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.
Josh, Harold Katcher and I also believe in programmed aging. You will be glad to know we did it! And it was spectacularly successful. We just completed our 2nd trial. We can’t reveal much till publication but we managed to do exactly what you mentioned above about signaling system and resetting gene expression pattern to a youthful one. Harold can probably tell you a tiny bit more about the results in really old SD rats.
Do you have a date for publication, Akshay?
Congratulations on your (to be announced) results!
Thank you Mark. Probably in 4 to 5 months.
Cmon Akshay give us a hint of this fountain of youth that you’ve discovered. Five months is a long time to wait. I mean in 5 months I’ll be 64, but if I start your elixir now I’ll be what, maybe 25 in five months?
Must be this https://joshmitteldorf.scienceblog.com/2013/03/25/young-blood/
Must be this: https://joshmitteldorf.scienceblog.com/2013/03/25/young-blood/
Thank you Larry for bringing to my notice such a brilliant article by Josh. Is this before Horvath clock came out or after?
OMG what a phenomenal estimation by Josh then proved by Horvath clock to be presciently correct!!!
Interesting. There is a series on phoenix rising blog about how IVIG is good for Chronic Fatigue Syndrome when next to nothing else other than NAC shows improvement. But there is a big shortage of it and it gets rationed to those neurological diseases that have the worst symptoms.
Another great article, Josh, thank you.
[ Josh said: “I’ve been moving the timeline out, as he has been moving the timeline in, and there is much that we agree about.” ]
In reading a few of your interviews on the internet, I have noticed that you have moved the timeline out.
I have felt that way for a while, regarding extending lifespan. There are exogenous substance that effect endogenous processes but by my observation they preserve the human in a healthier state for a longer period of time while only extending life span minimally.
I am okay with that. I would rather die younger and still functional for longer rather than live longer in a debilitated state.
Still, it would be nice if we could figure out how to do both.
I think it is too early to be pessimistic about the prospects for life-extension by restoring telomeres. After all they are extremely important for regulating gene expression. So I still think – like you used to – that it could be an easy win. Might be a good idea to run a course of senolytics first to clear out the ‘far-gone’ cells, and then rejuvenate the rest.
There are tissues which don’t replace cells, that lead to death due to cell loss over time. In small animals like rodents, having far fewer cells, they may be more affected by such, such that even if they were fully rejuvenated you may still not see indefinite life extension.
For example the group of neurons controlling the automatic breathing reflex experience cell loss, after a certain amount of time and sufficient cell loss, it becomes a significant probability that breathing will halt while asleep and kill the animal.
Nice, though Aubrey and I have had our disagreements I will credit him with creating a ’cause’, an organization actually attempting to do something about aging, at a time when others took the advice of folks like Leonard Hayflick, Tom Kirkwood and others, to just not bother with the possibilities of extending life by significant amounts, that just wasn’t possible. Now, both Hayflick and Kirkwood are in Aubrey’s corner. To me, the basic concept that Nature just ‘doesn’t get it’, and that we humans can engineer a better system that would give us the near immortality that Aubrey desires, is arrogant. To begin with, engineering a system as complex as a living eukaryotic cell is clearly beyond our abilities until we understand that system, and we do not. Life it is still complex beyond our understanding and the best we can to understanding living systems in all their complexity is to make simplified computer models that sometimes act as our cells do. However, most of the clues to reverting cells and bodies to an earlier (though still differentiated state) have already been discovered. We (our group in India) have taken full advantage of these clues and have had some remarkable successes already. It is extremely arrogant to think that Nature is a poor dummy that we can help to ‘get things right’. Nature set limits on lifespan as an adaptation to the niches of living things, (it amazes me that there are ‘annual’ and ‘biennial’ plants with lifespans of one or two years respectively, yet biologists can’t accept programmed aging in animals, when it is so clear in plants); do annual plants have yet to discover how to live for years, or is their habitat (they’re weeds that grow in disturbed areas)? Human beings have gone beyond the dictates and rewards of evolution, without spending a million years doing it, we can fly, travel underwater for thousands of miles, and even journey through the vacuum of space, all without (biological) evolution’s help, and it’s now time to control our own lifespan lengths. Sadly I’m still debating whether humanity deserves extended lifespans, (Gilgamesh, (the semi-mythical Sumerian King), who discovered a plant that conferred immortality threw it away with the conviction that “immortality is not for Man), so perhaps we’ll start with dogs.
Of course I agree with programmed aging. I know (no doubt) that A PROGRAM FOR AGING EXISTS (and has been selected for), THAT AGING IS GENETICALLY PROGRAMMED, I know it since I entered the field in 1988. Because I am a biologist (and biogerontologist), and therefore I perfectly know that every animal species has an species-specific (maximum) longevity (rats 4 years, horses 56, humans 122 years). This means that longevity is surely written in our genome (impossible to be untrue, no need to do any experiment to demonstrate such an obviousness). Do you think that body size can NOT be written on the genome of each species? Same case for aging.
Also, I worked 25 years at the laboratory with isolated well coupled functional mitochondria and measured properly their mitROS production (mitROSp) rates. They “spoke to me” repeatedly, and they said well aloud: “Whenever we want, we decrease the mitROSp PER UNIT OF ELECTRON FLOW AT THE RESPIRATORY CHAIN! (we lower the FRL%-abbreviation invented by Gustavo Barja many years ago, “they say to me”). They do it in birds like pigeons (compared to rats), and canaries and parakeets (compared to mice), they do it (lower FRL%) also in caloric restriction, and in protein restriction, and in methionine restriction in rodents, and in rapamycin-treated mice, and in at least 1 bat (Andja Rossini et al. showed that years ago). All these are long-lived models either within or between species. In other words: mitROSp is by no means an “unavoidable byproduct” of mitochondrial respiration as hundreds of papers Introduction´s sections have repeatedly stated without any evidence about it! (ignorance is a very bad companion in this world..).
Also, I do not think it is chance that Valdimir Skulachev, a good scientist at the Academy of Sciences of Russia, who has also worked, independently from me, for decades with functional mitochondria and measured their mitROSp rates (different method but similar conclusion) is one of the earliest advocates of programmed aging [Skulachev et al, Biochemistry(Moscow), 1997]
In spite of that, authors such as Tom Kirkwood have written large amounts of papers (and talks) even in Nature! , and have stated that “longevity (death) genes can not exist ( his book front cover “Time of Our Lives, Weindenfeld & Nicolson, UK,1999”), and proposed the most nonsense and impossible to be true among the 3 (unfortunately) “still today Mainstream” evolutionary theories of aging: the so called “Disposable Soma theory”. This is not a “theory”, it is simply something impossible to be correct.
The MOST important reason why it can not be correct is the well known (for a physiologist) inverse relationship between weight-specific metabolic rate and body size (known since 120 years back, see Max Rubner 1902!, … to the disregard of T. Kirkwood). That rate is enormously greater in mice than in elephants (energy flow is huge in mice, per gram of mice, and it is tiny in elephants!) and, absolutely opposite to T. Kirkwood´s DS prediction, it is the mouse that dies before 4 years and the elephant lasts at least around 7 decades…
In addition, women expend huge amounts of energy in 9 months of pregnancy, long months/years of lactation, and years of child care (at hunter´-gatherer´s state at least…many also even today, to the dislike of MeToo followers I suppose..), and, in spite of that, they live even around 10% more than us men, whereas according to Tom´s DS they should live much less than us if “energy” were the key, because we expend on sexual intercourse a ridiculous amount of energy (less than 0.04%! of a man 24 hour´s metabolic rate).
And above this, the DS is a “physiological? -proposed- theory, proposed by someone not a physiologist, not a laboratory experimenter, not a filed zoologist, just a man at his desk….who do not want to compare his hypotheses with data from real world (lab., and nature in the wild).
But Tom has never explained in detail (instead of speaking about “energy in abstract” as he usually does) how could it be that one man performing one session of sexual intercourse with a women would loose “energy” so that the rest of his body organs (liver, brain, heart etc) would be run out of energy for maintenance (defense plus repair) …………………¿? Non sense.
Do you think, Tom, that performing sexual intercourse decreases your blood glucose levels (you forgot about hormones like glucagon, insulin etc that regulate blood glucose!), Or perhaps you were thinking that the ATP that a man expends on his skeletal muscles during sexual intercourse, leads to running out energy in organs far apart?, or perhaps lower ATP levels traveling through the blood perhaps! (impossible biochemically) ¿?
Nonsense again. If one proposes a physiological theory, one has to propose a “mechanism” for it, instead of speaking about “energy” “in abstract” (not scientific at all!).
I am a senior Professor of Physiology, and an Animal Biologist (Comparative Animal Physiologist) since 40 years back already, and I can not believe that DS can be considered a serious (physiological!) evolutionary theory of aging…
You can also read about many other reasons why DS can not be correct on Josh Mitteldorff excelent 2016 book on Evolution of Aging, including that: CR-caloric restriction (less energy ingested) increases longevity whereas Tom´s DS again predicts the contrary………
Concerning George Williams much more rational idea of antagonist pleiotropy I am happy Josh, seeing that you liked my idea that yeast had NO PANCREAS. I told you that on the phone last September 28th between 23:00 and 13:00 (local Madrid´s time) as I suppose you are ready to recognize.
Aging is very old (Clarck, Advances in Gerontology-2004), so, since unicellular protists cannot have a pancreas (non sense, since they are unicellular), this means that the original function of insulin/Igf-1 genes in yeast could not be to regulate blood glucose! Instead, the original function should have been to promote aging (good for them, as it is good for multicellular animals today, good: “for the group”, group selection, of course..). And only after hundreds of million years, when multicellular animals with vascular system and PANCREAS appeared, they were used also to regulate blood glucose. This is pleiotropy, but exactly ON THE REVERSE COMPARED to what G. Williams proposed! It is G. Williams idea UPSIDE DOWN!
And the 3rd Theory P. Medawar has been discredited by field studies of zoologists showing that yes, there are old animals in the wild, so, Aubrey, you were wrong:
Yes there “is a phenotype” to be selected! (by group selection, surely, obviously not by individual selection, because aging decreases individual fitness and at the same time increases group fitness…
I also used to be in the past an Aubrey´s friend, and then admired his first Landes book (before 2000). But then he produced that –absurd on my opinion- somewhat before 2013? much thicker book with his 7 measures (Josh mentions it) to win against aging. He proposed cleaning (engineering) one by one the 10 elevated to 11 cells of the old human body with those 7 measures (which include taking enzymes form the soil¿? etc). Simply impossible and not worth trying in my opinion so inefficient approach…. (much less expensive to make a new child…). And at the same time he tried to dismiss R. Weindruch life-long rhesus monkeys caloric restriction study (Colman et al Science 2009), while at the same time supporting the other one (Mattison et al 2012 Nature) on which the “control” animals were already restricted! And “restricting the restricted” (what design! ¿? Designed “for failure”?,…. or by “fear of failure”?) surprisingly such study still improved the age-related diseases!…(not calculated before I imagine..). And Aubrey even predicted (theoretically again, no evidence as usually..) that CR will not work in humans even though it works in yeast, fishes, insects, nematodes, mammals etc..and Aubrey dismisses programmed aging (which agrees with practically all relevant facts discovered on the last two decades), and etc etc. He surely knows why he, so intelligent a man, behaves that way….Josh obviously does not……but I (sorry to say it..) suspect it….
That´s enough for today Josh. I must work somewhat today on research…Too much teaching here due very hard application of Neoliberal rules at our PUBLIC (1.500 eur students pay per year still, “thanks god”…) UCM University. Thos neo-cons are trying hard to do “apoptosize”it, University-ptosis! (new word): Tatcher and Reagan triumph from their tombs! It is decades ago that they are dead! But still…)
There is absolutely no doubt in my mind that mtROS sets the pace of aging (or rather mtROS per unit volume of cell).
This is because it is this factor more than any other that leads to the DNA damage that can then lead to 1. Repair, 2. Failure to repair and senescence or apoptosis, either of which lead to other cells having to enter the cell cycle and losing telomere (which eventually leads to a more senescent phenotype across tissues), or 3. Failure of arrest, which leads to proto-cancer.
But although mtROS may be at the root of the cause, it is not necessarily the solution to rejuvenation – as even resetting ROS levels in a 70 yo man to, say, 10% of that level – he would still have a body full of old, many times cycled cells (who aged at a slower rate from then on).
At a genetic level, the amounts of mutations is minimal, even in a centenarian. It is the gene expression which has changed. David Sinclair and collabs, iirc, has shown that aging phenotype can be induced by altering just gene expression.
At a cellular level, rejuvenation of gene expression, rejuvenates cellular function and makes cells indistinguishable from young cells in a microscope.
Some like Michael Fossel, iirc, believe that if gene expression is rejuvenated the body will be able to ramp up repair and maintenance and rejuvenate tissues. He indicates the body’s age related changes in gene expression drastically downregulate the repair and maintenance of intracellular and extracellular molecules.
Exactly what I believe is happening. As Professor Hayashi at Tsukuba University shows: rate of damage remains the same what changes is the rate of repair. Age induced methylation of TSG silences them progressively thereby increasing our vulnerability to cancer as we age. But there is a nature derived intervention that reverses this methylation thereby restoring TSG expression. Which nips emerging cancer in its bud.
Another great post and learning experience ! Thank you !
On one side I find that the exciting Belmonte’s team results at Salk are supportive of the programmed hypothesis. See their “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming” and possible future extension to non progeric mice models.
On the other I cannot be other than happy of a possible convergence with the damage hypothesis and this seems also supported by evolution as I learned from a nice review by Tapash Jay Sarkar and Vittorio Sebastiano (“Rejuvenation on the Road to Pluripotency”):
“…The key concept this strategy has tapped into is the so‐called programmed aging hypothesis . This idea holds that the aging phenotype is driven in large part by deterministic and programmed changes, and thus is reversible. At the cellular level, this directly points to changes in gene expression, which is reversible especially through the modes of epigenetic and nuclear lamina modifications. So if age is programmed, iPSC technology could possibly reprogram age—truly apt naming in hindsight. The dual theory is the damage‐induced aging hypothesis, which holds that aging is driven by the stochastic degradation of multiple cellular components. This damage is driven by environmental interactions as well as internal degradation as a result of metabolic processes . We discussed manifestations of this in previous section, such as DNA damage, ROS damage, and proteotoxicity from accumulated macromolecules. Unlike programmed aging, the results of this damage are random and thus are not inherently reversible. iPSC reprogramming cannot directly oppose damage but it can help to mitigate some of this damage. As we have seen, it can boost expression for natural repair mechanisms, like homologous repair of DNA damage; it can promote the synthesis of new organelles. From an evolutionary perspective, the two hypotheses may be fundamentally linked. The continued accumulation of age‐related damage and the resulting loss in functionality may make retaining older individual less beneficial from a species‐level perspective. Older individuals would be less fit and less capable of performing their role in a communal society, more susceptible to and may further transmit pathogens, more likely to produce mutated or dysfunctional offspring, and still take up resources that could go to the younger generations. Thus, species may have evolved programmed mechanisms to further the decay with age and thus increase the mortality and clearing of the older individuals. This could explain why a natural rejuvenation exists but only occurs in the production of the next generation, instead of somehow being applied to retain the youthful phenotype , like in the case of mitochondrial biogenesis, and it can boost the clearing of damaged components by transiently increasing proteolytic activity…”
Thanks – I’m really glad to know about this chapter by Sarkar & Sebastiano. Though they’ve come to the right conclusion about programmed aging, they have the wrong evolutionary mechanism, and in fact they have repeated the fallacy that Weismann fell into 130 years ago. That is, they imagine that aging is a way for the community to get rid of individuals who have become damaged by aging…circular reasoning, as pointed out by Medawar in 1952, who said Weismann “canters twice around the perimeter of a vicious circle.”
Nice to know about this circular reasoning made by August Weisman. I only knew about his (early ) idea (before “changing army”) that aging was “good for the group” because this way the old are substituted by the young (their children): the very common vulgar non-biologist people believe, by the way….
In my opinion that is not enough. Simply substituting old with young individuals does not give any clear advantage. For me the key is, as I think that you know I think, that the young have different gene combinations than the old ones, because “cards are played twice” at reproduction:
a) at meiosis in testicles and ovaries (eggs-ovocites and spermatocites)
b) when boy chooses girl and the reverse
So, aging helps to get new diversity, the raw material on which natural selection works.
That is the way I always thought about this.
Please tell me if you consider this wrong
Firstly I will state that I am only now, just (at age 43 as an engineer and father of 2) beginning to study basic high school biology as it is a passion of mine to better understand life and ultimately aging and health.
My question may be ignorant/foolish but I wanted to just ask: if we discuss programmed aging as it affects plant and animal life; how does it affect the other kingdoms of life (protista, fungi, eubacteria, archae/archaebacteria), and also does it affect viruses in any way?
The reason I ask is that if ‘aging’ is conserved even in the simplest forms of life, would it not be simplest/easiest hunting for it’s origin therein?
Even the brief discussions above about yeast and prokaryotic cells, is quite relevant (imho) in this regard, since the ‘solution’ to understanding this aging program must lie (??) in plain site in even the simplest cell.
There are two chapters of my book about aging in protozoa (called “protoctista”). Viruses don’t age, but there are some forms of aging that exist in bacteria. 2006 article
Aging has not been absolutely conserved, and many of the mechanisms of aging have been coopted to other functions, just as functions that evolved later in the history of life have been coopted as part of the aging program. So yes, we can learn something from looking at the evolutionary history of aging, but we won’t find simple explanations there or anywhere.
Great article Josh.
I too have evolved in my thinking about aging , but while your thinking is centered on the causes and mechanisms, as a doctor I’m mainly focused on the possible interventions, and I’ve certainly changed my mind in this regard.
At one time I was convinced that we should be aggressively taking all sorts of supplements on a daily basis in an attempt to at least slow down the aging monster . It is now clear that this is all terribly complicated, at least in humans, and none of it is black and white.
We want to prevent telomere critical shortening but have to be careful about over activating telomerase. Inflammation is good in some settings, bad in others. Exercise can be overdone. Senescent cells and SASP isn’t all bad and in fact can be very important in cellular repair and rejuvenation, so we must be careful with senolytics. This is especially true of those which inhibit topoisomerase 1 and 2 enzymes which can lead to tendon rupture and leukemia. We all know of the dangers of too much mTOR inhibition.
Of course we also never know how mouse studies will translate to humans and human studies remain far and few between.
None of this is to suggest that we shouldn’t try interventions but my own approach has been modified to cycling everything. More than ever I now believe in the importance of intermittent dosing.
Paul you are a true crusader of the anti aging brigade. I too subscribe to cycling key supplements and hormesis generators till a real anti aging remedy is available for humans. Although this strategy does not stop the daily deterioration we suffer it slows down some of the damage.
On our research: most scientists, researchers would be happy to have one great success in a thinly researched and complex field of aging. We have had spectacular success in two studies with entirely different strategies. But the reason Harold and I are withholding sharing information is of course due to requirements for publishing and patenting but also because both the successes in reversing aging have been in old rats. We don’t know for sure that it will translate to humans yet. It encourages us though to raise more funding to do more pre-clinical studies including on larger animals and work towards launching human clinical trials. We are following rigorous standards set by Harold and our team. So fingers crossed for humanity that soon we will have an option to keep ourselves and our loved ones longer in this world from our group or another. If it’s so dramatically possible in rats there is hope.
I too have largely moved away from daily supplements towards attempting to push cells in a useful direction using cycled strategies. For example I think there is merit in replenishing stem cell niches, extending telomeres, and senescent cell clearance – but each is done for a short duration and would probably be harmful otherwise. Of course we must find the right buttons to press, but I’m confident we’ll get there.
I agree regarding the cycling in intermittent dosing.
Meant to say “cycilng and intermittent dosing.
It is the first time I post on your blog but I’ve been reading you form several years now (including your very interesting book). You convinced me about the programed nature of aging with very strong arguments (I’m not a biologist but have a scientific background). Nevertheless, both approaches (tinkering the biological signals to get the rejuvenation of the body or repairing the aging consequences) should be followed at the same time. As you said, your approach appeared to be way more complicated than you thought at first, and it may take a long time before we get strong results. Maybe the repair approach could give us more limited but faster results in the meantime.
In the signaling field, I am however surprised that the studies on Yamanaka factors didn’t found more enthusiasm from the antiaging community. I don’t have the link, but intermittent doses of those factors show rejuvenation results in mince (but yet there were no data on life expectancy). With only fore molecules they got it! Isn’t that what we are looking for?
You might be interested in the following Yuri Deigin of Youthereum Genetics as he is the only one I know aiming to apply this by inducing OCT4 intermittently, something that look particularly attractive after the work by Nelly Olova et al (https://www.biorxiv.org/content/early/2018/03/31/292680) showing temporal uncoupling from epigenetic de-aging and reprogramming.
I quite stand with you in both following different paths in parallel and being astonished by the lack of more discussion on the intermittently dosing of OSKM reversing hallmarks of aging. The paper to refer to must be “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming” I mentioned in my previous post:
I expect a follow-on on this on different animal models too. I am also following a thread on LongeCity where I also try to contribute and you might also be interested:
And what Yuri Deigin at Youthereum (see post by Guillermo Fernandez) is trying to do with OCT4 and starting on pets is also interesting and courageous.
Staying for yet another moment on the very slippery path of the “theories” I am always bothered by the question: to which extent the “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming” experimental results are supportive, non supportive or simply neutral on the “programmed aging” whatever that means? Coming from physical sciences, I think finally what is important is putting theories to test and let experiments decide what really Nature tells us and which theories should be superseded to favors others with more explicative power.
It’s fascinating stuff Albedo but is it actionable at this time or are we a long ways off?
Thank you Paul. If results are repeated on non progeric mice, which is likely a next step by the team, then maybe trials can be accelerated. Also, maybe approval for a reduced scope trial, e.g. for a therapeutic treatment of skin wounds, where tissue repair mechanism are impaired, could happen. The huge impact of neurodegenerative diseases might also help in accelerating developments as well as the development of organoids or tiny organs. Also the two paths of trans-differentation and the transient induction of OSKM (or a subset of the factors) for rejuvenation would need to run in parallel bringing huge therapeutic potentials. It is difficult for the amateur researcher I am (and moreover a physicists trying to learn biology of aging !) to estimate how far we are in the future. Courageous initiatives such as those at Youthereum should also be supported. I have posted much more on the LongeCity link I mentioned but maybe concluding here on both the challenges and the hopes using Belmonte’s et al. words is prudent:
“…The resolution of ongoing clinical trials using human pluripotent stem cells over the next 2 to 3 years together with all these advances could finally result in exciting new findings in the decades to come, and thus provide fundamental knowledge on either autologous or allogenic iPSC translation into a clinical setting…”
Garreta E, Sanchez S, Lajara J, Montserrat N, Belmonte JCI. Roadblocks in the Path of iPSC to the Clinic. Curr Transplant Rep. 2018;5(1):14-18.
“…The scientific community should communicate the utility of iPSCs in future medicine to the general public while carefully guarding against unrealistic expectations. With the understanding and support of the broader public, we should expect, in the not too distant future, to uncover disease mechanisms, approve personalized therapies and discover more useful drugs with the aid of iPSC technology…”
Li M, Izpisua belmonte JC. Looking to the future following 10 years of induced pluripotent stem cell technologies. Nat Protoc. 2016;11(9):1579-85.
(re-post, previous reply went lost for some reason)
The paper you mention must be:
Ocampo A, Reddy P, Martinez-redondo P, et al. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell. 2016;167(7):1719-1733.e12.
Just in case you might be interested there is also a thread on the Longecity forum:
I am still not clear to which extent these results might help in the discussion on the various theories of aging but surely would deserve more discussion as you say.
Nice article Josh, but I have a few comments.
1) You exaggerate the extent to which SENS has changed:
– the fact that catabodies already exist naturally in the body does not change the fact that we need to engineer them to get rid of TTR (they don’t get rid of it naturally, even in youth).
– I have always viewed tissue engineering as inferior to stem cells, simply because it involves surgery, and I still think that engineering stem cells and injecting them is much more powerful (and safer) than stimulating stem cells in vivo. AgeX’s “iTR” technology may change that, but not yet.
– I have noted the signalling role of ROS since the dawn of SENS – I mentioned it in the second SENS paper (BioEssays 2002), for example. I see that I didn’t mention it in my first book, but that predates SENS.
2) You quote me (accurately) as follows: “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.” (This is what in my paper I called the “cancelling-out argument”.) But then you say “My response is that we have pro-aging and anti-aging machinery that are activated at different times of life”. Previously I had heard this challenge only from Ted Goldsmith, shortly after my paper came out, and I countered that such an argument is inapplicable to slow-aging species (such as humans) because those species’ anti-aging machinery is ALWAYS active, from conception until death. I’m sure you were copied on that exchange, but I don’t think you (or Ted, or anyone else) ever offered a counter-counter.
I’m in the camp that we need to grok the epigenetic data related to differences in aging rates across species, since a priori claims of death program impossibility aren’t convincing to me. For example, the higher order effects that deliver a benefit from systems utilizing simultaneously opposing forces such as this mechanical system:
are hard to predict but relatively easier to understand once discovered. Stuart Kauffman is discussing using a similar concept he calls the Poised Realm to explain features of consciousness of all things. Control systems in biology can likely easily derive a benefit from always-on opposable programs modulated from a higher order program.
Perhaps it’s a matter of semantics, but if aging is defined as an increasing probability of death over time, then I don’t see why it’s not possible to have anti aging and pro-aging mechanisms which coincide.Some of these, like sirtuins,autophagy, NAD, among others decrease the probability of death, whereas others such as mTOR increase the probability.
Of course , some would define anti-aging as stopping or even reversing the aging process back to a youthful state. Under that definition I would say that our anti-aging mechanisms are woefully inadequate to say the least.
Paul our mechanisms are constructed brilliantly by Nature but up to the point of puberty for continuation of species after that it is programmed to dysfunction progressively. mTOR for example itself is an incredibly useful sensor probably the most important and does a great job of managing between growth and repair in our youth so it is not an aging mechanism – there are none – as we age mTOR is programmed to dysfunction. The various dysfunctions slowly turn very useful mechanisms to harmful ones. Our body continues to adapt to survive but the relentless progress of dysfunctions finally ensures systems failure – death. If we can reprogram for the dysfunctions to not happen Nature brilliant engineering should help us avoid almost all non infectious causes of death. There are various approaches to reprogram: George Churche’s way, Yamaka factors, hacking the methylation pattern to youthful gene expression, etc. The key is to find one that is safe and sustainable. Recent developments encourage us to believe it can be done – we are probably very close.
I certainly see your point. Aubrey stated that you cannot have anti-aging and pro- aging mechanisms coexisting, but it seems to me that that state of affairs does in fact occur and I was hoping that he would clarify the statement. For example, we have the anti-aging FOXO3 coexisting with the pro-aging mTOR ( at least we do after the stage of growth and development). Perhaps I’ve misunderstood his statement.
Please, at least for once in your life, you both, the creator of this blog (JM, the “Me”), and you, the other one (ADG), will you listen to me at least ONCE?:
THERE IS A PROGRAM FOR AGING, and is composed of hundreds of genes, strongly interrelated in complex ways. Only KNOWING IT and UNDERSTANDING IT reasonably well will we be able to properly manipulate it (slow it, or even reversing it).
Blindly taking pills or analogues of “chemical substances” travelling in the blood, even TFs (even if they “go” and target the program) etc,…. or, even worse, trying to fix the damage like a “car mechanic” on a repair shop, will not work (that last is absolutely impossible).
Running fast is nonsense (please think about your children and grandchildren instead of about yourselves). We (the biologists, the scientists, the ones who know how to do it) must understand the program first, and then try to manipulate it, not the other way around. Trying to manipulate the aging program from the outside without knowing how it works is nonsense. It is the same as e.g., a beetle trying to repair a computer….(nonsense).
The proper job that must be done is to know how nature is, how animals are, and function (that is the job of physiologists like me, people well prepared to do that job). A hard and long job…. Therefore, the sooner they, the genomic SCIENTISTS, “open the nucleus” the best… There is a lot of work to do.
In the meanwhile, JM and the others in this blog, please do not take pills or “treatments” . You are only risking your own life.
And please do not listen anymore to car mechanics, and/or to “deceitful salesmans”…….
The BIOLOGIST (THE SCIENTIST) spoke. The Physicist and the Engíneer should listen to him. Why? Because aging is a BIOLOGICAL problem. Not to be solved by the car mechanic…..surely not. Due to the body not aging like a car (no wear and tear, because we are ALIVE), AND DUE to solving aging not beeing a job for car mechanics… Solving aging being not possible, also, by a car mechanic so intelligent that he knows well about this impossibility, although he tells everybody else otherwise…… And JM, incredibly enough, listens to him.
I am very much of this opinion as well. I think the discovery of epigenetic ageing clocks has strengthen this point of view considerably.
We are not like one of the machines we manufacture but rather a collection of them. This much should have been clear since we discovered we are multi-cellular organisms. We are a community of clonal cells cooperating for the survival of a subset of themselves, the germ line. Cars or computers have discrete, different parts, they do not grow, repair or multiply the way a living organism does. So the machine analogy, if anywhere, should lie at the cellular level and build up from there.
Unfortunately we do not have a clear view of how microscopic, cellular changes translate into macroscopic ones. The closest candidate appears to be the SASP and associated inflammation. But given the positive roles of S.C. that’s unlikely to be the whole story so I like to keep an open mind.
Like you, I think we should focus in understanding the epigenetic program that seems to determine aging, but this is also likely to be a slow road.
Good thing we didn’t wait until we ‘understand’ turbulence before we built airplanes that flew since last I checked we’re still using Reynold’s number for an emperical calculation (if we ever truly can mathmatically describe turbulence it will earn the researcher the Nobel prize for sure); yet we’ve been flying airplanes for over a century.
But I do not think a program with hundreds of genes interrelated on complex ways is like flying in airplane a device with 10 elevated to 15 less pieces and their interrelationsips than the human body. I you ever study physyiology you will understand my point I think.
I do not know how the airplane history started but I suppose “sensatos” people did not fly on any airplane until it was shown to be reasonably well.
I know you like speed at USA. Incidentally, that’s why I do not like amarican films any more (golden age ones from the 50′ s were much better than the present ones that are made for adolescents). When one thinks of taking a treatment WHOLE life from now, it is reasonable to wait until its efficacy and safety is scientifically demonstrated. Thats the way we think here at the old Europe (we still read much old greek phylosophy…)
But if you want to take risks…go ahead. It is your body and your freedom to do it. Not mine..
You know far better than I the complexities of biology, aging, etc.. I am only trying to point out (as an engineer) the anaology of turbulence in order to ask the question: ‘is it absolutely a requirement that we completely understand the entire process of metabolism, aging, interactions (this entire utterly incomprehensible machine) in order to discover or engineer safe and effective interventions.
You are clearly stating you believe this is nonesense, and I appreciate your input; again I am not challenging YOU, I am only here to learn really.
We do not need to understand the Aging Program lying on the cell nucleus PERFECTLY. But we need to understand it reasonably well.
Even though hudreds of genes are involved, there must be a hierarquy. Going to second, or third (or etc.) level MASTER GENES should be enough to obtain people with 2, 3 fold! etc higher longevity than nowadays (122 years) without them being the size of an elephant or having children only after 150 years (for insttance).
You can see the details on my hypothesis paper published 10 years ago (Barja-G, Biogerontology, 2008). There you have even an scheme drawned by myself on how (in essence, not in the details) the nuclear AP should be organized (no one saw it never because due to the wrong evolutionary theories of aging (all of them wrong “wear and tear” theories, everybody has been working on the cytoplasm and no one at the nucleus.
The sooner the big genomic labs. at USA “open” the nucleus the better. There is a lot of work to do..
You can also read my open “CARS” article on the subject : Barja-G, ROS Journal, 2017.
Another much better one will soon be published.
I have checked that you are right. My criticism on C. elegans ( on the wrongly done experiments and why up to 10 fold increases in longevity obtained on this animal but never on other species, and never in mammals…) is not included inside the text of my 2013 ARS review. I have published so many (180 scientific papers) that my memory failed this time.
I do not have time to look among my too many reviews (they were asked from me by editors…that´s why so many, …) to know on which one I entered that issue.
But it is much better that you go to the original paper by David Gershon. He is the one that warned us all on the European Congress of Aging at Barcelona many years ago about pitfalls on C. elegans aging research. In addition to his talk there, he simultaneously published a whole paper to warn about those problems with C. elegans (I do not kow if Cyntia Kenyon, Calico president, is aware of this most importan issue for her past research on C. elegans). So, go and read directly yourself the original paper (much better than my secondary commenting on it). It is this one:
-Gershon H(1), Gershon D. Caenorhabditis elegans–a paradigm for aging research: advantages and limitations. Mech Ageing Dev. 2002 Feb;123(4):261-74.
If you can not have access to it, just send to me your email address and I will send the pdf to you.
Hmmm, amyloid deposits can exist even in the brains of relatively young individuals, but if the glymphatic system is functioning properly the accumulation is kept in check and advanced neurodegeneration does not occur. The aging process takes a toll on the glymphatic system, which may be one of the reasons things like Alzheimer’s are seen more prevalently at more advanced ages.
The rest of the body has the lymphatic system, that appears to also work in disposing wastes, and whose function is also compromised with aging. Is there evidence to suggest that it too could not keep amyloid diseases in the rest of the body in check if kept youthful?
What of the negligible senescence animals. Unless they have novel molecular machinery to process this stuff, it should most certainly accumulate in them.
In any case rather than processing all possible different kinds of molecular garbage, the transportation and expulsion from the body seems like one potential strategy. That is what we humans do with our garbage trucks and recycling trucks, send the garbage elsewhere. It would be surprising if similar mechanisms, don’t exist in us or other organisms.
Darian (an many other bloggers)
I absolutely agree with what you say that changing gene expression is most important (at least in the case of variation in aging rate between different individuals, e.g. in caloric restriction or protein or methionine restriction).
But I disagree with the generally held notion by many people that the increased maintenance is due ONLY to increased defense plus repair (this concept has been disseminated by non-PA proponents repeatedly)
In my opinion, not only increased defense+ repair, but also a DECREASE in the RATE OF GENERATION OF ENDOGENOUS DAMAGE (e.g.; mitochondrial ROS production rate) is also most important and occurring. BOTH things occur. The problem is that non-PA proponents “do not like” the decrease in mitROSp because it means that it is decreased “ON PURPOSE” (which then means that there is a Pro-aging program in the cell). I think, no doubt, that there is such a program. It is the program that (best e.g.), in response to DR (and MetR), lowers mitROSp (I have seen this many times at the lab) in rodents (and can also increase defense repair), increases autophagy and many other things to slow down aging.
Please note that the lower mitROSp also works across species (which is the MOST important fold change in longevity-200 fold in mammals, 1 million fold in general, NOT in the inter-individual differences around 1,4 fold maximum in rodents and other mammals, in comparison with the species issue, just the “gout in the ocean” as Josh commented to me some time ago).
But concerning defense+repair there is much less evidence in the interspecies case, at least in TOTAL tissue. I have recent evidence that the situation is, at least for some parameters, very different, absolutely opposite, at mitochondria when compared to nucleus or total tissue (to be published soon). In the case of mitochondria there is evidence already that BOTH low mitROSp and high repair of at least some forms of endogenous mtDNA damage occur. So, both work together to lower mtDNA damage (see our FASEB Journal 2000 paper on this, the strong negative correlation between 8oxodG in mtDNA and mammalian longevity, not seen for nuclear DNA).
Please remember that Stuart et al. (Vilhelm Bohr´s group) have shown clearly that total (nuclear) repair of various forms of DNA damge is NEGATIVELY correlated with longevity across mammalian species (and is also lower in CR than in AL animals) (or not correlated, but clearly NOT positively correlated).
Concerning antioxidants they are negatively correlated with longevity in TOTAL tissue: please see our J. Comp. Physiol. 1998 review on this consistent across all different labs.; or Pamplona and Constantini 2010). But perhaps also they are positively correlated (again) in the case of mitochondria (there is evidence of this at least for MnSOD: Brown and Stuart, 2007, Mech Ageing Dev 128: 696-705; and Page et al. 2010 Age (Dordr) 32: 255-270. doi: 10.1007/s11357-010-9131-2.).
All this highlights (again) the paramount relevance of mitochondria for aging. Even though people that do not understand the issue have claimed that the MFRTA theory “is dead”-because changing ONLY ONE single enzyme, which is only one small part of a single aging effector (among many different aging effectors) did not change longevity in mice (that is “childish” or “non-sense” if you allow me to say it that way, because many many things change when longevity increases substantially; even in CR hundreds of genes vary….)
Myself not having the expertise to challenge either theory I do look at what to do next. I see both theories accepting that there is damage which causes aging, Aubrey says it is metabolic and Josh says it is genetic. Aubrey however is the one who does have methods to turn back aging in the pipeline. Josh does have a theory which may well be right. Still I would put a lot of efforts on a method we can expect to work and less effort to verify a theory.
Before we are sure aging is genetic, if it is at all, and we know what to do about it my take would be to support Aubrey heavily.
I would advise reading through past blog posts. You’ll see Josh has a proposal of how to find synergistic anti aging strategies and measure their effectiveness using the Horvath clock.
Yes Cris, or say the Levine’s DNAn PhenoAge clock which likely tracks biological age better being based on first regressing clinically relevant biomarkers on mortality/morbidity and secondly regressing the phenoage on the CpGs DNA metylation sites. However I feel more and more a system biology approach to biomarkers would be even more productive somehow paralleling a system approach to aging research itself. BTW does someone know if the Levine’s clock is commercially available? See “An epigenetic biomarker of aging for lifespan and healthspan” (PMID:29676998)
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.
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,
Do not worry Aslan.
I love all the 7,000 cousins that I have on this Earth. I only want to help. Thats why I worked so hard (65 hours per week whole year round for the last 30 years dedicated to study how and why aging occurs and exists).
We are in a too special moment in thus world. We are approaching Collapse if we insist in Not doing the right thing: to forget about competition (Hate) and embrace true LOVE
Only LOVE among ALL humans will save us from total Collapse (either global atomic war or Climate Change’induced Collapse..
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
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.
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$!
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).
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.
Have you considered the strange case of the naked mole rat? They do have a remarkably efficient damage repair mechanism and so, as you would predict, they live an inordinately long time. The odd thing thing is that on autopsy there is such little organ damage that no one really understands what kills them. It’s as if they reach a certain ageless point and just keel over due to no apparent organ system failure.
A recent paper from Leibniz also demonstrates, contrary to all expectations, that the NMR breeders outlive the non-breeders.
Strange creatures indeed.
Yeah NMRs are really interesting in so many ways. The fact that breeders outlive non-breeders is not useful in itself though for the question being discussed here, because they have the same genes. As for what kills them, well, that’s not so exceptional – after all, centenarians also tend not to die of specific pathologies so clearly as younger deaths – it really just means that the failure is more evenly distributed across tissues and even across cells.
That’s an interesting point and you’re quite right that those over 100 years tend not to die of the usual causes such as cancer and cardiovascular disease. However, this group tends to die from congestive heart failure secondary to Senile Systemic Amyloidos, which is rare in a younger population but rather common in the very old.
I’m not certain that even if there existed a diffuse pattern of organ necrosis in the NMR that that would , in and of itself , be enough to kill them .
Naked breeders outliving the outbreeders
That is like the ants and other social insects on which longevity dramatically differs between castes and that is known to be epi-genetic.
By the way all that work published by Buffenstein on naked in Aging Cell is bull shit: bad techniques for the majority parameters (kits colorimetric plagued with interferences; incredible that accepted by tha high impact factor journal…
In any case she did not demonstrate at all that NMRs are “more oxidized” as everybody was cheated to beleive due to lack of methodological expertise on the subjetc. Too bad a history…Attacking MFRTA with such a misery of unreliable data. I never understood why Aging Cell suported so stongly so weak and bad science. I suppose this is the endless story: Science-politics or Political-Science as we say at our country. In any case it does not seem to me appropriate fir a high IF journal to be against some mechanistic theories of aging and not against others. Specially whe it is still unclear what part of the truth each one of them is able to explain.
And she (RB) did not stated in those 3 “papers” if she used queens or workers…..(I asume it is unlikely that she used kings because they are scarce…Any one of you knows how long does it live a worker naked mole rat? I am “afraid” not at all 30 years…
You can read about this very “strange” 3 consecutive papers “affair” on my 2013 review on ARSignaling.
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?
Ah, no, not at all. These mutants were both previously found, in protected conditions, to increase lifespan without decreasing age-specific fertility, so the initial interpretation could have been that the non-mutant condition was the result of genuine selection for aging. But the finding that the mutant lost out in natural-like conditions shows that actually there IS an AP thing going on, i.e. that the impact of the mutant is to reduce real-world fertility. That’s exactly what you were proposing, isn’t it?
One important aspect of this that I neglected to note earlier is that the oscillation in nutrient availability that was imposed in these experiments was rapid, i.e. each individual experienced it. That’s in contrast to the situation where there is change in such environmental features over many generations but each individual sees a reasonably constant environment over its life. The main reason why this matters is that in the slow-variation case one can argue for a value of “evolvability”, the ability of a population to respond nimbly to environmental changes, which is in fact the main logic appealed to by most proponents of programmed aging (though Josh actually prefers a different logic). It still doesn’t work, for reasons that again are discussed in my paper, but the argument is a bit different.
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).
Oh, not at all, it’s perfectly simple. First find a mutant that extends life in the lab, then test whether it reduces fertlity, then (if it doesn’t) test its competitiveness in reasonably nature-mimicking conditions. The problem is not that the experiment is difficult. The problem (for PA protagonists) is that the experiment has never come out as the mutant winning, or even surviving for long. The only recourse for PA protagonists is that the experiment has not been performed for most longevity mutants – but that’s not my fault. They are free to perform it.
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?
I don’t understand your difficulty here. The competition experiment asks exactly the question you describe. If aging is being selected independent of anything else, then there will be a gene we can disrupt that will disrupt aging (i.e., extend lifespan) without affecting anything else negatively – and the competition experiment asks precisely whether anything else is affected negatively. Of course it could be that the disruption of aging is too subtle to be seen in the lab, but we’re not talking about that case, we’re starting with the clear life-extenders.
Separately, let me address your mtROS question. Be careful there, because it matters (for the PA question) how you do it. If there were a gene whose sequence you mutate randomly and you found that you reduced your mtROS production more often than you increased it, and lifespan increased as a result, then that would say that the gene was a pro-aging gene (unless, of course, it did have outweighing negative consequences that caused it to lose out in competition experiments). But the other way to reduce mtROS production – and this is why I always regarded Gustavo so highly until he started getting all Latin about PA, since he did much of the key work in this area – is by very gradually, over many generations, evolving many subtle and cooperative tweaks to the genome that jointly gave a reduction in mtROS production. And that … evidently only happens in nature when extrinsic mortality is low, e.g. if you can fly. Whereas, the former scenario (reducing mtROS production by random mutation) has never been seen except in C. elegans, in which lifespan can be increased to a similar degree by knocking out pretty much anything.
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).
I doubt that reducing mtROS production would have the same sort of proportional impact on longevity that we see across species, but it might have a little. We don’t have mutants that do that, though, so we can’t ask the question within species.
Regarding your concern about the competition experiments: that was my point when I mentioned the speed at which the mutants lose out. In natural conditions, there is less aging in the population in the first place, so there’s no way that that could be the main pressure over so few generations.
You should not fall in the trap of the Deductive method that starts from undemonstrated axioms, then reasons perfectly when the reasoner is extremely clever, and thus fascinates people. But if the initial axiome is false, the final conclusion can very easily be false also. This is the method of the ancient greek phylosophers (there was no Science back then, 2,500 years ago….). E-g-, .using it, Plato, one of the most intelligent among men, reached Absurd conclusions for today´s standards, like finally stating that you existed before you were born, or e.g. that things like chairs, etcétera do not exist in the real world. That they are only imperfect copies of the IDEA of a chair,which would be the only “chair” really existing in another world different from us: the world of the Ideas. (all that is clearly nonsense today).
Science today uses the oposite method, the Inductive one (instead of the deductive one). It starts with real observations of Nature (instead of with dogmatic undemostrated axiomas merely stated: e.g.: that “evolution maximizes reproduction allways as the only important thing”..), and then goes from the particular to the general, trying to obtain more general conclusions from the real initial observations.
At variance with the deductive method (that STARTS WUTH A DOGMATIC NOT DEMONSTRATEED AXIOM), Inductive method STARTS WITH REAL OBSERVATIONS.
THUS, TAKE CARE WITH VERY CLEVER EXCELLENT DOUBLE-SELLERS WHO, USING the wrong DEDUCTIVE METHOD DO NOT DEMONSTRATE ANYTHING AND, IRONICALLY ENOUGH, PRETENDE THAT IT IS THEIR ANTAGONISTS (e.g. pro-PAs vs. Non-PAs) WHO HAVE TO DEMONSTRATE THAT THEY ARE WRONG!!!
(Neodarwinian Evolutionists in general have abused this method to maintain their (mathematical) wrong theories of evolution “Moldern Synthsis” from the 1930s, really an “Old Lady” that they want to maintain unmodified in spite of thousands of new discoveriesd in biology).
But the very clever double seller (and its disguised of opposite advocate) is a master in cheating and confusing the bloggers with it……
His real objectyive is to POSTPONE AS MUCH AS POSSIBLE solving aging (EXACTLY THE OPOSITE OF WHAT HE STATES ALOUD CRYING ALL THE TIME WITH THE HELP OF HIS GATHERED MILLION $). He needs that , so that his millionaire business can continue taking money from inocent people including inocent billionaires who do not want to die………
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 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.
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.
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……
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.
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.
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.
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.
The data with CR shows a substantial but lesser effect in mice and conflicting results in primates.
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.
The more items I use from the list of age extenders, the lower my body temperature. I now average 96.3 F.
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?
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: firstname.lastname@example.org
I tried many times. I observed that when my response is long it does not enter the blog….
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.
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).
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.
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.
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)
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