Didier Coeurnelle on Advocacy and the Transition Years for Rejuvenation Therapies
The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed Didier Coeurnelle of the Healthy Life Extension Society (HEALES), a long-standing advocate on the European side of our community who has promoted research and development of therapies to treat aging for many years now.
Insofar as the treatment of aging goes, we are living through the early stages of an enormously important transition, a tipping point in the progress of medicine. It will be of far greater impact than the advent of antibiotics. The development of rejuvenation therapies, treatments that can reverse or repair or bypass the known root causes of aging, will bring sweeping change and improvement to the human condition. The first legitimate, functioning rejuvenation therapies already exist, senolytic drug candidates that can remove a sizable fraction of senescent cells from old tissues. These drugs are in some cases very cheap, being generic and widely manufactured for other uses, but the world at large has not yet caught up to this point. The millions of older individuals who might benefit from removal of senescent cells do not yet appreciate that with just a modest effort, they could most likely experience significantly improved health, a reduction in the burden of aging.
Nothing happens quickly. It will take time for the realization to percolate. For the human trials to complete and be publicized, and then for people to understand the implications of the results. The usual suspects are ahead of the wave, by which I mean some researchers, some self-experimenters, some venture capitalists, some advocates. Their job at the present time is still largely to persuade everyone else, the people who will one day be customers, developers, and investors. An enormous industry is waiting in the wings to come into being. It will ultimately provide the majority of all medicine and medical services, approaches that will control the progression of aging and put an end to age-related disease. It is inevitable, but the necessary steps along this road are running all too slowly, for reasons that have little to do with the technology and everything to do with human nature.
An Interview With Didier Coeurnelle
You have been an advocate for quite some time now; how successful do you think collective advocacy efforts have been over the years?
Not enough yet and not fast enough. The "pro-aging" narrative is, sadly, powerful. Defeating aging looks "too good to be true" and makes people feel uneasy. However, there are changes. For example, in the French-speaking world, sometimes we see articles about "amortalité" (life without senescence) in the press; a few years ago, you would see only articles speculating about billionaires wanting "immortality" (which makes people afraid).
In November, HEALES will organize the next Eurosymposium on Healthy Ageing (EHA). EHA and Undoing Aging each have a section focused on advocacy. Why did you decide to include it?
I think most scientists wanting big progress for longevity know that having public opinion on our side will help. Also, PR is useful in order to raise money. However, many scientists feel uneasy about these issues. That's why we decided to have a day dedicated to social aspects. Not all scientists will stay for the last day, and we will also try to reach a larger public on the last day. Another aspect is that Brussels is the European capital. One of our goals is to convince people there. Let's be honest: there is a long way to go. However, for a year or two now, some European civil servants who have been promoting "healthy aging" (we know it is an oxymoron) seem to be very interested in big data on health and scientific research. We will be keeping an eye on these developments.
You don't need to convince people that saving the lives of children is a good thing to do; however, you do need to convince them that saving elderly lives is a good thing. Why do you think this difference exists?
Nor do you need to convince people that defeating cancer or Alzheimer's disease would be good, but death by old age is a step too far. For me, the fundamental reason is a variant of Stockholm syndrome called the terror management theory. Death by old age is awful and unavoidable. We must think that longevity is not better, otherwise it would be too awful to die. This process is unconscious.
How far do you think we are from the point when people won't need persuading anymore, if ever?
Aubrey de Grey said it will be when a mouse becomes "immortal", because people will feel that rejuvenation therapies will be available soon. I think that it could be sooner if more and more scientists start to speak out more about it.
With some luck, the effects of first-generation rejuvenation therapies, such as senolytics, will be tangible soon. Assuming that the effects are measurably positive, how do you think the world will react to the news, and how do you think that this will affect advocacy?
It would be interesting even if senolytics have only a moderate effect. I think some groups who are not in the "longevity camp" will start asking to use them. Maybe, in some countries, they will even start asking for reimbursement from social security programs. Some groups on the other side will probably ask not to use these products or will stress risks, but it will be especially difficult for "deathists" to fight against senolytics, which are, in a way, very classical drugs.
For a mouse to become "immortal" (or 5+ years old and healthy) we'd have to replace a significant percentage of its stem cells in the niche, we'd also have to deal with a fair percentage of its hardy intra-cellular and extracellular wastes. Perhaps cancer and senescent cells are a problem solved well enough for now to get a mouse past 5 years, but the other problems could take decades to demonstrate at the current rate of research.
Maybe with senescent cell removal in humans when it becomes widely known that the drugs confer health benefits on everyone over the age of 35 and will probably extend life by even as little as 5 years, there might be a swing in public opinion and demands for these drugs to be made available to anyone who wants them, not just people with named diseases. Hopefully that will get the public and investors asking what is the next "cause" of aging that could be tackled?
It doesn't need to be full rejuvenation by 5 years. On the other hand, if you can look and feel, and perform like 5 years younger that would be adopted by Hollywood and the big spot because even if it was reducing your lifespan an atheist out actress in her prime can make millions of not greens of millions of dollars before sliding to second place... So the trade-off will be obvious.
Proving that it actually is slowing down the aging would be harder, unless it works very well for the really old cohorts. If it can only reduce the mortality acceleration , it statisticalky slows down the aging. But proving that must take at least a few years, even if using quite creative statistics...
After that the floodgates will open and the friending will enter the mainstream media, and hopefully will get a rush of investments.
As lurker coming out of the closet, I would name the following milestones:
1. First senolitics work
2019 Oisin finishes the p53/p16 mouse study, and hopefully have good results. I wold assingn over 80% probability.
2019-2022 human studies phase I, II.
2021-2025 a few senolitic spin outs either as anti cancer or antiinflammatories.
2019-2020 small molecule senolitics from other companies. Dasatinib kinda works, but we don't know how well and what are the side effects. So 60-70% probability of success . Not too shabby..
2023 venture capital interest in rejuvenation technologies. How much funding coluld we expect? Probably on the same scale as the self driving cars. It is a good comparison because it is hard, but not proven impossible. Will require lobbying, legal changes and will bring social shocks and promises huge rewards. And will safe lives...
I arbitrarily choose the milestone of successfully finishing the senolitics study in mice as as the equivalent of the DARPA self driving challenge. If I am not mistaken, the first self driving car succeeded it in 2005.
And that wold be , with some luck, by the end of the year or really 2019 for the senolitics.
Hi, just a 2 cents. I have finally determined what dictates maximum longevity in any non-progeroid healthy animal, thus what determines its total maximum lifespan and thus its speed of 'normal' endogenous aerobic respiration (O2 fueled) aging.
There was discrepancies, such as why do long lived mammals have Less antioxidation levels than short lived mammals - long lived ones did not Need antioxidation while short lived ones do, as they are excessive oxidative stress load and cell homeostasis loss very rapidly, but then why so many failed studies on antioxidants supplements; they don't extend lifespan or if mitochondrial targeted they do but clearly long lived mammals don't benefit.
Now, I understand why, antioxidants are not needed when long lived mammals have low oxidative stress in the first place, but more precisely antioxidants are Not what determines lifespan longevity in mammals.
Mitochondrial ROS at Complex I and III by O2 ETC respiration and OXPHOS ATP production are the source 'needed' to create the damages that 'age' and oxidize DNA, both mitochondrial and nuclear.
Still then, why do mitochondrial targeted antioxidants not stop aging then? Because it's the Cascade of what happens next after mtROS are produced. mtROS attack the PUFAs of mitochondrial membrane phospholipid. Polyunsaturates DHA EPA ARA are highly peroxidizable and upon their peroxidation, there lipid peroxidation created, which then creates the most important element that determines lifespan :
Reactive Aldehydes (4-HNE, MDA, Acrolein), the aldehydes have immensse mutagenic and reactive toxicity on nanomolar levels and cause catastrophic long persistent chain reaction in the firm of protein adducts, GSH conjugates, Protein Carbonyls, Isoprostanes, glyoxals, even AGEs like CML or pentosidine/crosslinks. But more specifically they cause ALEs (Advanced Lipoxidation Products) and RCs (Reactive Carbonyls). Now, there is proof they determine Maximum Lifespan because studies have demonstrated that antioxidants gene were Not selected for by evolution to optimize longevity, instead Lipid genes and ECM collagen were under selection pressure in the longest lived animals. It makes sense, animals who live the longest show a mitochondrial lipidome lipid composition rearrangement towards monosaturated fatty acids composition because low unsaturation dramatically reduces ALEs production and lipid peroxidation. This was demonstrated in long lived animals's mitochondrial membranes, for example the naked mole rat having a much lower PI (Perodizability Index) and DBI (double index) in the mitochondrial membrane phospholipid fatty acids. The naked mole rat lives 35 years Because of that perk. The mouse lives 3 years, it produces much more Reactive Aldehydes and ALEs, because it has 10 times more DHA in its mitochondrial membranes, this means a much higher PI and DBI. Thus, a much shorter life. C.elegans nematodes mutants (age-1 mg44 f2) lived 250 days, which 10 times longer than regular wild-type C. elegans nematodes (20 days), the longest lifespan extension ever in biogerontology - these ultra long-lived mutants display, not so surprisingly, a particular mitochondrial membrane phospholipid composition reordering. Exactly like what evolution optimized for the longest lived mammals. These mutants had a drastic polyunsaturation reduction, their PI and DBI dropped, their desaturase and elongase enzymes (responsable for polyunsaturation of fatty acids)
reduced in activity, just like humans who have low enzymatic activity of desaturase/elongase. It amounts to low polyunsaturation and high Saturation. Saturated fatty acids are Extremely Resistant/Unsusceptible to mitochondrial ROS causing lipid peroxidation. What is the meaning of this?
Much lower production of ALEs and Reactive Aldehydes that are the Major contributors to oxidative stress caused damages to mitochondrial DNA and nuclear DNA. These end products of lipoperoxidation Dictate Maximum Lifespan. How so? Because they create protein carbonylation, protein unfolding, protein denaturing, protein aggregation, macromolecular changes, extracellular matrix destruction, crucial proteins are destroyed directly by ALEs and Reactive Aldehydes, from the lipid peroxidation chain at the mitochondrial membrane phospholipid. This, in turn, causes severe oxidative stress manifested as DDR signaling at telomeres and mitochondrial DNA lesions formation (8-oxo-dG, 8-oxo-dG is inverselycorrelative to MLSP in mitochondria)/mtDNA deletions after that, once sufficient mtDNA lesions form..Over time, damaged mitochondrias will face ATP energy production catastrophic loss. The cell will be energy starved, causing apoptosis. At the body level, this manifests as 'aging', your organs are aging, until threshold too much dysfunction - dying.
Plus, now I get why the GSH redox determines lifespan, it's not its antioxidant function -it's its DETOXIFICATION function that regulates lifespan - redox GSTs (Glutathione S Tranferases) detoxify Reactive Aldehydes and ALEs, in fact, 4-HNE is directly detoxified by GSTs and GPXs (Glutathione Peroxidases). Also, naked mole rats maintain a pristine redox for over 20 years, mice don't. Proving, that mitochondrial ROS lipid peroxidation chain causing Reactive Aldehydes and ALEs are the ultimate cause of why we 'age', and why the longest lived animal such a bivalve quahog (clam that lives for 500 years), has a low PI, DBI, low mtROS, low protein carbonyls, low Reactive Aldehydes and low ALEs - all its life. It keeps its mitochondrial environment pristine and it detoxifies any lipid peroxidation chain Reactive Aldehydes and ALEs.
Just a 2 cents.
@Cananomymity: So what kind of diet should we be eating to optimize or lifespan at present? Is the Mediterranean diet with an emphasis on monosaturated oils such as olive oil and avocado oil, but without the fish, since fish oil is high in DHA and EPA cause more oxidative stress, the way to proceed with diet? Or, what do you propose as a better diet for lifespan extension from your discoveries? Thanks in advance.
Hi Biotechy, thanks for asking. There is this thing going around that the paleo diet is 'the thing' (high amounts of meat, very low carbs and high fat), but it's not healthy in the long run. Food diets Studies demonstrated that this diet increases mortality, due to animal protein consumption, it was shown that animal protein is less stable than vegetable protein. The amino acid composition of animals has a stronger effect on myocytes/muscle fiber generation via IGF mTOR growth factors. You can pack more muscle on animal protein than vegetable protein. But, there is a problem, as said, animal protein 'structure' is less stable than vegetable protein, it can cause cancer/rogue cell mutagenic formation more than vegetable one. Also, certain bovine/ovine meats are raised on bad food (not freed grass pasture fed) and antibiotics injected, these animals are unhealthy and create unhealthy meat. This goes down the chain to humans who consume it, toxic food. Also, this bovine/ovine meat can contain higher levels of Methionine amino acid in its protein content, high intake of Methionine causes premature mortality, because Methionine raises Homocysteine levels (homocysteine levels are raised in nearly all pathologies from heart arrest to high blood pressure, it oxidizes the cell redox during transsulphuration pathway), plys Methionine was selected by evolution for elimination since it is far more susceptible to ROS amino acid attack and amino acid 'racemization', thus a weak link. Mice that are fed a Methionine-restricted diet have lifespan extension via AMPK, mTOR inhibition, just like Calorie Restriction diet, By redcing Methionine a hormesis effect happens and thus longevity effect. Bovine/ovine meat is a substantial source of Methionine). Plus, Very Low Carbohydrate intake is poison also, causing Hypoglycemia attacks, and paradoxally increases Glycation via extreme production of Glucose by the liver glycolysis pathway. And, very low carbs deprives the brain that Needs them from proper neuronal function (very low carb can cause brain fog, comatosis, heart bradycardia, hypotension, blood gas osmotic change, death). Carbs are needed (150 gr per day at least) to regulate blood glucose levels and mess insulin signaling response. Also, carbs are energy fuel 'kJ' converted to calories for energy consumption. Too little of them you will be weak, your mind sluggish. Carbs and Glucose in Excess are just as bad and contribute to diabetes hyperglycemia and hyperinsulinemia... Eat them, in moderation, 150gr Carbs for 600-1500 calories a day.
Same thing for 'ketotic diet', good but also bad over long term, by formation of ketotic bodies/ketones which acidify the cell and can cause ovvert hormesis just like a Calorie restriction diet, they work on the same pathway by activating Autophagy.
Same thing with high fat, high carbs diet, very bad (it caused my atherosclerosis).
The trick? Moderate carbs with Moderate to low fat intake. Nut oil fat is better than animal saturated fat. Low sugar/sucrose/fructose intake and low sodium intake.Moderate vegetable protein intake. High antioxidants by vegetable intake combined with herbal/spice phenol intake. Avoid excessive fruit intake (fructose is 10 times more AGEs causing than sucrose or dextrose, natural sweetners like Stevia leaf or rhubarb are healthier).
This emulates the Mediterranean diets, but not just this one. The longest lived people are centenarians from the Blue Zones where pockets of centenarians live, suck Greek Island, Okinawa Island, Bulgarian place, South Adventist, Mormons, Latter Day Saints, USA Utah, and California, Peru, and few others. All of them eat a mixture of healthy foods, like vegetables, whole grains, moderate fruit and nuts.
Olive oil and avocado oil do improve mitochondrial lipid composition towards monounsaturates incorporation, which does help longevity wise (Jeanne Calment bathed all her food in extra virgin olive oil, she is the oldest human at 122 years), But, excess fat is dangerous depending on its fatty acids composition - saturated fat oils and Trans-saturated fatty oils can form atherosclerosis, Even olive oil or avocado oil, I know I went throught it. Eating tons of extra virgin olive oil from Greece contributed to my atherosclerosis progression. I stopped it completely and I'm still alive to tell you about it. The extra olive oil fat did not improve my atherosclerosic plaques and lesions, it increased it via excess liver stearoyl Cholesterol production, LDL production. My HDL cholesterol did Not improve on olive oil or nuts, I cut them all out. I had to drastically cut fat intake, only recently have slowly reentered very low dose monounsaturates and polyunsaturates fats in my diet. It is that fragile. Plus, one study had fed saturates to atherosclerotic rabbits, they all died of atherosclerosis. Anpther study fed Extra virgin olive oil to monkeys with atherosclerosis - they all died of atherosclerotic plaque rupture causing embolism by blood clot.
This means, fat intake is important but cannbe detrimental in a unhealthy state and Contribute to death, while it may have benefits in healthy people not pathology stricken. I reversed my atherosclerosis by Increasing HDL OVER LDL, this way I restored correct cholesterol composition, atherosclerosis is reversed the minute LDL species are replaced by HDL species. HDL signals macrophage invasion termination and inflammation stoppage. Thus, LDL stops accumulating in atherosclerotic lesions and thus atherosclerosis plaques are 'stabilized'. That's how I was saved.
Omega3 EPA DHA from fish oil improve membrane fluidity at the cost of increased lipid peroxide formation. Your brain needs Omega3 EPA DHA to function at its best, neurons rapid firing depend on a fluid membrane kinetic in the neurons mitochondrias, But polyunsaturates EPA DHA Increase mitochondrial damage by ALEs and Reactive Aldehydes over long term, in humans the cost vs benefit is better for benefit and outweigh the cost: your IQ is dependent on DHA EPA levels, low levels increase mental rwtardation. Children who show low brain IQ oftenly suffer brain delipidation by lack of brain omega3 DHA EPA. The only way to counter high polyunsaturates lipoperoxidation Is Detoxification of its end products (ALEs, aldehydes) or, less so, mitochondrial ROS scavenging, since it's the source.
Just a 2 cents..
2 CANanonymity
I am not ready to agree with you on a harmful role of fats, but on a practical note look at supplements that have a sulfonic acid group like Taurine, TUDCA, Trodusquemine as there is some evidence that they could help to inhibit the formation and even reduce existing plagues.
http://www.clinsci.org/content/ppclinsci/131/20/2489.full.pdf
https://www.ncbi.nlm.nih.gov/pubmed/23224908
https://www.ncbi.nlm.nih.gov/pubmed/25443293
@Biotechy
Fish consumption is associated with lower all-cause mortality
https://academic.oup.com/ajcn/article-pdf/105/6/1462/23801196/ajcn153148.pdf
and reduced Alzheimer's risk;
the beneficial constituent might be beta-parvalbumin:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882657/
CANanonymity, CD: Thanks for the comments on diet and fish...I guess I will definitely keep on eating fish and getting some Omega 3's in my diet. Regarding the HDL to LDL ratio you may have hit upon the main element in keeping the blood vessels clear of plaque and keeping atherosclerosis at bay. A Harvard study found that 50K men drinking 1 to 2 drinks of wine/day for 2 years had a 26% reduction in heart disease. Alcohol, when metabolized in the liver is known to cause a increase in the good HDL C levels. In fact another study of Type 2 diabetics drinking 1 glass of red wine/day for 2 years, had a 9.8% rise in HDL. In fact, Jeanne Clement, the oldest know human, drank port wine daily, which probably raised her HDL level and kept her blood vessels clear and increased her ultimate lifespan. The trick, of course is, don't drink more than a drink or 2 a day, as higher levels of alcohol can cause increased cancer and dementia risk among other health problems.
Just as an alternative opinion (from a vegetarian standpoint), I get all the Omega 3 I need from flaxseed in my daily bowl of porridge oats. Wholegrain oats also being a great cholesterol 'destroyer'.
As I mentioned, much of the benefits of fish consumption may be due to the beta-parvalbumin, not the omega-3's. Results of trials of omega-3 supplementation overall have not been all that impressive, regardless of source (fish, algae, plant). Flax probably has health benefits for males stemming from the lignan content, but as for DHA, an algae oil supplement might serve better.
https://www.karger.com/Article/FullText/345599
It is unfortunate that people who can't consume fish for ethical reasons can't get all the benefits. Blocking alpha-synuclein formation has implications beyond prevention of the synucleopathies. I'm not so sure all the root causes of aging have been correctly identified at this point in time, but protein aggregation is one I would put some money on. It would be great if someone could produce a GM yeast derived beta-parvalbumin supplement, or better yet developed a drug that would block alpha-synuclein formation even more efficiently and without the allergy concerns. As it stands, it appears the best veg alternative would be green tea:
https://www.ncbi.nlm.nih.gov/pubmed/27364962
@CD: Thanks for those two well-made points. I also have a Green Powder supplement in my diet daily that includes green tea extract so hopefully I have most of the bases covered.
I'm sure you're doing much better than most - pretty sure you'll outlive me at any rate.
A downside to fish consumption is of course the contaminants (PCBs, dioxin, mercury, etc.), so that's another reason to want a supplement/drug that can do the same or better job. It's interesting that Alzheimer's risk shows a fairly robust association with fish consumption but Parkinson's doesn't. That might be due to contaminants cancelling out the benefits or it might be due to Parkinson's having lower prevalence (I regret never taking an epidemiology course). Or it may be that beta-parvalbumin consumption isn't actually beneficial...