Last week Len Guarente announced his company will be selling a proprietary formula based on NR, the NADH precursor. This week, there’s an article about a project at Novartis to make a safe anti-aging pill from rapamycin. I’m more excited by the latter than the former.
An MIT Lab offers NADH plus Blueberries
Several readers have asked my comments on the Guarente formula, being sold through Elysium Health. Len Guarente is a solid, innovative scientist who has contributed a lot to our field and trained several students who went on to make substantial contributions of their own. He’s also an honest guy, with his heart in the right place.
The formula he plans to sell consists of Nicotinamide Riboside and pterostilbene. I wrote about NR a in November. I’m not convinced. It’s just too easy to extend life span in worms and flies–much more difficult in mice and people. I have see no data on NR and life span in mice. The most promising results I have seen show that NR slows progression of Alzheimer’s Disease in mice that are genetically engineered to be susceptible to AD [ref].
Pterostilbene has a chemical structure similar to resveratrol, and it is thought to be one of the beneficial components in blueberries.
Pterostilbene shows the same kind of benefit as NR in the mouse model of Alzheimer’s [ref], but it does not extend life span of outbred mice [ref].
The press release about the Elysium product claims that there is an expected synergy between NADH and pterostilbene. Len knows a lot more than I do about genetics and biochemistry, and I’m inclined to give him the benefit of the doubt. But I don’t think that theory about the biochemistry of aging is in any shape that we should rely on it without direct evidence, and I look for that evidence in mammals.
Rapamycin from Novartis
There’s an article from Bloomberg today about research at Novartis toward an anti-aging drug based on rapamycin. Rapamycin has the opposite issues from the Elysium product. It works great extending life span in rodents, but it is a powerful drug that may have too many side effects to be considered for general use by people who aren’t sick. It’s also prohibitively expensive for most of us, though it is not as difficult to get as it was a few years ago when the dramatic effect on mice was first announced in Nature.
The reason rapamycin is scary is that its primary use is as a powerful immune suppressant, preventing rejection by people who are receiving organ transplants. If rapamycin makes the immune system tolerates someone else’s kidney (so the reasoning goes), what else will it tolerate? Cancer cells? Invading viruses? Herpes? The Bloomberg article hints that rapamycin may be more selective than that, and there is at least one study which seems to show that a drug acting on the Target of Rapamycin (TOR) can enhance the immune response as well as suppressing it.
Novartis is not trying to market rapamycin, but to look for variants that might have the same benefit without the side effects.
The article mentions Mikhail Blagosklonny as a prominent researcher who has enough faith in rapamycin to take it himself. He has written an article making the case that it acts directly on the core of the aging metabolism. It really does slow aging.
“Some people ask me, is it dangerous to take rapamycin?” Blagosklonny says. “It’s more dangerous to not take rapamycin than to overeat, smoke, and drive without belt, taken together.”
For counterpoint, the Bloomberg article quotes Valter Longo,
“Rapamycin works on pathways that are too fundamental to normal cellular function to be used as a drug in healthy people until we have much more safety data,” says Valter Longo, a professor at the University of Southern California who discovered key pathways related to TOR. He points out that periodic fasting also shuts down the same pathways, without the side effects.
This same Bloomberg article mentions a claim by Brian Kennedy that metformin lowers mortality in diabetics so well that it’s actually 15% below mortality rates in age-matched non-diabetics [ref]. This is a remarkable finding, the best we can hope for, since there are no long-term data on effects of metformin for people who are not diabetic. It contradicts several meta-studies [ref, ref] that find no net mortality benefit for metformin. (I think that the balance of evidence favors metformin, and I take it myself. If you are overweight or leaning to high blood sugar, you might consider it.)
The Bottom Line
We are at a stage in the science where there is much promise and little certainty. How do we decide when to take a chance and what to take a chance on? All the scientific data are still only half the input; the other half is in each of us as individuals. There is a reason there is so much scatter in the statistics, and even inconsistency from one study to the next. We are all unique individuals, both in how our metabolisms respond to drugs, and in what we want out of life. We may try to choose a strategy for the long haul, but if a treatment helps us feel more energetic or more alive or better balanced in the short run, that is and should be a part of the choice that we make. I have written about my experience with low-dose deprenyl, which I take for life extension, but which also loosens my inhibitions a bit in a way that I appreciate.
A part of the calculus which is rarely discussed is our stage in life. The older we are (and the worse our health), the more inclined to take a risk on some treatment that may be our last best hope. I am 65 and can still hike all day, but I may have run my last marathon. I attend to the changes in my body from year to year, and I am willing to take some risks to slow down the loss. My friend, Stan, still works long hours at two psychiatry clinics at 86, and dances on the weekends. He is more willing than I to take a flier on a new idea. I hear rumors about 90-year-old tycoons who…but they are only rumors.
I am saddened when a prominent member of the anti-aging community consents to request for treatment with Lupron by his 12-year-old son. Lupron blocks testosterone and delays puberty. The boy should know that he will have far better options for a long and healthy life as science continues to progress. I tell my daughters, in their 20s, to take good care of themselves and plan for a life of 200 years. In the near future, aging may no longer be the dominant risk to our health and wellbeing. I am more confident that tomorrow’s technology will be there to delay aging for our children than I am in our collective ability to deliver to them intact ecosystems that support human life.
Visomitin Eye Drops — a Personal Follow-up
Last year, I wrote about a product developed by Vladimir Skulachev, veteran biochemist at Moscow State University, that targets Coenzyme Q to the mitochondria. It is available as eye drops, which in lab studies have brought horses and dogs back from the brink of blindness. (A closely-related molecule is available in pill form and as a cosmetic from Mito-Q, New Zealand.)
I have been taking Visomitin eye drops for a year and a half, and had an eye exam at the start of this period, and again this week. Results of the two eye exams were just about the same. Perhaps the beginnings of yellowing of the lens, an early stage of cataracts. I am fortunate to have eyes that focus well at mid-range (slightly myopic), so I still am comfortable without glasses most of the time. But over this year, I noticed that there are more times when I reach for reading glasses.
If any readers have personal experiences to share with Visomitin, with Metformin or with Rapamycin, I hope you will comment below.
I’ve been waiting for someone to use rapamycin as an anti-aging therapy. If the drug acts as suspected by encouraging autophagy (and mitophagy in particular), perhaps it could be administered on a discontinuous basis – say a week’s treatment followed by a period of several weeks of ‘recuperation’?
It’s certainly not my idea of the solution to aging – but perhaps a step in the right direction.
Interestingly, we’ve seen one protein the inhibition of which extends life-span (mTOR) and now it appears that MYC is to be added to the list of proteins which when inhibited increase lifespan (by about 15% when MYC is present in a single copy instead of two).
Well, what I like about all this is the fact that you have now big companies offering products (or announcing them) that should prolong your life and health span.
It looks to me that game is on! 20 years ago talking about this was in vocabulary of pharmaceutical giants.
I never thought that right approach is through different organizations that we have. Maybe those organization played the role of spreading the right massage, but I don’t see them as major players in the future.
Big money is somewhere else and big money needs to see opportunity to become even bigger. Now you will have companies offering better and better products for less and less money. Think of your cell phone 20 years ago.
This still doesn’t mean that we will have successful anti-aging strategy in near future, but at least it looks like we have finally started to move in the right direction.
Josh, have you looked up a person by the name of Marios Kyriazis? He seems very big on the idea that N-acetylcarnosine eye drops can cure cataracts.
This is an older interview:
I’m looking for a newer one.
He does seem to be active on Quora:
Thanks, Chris. I do know Marios and have worked with him, but I wasn’t aware of the carnosine eye drops.
It’s just another form of Carnosine.
A quick check of these drops on Amazon:
They’re not too expensive, and there are at least some positive reviews. Obviously we should not rely on Amazon as the end all be all here, but at least some people have at least anecdotes of getting good results.
There are other questions, with both the drops and with L-Carnosine itself. Kyriazis recommends a lower dosage than most – no more than 200mg/day, versus many of the supplements that sell around 500 mg capsules.
I would love to see some experiments with mice where rapamycin, resveratrol and metformin would be combined all together. To my understanding they all target different pathways, so there might be synergistic effect. Or not…
Don’t forget melatonin and deprenyl. Yes, there is some interesting work to be done here, and the logical person to do it would be Steve Spindler. Remember that Spindler came out with a study of combinations of supplements in mice a year ago, but focusing on supplements that individually had not proven to extend life span.
I was not aware of this study done by Steve Spindler.
Did I understand that his study showed that even rapamycin didn’t work? I thought that we are sure now that rapamycin can be/is beneficial.
In some ways aging resembles interest rate calculation in a way that aging causes us to produce smaller amounts of good things and more of bad things. In return this speeds up aging and so we have one-way aging spiral.
This might be the reason why we could expect some synergy effects. Look at this study:
I wrote about Spindler’s study last year. http://joshmitteldorf.scienceblog.com/2014/03/25/life-extension-supplements-a-reality-check/
Here is Spindler’s article in AGE: http://link.springer.com/article/10.1007/s11357-013-9609-9
And no – though he is a pessimist, Spindler has not claimed that rapamycin doesn’t work. I don’t know why he has spent so much energy focusing on proving what doesn’t work when, as you say, we have much to learn by seeing what pathways overlap, and which drugs offer synergies. We should also be studying dosages for known life extension drugs, both separately in combination.
The drugs reported to work to extend life span in rodents are (to the best of my knowledge):
Two others for which there is data from Russia, uncomfirmed in the West: epithalon and SkQ
I’ve read both of those articles, but it was not clear to me how those mice were fed and I don’t have access to full paper. It looks to me that point of Mr. Spindler is that if you eat proper food (and limit intake of calories) and do proper exercise, supplements will not help you greatly. In a way it makes sense, because most of those supplements target same pathways as CR.
Also, I am not sure how important is Vitamin D in mouse metabolism. Supplementing vitamin D for humans looks very important (usually)
That being said, I don’t expect that neither of those drugs will help us live beyond 120 greatly (although even if we get fighting chance to reach 120 it would be great).
I think for next step (reaching 135 or more) we need something else. This is why I look after latest experiments with NAD+ with some interest because it looks like it has different target/approach. Or some strategy addressing epigenetic changes, stem cells (with all its complexity)…
Here is a link to full text of the Spindler article on neutraceutical combinations:
What is your estimation of how far are we, regular people, from latest scientific breakthroughs? This is not some “conspiracy theory” related question.
I don’t think that there are some big hidden truths…
It’s just that maybe there are some things that scientist know (or think they know), but don’t publish because they need confirmation or something like this. Maybe some cutting edge technology which is being developed at the moment.
Do you see some new strategies to fight aging and age related diseases emerging in next 5 to 10 years?
My estimation would be that we are 3-5 years behind.
I’m writing about this subject all the time. I don’t hold anything in reserve. I’ve published both what I know and my speculations that go beyond what I know.
I believe the best prospects in the near term are in the areas of telomere extension and hormone profiles in the blood. I’ve written in this space on both topics. At present, we don’t know how effective they will be.
Love your blog Josh…
So Immune System Modulation appears to extend lifespan… The thing that I don’t get is this…
Why hasn’t the Life Extension Community–and my hunch is that this includes you–found the work of Kevin Tracey, and others, about the Vagus, Heart Rate Variability, Cholinergic Antiinflammatory nexus. It’s all about NF-kB inhibition and we know how important that is.
You’re not alone in never having written about it. Watson and Giuliano recently did a terrific post about HRV and obviously never came across Kevin Tracey.
I’ve created a few slides that illustrate why this is something we need folks like you to be thinking about…
Led by Karolinska Institute Honorary Doctorate, Kevin Tracey, dozens of scientists, in at least a hundred studies, with a first milestone study published in 2002, have been Settling the Science of our Innate Antiinflammatory process for Modulating Innate Immunity, the Cholinergic Antiinflammatory Pathway. The CAIP is Triggered by Vagus Nerve Stimulation and/or acetylcholine agonists, is responsive to Neuronal Muscarinic M1 Receptors, Inhibits NF-kB, and its effect can be measured by a computed statistic, Heart Rate Variability. And Higher HRV has been shown, in innumerable studies, to be profoundly correlated with Longevity, with Lower HRV correlated with increased Morbidity and Mortality.
And yet, the Life Extension Community completely oblivious to his work. Rapamycin? Instead, why not work at Optimizing the Innate Antiinflammatory process that Evolution itself came up with for us?
Can we get some help from the SENS folks to repair the damage over time to Vagus Nerve Signaling?
I understand that Tracey’s work is easy to miss… I found him by accident and describe how that happened here…
I recommend the following study as the place to begin with Tracey… Great graphic figures…
And Tracey’s latest study summary from 2012 is a Must Read…
Reflex Principles of Immunological Homeostasis
Love your blog, Josh. Looking forward to your insight about the implications of the Vagus-CAIP-HRV nexus for the Life Extension Movement…
I’d like to hear from Life Extension Movement thought leaders like you Josh … Please explain why we’d want to do Rapamycin before we take a seriously look at optimizing Vagus-CAIP-HRV functions…
Thanks, HDW – I’ll add Kevin Tracey to my reading list, but I ask your indulgence for awhile because I’m backlogged with things I want to read.
I’ve been on this Nicotinamide Riboside path for 390-days now. I’ve also closely followed the work of Leonard Guarente as many of your readers have. To begin with, I didn’t approach this avenue from a longevity standpoint, personally I had some inflammatory issues that literally began to affect my livelihood and I needed a solution my doctors failed to deliver. So I’m not here to debate the wishful thinking of the longevity crowd, I had severe debilitating issues and now I can once again keep up with the demands of my job which I attribute to the benefits of NR.
So Josh, I agree we can not readily scale the findings of yeast and worms to large mammals like us and expect similar results. http://genesdev.cshlp.org/content/27/19/2072.full I for one don’t see chasing the results of CR induced cellular changes as an end path to longevity for humans, its not that simple.
However this whole endeavor of study has cast a light on cellular repair and upkeep mechanisms that all require adequate NAD+, NADH and ATP levels to accomplish these tasks. Let’s also not forget the new emerging science of histone acetylation, DNA methylation and epigenetics which continuously adapts our DNA to changes in our environment. The availability of energy substrates such as NAD is necessary to at least maintain the status quo without decline.
In fact studies have shown that Nicotinamide Riboside helps induce mitochondrial biogenesis http://www.sciencedirect.com/science/article/pii/S1550413112001921 and anything we can do to halt or reverse mitochondrial decline due to aging can only benefit us in the long run.
So I do believe that there are enough facts in to suggest that there are a whole host of benefits to increasing intracellular NAD+ levels. At the moment NR seems to be the most efficient “Orally” administered path.
Keep you posts coming because many of keep up with your commentary, which is always thought provoking.
Link bellow is connected to this topic:
It gets really interesting after minute 17 of the clip.
Dr. Sinclair talk about altering epigenom – something, I believe, you Josh find very important…David Sinclair talked about this few months ago, but he didn’t say much – just that they had some success with rejuvenation with epigenetic changes. At that time he just said that paper will be published very soon.
This time he said that they are using CRISPR technology. I don’t remember reading about this in 2014…My bad for sure…
Is there (could there be) something in all this?
It’s also interesting to see how all anti-aging industry evolves and how it looks we have better and better products…
Can you tell me how and whereI may purchase Visomitin eye drops ? I have emailed Mitotech several times but have gotten no response. Thanks!
PS I am a physician specializing in geriatric, psychiatry and antiaging with a lifelong interest in longevity research. I am 69 yr and have practiced the usual lifestyle choices generally recognized to promote wellness. In addition I take multiple supplements including MitoQ, Niagen, Protandim, AMPK activators, green tea, L carnosine, resveratrol and many others. I am considering adding Metformin and telomerase activators such as product B or TA65; have been reluctant to take the latter for years due to Vince Guiliano’s opinion that it will not extend lifespan and lingering cancer concerns. What is your thought on telomerase? Thanks for your great articles that continue to help educate and inform all of us in the antiaging community !
PSS I’ve been using Acetyl L Carnosine eye drops for my 17 year old dog for several years. It may have been helping to slow down the nuclear sclerosis process but not reverse it; hence would like to add Visomitin if I can find a source.
Visomitin is not licensed for sale outside Russia.
Please clarify whether you mean “Acetyl L Carnitine” or “N-Acetyl Carnosine”.
First thing I wish to say is that I really appreciate the information and perspective you provide here. It’s a gift.
I’d like to share info about Berberine, which seems to have similar positive effects as Metaformin, but has no known side effects nor requires a prescription.
I first learned of Berberine from Dr. Wright who wrote about it here http://www.tahomaclinicblog.com/berberine-diabetes/ and cites several studies that underscore how well it controls blood sugar: “Compared with metformin, berberine exhibited an identical effect in the regulation of glucose metabolism, such as HbA1c, FBG [fasting blood glucose], PBG [blood sugar after eating], fasting insulin and postprandial insulin [insulin level after eating]. In the regulation of lipid metabolism, berberine activity is better than metformin. By week 13, triglycerides and total cholesterol in the berberine group had decreased and were significantly lower than in the metformin group (P<0.05).”
Josh, can you send me the link to your one page pdf on healthy aging suggestions – thanks
I don’t have a pdf, but the page you are seeking is AgingAdvice.org.
This is fascinating and I would love to try “Basis” but I am a former cancer patient and take several medications and don’t know how it might react with those….
Hi Josh, if you want to run a marathon, you need to start taking Niagen about a week or 2 before the run. Take 2 pills per day. You will be surprised at your running endurance when taking Niagen. At least try it for a month!
Josh,do you know any of the Nobel Laureats on Elysium’s advisory board?
Any other thoughts on the NR not so much as an age extension,but as a health span agent.
Would you have Harold Katcher’s email? Rob