher your inflammation will tend to be. This is based on various papers I’ve read on inflammation, stem cells etc. It would also explain why you report you no longer feel old, but neither do you feel young. This is because you have stopped the senescence program (geroconversion) from killing you, but not restored underlying regnerative potential. What do you think?
Hi Mark,
Thanks for analysis.
Feel lot better than 3 years ago at age 72; but not as good as age 65.
I think your low dose in 40s very smart.
I’ve been doing Rapamycin, aspirin, Metformin and NAD+ for over a year and I’m not dead yet.
My blood test showed everything was normal and also showed a number of improvements. If anyone want to know before and after on any specific test just ask here. 6 pages of test results is too much to post.
Hi LO
I’m taking pretty much the same things as you and would love to know those results which showed the most improvement.
Glucose went from 98 to 89 mg/dL. Creatinine pre: 0.9 post: 1.0. Cholesterol/LDL pre: 3.33 post: 2.73. All due to an increase in HDL from 72 to 88. Triglycerides pre: 137 post: 86 mg/dL. Testosterone pre: 616 post: 719. Free testosterone test pre: 8.7 post: 9.0 ng/dL. Blood pressure yesterday 100/68. That’s down a bit. usually 110/80 range. ALT pre 30, post 26 U/L. Lost 9 pounds. 6’2″ 175. 57 years old. Stronger on road cycling but not quantified because my power meter broke. No major changes in diet which is better then SAD but not ideal. Sick for a week in March with bad cold but otherwise no flu or colds/infections.. If you want any other specific test ask.
LO
All of those numbers are good. Very significant weight loss. HDL and triglyceride changes. The only known elevators of HDL are exercise, alcohol, and saturated fats.
Triglycerides are very sensitive to changes in body weight.
I assume the drop in FBS is from metformin.
If you’re interested I can let you know what mine are so far.
Would you mind sharing the doses that you take? Also, how do you feel? Is there a difference?
Hi LO
Those really spectacular numbers.
Very interesting testosterone and HDL went up
Doses? I had 100 1 mg pills that lasted one year so about 2 mg/week with grapefruit juice. I had mouth sores 3-4 times so I know how much juice to use after much experimenting. I think it will vary with your age and weight.
How do I feel? I feel fine. Not really different then pre dosing. I weigh less so that makes a difference. I still wake up with aches and creaking. My chronic lower back pain has not changed. I am more powerful on a road bike when it comes to beating up on guys I’ve rode with for years. The hard efforts are just so much easier. Some of that is due to a new bike and the weight loss. Muscle mass does not appear to have changed and that must be the rapamycin. I don’t have accurate power data but I will in about 6 months to compare pre/post power outputs.
Post your data if you can otherwise just email me. Very interested in your results. Not many of us around to get this kind of info from.
Ok LO
I am 6’1″ and now 180 lbs. 62 years old. Rapamycin for 6 months at 2mg/week. But my blood values weren’t at 3 months.
I take what you take minus metformin
I also take about 40 to 50 supplements a day.
Since rapamycin my glucose rose from its usual 100 to 115
My insulin level dropped 25%
My IGF1 is149 ( no baseline level) but that is a good number
My creatinine went from1.3 to 0.9 ( kidney)
White blood count 5.2 down to 4.7 ( some evidence that lower white counts are associated with longevity)
I don’t check lipids since I prefer the more reliable coronary calcium score
I also don’t care about the elevation of my FBS since it’s predicted for Rapamycin, and metformin seems to overly inhibit my TOR levels.
That’s interesting Paul, where did you hear about low white blood cell levels being associated with longevity? I had some blood tests done 3 or so years ago and my white blood cell count was low. The doctor kept asking me if I’d just recovered from an illness. I hadn’t and was and am very rarely ill. I wasn’t on rapamycin then but had been on Berberine for a year, so maybe that explains it.
It’s very interesting that heart disease, cancer, and overall mortality are related to the WBC count. There was a Japanese study that showed that half of women at age 85 who started out with a WBC count of 5.6 or less were still alive, whereas 80% of those who started with a count over 7 were dead. It seems to be a marker of inflammation, predictor of longevity, and also a causal factor.
A very interesting study was done in the Baltimore area in 2007 and reported in the journal of the American college of cardiology. They followed 2800 people over 40 years and found that those with counts between 3500-6000 had the lowest mortality rates.
Forgot to mention that vegetarians often have very low WBC’ counts.
My pre rapamycin wbc was 4.1 and post is 3.6. Rarely sick.
Nice. You might go forever.
I’m definitely going to have some bloods done again this year to see the pre and post rapamycin changes. I believe my WBC was 4.5, with neutrophils being particularly low.
Could you please put it out in a blog?
Its really easy to make. For example if you have a gmail account you can start blogs with a few clicks .
Hi Josh,
I’d like to collaborate on the online registry. I’m a software engineer with some spare time to work on it. I had a similiar idea, allowing people to record their results from various protocols like the Bredesen protocol for Alzheimers, Wahl’s for MS, Gundry’s for heart disease and autoimmune conditions, Seyfried’s for cancer. Most of these include supplements and look for changes in blood markers or have other ways to gauge effectiveness that give fairly quick results.
Josh,
You are one of the most brilliant people I know. However, in this case, I question the logic of what you are suggesting. In engineering, my entire goal is to always approach things by keeping them as simple as humanly possible. While everyone agrees that there clearly are at least 4 mechanisms to the aging process, this does not mean that we should give up on trying to find one standard approach that will affect all of them. What I also found the most interesting is that to me, the most important influencer (IMLO of course) wasn’t even listed, which is a ketogenic diet (ideally combined with regular fasting). So not to take up too much more space, I will list just a few of the items you listed as an example to prove my point.
– Rapamycin – (Study: The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway)
– Aspirin – (Study: The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.)
– Metformin – (Study: Insulin Sensitivity and Glucose Tolerance Are Altered by Maintenance on a Ketogenic Diet)
– ect…
– Insulin – (Fasting is the ultimate insulin suppressor. KD is second most powerful)
– mTOR – (Fasting is the ultimate mTor suppressor. KD is second most powerful)
– Inflammation (Fasting and KD both suppress chronic inflammation NLRP3)
– etc…
Josh I notice that you did not include Magnesium & Potassium supplementation in your list. Yet there is significant evidence that these two minerals help prevent & even reverse some chronic diseases which are the hallmark of mother nature’s programmed aging program.
Some folks have made the same point about Vitamins C, D2, E, & CoQ10 ( Ubiquinol )
On the wider issue of trying to work out how anti-aging supplements, etc. intereact with each other, I agree there is a need for research.
However a capitalist type system operates on the basis of maximising the sales and profits of each product to consumers. This basic modus operandi applies in the anti-aging field. Companies have no interest in funding research which might limit or reduce sales.. So I think we are stuck with what we’ve got mate; a suck it & see methodology.
Josh … Thank you for all you do. I am 72 years old and extremely healthy although I probably take too many supplements etc. I would like to know what do you take?
Bill in Oz:
I agree. We are stuck with the “suck it and see methodology”
Unfortunately, at this point the only way to discern whether something is helping or hurting is to gauge how you feel after taking it, and factoring a short period for a possible Herxheimer reaction to the substance.
Also, follow up with blood work to ensure nothing is out of proper parameters.
Also it is possible to over inhibit MTOR.
For example some have mentioned feeling terrible if adding a herbal or nutritional AMPK activator to Sirolimus (Rampamycin)
In that case lowering the dosage of both might help.
I prefer to take both because they work by different mechanisms.
Another metabolic pathway I didn’t see listed which has been implicated in aging (anti-aging rather) is NRF2 (NFE2L2). Perhaps critically important in detoxification, oxidative stress defenses, and DNA repair. Also the ridiculously inexpensive, effective, and easy way to activate it via sulforaphane (broccoli seeds/sprouts) which is amenable to research.
Otherwise, a great article that provides a detailed look into promising anti-aging interventions and a lot to chew on. I don’t have much to offer on driving the research forward, other than willingness to share my data if such a cooperative online database is set up.
Thank you – this is something I need to learn more about. Can you suggest readings?
Nrf2 is the antioxidant response pathway, intimately linked to mitochondrial maintenance and the SIRTUINS. This might be complementary to MTOR inhibition, but probably duplicates the benefits of calorie restriction. I made myself a Nrf2 activator from Ginger extract, Rosemary extract and luteolin, but the effects were minimal – probably because my antioxidant status is good anyway. But for some people it could be transformative.
Andrographis is the strongest Nrf2 stimulator
Andrographis can cause leaky blood-brain-barrier.
Hi, Nrf2.
According to current theory leaky BBB initial step in AD in APOE4 carriers.
Very hard to believe Nrf2 causes leaky BBB.
More info on substances raise Nrf2 would be of interest.
pubmed/23930775/
In “A novel bioactivity of andrographolide from Andrographis paniculata on cerebral ischemia/reperfusion-induced brain injury through induction of cerebral endothelial cell apoptosis” the in-vitro concentration of andrographolide that damaged Cerebral Endothelial Cells was about 20,000 times higher than the in-vivo concentration that I calculate for 1 capsule of Now Andrographis based on “Pharmacokinetic analysis and tissue distribution of andrographolide in rat by a validated LC-MS/MS method”. The in-vitro concentration was maintained for 24 hr whereas the in-vivo half life is about 2.45 hr making the in-vitro AUC about 200,000 times higher than with a capsule of the supplement.
Hi Robert,
A spectacular example of how worthless in vitro can be.
Josh,
Rhonda Patrick (PhD) has a couple of the best videos on youtube regarding the benefits of sulforaphane and upregulation of NrF2 and how to get this from broccoli and far more potently from broccoli sprouting.
Best Regards,
Aslan
Josh – This is one of the most fascinating recent areas of research. There are now more than 1000 studies on PubMed, where sulforaphane and isocyothyanates are associated with everything you can imagine – DNA repair, detoxification, reduction of inflammation, apoptosis, cancer prevention, even reduction of autism symptoms.
I had some links to share, but any attempt to post them resulted in a “CleanTalk” dialog that said **Forbidden** and my replies were rejected. You are welcome to contact me directly.
Oops – isothiocyanates that is
Mitochondria fission/fusion housekeeping cycles can occur several times an hour. During fission the “junk” is segregated to one side and goes into a daughter marked for mitophagy. The other daughter is now cleaned up and proceeds to fuse with other clean mitochondria. Sulforaphane inhibits fission. This produces large multi-fused mitochondria which are very efficient short term, but the long term effects from less housekeeping may be problematic.
Yes you’d want to cycle supplements that inhibit mitophagy.
Here’s a big one that needs attention- Mitochondria is our energy factories. Think about that a minute- Taking care of our mitochondria is the most important health option for all of us. Mitochondria need vitamins and minerals as co-factors. If they don’t get them then they can’t turn the oxygen we breathe and the food we eat into energy. Specifically Magnesium and Thiamine (B1) Energy is everything- without energy life quickly tailspin’s and dies in a myriad of ways. Even if your diet is good-like a car, it won’t matter how much gas we have in the tank- if it can’t get to the tires. Mitochondria need a full array of vitamins and minerals- but it seems Thiamine is in charge- along with magnesium. We look for exotic supplements but what are vitamins? Vital to life!
And methionine/protein restriction to avoid damaging mtDNA. It’s not only about what we should eat, but also what we should avoid in excess.
Mitochondria have a role in aging, not to be confused with their vital role in keeping us alive and healthy.
Hi Josh
In addition to what I mentioned earlier there is the simple fact that cancer rates grow with age. I have just read an article which suggests that these higher cancer rates are due to the shrinkage of the thymus as we age.
https://theconversation.com/could-ageing-immune-systems-be-a-better-predictor-of-cancer-than-genetic-mutations-91176
Now what restores the thymus and restores function ? The only one I know is Human Growth Hormone. ( HGH )There may be others.
HGH has deleterious effects if taken in the long term. But I wonder about taking it for short ( say 12 months ) occasionally to restore thymus function. Any thoughts on this ?
If thymus does have such important functions, then thymus engineering comes handy. They are already able to reprogram mouse embryonic fibroblasts into thymine epithelial cells, and transplant back into mouse kidney. Of course, none of us have embryonic fibroblasts. But they maybe able to reprogram regular fibroblasts into thymic cells.
I am aware of a clinical trial in California the last 2 years using HGH to try to regrow the thymus. These were based on Greg Fahy’s successful self-experimentation a decade earlier. The trial has not produced any reports yet, but rumor has it the results have been disappointing.
New paper hot off the press.
‘Thymic involution and rising disease incidence with age’.
Apparently immune decline is a very accurate model for rising cancer incidence, far more so than mutation rates.
co occurence is not causality.
They have not even compared actual thymus degradation metrics to actual cancer incidence in humans. They just published a mathematical model about average thymus involution and average cancer incidence in the population.
I guess they had the same results if they tried to compare wrinkles per face area to cancer incidence.
LOL. But I do think they will be proven right. You are certainly correct however – they need to show a strong immune system prevents cancer/ a weak immune system permits cancer.
Hi Mark
Please send me email
[email protected]
My bad for posting the paper before reading further than the abstract.
I think that one of the points of the study, if I recall correctly, is that immune dysfunction is part of the cancer story along with mutations. The role of the thymus in all of this is still unclear. There is certainly evidence that with aging there is a deterioration of the innate immune system, most specifically the natural killer T cells, which are important in combating both viruses and cancer.
The natural product, enzymatically modified rice bran, can increase these nk cells by up to 84%. I take it about 3 months out of the year.
Yes you are right Paul, there might be easier ways than restoring the thymus to keep our immune system working.
Paul, do you know if the enzymatically modified rice bran raises your WBC?
I’m assuming that it would, at least transiently. That’s why I’m very careful with it and restrict its use to flu season, maybe 2-3months.
Melatonin rejuvenates the thymus gland in old mice
That’s interesting. Do you have a reference for that?
Sure, “Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice https://www.ncbi.nlm.nih.gov/pubmed/12880677
This is a remarkable paper. Even in old mice (22-24mo), melatonin was able to turn back the clock someway on thymic and splenic involution as well as the responsiveness of NK cells to cancer. The dose was achievable in humans too. I did a rough calculation and I think the dose the mice were on for 2 months is around 14mg/day for a human of 80kg.
Do you know if any follow up work on this has been done? Given how much effort has been put in to rejuvenating the thymus is humans, this cheap supplement could be incredibly useful if these results cross over into humans.
I would be happy to try out this protocol for 2 months; are there any biomarkers I can test for to see if it is having a beneficial effect on my thymus, spleen and immune cells in general?
That is remarkable. You can get a blood test called a lymphcyte profile or subset profile. They will give you the breakdown of:
B lymphocytes
T lymphocytes
NK cells
If I can find anywhere to do that test Paul, then I will conduct a 2 month melatonin experiment later in 2018.
Metformin damages Mitochondria. Stay away
does PQQ + Astaxanthin protect mitochondria. Austch, astaxanthin extends life about 3 times as effectively as Metformin, so not point of poisoning yourself with metformin if you take astxanthin.
Can you give us a reference for these statements? I know of no lifespan studies in mammals for astaxanthin or PQQ.
I’ve found published studies only on worms and flies where it extends lifespan by 18-30%. I’ve found no study on humans so far, except cicumstantial evidence. But, having flu recently, I observed that astanxanthin (4-6 mg daily) combined with PQQ (2x20mg) taken together worked more effectively as antipain and anti-inflamatory remedy than 3×1000 mg paracetamol (acetaminophen). Taken together with the fact that it is an antioxidant that won’t turn into oxidant with overdose, it is a high probability that it will replicate this effect in mammals.
I’ve recall seeing only mentions of studies of effects of astaxanthin on macula of retina and its’ neuroprotective effects, very promising. Having problems with retina (although centella asiatica combined with hericium erinaceus regenerated it a bit) I inluded astaxanthin in my daily dose of essential herbs and vitamins.
I think most here are aware that taken Metformin as an anti-aging drug is controversial for many reasons.
IMO, some of the damage is caused by B12 ( cyanocobalamin or methylcobalamin) deficiency created when taking Metformin and perhaps B9 (folate or Methylfolate)
That is why when taking Metformin it is important to supplement with a B complex nutrient that contains methylcobalamin to offset that depletion.
Methylcobalamin is the more asborbable form of B12 and methyfolate active form of folate.
B vitamins should always be taken as complex because they work synergistically and if each is taken alone, side effects can ensue.
The lack of the B vitamins is, IMO, is the cause of fatigue and reduced aerobic activity in reported by some people taking Metformin.
Statins, depelete CoQ10 and if taking a statin the ubiquinol form of CoQ10 should offset that depletion.
According to some reports: ” Studies have also shown that diabetics taking metformin live longer than people who don’t have diabetes – despite the fact that the condition (diabetes) normally takes eight years off people’s lives.
“People on metformin get 30 percent less cancers, almost every cancer except maybe prostate cancer.”
Still, yes, you are right, taking it for antiaging is still experimental.
TA65, more effective than all substances mentioned in your artictle… missing. Scuttelaria baicalensis, even more effective than TA65, missing too. Even more effective TAM818 (although they can’t still get it through digestive tract, pity…) missing…
Josh did mention astralagus extract, so TA65 and (probably) TAM818 are covered. I’ve read the patents on these, and I too came to the conclusion the issue with them is not the telomerase activation potential in cells, but the absorption. I expect liposomes would help with getting them into the blood stream.
I agree with you Heather. In fact, lack of folate is as destructive to DNA as radiation. People seem more scared about tiny amounts of radiation from Fukushima than the danger of folate deficiency.
Ole:
Agreed.
Nice job Josh
Very comprehensive review of where the field stands at this time.
The mice protocol that you suggest would really help. I’m wondering if rapamycin could be the baseline drug, since we know that it works, and then add two other substances to it that don’t act via the mTOR pathway.
Sulforaphane is a very potent Nrf2 activator , and is lipophilic and therefore very bioavailable. I grow my own broc sprouts and chew them . Sulforaphane was more effective than curcumin, milk thistle, and resveratrol at activating Nrf2.
” Sulforaphane and other nutrigenomic Nrf2 activators”. Christine Houghton. Oxid Med Cell Long. 2016, 7857286
Rifampin and rapamycin worked well along with allantoin in worms and fruit flies but I’m concerned about the hepatotoxicity risk in humans.
I agree that as we know rapamycin is effective, we should start with that as drug 1 and then look for complementary pathways with the other 2 for mice experiments. We know the effect of rapamycin, so we’d already have a rough control.
I think it’s also a good idea if we could all agree on some basic biomarkers in humans. I sometimes do get tests done, but apart from checking nothing drastic is going wrong they don’t give me that much actionable information. If we could agree on some worthwhile tests I would not be averse to paying for them once or maybe twice a year. We could then all share this information and if anyone’s results looked surprising we could focus in on why and maybe learn something. If we did this over a number of years the information we gained would continue to accumulate. We might unearth a supplement that effectively extended telomeres, or something that slowed the epigenetic clock, or find substances that effected hormones, etc, etc. Who knows?
Btw Paul there are some patents which give away what substances work together to synergistically activate Nrf2 (far more than brocolli on its own). I’ll see if I can find them.
Patent publication number WO2017041054 A1
‘Compositions for improved nrf2 activation and methods of their use’
I put together a combination using ginger extract, rosemary extract and lutoelin.
Ginger (boiled in low heat for at least one hour) is what I take for cold damp weather induced joint pain. It works almost instantaneously. I would say it reduces the pain by about 60-80%. But the effect disappears in 3-5 hours.
Next time I will try rosemary, ginger, luteolin combo.
Cassia, can you please share how you are preparing the Ginger before boiling?
Thanks!
Not much to prepare, really. I wash the ginger. I leave the skin on, but cut them into thin slices. Bring them to boil, them turn down the heat and let it simmer for an hour or so. A quarter pound prepares for about 4 cups, which I drink them throughout the day. Drink it hot to ensure slight sweat. Same way my grandmother used to give it to me when I had a cold. I drink the tea without any sweetener. But the taste is quite pungent. You could also add stevia to sweeten up.
Thanks so much.
Thanks Mark
I’ve tried rosemary multiple times and it always gives me reflux. I’ll try it again.
I really like the idea of identifying and following certain specific biomarkers. Not sure which ones to follow though. Maybe:
IGF-1
Insulin
CRP
White Blood Cell
If you have a baseline coronary calcium score over zero we could see if anything reduces it ( my associate here just got a 50% drop in his score over 3 months taking vitamin k2 as MK4)
Detailed telomere distribution evaluation
Anything else?
Heart Rate Variability?
Epigenetic Age maybe?
Any other ideas?
Can we measure epigenetic age somewhere?
Sure, I’ve had an epigenetic test from mydnage.
Thanks
I would add a category for some sort of physical performance benefit since if the biomarkers don’t translate into tangible ability to perform at the level of a much younger person then one has to question if they are really valid. Additionally physical performance pulls in a bunch of other issues that don’t get much discussion here but which are top priority for many of us, such as preventing and recovering from minor injuries, and maintaining strength. It might not be reasonable to use the same measures for everyone since endurance people will have a very different set of measures from strength and agility people, but Josh listed some times that he uses for running and swimming a few posts ago and I think any database of anti-aging should attempt to address this. Personally I think the ability to play basketball (fairly competitively) with younger people is the best measure since it involves some of everything, but there is a skill element that most people won’t have.
Many here love to bash things that work through the anabolic or HGH pathways, however without some sort of fairly rigorous physical performance component there is no incentive to look for ways to maintain youthful performance and recovery ability. And from the perspective of creating widespread benefit in the general population, there are still people who have physically demanding jobs, believe it or not.
Long-lived bats don’t shorten their telomeres
Great article Bill
Fascinating
Might have to seriously restart my ta65
Of course it’s also possible that maintaining telomeres through means not involving telomerase, like these bats are able to do, is the important piece of information here. Perhaps artificially inducing telomerase isn’t as effective or as safe.
I’ve been reading the Patents and it seems the issue with astralagosides (including cycloastragenol) is absorpiton into the blood. They thought they’d cracked it with cycloastragenol as in mice it’s ten time more bioavailable than astralogosides IV, but it’s no better in rats and beagles (and presumably humans). They’ve now found another compound that seems to be absorbed to a reasonable amount, atleast in Beagles. I am guessing this is TAM818, but they don’t say. Check out the Patent for yourself. ‘Compositions and methods for increasing telomerase activity US 9403866 B2’.
In the meantime I’m wondering why they don’t try liposomes to get astralagosides into the blood. I see you can buy it from Actinovo.
really interesting.
either these bats achive true negligible senescence or their reproductive age is much longer than the 15 years they can survive in the wild.
I think this is a very interesting theorethical question
What is also interesting is that the longest lived bats, whose telomeres do not shorten they with age, have no active telomerase (like humans). The authors speculate that they must use the ALT method of telomere elongation, which I know nothing about, but which is apparently mediated by the SETX helicase in this case. Also of relevance, these bats very rarely (how rarely?) get cancer.
Yes. That does seem to be the case with these bats. Apparently , the ALT system, present in about 15% of cancers , shows a preferential lengthening of lagging telomere strands over the leading strands, giving a ratio of about 1:2.5 of lagging/leading, as opposed to telomerase systems where the ratio is closer to 1:1. This results in a rather extreme heterogenous distribution pattern.
And as you say Mark, protection against the otherwise predictive cancer risk ( Haycock).
This could turn out to be very significant as we explore the means to best maintain our telomeres.
” Alternative Lengthening of Telomeres can be maintained by preferential elongation of lagging strands” Jaewon Min. Nucleic Acids Res 45 (5) 2017. March.17. 2615-28.
Bats have a number of interesting adaptations relating to their genomes. As in the case of birds, these adaptations are thought to be related to the metabolic demands of flight.
The bat genome: GC-biased small chromosomes associated with reduction in genome size.
https://www.ncbi.nlm.nih.gov/pubmed/23881029
Another technique…
Plasma donation at the Red Cross.
Angiotensin II inhibitors are interesting, especially AR1T blockers (e.g. lorsartan):
pubmed/25934099
For now, I’m just going to eat my lentils:
pubmed/24142613
Would like to read this paywalled (grr) article:
The loss of muscle mass and sarcopenia: non hormonal intervention.
pubmed/21920428
Here’s another interesting article, and it’s open access:
From rapalogs to anti-aging formula
PMC5482593
~~~
I’d add glucosamine and chondroitin to the list:
Use of glucosamine and chondroitin in relation to mortality.
pubmed/22828954
Proper dosing is important:
Too much glucosamine can cause the death of pancreatic cells, increase diabetes risk, researchers find
sciencedaily /2010/10/101027111349.htm
“In our experiments, we used doses five to ten times higher than that recommended by most manufacturers, or 1,500 mg/day,” stressed Professor Picard. “Previous studies showed that a significant proportion of glucosamine users up the dose hoping to increase the effects,” he explained.
{had to take out full links due to CleanTalk issues}
It’s great to see so many people taking intermittent Rapamycin. In 20 years might fulfill Blagosklonny prediction of Rapamycin being standard treatment for anti-aging.
Can you say something about once-a-week vs daily?
Also about a few months per year vs continual?
Yes it is great to see that many people takes rapamycin and up to
my knowledge, nobody has reported any serious side effect so far. What we need now in my opinion is a network of doctors aware of the anti-aging benefit of rapamycin and willing to prescribe it to their patients. In addition, a follow-up human trial on rapamycin would not hurt.
How can a layman obtain Rapamycin in Canada for self-testing?
Hi Stephan,
Unfortunately, I don’t know where to find a reliable source of rapamycin. I hope that in a couple of years, more doctors will be willing to prescribe it for anti-aging purpose as I think it is best to take it under medial supervision (just to be on the safe side).
Dropshipmd. com
India very reliable. Paid $1.75 mg for 300 1 mg sirolimus. Lower amounts more expensive. Wire payment only. Free 5 week shipping or upgrade. Bicon brand, largest pharm manuf India. No Rx needed
The results for the Rapa trial at University of Texas with Dr. Kellogg has been published. First human trial on healthy elderly people. Still looking for official trial results.
Were they looking at longevity?
Texas
They did 1mg a day instead of intermittent so got nothing
Thanks Van.
The paper is available but not open access:
“A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects”
This was a short pilot study of 8 weeks, 1mg RAPA / day in the RAPA group. No serious side effects were reported. Not sure why they use daily instead of weekly rapamycin. Maybe some doctors here can comment on that.
The authors conclude:
“Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a larger trial with a larger samples size and longer treatment duration is warranted.”
Used daily Rapamycin because never heard of Blagosklonny, not following literature and generally totally clueless.
Rapamycin dosage requires a complicated dosing strategy to reduce mTORC1; but not mTORC2. Rapamycin destabilizes mTORC1 by competition with Phosphatidic acid; but can not destabilize mTORC2 due to different Kds.
However, Rapamycin can prevent formation of nascent mTOR which will prevent new mTORC2.
Therefore, want low nadir dose before new dose. It is the nadir dose which determines inhibition of mTORC2 and side effects. Note in this 12 people had few with mouth sores.
Figure half-life @65 hours these older persons. If do the math and compare 6 mg once a week vs 1 mg daily, see not only much higher zenith dose with 6 mg; but also lower nadir dose. So with 1 mg daily get the worst of both worlds; a low zenith with small reduction mTORC1 and S6K activity combined with a high nadir dose and more inhibition mTORC2 and side-effects.
Just done the calculations based on an assumption of linear clearance from the body. 6mg/weekly converges on maximum of 9.8mg and minimum of 3.8mg.
1mg/daily converges on a maximum of 5.4mg and a minimum of 4.4mg.
Therefore per week dose of around the same (6mg vs. 7mg) gives completely different dose profile.
Hi. Mark,
Did calculation wrong.
Half life is not linear.
Example
6 to 3 to 1.5 in 130 hours
Then .6 half life so about 1 mg
As nadir. Dose after 1 week
New max dose 1 plus 6 is 7
After few doses levels off with zenith little o ver 7 and nadir just above 1
Also, if you took 12mg/bi-weekly you’d get a maximum of 14.9mg and a minimum of 2.9mg.
Something to think about?
Hi Mark
12 mg bi- weekly
I get zenith 28
Nadir @11
That would be more than enough for organ transplant
Good for chemotherapy some cancers
Very bad for longevity
For those like me who are on a low dose of 2mg/weekly, this gives a maximum of 3.3mg and a minimum of 1.3mg.
But a change to 4mg/bi-weekly (the same dose over time) would give a higher maximum of 5mg, but a reduced minimum of 1mg.
Again, something to think about. To be honest, I really don’t understand enough about the mechanisms of rapamycin and MTOR to comment further on whether this would really be better.
Hi Mark
Suggest recalculating
Using half life 65 hours
at 65 hours 1.0
At 130 hours 0.5
At 168 hours 0.3
At 169 hours 2.3
Levels off didn’t bother calculate estimate
Steady state @ 2.4 zenith
Nadir @ 0.4
0.4 nadir dose low enough avoid inhibition mTOR2.
Oh whoops, how embarrassing.
New Calculation
6mg/weekly
Max 7.2mg
Min 1.2mg
12mg/bi-weekly
Max 12.3mg
Min 0.3mg
2mg/weekly
Max 2.4mg
Min 0.4mg
4mg/bi-weekly
Max 4.1mg
Min 0.1mg
I did not access the paper.
Aldebaran wrote that it stated: “Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a larger trial with a larger samples size and longer treatment duration is warranted.
Was the purpose of the study only to verify a baseline of safety related to dosage and length of use, in the elderly?
Or was it anti-aging benefit?
If it was to establish safety baseline, that may be why the dosages are at odds with the intermittent anti-aging use schedule.
It was strictly to establish safety
Thank you Paul.
Just in case, sorry if this duplicates as I am having issues with posting on this site.
@Patrick Stanley in reply. Another great post from Josh! Yes, working with LEF could be an option also to gather funding. They are in the business of selling supplements but the Foundation sponsors research. I even suggested Bill Faloon to launch a “personalized supplementation” program many years ago and include genetics. The approach of Insilico is very interesting as artificial intelligence (AI) and machine learning (ML) can guide understanding the complex and non-linear interactions of compounds to extract insight. This parallels also the critical research on finding the right aging biomarkers; in a recent Insilico paper, their ML approach in guessing, quite well it seems, the chronological age was shown to correlate also well with mortality risk, hence biological age, IMHO. There is a trend in the personalized nutrition (an area which overlaps with precision medicine when it gets to prevention) of using ML and AI to generate hypothesis and complement mechanistic understanding. Just in case, I am learning/posting a bit on Longecity on these topics.
I am experimenting with several of the molecules on Josh’s list, particularly NR, NAC, Curcumin, Resveratrol, Quercetin. Also included stabilized Sulforaphane and IP6. So far I have been only on 250mg metformin. Probably the most notable results have been on inflammation biomarkers.
Hi Josh,
here again in the right email many many thanks for your work. I also take
a lot of supplements and try to optimise them from week to week.
It’s good to see that other people do the same.
Best wishes
Mike
I’m curious why Glycine didn’t make the list since you seemed to be high on it in your post from a year ago.
Also, as long as we’re piling on with suggestions, I will put in a plug for hemp oil AKA cannabidiol oil. I take a large mountain of stuff and hemp oil has had more of a noticeable impact than anything else as far as I can tell. It seems to have benefit for a ridiculously long list of things and there seems to be decent evidence that it benefits anti-aging pathways, particularly those related to excessive inflammation signaling.
I would encourage everyone to read Vince Giuliano’s new piece on NAD+
http://www.anti-agingfirewalls.com/2018/01/16/tales-nad-presentation-coming/
Allways a pleasure reading Vince’s stuff!
Anyone played around with The NR, Resveratrol, Apigenin combo?
I was wondering if some form of rejuvanation could be obtained with Endless amounts of useable NAD+, CD38 down regulation, and sirtuin-1 activation.
Once again, bioavailability seems to be the biggest hurdle, the fact about directy sirtuin-1 downregulation with fat (not just “breaking fast” with whaterver calorie) is new to me, it sucks partially because most of our arsenal of phytochemicals are lipophilic, but maybe it does not mean much.
but there a tons of things to improve outcome, i newly discovered a tea that powerfully inhibits the enzyme that “breaks down/clear’s” resveratrol. (Dandelion root tea), these “known’s” are what i call gems, i have a lot of gems and i know alot of josh’es blogs readers got a lot of gems too. The thing is that the commentary field below josh’s blogs post might not be the best setting to discuss these things, (pathway cross talking, quickly gets messy) and try to work together to make a very sound anti-aging protocol…
I’ve tried a protocol of liposomal resveratrol every 3 hours (approx half life) for approx 24 hours. I wasn’t convinced that there was any good evidence for interfering with digestion enzymes, but I’m happy to review any evidence you’ve got and try it out on my next attempt. Resveratrol has always struck me as a great molecule in vitro, if only we could get it to do the same in the body.
I took 32 oz of liposomal resveratrol/curcumin over 24 hrs (including every 2 hrs overnight). The only result I saw was a bit of diarrhea.
For a drug with an exponential decay the steady state Peak converges to Dose/(1-x) and the trough to (Peak)(x), where x = the amount at the end of the interval divided by the amount at the beginning of the interval. The smaller the x the fewer doses it takes to reach steady state.
A Half Life Calculator on the web will give you x if you enter half life, interval, and 1 for the dose.
Example: 65 hr half life and 168 hr interval (1 week) gives x=0.166. Peak = (Dose)(1/(1-0.166)) = 1.2 Dose Trough = 0.2 Dose.
That matches the calculation (I eventually got right) for rapamycin. Main difference for resveratrol is half life is around 3 hours instead of 65 for rapamycin. So would need much more regular dosing. I did that for my dose every 3 hours with liposomal resveratrol, although the half life is likely somewhat longer because of liposomal encapsulation, but like you I didn’t notice any great effects. Not sure why, but the great in vitro effects of resveratrol were seen in a dish of mostly senescent cells, something that doesnt tend to happen in even old human tissues. Who knows, maybe our senescent cell population has been rejuvenated. Would we notice?
We all agree that inhibition of mTORC1 promotes longevity and inhibition of mTORC2 is detrimental. One of the known bad effects of mTORC2 is glucose intolerance, which could be measured. Are there any other detrimental effects we don’t know yet? We also all agree that prolonged treatment of Rapamycin inhibits mTORC2. Now what is considered prolonged use? Rapamycin advocates suggest intermittent use such as once a week is considered safe. But nobody has done any research to see whether rapamycin once a week inhibit mTORC2 or not. From the results of readers of this blog, it does seem weekly use of Rapamycin does not cause glucose intolerance. Also, the instruction sheet says half life of Rapamycin for male is longer than for female at 72 hours. So I would definitely take it once every 2 weeks to allow recovery of mTORC2 especially for people who cannot tolerate metformin.
Well we’ve been using the half life calculation to see the max and min doses. You could either recalculate it for 72 hours, or for a smaller dose. I’ll do it for you later. I suspect so long as the min dose converges to some tolerable amount and doesn’t continue to build up, you don’t need to worry about MTORC2.
Hi Mark, I know how to calculate peak and trough concentration using half life. What I am trying to say is that research done on prolonged use of Rapamycin is done on cell lines. “cell lines with rapamycin-sensitive Akt/PKB phosphorylation (PC3, BJAB, Jurkat) had less intact mTORC2 following 1 hr of drug treatment and an almost complete loss of complexes by 24 hr”
Article: Prolonged treatment of Rapamycin inhibits mTORC2 assembly
and Akt/PKB.
It seems to me that we base our assumption that weekly (or intermittent) treatment week after week is not considered prolonged treatment. However on sensitive cell lines Rapamycin presence of 1-24 hours is considered prolonged treatment. Of course in vivo is very different from in vitro. We just don’t know anything in vivo, not in mice, let alone humans. I still believe Rapamycin has longevity effect. I would use it biweekly and take a month or two off yearly just to be on the safe side. Of course everyone is free to design their own regimen.
Well we don’t really know much at all about mTORC2. I would hazard a guess that most of the bad effects are coming from blocking cell proliferation in tissues that need it, hence mouth sores being a good warning sign. I got skin problems when I took too much (with grapefruit juice – not a good idea). From the in vitro studies I’ve seen, mTORC1 seems to be knocked down very effectively within 4 hours; i don’t know any cells that need to replace that quickly.
In vitro they just keep the cell in a constant solution of whatever compound they are studying, so that would be the equivalent of you never letting the rapamycin cycle out if your system. Taking breaks of weeks or a month every so often might be a good idea if you’re worried.
Well we know from Alan that you can take a 6 mg dose once a week for two years now with no apparent adverse reactions. I’ve been on a weekly dose for 6 months and show no evidence of immune deficiency. It would show itself as stomatitis, delayed wound healing, prolonged infections or bacterial superinfections . We also know from one study on The elderly that the immune response went up by 20% on rapamycin.
So it’s not apparent to me that TOR2 is being significantly inhibited.
I’m also not aware of hyperglycemia being an effect of TOR 2 inhibition. Blagosklonny makes it rather clear that it’s a benign condition frequently associated with rapamycin therapy.
I’ll stick with weekly until I see some evidence that it’s dangerous.
Wikipedia under mTORC2:
“Loss of mTORC2/Rictor in pancreatic beta cells results in reduced beta cell mass and insulin secretion, and hyperglycemia and glucose intolerance.”
Yes but that’s more of a classic diabetic state, almost like type 1 from damaged beta cells in the pancreas, and not the starvation diabetes pattern seen with rapamycin, as well as those countries where food is very scarce. With rapamycin your cellular TOR is sensing very low nutrient levels, as a response you develop a certain degree of hepatic insulin resistance which allows for continued gluconeogenesis so that your brain always has an adequate glucose supply.
This is quite distinct from the disease state of diabetes where there is generalized insulin resistance and concomitant organ damage. That is not the case with rapamycin taken on a weekly basis.
For instance, my FBS went from 100 baseline to about 115, but
My renal function actually improved by 10%. Also , a diabetic will get a massive jump in blood sugar with any type of infection, but in the presence of a brief viral illness my FBS didn’t jump even one point.
But like Blagosklonny says, if it worries you just take metformin, and it’s all reversible upon stopping the drug.
“Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity”
Dudley W. Lamming etc.
Hi Cassia,
Very good points.
Best indication of inhibition mTOR2 is apthous stomatitis. In recent 1 mg/day study few people out of 12 had these mouth sores. That shows some inhibition mTOR2.
Inhibition mTOR1 and mTOR 2 not associated increased lifespan.
Note in Mannick 12/2014 study 5 mg a week rapalog less mouth sores than controls.
I don’t think they showed 1 mg/daily is safe.
“Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco carcinogen-induced murine lung tumors.” The multiplicity of tobacco carcinogen induced lung cancer was decreased by 90% with Rapamycin treatment in mice.
Interesting for smokers or former smokers.
Hi Cassia. That study used a daily dose of rapamycin so it did what we expect, blocked fast proliferating cancer cells via mTORC2 inhibition.
The results I cited was using every other day administration. ????
5 of 7 days I grant you, from the paper:
‘Rapamycin was administered on a daily (5 of 7 days) regimen’.
That would definitely effect mTORC2.
“Comparing this regimen with an every-other-day (qod) regimen revealed that rapamycin levels were better maintained with qod administration, reaching a nadir of 16.4 ng/mL, a level relevant in humans. When begun 1 week after NNK, this regimen was well tolerated and decreased tumor multiplicity by 90%. Tumors that did develop showed decreased phenotypic progression and a 74% decrease in size that correlated with decreased proliferation and inhibition of mTOR.”
Hi Mark, Hi Paul,
I am not trying to be argumentative. I am only trying to look at things from all the safety concerns I can think of. Even though I don’t know anything about medicine, I have a M.Sc in biology and did some cell culture and some other research on drug induced diabetes in rats in my youth. Probably because my background in basic research, I sometimes get stuck with little details. I apologize if I sound aggressive or offensive.
No you’re quite right Cassia, we need you to push the details so we get this right. I still think this study , which aims to maintain a certain level of rapamycin in the blood, is not applicable to our intermittent usage, especially when a low dose is used.
Hi Mark
Agree
1 mg a day is worst of both worlds.
M2 inhibition shown by mouth sores.
Too low a level M1.
No not at all offended Cassia. It’s a great and very important discussion!
I wonder if you have followed up on Metformin causing Alzheimer’s due to AMPK over activation and autophagy of dendrites that I mentioned to you back in August 2015. on your thread of Is Metformon an Anti Aging Drug? :Here is a quote from the Scripps News Press release, “In addition to having implications for Alzheimer’s drug discovery, Polleux noted the findings suggest the need for further safety studies on an existing drug, metformin. Metformin, a popular treatment for Type 2 Diabetes, which causes AMPK activation.
“https://www.scripps.edu/news/press/2013/20130410polleux.html
Here is the PubMed study. https://www.ncbi.nlm.nih.gov/pubmed/23583109 “The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation.”
If there is a link with Alzheimer I wonder if that is mediated by metformin reducing the B12 level which is quite known but can be easily compensated by supplementation and recommended. Did Polleux followed on that? The real question would be whether or not metformin, without any compensation for the induced deficiency in B12, would be causative: at least I recollect many conflicting studies on the for/against of the AMPK activation.
There was a study in 2016 which showed a 76% decrease in risk with metformin and then a study out of Taiwan in 2017 showed just the opposite. . Maybe it has to do with dose, duration, underlying diabetes, and who knows what, but this needs to be sorted out.
Here is another quote from the article, “In 2011, he and his colleagues reported that AMPK overactivation by metformin, among other compounds, in animal models impaired the ability of neurons to grow output stalks, or axons. Around the same time, separate research groups found clues that AMPK might also have a role in Alzheimer’s disease.”
There is a probably a sweet spot for AMPK activation – more is not necessarily better, rather like how you wouldn’t want to totally blockade mTOR, but intermittent inhibition is very beneficial.
I remember an in vitro study with ALCAR vs methylene blue, and MB was much more successful at extending the life of the culture. Strong AMPK activation was much too severe.
Neurons have many mitochondria (far more than even heart cells), and their functioning is paramount to cognition.
What are some of the dangerous interaction with Epithalon?