I’ve been in the field of aging research from the late 1990s, just the time when Aubrey de Grey was getting his start. Before others, Aubrey had the vision to realize that cancer, heart disease, and Alzheimer’s would never be conquered without addressing their biggest risk factor: aging.
From the beginning, I admired Aubrey’s successes in communicating with scholars and the public, and I reached out to him. He has always been gracious and supportive of me personally, appreciating the large common ground that we share. There is, however, one foundational issue on which we disagreed from the start.
Aubrey regards aging as an accumulation of damage. Evolution has permitted the damage to accumulate at late ages because (as Medawar theorized in 1952) there is little or no selection against it, since almost no animals live long enough in the wild to die of old age. Aubrey’s program is called SENS, where the E stands for “engineering.” The idea is to engineer fixes to the 7 major areas where things fall apart with age.
I regard aging as a programmed process, rooted in gene expression. Just as we express growth genes when we are in the womb and ramp up the sex hormones when we reach puberty, so the process continues to a phase of self-destruction. In later life, we over-express genes for inflammation and cell suicide; we under-express genes for antioxidants, autophagy (recycling), and repair of biomolecules. I believe in an approach to anti-aging that works through the body’s signaling environment. If we can shift the molecular signals in an old person to look like the profile of a young person, then the person will become young. The body is perfectly capable of doing its own repair, and needs no engineering from us.
Over the years, research findings have accumulated, and both Aubrey and I have learned a thing or two. I’m happy to say that our favored strategies are converging, even as our philosophical underpinnings continue to differ.
A unifying idea in my research has been that aging is an evolved adaptation. This is a statement about evolutionary biology, but I came to it before I studied evolution, by looking at the phenomenology and genetics of aging.
- The body does not appear to be doing its best to stay young. We can see this because when the body is under stress, it has less available resources, but manages to a better job of protecting us from aging damage. This phenomenon is called hormesis.
- There are single genes that can be disabled, greatly extending lifespan in worms. Some of these have no known detrimental side-effects (pleiotropy). These could only have persisted in the genome if natural selection is favoring aging for its own sake. Similar genes exist in higher organisms, though their effects on lifespan are not as dramatic as the 10-fold increase in worms’ life expectancy in worms that comes from eliminating both copies of AGE-1.
- Most genes that affect the rate of aging have been around for a long time, and do the same job. This means they are evolutionarily conserved. For example, insulin is the most effective modulator of aging in mammals (including humans). In higher animals, insulin is secreted by the pancreas, from whence it regulates blood sugar and fat storage. But yeast cells existed half a billion years before the first mammals, and have no pancreas, as my friend Barja has pointed out; and yet insulin was already a primary modulator of aging in yeast.
Programmed aging and optimism
There was a time when I spoke of “aging genes” and looked for drugs that could jam their targets and turn the genes off. Meanwhile, the science of epigenetics, or gene expression, was coming of age, so to speak. We learned that genes are turned on and off, not just in different tissues, but at different times of life. I came to think less in terms of “aging genes”, more about multipurpose genes that are deployed in appropriate combinations when we are young, keeping us strong and healthy. But as we get older, the proportions change. Aging is not accomplished via new mechanisms of self-destruction, which evolution invented for that purpose. Rather, the proportions are re-shuffled and change gradually, with effects that are more and more detrimental over time.
- For example, the immune system is vital for protecting the body, but it becomes indiscriminate with age. In older people, the immune system fails to protect us from microbial infections, and simultaneously, immunity turns against the self. Autoimmunity contributes to arthritis and to Type 2 Diabetes (metabolic syndrome), as well as playing a role in AD.
- For example, p53 is a gene that promotes apoptosis, or cell suicide. We need for cells to be smart enough to destroy themselves when they are infected with a virus or if they are cancerous. But later in life, apoptosis is on a hair trigger, and we lose muscle and nerve cells that are still healthy and functional.
- For example, inflammation is used as a primary defense against microbes, and a way to eliminate tissue around a wound so that it can be replaced; but as we get older, signals that promote inflammation are dialed up higher and higher. Chronic inflammation contributes importantly to all the diseases of old age.
Twenty years ago, I imagined one or a few medications that would block the effects of aging genes. I wrote that the thesis of programmed aging implied great optimism about the ease with which aging might be combatted. I thought that merely lengthening telomeres might add many years to our lifespan.
Ten years ago, I saw that what was needed was re-balancing of signaling molecules to create a more youthful environment. My hope was that a few transcription factors (master regulator genes) might control a large number of signal molecules and we might set the clock by controlling just a handful of master signals.
More recently, I have come to realize that shortening telomeres are only a small part of the aging program. Worse, there is no clear line between transcription factors and hormones. Most hormones affect transcription, and most transcription factors have direct metabolic effects. There are thousands of transcription factors in the human genome. As a result, my robust optimism has been tempered, and I have come to think that we need to look for ways to re-balance a great number of genes to effect rejuvenation. I still believe in a signaling approach, but I see signals as a tangled web of cause and effect, in which every cause is also an effect, and every effect has a side-effect. Modulation of the signaling system toward a more youthful state is possible, but not easy.
Aubrey’s program, too, has changed over time
Aubrey has never believed that aging evolved as a program, but rather that aging is a manifestation of damage that is permitted to accumulate because of evolutionary neglect. Recently, he has argued explicitly against the idea of programmed aging, not for the reasons that traditional evolutionists offer, but by an argument that is uniquely his own. In his words, “it is impossible for a species to maintain two sets of genetic pathways whose selected actions diametrically oppose each other. Specifically, since we clearly have a great deal of anti-aging machinery…we cannot also have pro-aging machinery.” (My response is that we have pro-aging and anti-aging machinery that are activated at different times of life.–see Aubrey’s comment below.)
Over two decades, Aubrey, too has paid attention to research results, and his thinking about what is necessary to achieve rejuvenation is changing. I see changes in the combinations of signal molecules and call it an evolved program. Aubrey sees the same thing and calls it “dysregulation”, which is a kind of damage. Aubrey and I agree that re-balancing of hormones and other signal molecules is going to be essential.
Aubrey now finds optimism in the existence of what he calls “cross-talk”. If we engineer a fix for one kind of damage, the body may sometimes regain the ability to repair other, seemingly unrelated kinds of damage. Hence, we may not have to engineer solutions to everything—some will come for free. A dramatic example is in the benefit of senolytics. Cells become senescent over time. I see this as a programmed consequence of short telomeres; Aubrey sees it as a response to damage in the cells. But both of us were surprised and delighted to learn, a few years ago, that elimination of senescent cells in mice had 20-30% benefits for lifespan. Even though only a tiny fraction of all cells become senescent, they are a major source of cytokines (signal molecules) that promote inflammation and can cause nearby cells to become senescent in a vicious circle; this apparently accounts for the great benefit that comes from eliminating them. If we find appropriately selective senolytic agents that can eliminate senescent cells without collateral damage, then the signals that up-regulate inflammation will be cut way back, and a great deal of the work needed to repair inflammatory damage is obviated.
The SENS 7
The SENS web site still lists the same 7 categories of damage that Aubrey has used for many years. But the program to address these 7 has shifted a bit from bioengineering of exogenous solutions to signaling approaches that support the body’s innate mechanisms (which we know are sufficient to keep the body in good repair through several decades of early life). For eliminating the plaques associated with AD, SENS at one time favored the engineering of artificial antibodies that would attack them, but more recently they see promise in the discovery of Dr. Sudhir Paul that our bodies already have catalytic antibodies, each capable of destroying many antibodies and re-cycling itself for the next one. Where once Aubrey saw the need for tissue engineering to replace worn-out body parts, he now sees promise in reprogramming somatic cells to become stem cells, so that our bodies can regenerate damaged tissues endogenously. Aubrey’s 1999 dissertation in biochemistry was about the theory that aging was caused by the damage inflicted by free radicals generated in our mitochondria, but he has long since embraced the fact that free radicals have an important role as signal molecules, so that anti-oxidants are not helpful for anti-aging.
Aging is not the only threat to human life
One respect in which my thinking has always departed from Aubrey’s is that I see humans as part of a continuous web of life on earth, integrated into a global ecosystem. Aubrey doesn’t worry about the Sixth Extinction that human activity has initiated because he anticipates that future humans will invent ways to support future human life as necessary. I value nature for its own sake, and I also believe that human life depends on ecoystem support in ways for which we have seen hints, but that we have not yet begun to study. Aubrey draws a sharp line between the value of human life and the value of other life, and he is highly optimistic about the ability of our species to find new ways to sustain ourselves in a post-ecologic world.
The Bottom Line
In my youthful enthusiasm, I was entirely too optimistic about the prospects for near-term anti-aging fixes. Aubrey was probably too conservative about the scope of what needed to be done to generate man-made solutions for problems the body can’t solve itself. I have come to understand the complexity of the body’s signaling network, and the fact that it is inseparable from cellular metabolism. Aubrey has come to realize that the body has endogenous solutions that can be activated more easily than we can engineer substitutes for them. I’ve been moving the timeline out, as he has been moving the timeline in, and there is much that we agree about.
I’m grateful to Aubrey — we all are — for the energy, the expertise, and the humor that he has brought to his chosen role, as a public advocate for bringing anti-aging strategies into the mainstream of medical research.
Discussion
116 reader comments
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I don't know how old either one of you are - but you sound much younger than I am. My views on aging is that it is much more than an evolutionary, biological process. It is a combination of physical and mental/emotional conditioned process. Our attitude and stance in life greatly influences the physical cell structure of our bodies. Decisions about lifestyle - be they conscious or unconscious - not only determines the quality of life but it rearranges the cellular structure of our being!
In all practicality - our aging process is a great exercise in learning and adapting. At the age of 89 - I choose to accept my aging process as a wonderful opportunity to gain different skills and knowledge and apply these with love and compassion!
Ilona Montel (PhD)
Josh, you write: "There are single genes that can be disabled, greatly extending lifespan in worms. Some of these have no known detrimental side-effects (pleiotropy). These could only have persisted in the genome if natural selection is favoring aging for its own sake. Similar genes exist in higher organisms, though their effects on lifespan are not as dramatic as the 10-fold increase in worms’ life expectancy in worms that comes from eliminating both copies of AGE-1." I submit that nearly all such genes have been clearly shown to have detrimental side-effects, and the lack of *known* fitness loss in a few cases is due to scientists' not having looked for it yet. You cite AGE-1 as an example, but as I pointed out to you on the CR List in 2004, this mutation has been shown to reduce fitness under conditions of food scarcity (PMID 10830948) . Additionally, hermaphrodite C. elegans —which account 99.9% of the C. elegans population — suffer a 75% decrease in self-fertility when they have AGE-1 longevity mutations (PMID: 8608934).
Michael -
As far as I know, this decrease in fertility was reported in Johnson's first paper on AGE-1, but subsequently he realized that the long-lived worms he was working with had two mutations, AGE-1 and FER-15, and that it was possible to separate the longevity from the infertility. Please let me know if I've made a mistake about this.
- Josh
Ok Michael
And there are not counterexamples?
E.g. insulin-like signaling many KOs live more but yeast had no pancreas. So ancient function of those likely aging. Impossible blood sugar regulation because yeast is unicellular as all protists. This puts head-down George Williams Antagonist Pleiotropy. This idea came to me this summer at my Tao-like place on the wonderfull Spanish still not polluted remaining areas (who escaped that awfull slogan coming -mainly- from USA: The most important thing is "TO MAKE BUSSINES" (Awfully enough in our field to make bussiness with DEATH! (HOW UN ETHICAL HOW ANTI-HUMAN HOW ANTISOCIAL AND MOST DIRTY THING.....
CYNTHIA Kenyon HAS recently published on C.elegans longevous mutant being inferior to WT only due to contamination with gut bacteria....so the answer to your question Mark is surely more complex.
Something exists in eusocial insects allowing some queens to live for many decades, 30+years, while the workers die in a far shorter timeframe, even in protected environments. A 10+x, think I heard in some species it is 100~x difference in lifespan between queen and worker.
The queens appear to experience mechanical wear and tear eventually being replaced by clones. Apparently this is easier than just repairing all aspects of the queen.
Forgot to add that in some of these species the worker and queen are genetically identical and mere changes to gene expression induced by diet are enough to lead to an order of magnitude difference in lifespan.
That tells us the same exact genome can with tweaks to expression lead to vast differences in lifespan.
Any opinion, in the light of a possible convergence or integration of approaches, as also foreseen in my previous post, on the "deleteriome" concept put forward by Dr. Gladyshev whose paper I read already time ago? It looks to me as an honest effort toward an understanding.
Gladyshev VN. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell. 2016;15(4):594-602.
It is rare to see so much commentary and even fever surrounding one of gentle Josh's essays. Spirited controversy is healthy, but I worry about the content of some responses. Unless one presents hard evidence, attacks on the character or motivations of our family members does not advance solutions to the problem, and tends to soil the source more than their target. Even if SENS and Aubrey are terribly misguided, the attention they have brought to the terrible tragedy of longevity-mediated degeneration is beyond doubt, and highly laudable.
The rift seen here seems exaggerated. Is it so unlikely that there are evolved, unintended, and chemistry-limited elements to gerontological decline? We know for certain that many species die by the clock, clearly programmed and having nothing to do with accumulated damage except insofar as damage accumulates by programmed withdrawal of repair and maintenance functions. We also know that some damage begins to slowly accumulate from conception, with no inherited mechanism for its repair. We also know that genetics has ultimate limitations; e.g., no amount of evolution will allow us to live very long in the sun's interior. It would serve us best to reframe the discussion around the degree to which each factor contributes to the problem and solutions, rather than tightly lashing ourselves unnecessarily to one or the other as the only factor.
The insight that some outliers of high longevity never stop growing especially catches my attention. Years ago, at a much lower state of knowledge, I fantasized about writing a novel in which there were extreme elders who had received anti-aging treatments prior to an apocalypse, during which the recipe was lost. These elders dominated the masses, and were visible from a distance due to their stature, which continued to increase by about one millimeter per year. Literary dreams aside, glandular involution seems to be a big factor in unmitigated age-related decline that does not fit nicely into accumulated damage theories. The energy required to maintain the pituitary, sex organs, and thymus (among several others) is trivial, and the argument that nobody lived long enough to benefit from their maintenance does not wash, since healthy elders have always existed and undoubtedly contributed disproportionately to our survival and advancement. No?
Dear Crompton
I am FOR the aging program, absolutely. You will not find any scientist more pro-aging program than myself. And yes there is accumulation of damage because the program generates it on purpose (not only by "decreasing repair, but also producing the damage itself: the rate of mitochondrial ROS production, fast in rats and slow in humans is the best example. Other parameters, telomers etc DO NOT CORRELATE WITH SPECIES LONGEVITY. Correlation is not causation. But a "theory" that can not explain why different species differ up to 1 million fold in longevity is not a correct theory. Correlation with species longevity is not enough to demonstrate a "theory" of aging, but it is NECESSARY. Up to know ONLY the mitoc ROS theory has demonstrated correlation with species longevity (both at the leavel of cause-mitROS production rate -Ku et al, FRBM1993, Barja many many papers specially in birds compared to mammals, and Lambert...and Martin Brand et al. 2007), and also at the level of consequence oxidative damage in mitDNA, and NOT in nuclear DNA, Barja and Herrero FASEB J 2000).
YOU SHOULD READ THE ORIGINAL PAPERS INSTEAD OF LOSING TIME DISCUSSING PLATONIC DEDICTIONS ANCIENT GREEK LIKE (adg METHID TO CATCH NAIVE PEOPLE ON HIS NET).
Concerning too heavy discussion, ADG is clearly against the program! He says so aloud.
In fact, supposedly my friend for 15 years since he asked me to visit me at Madrid on 2000 and I said yes and listened to him! (he came again to see me on 2103 and I accepted to present his horrible book at my Univ. only because at that time I still believed he was what he said he was...
But being my friend, he rejected my paper on the program, but Biogerontology Barja 2008 (gene cluster of aging paper) accepted. I even drawed an scheme on how could be (not in details) the Aging Program (AP). Look at it iif you want. It is the only drawing of the AP ever on any scientific publication. It is also on Chapter 6 of my Longevity and Evolution Book (New York, Nova Science publishers, 2010).
ADG was angry when I published my theoretical paper supporting the AP. He was absolutely against it.
The, we discovered at 2010 (Mitochondrion paper Caro et al, Mitochondrion 2010) that mtDNA fragments accumulate in the nuclear DNA (in rats and mice), precisely much at the pericentromeric regions of the chromosomes. Andreas Ivessa´s group found exactly the same also at 2010 in yeast and they demonstrated that this accelerates aging. We also found that treating middle aged mice with rapamycin decreases both mtROS production and such accumulation of mtDNA fragments inside the nuclear chromosomes, in fact there was 100% reversion of them back to young levels! (Martinez-Cisuelo et al., 2016).
mtDNA fragments history is most important because it is the ONLY known way out to the MFRTA (mitoc ROS theory of aging) because the deletions accumulate in heteroplasmy in most old tissues at very small levels not enough to cause damage (thousands of copies of the mtDNA circles per cell, so a few hundred mutated do nothing!). But people has lost time looking at the mtDNA mutations. Instead of looking at what remains after the break of mtDNA by mitROS, they should look at what is missing after breaking the mtDNA circle: that is the mtDNA FRAGMENTS INDEED!
Ok I sent first our mtDNA fragments ms. (at around 2008 aprox.) to Rejuvenation Research, the journal of my then "friend" ADG. And do you know what he did? He rejected it energetically. He was absolutely against this. Of course this was a clear advance towards resolution of the aging problem, so this was why he was AGAINST this new finding! He, my "friend"!
I can not continue telling Science on this blog. This is JM blog. And JM, strangely enough for someone so clearly on the side of us the pro-Aging program, he is a friend of ADG who is one the contrary champ. And ADG manages milions of US $...
I can not have any confidence on JM (who continues to insist on his mails in saying that he continues to be my "friend", even after I strongly criticized him on his own blog! see nutrition geometru blog!
What is all this?
Is JM really on the side of ADG? and pretends the contrary?ç
I do not know but I can not continue to have friendship with him. Not telling him my ideas after what happened with the "yeast having no pancreas history"...(my idea, he finally recognized it but put it up at the end of the explanatory start of the blog, not in the commentaries where every body could see it. I sent to him, after his request, my best 8 ideas on why the maistream non-AP theories of evoaging are all wrong (one was the "yeast having no pancreas" history putting upside down George Williams AP theory). He still has all the other 7. I asked him not to use them before I publish them.
So, I can not have confidence on JM anymore after all that (we have been "freinds" interchanging many things since I accepted he visiting my hous on the Spanish coast on the summer late august 2012, 2 days together discussing at my house. He was interseted on me clearly. I suppose ADG is also interested in what Gustavo thinks after I cut all relationship with him on the summer of 2015.
You Americans are very nice people in general. But I am afraid that you are too naive. We at Europe have thousands of years of experience with doubl-sellers. People does not believe the first think that a predicator tells them at their door.
Take care. ADG is among the most intelligent persons I have known (but no more thatn myself, by the way). But he is not a scientist at all. He despises us. He even pretends people to believe that the AP (hundreds of genes strongly interrelated) cant solved by the car-repair shop procedure: cleaning with a coffe spoon the 10 elevated to 11 cells of our body...
Of course he is so intelligent that I know that he knows this ridiculous. but he tells to you, honest but naive american people, that that "thing" can work: Repairing a car with 10 elevated to 17 "pieces plus relationships" without having any idea on how it works inside!
Please think WHY
and please do not fall in the trap of ancient greek deductive reasoning from dogmatic false axiomes. Science is exactly the opposite of that. ADG is not a scientist and he is against Science.
But aging is a biological problem. And Biology is a Science. Only Science, the good one will solve aging. Not the double sellers of "growing hairs for bald people"...
I sent first my mt
WHAT A BLOG!
I wrote a long answer and it does not appear on it!
Thanks for taking the time, Gustavo. Feel free to send it to me directly at: [email protected]
I tried many times. I observed that when my response is long it does not enter the blog....
The more items I use from the list of age extenders, the lower my body temperature. I now average 96.3 F.
Gustavo
I’m not in total agreement with your rapamycin/ CR comparison. Just looking at life extension, mouse studies show 22% to 25% increase depending on the sex and based on daily dosing. However, if we look at transient dosing, the Kaeberlein study demonstrated a whopping 60% life extension effect, at least in males.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996648/
The data with CR shows a substantial but lesser effect in mice and conflicting results in primates.
https://www.theverge.com/2017/1/17/14287708/caloric-restriction-diet-monkey-health-longevity
As far as side-effects are concerned, I would say that rapamycin has the clear edge, at least when properly dosed on a weekly basis. A recent study in the elderly population with rapamycin demonstrated a 20% increased immune response with no adverse effects, and a very recent 6 month human study also showed no side effects even on 14mg’s per weekly dose.
On the other hand CR, when done on a chronic basis, is very difficult and compliance is poor. It is not free of adverse effects and has been associated with fatigue, impaired immunity and fertility, as well as muscle loss and iron and B12 deficiency.
I’ll take the pills.
It's often said that CR doesn't work in humans, or that it only has a marginal effect on lifespan (a few years, perhaps) with a larger effect on health span. But I wonder if humans are really an exception. We probably DO fully reap the full benefits on lifespan, but that is not apparent because humans look after their old rather well, keeping them ill but alive - so we've already 'banked' many of the extra years CR provides, albeit in illness rather than in health.
Regarding pills Vs CR, I too am not convinced CR is preferable - as strict CR is hardly a recipe for an enjoyable, energetic life. I expect that the bulk of the benefits of CR come from reduced mtROS generation, as Professor Baraja would no doubt agree (although there is surprising confusion in the literature about this) - and there are now numerous ways of achieving this with 'pills', although it is not yet clear whether they can do this as well as CR. I suspect though that they probably can.
One of the problems with more extreme CR in humans is the significant loss of bone mass, even if it is delaying aging massively that could handicap its ability to extend lifespan.
An interesting thing would be if substances or an eating regimen could be found that negated the significant bone loss of high CR in longer lived species like humans.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546525/
This study led by Professor Richard Morimoto discovers a 60% to 80% collapse of the protein folding support machinery including HSP and other imp components of UPS. This collapse is triggered by a germline 'switch' just after reproductive organs are formed. The only explanation for the timing, extent and how conserved it is seems to be that it is programmed.
Sure. No one is arguing that development is not programmed. I think you are implying that because the unfolded protein response is an important anti-damage pathway, its downregulation counts as a programmed acceleration of aging. However, in order to reach that conclusion one must (as usual) eliminate the AP option, specifically in this case by determining whether animals that are genetically modified not to downregulate the UPR outcompete normal ones in natural conditions. The paper you cite shows that such animals live longer in standard lab conditions, but only to the same sort of extent that worms' lifespan can be extended via inactivation of literally hundreds of genes (including rather important ones like for OxPhos). Also, as you may know, age-1 mutants outcompete normal worms in standard lab conditions but are rapidly outcompeted in conditions of variable food availability.
"I think you are implying that because the unfolded protein response is an important anti-damage pathway, its downregulation counts as a programmed acceleration of aging." Yes that's what I was implying. I wasn't alluding to lifespan as various factors influence rate of aging and death. I was just sharing an observation of Nature's planning or program or whatever we want to call it: As soon as it's primary goal of reproductive maturity for continuation of species is achieved it makes a sudden and significant downregulation of an important anti-damage pathway. We know what begins to happen soon after. If it happens after a certain number of years we can blame it to wear n tear but the sudden occurrence and its timing and it's extent and it's source......
Atomic,
Do not fall in the trap of sophistic ADG.
THESE Neodarwinian guys have been 8 decades doing the same:
They invent wrong theories and the others (e.g. PA proponents like JM or me HAVE TO DEMINSTRATE that their AP us wrong! (You see. The falacy...)
Why they do not have to demonstrate anything?
In this way, no matter what new discoveries are made on the lab. or in the wild, their false "maistream" theories will last another century.
They DO NOT WANT AGING TO BE SOLVED! DO NOT YOU SEE IT?
These guys only want more time to take your money while they delay solving aging...
If aging is solved their business is finished!
That is why they do NOT take care of their own bodies, they drink as drunkards, eat fried things, are involved with a lot of women simultaneously, and hate exercising, and they look already more aged than their chronological age is..
(Exactly the oposite of what JM and you the inocent bloggers do...)
They do not count with living a lot, otherwise they will not mistreat their own bodies so much...
They lie all the time to inocents that believe in them and give their money to them, specially the old billionares that do not want to die...
And they disguise smsrtedly with poor clothes and habitudes to cheat you.
One day they will dissapear with all the million $ they took from you.
Professor Barja,
I really liked this line from your recent posts on this blog: "Epidemiology is not a hard science at all. I am a scientist. If well done, it is very very reliable. You repeat the experiment, and you always get the same."
Many of the studies are suspect because they do not give same result when repeated.
I don't know ADG is surely a pioneer in his own right. One can always agree to disagree. Josh has created a great platform to share our ideas, discuss and debate. I do research by deduction and therefore presented evidence.
But I too have my pet peeve :) a start up that discovers a synthetic molecule that clears senescent cells manages to raise $300 million at pre-clinical stage with the world's richest man as one of their investors and world's top 2 investment banks taking them public on Nasdaq. They may only find out whether they win FDA approval 7 years or so later. Plus I don't know if you agree that using a synthetic senolytic in isolation can be dangerous. Also they spent $75 million in one year at pre-clinical stage. Whereas our team of scientists believe we have a better solution in sync with Nature also with spectacular pre-clinical results but struggle to raise 10% of what they spent in a year. So I asked a leader of America's largest Anti Aging Organization why and his answer was that they have ivy league background, at the right geographical location and have old boys club connects. Anyway I wish them luck because I consider anyone in anti aging field community brethren and hope they do bring anti aging benefits to all of us.
Sorry Akshay I wrote long to you but JM closed the blog to me and I lost everything I had wrote to you
Sorry Akshay I wrote long to you but JM closed the blog to me and I lost everything I had wrote to you. I am leaving now for long weekend
I don't think it's fair to say Aubrey does not want to cure aging. Like you, he's given his life to this cause.
" drink as drunkards, eat fried things. involved with a lot of women, and hate exercising"
Sounds like a cruise ship. Or maybe the American dream Gustavo.
Gustavo
I brought up the naked mole rat and the fact that the breeders outlived the non breeders because this is an exception to the rule in mammals. It has always been believed that the energy required for reproduction takes a toll on longevity, and therefore there is a certain trade-off, at least in mammals. With the NMR this was shown not to be the case.
One possible explanation seems to be that the NMR has developed a very efficient mitochondrial utilization of free fatty acids. While this may not be germane to the present discussion, it does show how little we know and how a long standing evolutionary idea can be upended.
Thanks Aubrey for the detailed clarification of your position. I define aging as an increased risk of death over time to which you responded that that is more an outcome of aging than a cause. Of course it could also be argued that your definition of aging as a progressive accumulation of damage is also merely an outcome, and not a cause of aging.
It also perplexes me that there are members of species such as tortoise, lobster, and rockfish which exhibit negligible senescence. The odds of them acquiring repair efficiencies close to 99.9% seems unlikely to me , whereas the idea of a partially disabled programmed aging mechanism seems more probable.
Nonetheless, you are a true pioneer and leader in your field and we are enormously grateful for your contributions.
You seem to be assuming that everything is either a consequence if aging or a cause of aging. Clearly that cannot be so - something has to be aging itself! If the accumulation of damage is a consequence of aging, that doesn't leave much for aging itself to be.
As for the species you list, yeah, and I addressed those in my paper too. My belief is that they age just like us, but that their aging is harder to detect demographically because their continued growth (and consequent rise in reproductive capacity) in adulthood means that the age at which their risk of sickness and death starts to increase is much later than the age of sexual maturity, whereas in species like us that have a fixed size in adulthood the age at which that inflection occurs is only slightly after sexual maturity. I accept that there is no definitive evidence for this position at present, but I contend that there is no evidence against it either, and moreover that it is absolutely the parsimonious prediction of evolutionary theory.
I think both theories are wrong, or at least moot. Aging is obviously inherited, going back to the earliest homo sapiens. (None of them are still around, to our knowledge.) And genes coding for longevity have shown us diddly squat. (I'm not impressed by old looking centenarians.) So we need to look at the non coding region of the genome, going back thousands of years of human evolution (200,000 years, or whatever) through bioinformatics. Senescent cells only happen after one is born; those DNA elements have been there for 200,000 years (or whatever). My guess is, senolytic agents will treat disorders like osteoarthritis, but those treated individuals will still age. Telomerase gene therapy may treat Alzheimer's disease, but those treated individuals will also still age. Studies showing treated mice that appear more youthful don't tell us anything about complex molecular pathways that give each one of us unique morphological features, youthful versus aged in appearance. Too complex? We have to look at it.
Here's a brief elaboration of my assertion that a species cannot maintain (not for more than a few generations, anyway) both pro-aging and anti-aging machinery that are active at the same time. I do not define aging as an increasing probability of death - that is merely an outcome of aging. Aging is the progressive accumulation within the organism of damage, which can be defined as molecular and cellular changes to its structure and composition that, once they exceed some threshold level, impair and eventually preclude the level of functioning of the organism that is typical of a young adult (and, eventually, any functioning at all). In all species, there is a huge arsenal of genetically-encoded machinery that eliminates metabolic byprodcts, replaces dead cells, kills off mutant cells, etc, without which damage would accumulate much faster than it does. Thd only reason damage accumulates at all is because that machinery is not 100% comprehensive, i.e. there are some types of damage that are not repaired. As such, there are two types of genetic (most typically, gene expression) change that can bring about a more rapid aging process: either (a) the creation (or increased expression) of genes that actively accelerate accumulation of damage (e.g. by inhibiting the action of repair machinery), and (b) the downregulation (including by mild loss-of-function mutation) of the repair genes themselves. The cancelling-out argument begins from the acknowledgement that there is an optimal rate of aging for a given species in a given situation (which may be defined by the individual's age or by environmental conditions such as nutrient availability). It also acknowledges that that optimal rate is partly determined by the linkage between the rate of reproduction (i.e. the age at maturity) and the rate of aging, as well as the need for an individual's offspring to be born into an environment that is conducive to their surviving long enough to have their own offspring (e.g., not a famine). So the COA merely states that when a condition occurs (whether it be an environmental change such as famine, or an eccological change such as the arrival of a new predator, etc) that makes it optimal to age faster, that acceleration of aging will always be implemented by option (b) above rather than by option (a).
So, is that true? Well, mTOR has been cited as a gene that looks like it accelerates aging, because it is less active in conditions of famine when aging is slower. But it would also be accurate to describe mTOR as a gene that accelerates reproduction - and that's ultimately what evolution cares about. Thus, the pro-aging action of mTOR is most accurately viewed as a maladaptive late-age side-effect, i.e. an example of antagonistic pleiotropy, not an example of programmed aging. In other words, mTOR is not an example of a gene that exists to make aging go faster.
This is all explained in my paper, of course, but it seems to bear repeating.
Bloggers,
George Wiliams is dead, and his theory too. I put George upside down when I told Josh by phone the night of September 28th that yeast has no pancreas!. I am still waiting for Josh recognizing this on this blog. It is absolutely necessary that he states this truth!
Concerning T. Kirkwood.s DS "theory" I explained a few days ago on this blog why it is not a theory. It is just impossible, non-sense for many many important reasons.
And Peter Medawar, the oldest one 3rd evolutionary "theory" of aging, it has been fully discredited when zoologists went to the wild and found a lot of old animals...(we were all cheated by those theorists postulating things from behind their desks without ever going to the field to see if their claims are true or not! And they ask us to demonstrate things, but they do not demonstrate anything at all!
The car mechanic used to say aloud that "if there is no phenoptype -no old animals in the wild- there is nothing to be selected". And now that we all now that it was a lie that old animals did not exist in the wild, what does he say? mTOR pleiotropy? Ok my answer is: yeast HAS NO PANCREAS! so pleiotropy of insulin/igf.-1 is but on the reverse . The ancient function of those genes was aging, and only millions of years afterwards, when multicellularity and blood glucose appeared, they were secondarily used to regulate blood glucose...
So, what is the next invention of the Mainstreamer theorists? They: no laboratory, no zoologists in the wild (we say in Spain "ni bota ni bata!). What do they know? Nothing. And they pretend to teach us? I am the teacher (Full Professor of Physiology!), and they pretend (TK) to teach me nonsense physiology?
Will they now invet a 4th false theory? Sure. What for? to delay one more century how to delay aging. Why? Because, greedy as they are, some of them want to continue collecting your money, and the others,,,want to sell you the CR-mimic pill at 1,000 US$!
That´s why
I suggest you not to continue listening to those doble-sellers, to those cheaters, to those selling bottles of false elixirs that supposedly will make grow your hair (in the far west..) if you are bald...
Instead, I suggest you to listen to thousands of good scientists, biologists, that fortunately, you have on your own country, USA.
And specially, I suggest you not continue listening to the engineers car-mechanics.....
Aubrey, am I correct in thinking that you are saying a faster turnover of genes can be selected for in some circumstances (new predator, etc) - but that it is the faster growth and reproduction that is being selected for, with the faster aging being merely a byproduct of pleiotrophy (although that would also aid in faster gene turnover in a population)?
Of course we know that faster growth and reproduction does not preclude the co-evolution of slower aging, as has been shown in various fly experiments, and also in the wild with birds and even some mammals like squirrels, for example. So growth and aging can be de-coupled (by more efficient mitochondria, for example).
Best Regards
There's a rather tight correlation across the animal kingdom between age at reproductive maturity and lifespan, but you're right that it can vary somewhat. However, yes, the correlation exists because both numbers are driven (in the long run) by the level of extrinsic mortality: the higher your risk of death from causes unrelated to how long ago you were born, the greater the selective pressure to mature rapidly and the less the selective pressure to age slowly. The AP aspect arises because there are indeed mechanistic links between the two - basically, growing fast entails growing sloppily and accumulating more damage, especially epigenetic imprecision. But there are independent aspects too, hence the deviations from the regression that you mention.
Thanks for the elaboration Aubrey.
The AP argument is always going to be very hard to resolve as all genes have multiple functions depending on splicing factors, etc.
I wonder if we could cut the knot somewhat, and create a fly, for example, with normal growth and fertility, but extended lifespan, and then do some competition experiments with wild type flies, to see if aging itself was selected for or against, and in what circumstances.
That's exactly the experiment that Lithgow and Melov published with regard to age-1, and Pellicci with regard to p66shc, and indeed they found that when even rudimentary attempts were made to mimic natural conditions, the animals that lived longer in protected conditions were outcompeted rapidly. I know of no case in which this kind of test has gone the other way.
But if the result of the natural competition experiments was the elimination of the long lived mutants Aubrey, is that not evidence of selection by evolution against aging directly? Or were the mutations pleitrophic, and in fact DID affect growth and fertility, in which case they do not meet my criteria for the experiment?
I wrote "the impact of the mutant is to reduce real-world fertility" - perhaps it would be clearer to say "the impact of the gene (i.e. the non-mutant) is to increase real-world fertility, in spite of the accompanying acceleration in aging".
Hi Aubrey. I was hoping it was possible to find an aging mutation independent of fertility/growth in order to prove aging was an advantage on its own - but it appears this is not so simple (in real life as opposed to the lab).
Hi Aubrey. But to me I don't care if the mutant wins or loses, I only want to see if aging can be selected for independent of anything else. That would settle the PA argument as far as I'm concerned.
The question is whether aging is ever independent enough of other factors to know this definitively.
A more practical question would be, if I can reduce my mtROS by 30% and potentially increase my lifespan, what would the downside be, if any?
Hi Aubrey. No argument from me on the efficacy of gradual evolution of longevity when extrinsic mortality is low - we see it time and again, with birds, lizards living in isolated caves, squirrels up in trees, naked mole rats deep underground, tortoises with shells, humans with intelligence, the list goes on...
What about reducing mtROS pharmacologically? It's certainly possible, but would a human live longer?
I think the confusion with the competition experiments comes from a different interpretation of the result. A mutant losing out in your explanation shows there is some subtle negative to the mutation. But it could also be that that the non-mutant is being selected for because aging itself is being selected for (because of its advantage eliminating older animals leading to faster gene mixing and adaptation to changes in the environment).
?
What of experiments transferring neurons from mice to rats, and showing these same neurons exhibit double the lifespan only limited by the new host? Keep in mind that whatever maintenance and repair can keep a very high metabolism cell such as a neuron alive for twice the lifespan of the original organism, should be more than sufficient for all the other lower metabolic activity cells of that original organism.
What of experiments showing that changes to gene expression alone induce the aging phenotype?
What of experiments showing that aging cells whose gene expression is rejuvenated exhibit a rejuvenated phenotype and are virtually indistinguishable from young cells under a microscope?
What of the fact that even the most rapidly dividing of stem cells in the body, even of a centenarian only show a minimal negligible amount of mutations? This despite the downregulation of the repair and maintenance due to aging.
I think I once read of an experiment wherein enhanced mitochondrial maintenance and recycling removed some detrimental mutations from the mitochondrial population of the cell.
I think Gustavo that you underestimate both the creator and readers of this site. We view this like being on a train that is rapidly approaching a cliff, and while we don’t fully understand the workings of the train, we’ve done the risk/ benefit analysis and feel that doing something to slow down the train is infinitely less risky than doing nothing at all.
The “ pills” that we take are not taken haphazardly or at random but rather after a great deal of thought and consideration. I admit that it’s not perfect, but if we do nothing at all until all of this is fully understood, then most of us will be dead.
Thank you Paul.
This was my opinion only, of course. As far as I am aware, the only drug that has demonstrated to increase (maximum) longevity in a mammal is rapamycin. All the other things can be promising or not bu have not demonstrated such an effect (increasin man survival is no good, the maximum must increase too, and the longevity of the CONTROLS MUST BE THE NORMAL ONE for the species. Many people say that their drugs worked but what they did at best was correcting a defect. In other words, do you think that a pill that increases the mean survival of a population of humans from 60 years of age to 80 has increased the longevity of the species? Clearly not. The drug must increase over 122 (the maximum recorded for a person, Jeanne Calment, the french woman. Obtaining some human indivuals of 160 years of age (expected from caloric restriction if applied to many millions of people) necesarily means that aging rate was decreased. The same is obtained with Ames dwarfs. C. elegans no good. I explained why on my ARS 2013 review. This animal lives at very low pO2 in the soil, around e.g. 5 mmHgO2?. And they brought it to the lab. and experimented at normal atmospheric O2 pressure: 159 mmHg pO2, which is enormously hyperoxic for this little animal..... And then, they give antioxidants to it, and lives up to ten times longer! (not extrange, but wrong experiment to translate to us, humans. An in addition, the survival curve of the controls has much shoerter longevity than the wild tipe animal because all the C. elegans in the world labs. come from the lab. of David Gershon at Israel and have suffered generations of inbreeding which decreases their longevity. So this is also why drugs antiox, etc increase up to ten fold the longevity of the artificial lab. worm. But no drug ever increased 10 fold the longevity of proper controls in mice. If you look at curves of many people pretending that resveratrol, metformin, etc etc increase mouse longevity, you will see that they use as controls mice that live 2-2,5 years only, whereas the tru maximum longevity of a mouse is 3,5-4 years! (so the problem of the 60 to 80 years in humans above applies.
Then, in mammals we ONLY have rapamycin. And it increases longevity only 12%, while simply restriction the animal (CR) you get up to 30%-40% increase in max. longevity. That is between 1.3 and 1.4 fold (30-40% longer longevity) longer longevity than the proper controls. Rapa was done under ITP and in 3 independent labs. But rapa is only around 1 fourth the effect of CR. Why? because it inhibits mTOR signaling to the aging program which is held inside the cell nucleus. Whereas CR, in addition to inhibiting mTOR, does many other things, like decreasing insuling/igf-1-like signaling to the aging program present in the nucleus too. That is why CR is superior to rapamacyn. And to finish, rapamycin, as most drugs, has negative side effects on mice, in spite of the fact that it slightly increases longevity. So, why to take a rapa-pill. Rapa is the best drug proven in mice, but it is no good. Doing CR is much more effect on longevity and much safer. And rapamycin overlaps but is only around 25% of the CR effect. So, why take it? For me it is dangerous and non-sense. Go and restrict yourself without undernutrition and you get the effect. And do not believe on the Mattison et al. 2012 Nature paper. The controls were already restricted. So, restricting the restricted...... Please believe on the rhesus macaque experiment of Richard Weindruch (the best CR researcher worldwide) at Wisconsin primate center (Colman et al, Science 2009). Impresive positive results on both survival and the diseases (e.g. diabetes type-II a problem for many ameraicas, I know, drops to just zero with CR in the macaques..)
In summary, why so much interest at USA (many people there, many with power enough) in discrediting CR?
For me the answer is simple. Because you can not sell CR. Negative calories can not be sold. And those people can MAKE BUSINESS with you, they do not want to help you to avoid all those horrible denerative diseases. I do want to. I do not want companies to finish patenting th first antiaging pill, and selling it, lets say, at e.g. 1.000 $. I want it for free, or at cost value (1 $ perhaps?. That is the reason I worked so hard at the lab. during the last 40 years of my research. Because the ONLY thing that I want is to help the 7,000 million "brothers" (cousins, really) that I have on this earth. To ALL of them, including even Donald. And I, a spaniard, do not want to make bussiness with their desire to live. NO, absolutely not. And I do not want the poor peole in my country at least to be left out of this big advance because they can not pay for the pill of the rich". I am absolutely against that possibility.
Going to the future, do you imagine Paul that 2 types of persons as these can be tolerable?:
a) the rich and living a mean of 600 years healthy and young
b) the poor and living like today, 40-60 years at best.
No I do not think this tolerable. It will be a future world (a nightmare, rather) even more unfair than the present one, if that were possible.
My suggestion was that the present knowledge means that taking any suppossed antiaging pill at present is not justified (you can do CR easily), and is even dangerous. That is my opinion after 40 years working at gerontology. But of course you can do what you want with your own body...
I personally listen to serious and prestigious scientists and never to charlatáns trhat want your money and do not care if you damage your body with the supposedly good treatment, or directly take your money as donative...
I believe Vince Giuliano discusses here that Glucosamine sulfate 2x750mg per day decreases mortality in humans better than rapamycin or metformin ... for ?? 13 cents per day at Costco in Canada. This is FAR better than anything you can expect from resveratrol (keep taking green tea though!!), nicotinamide riboside or anything else at this time.
http://www.anti-agingfirewalls.com/2014/06/09/glucosamine-for-longevity/
Anyone can add that with some some vitamin D3, K2-MK7 and vitamin B12 ... eat a diet loaded with micronutrients (beans, greens, nuts, fiber, O3's etc.) and don't spend $$ on anything until it is both proven to be 1-SAFE and 2-EFFECTIVE in multiple human trials and 3-becomes CHEAP.
Thank you Aslan. I did not know that work.
But please understand me. I am a (hard) scientist. I do not believe at all on epidmiology or in the acurateness of ANY study made in humans. Since Adolf Hitlers times no one has performed true experiments on humans.
Epidemiology is plagued with confounding factors (impossible to truly eliminate), abuse of the computer to obtain significance (if not, just change the statistical test and that´s all...) , and strong economic interests from pharmaceutical industry (number 2 after guns industry which is nº 1 worldwide...).
That´s why MDs recommended from 5-6 decades ago: first olive oil bad, butter good (I was child then..), then olive oil good, omega -3 good (bull shit omega-3...), equilibrated carbohydrate rich diet good (complex carbs, not simple ones as sugar), now, confusing complex and simple carbs, carbs are demons and 40% fat saturated (crazy Longo diet, surely bad), the french guy high protein diet to get thin,
before no eggs, then recognized blood cholesterol not dependent on cholesterol in diet, only dependent on saturated fat in diet...
And all this is nothing compared to inter-species differences in longevity. And very little compared to CR clearly positive effects...
And before coffe bad, and now coffe good (it was hot water on it no coffe, coffe protective). And red wine, and french paradox back in the eighties and bla bla bla
And oncologists cetuximab big study 20 countries 500,000 patientes, 25% increase in "longevity" of cancer patients published around 2008. And 4-5 years later a bigger study 30 countries arouns 700,000 patients, no confounding factors? and cetuximab effect on longevity of the patients zero! (what shame, what shame, to make business with death
Pharmaceuticals put Jhonson at white house, someone told me decades ago, not you inocent americans..
And, of course there were no guns of mass destruction at Irak, not at all, George, and Rumsf*, and Chen*. And what did you do, americans to these liars? Nothing at all. They are surfing on the waves with the money...
Epidemilogy is not hard science at all.
I am a scientists. If well done, it is very very reliable. You repet the experiment, and you get allways the same. During 40 years I can say that.
My papers are not in Science and Nature (of course I am Gallego, not Anglo). But, what I said on my sci. papers 30 20 and 10 years ago continues to be correct today! I am proud of it.
And the theorists and egineers who never did any experiment can not teach me. The teacher (Full Professor of Physiology) it is I.
Take care with those pills etc. That is only my advice, of course
Professor Gustavo Barja,
You make excellent points,
I humbly thank you for taking the time to respond to my post,
Sincerely,
Aslan
Well written Gustavo. Lets imagine for a second that we combine CR, exercise (aerobic, HIIT, strength training) , cold/heat schock, intermittent fasting, enough sleep, meditation and most importantly avoiding junk food and chronic stress.
"This is FAR better than anything you can expect from resveratrol (keep taking green tea though!!), nicotinamide riboside or anything else at this time."
resveratrol has increased the lifespan of yeast, short lived fish, obese mice, mice with several types of mytochondrial dysfunction, and other organisms. It changes the gene expression of hundreds of genes to mimic the changes seen in calorie restriction.
It is able to activate multiple sirtuins, and even FOXOA3, the centenarian linked gene.
"The scientists confirmed the interaction in mice injected with resveratrol. TyrRS's activation of PARP-1 led, in turn, to the activation of a host of protective genes including the tumor-suppressor gene p53 and the longevity genes FOXO3A and SIRT6."-sciencedaily
Able even to reverse near senescent cells to a more youthful state by significantly extending telomere length.
"A team led by Professor Lorna Harries, Professor of Molecular Genetics at the University of Exeter, has discovered a new way to rejuvenate inactive senescent cells. Within hours of treatment the older cells started to divide, and had longer telomeres -- the 'caps' on the chromosomes which shorten as we age."-sciencedaily
It's failure to lengthen lifespan in longer lived organisms, I hypothesize may be due to the age related declines in NAD+, as resveratrol acts through sirtuins that need NAD+ to function properly.
Dr Barja, that's all very compelling. I'm reading your ARS 2013 review and don't see any mention of your concern about C. elegans in the wild vs lab or the pO2 difference. Can you elaborate or tell me where to look?
Also, calorie restriction has been tested in wild mice and doesn't appear to work, so the same problem may exist there. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2006.00236.x