“The way evolution works makes it impossible for us to possess genes that are specifically designed to cause physiological decline with age or to control how long we live.” —from a Scientific American article by Jay Oshansky, Bruce Carnes, and Leonard Hayflick (2004)
Most biologists still think this way, even among people who study aging, even those working on anti-aging medicine. If you believe this as a matter of bedrock theory, then what do you say when a gene is discovered that cuts life short, but still manages to dominate the gene pool? You say that the gene has benefits that outweigh its costs. It is a fertility gene, but it has side effects that kill you slowly. Or it has survival benefit in the wild that are difficult to study in the laboratory. This is called the theory of antagonistic pleiotropy. “Pleiotropy” is the biological term describing a situation where one gene has two or more effects on the phenotype. In 1910 when the term was invented, this was thought to be a special situation, requiring a special name. We now know that almost all genes have multiple effects.
In theories of aging, antagonistic pleiotropy (in different variants), is considered the unassailable king of the roost. It is not questioned. There is no such thing as an aging gene, so as more and more aging genes are discovered, they carve out more and more excuses and exceptions to preserve their bedrock evolutionary theory. Just this week, there are two new examples, in worms and in people.
The First Aging Genes
In the 1980s, Tom Johnson, working at UC-Irvine, was studying aging in the lab worm C. elegans. Johnson grew worms with a defective gene, which he named age-1 after he discovered that worms without it lived half again as long as normal worms. No one had ever imagined that a single gene could have such an effect on life span. In fact, the best experts in evolution had theorized that “everything ought to wear out at once,” so that no single gene could have any noticeable effect. Johnson’s discovery was the more remarkable because longer life required nothing new but rather the deletion of an existing gene. This implied that the effect of the age-1 gene was to cut the worm’s life short. What was it doing in the genome? How did it get there? And why did natural selection put up with it?
Johnson had a ready explanation. He believed (and still believes, I believe) in antagonistic pleiotropy. The worms without age-1 laid only a quarter as many eggs as other worms. It was easy to see how they had been losers in Darwin’s struggle. In fact, Johnson’s finding looked like a dramatic confirmation of the theory that aging was a side effect of genes for greater fertility, greater individual fitness. Aging had not evolved directly, selected for its own sake, but as a cost of greater fertility, a real-life example of antagonistic pleiotropy.
But a few years later, this story unraveled, and what had been confirmation of theory became a direct contradiction. Johnson discovered that his mutant worms actually had two genes that were different. In addition to age-1, there was another, unrelated gene defect (fer-15) on a separate chromosome. By crossbreeding, he was able to separate the two. Worms with the fer-15 mutation had impaired fertility without extended life spans. Worms with the age-1 mutation had extended life spans with unimpaired fertility. This was a full- fledged Darwinian paradox: the age-1 gene found in nature was the one that gave the worm a short life span. It was the “defective” gene that caused the worm to live longer. Age-1 looked not like a selfish gene but an aging gene. It was just the kind of gene that natural selection ought to eliminate handily. How had this gene survived, and what was it doing in the worm genome?
Age-1 was only the first case of an aging gene in worms. There are now hundreds of genes known that lengthen life span when they are deleted. In other words, these genes, when present, have the effect of shortening life span. Some of them tend to improve fertility; some don’t. Some have other beneficial side effects, but about half the known life-shortening genes offer nothing in return, or at least nothing that has yet been identified.
Still, the pleiotropic theory is rarely questioned.
Fertility in male worms
A recent Nature paper from the Shanghai laboratory of Shi-Qing Cai identifies a pair of C. elegans genes that affect the span of fertility in males. The group collected worms from many different locations around the world. They found that in some worms, the males remain fertile almost their entire lives, while other males undergo rapid reproductive senescence. With some excellent detective work, using database searches and genetic manipulation that would have been impossible a few years ago, they identified the genes rgba-1 and npr-28. Each exist in two versions in wild populations, even though they have powerful effects on reproductive fitness. Evolutionary theory tells us that genes with a close relationship to fitness should be subject to strong selection, so that the high-fitness version should promptly wipe out the low-fitness version. In accord with theory, the authors cite statistical evidence that the high-fitness version of npr-28 has recently displaced the low-fitness version. But, paradoxically, the low-fitness version of rgba-1 has displaced the high-fitness version.
Do they raise a flag in their article and protest that the theory is all wrong? No, they are almost apologetic, and don’t dare to suggest that there’s anything wrong with the theory. Such stark contradictions between empirical findings and the evolutionary theory of aging have become so commonplace that most everyone has become inured to them. They shrug their shoulders and say, “there must be some hidden benefit associated with the wild-type gene that we have not yet identified.” Part of the reason that they do this again and again is that this is happening in many different labs. Perhaps each researcher in experimental genetics has only discovered one or two anomalies—they may be unaware that their finding is part of a larger pattern.
Fertility in male mice
In August, a very similar discovery was made by a research group (Xiao-dong Wang’s) at the National Institute of Biological Sciences, Beijing, where I have been resident the last two summers. Wang published a groundbreaking study demonstrating programmed reproductive senescence in male mice. The RIPK1-RIPK3-MLKL signaling pathway in wild-type mice was identified as causing a kind of necrosis in male reproductive organs. Inhibiting this pathway caused the males to retain fertility longer.
In their Discussion, they say right off the bat, “The above presented data indicated that the previously unknown physiological function of necroptosis is to promote the aging of male reproductive organs.” But they don’t challenge the pleiotropic theory. Instead—quite typically for experimentalists—they speculate on a possible loophole that will save the theory: Mice sired by older males are less healthy than those sired by younger males. Aha—maybe this is completely unavoidable, and evolution has had to do what it could to prevent these less healthy pups from coming into the world. “We therefore propose that necroptosis in testis is a physiological response to yet-to-be-identified, age-related, TNF family of cytokine(s) that transduces necroptosis signal through the canonical RIPK1-RIPK3-MLKL pathway.” One thing they omit is that cutting off fertility to prevent the births of offspring that are (statistically) less healthy is no more consistent with the orthodox evolutionary theory (based on selfish genes) than are the theories that say aging is an adaptation. Both require group selection, about which orthodox theory is in denial.
An Amish family lacking a death gene
Just this week, Douglas Vaughan’s group at Northwestern University reports identification of a rare genetic “defect” that gives some Amish families longer, healthier lives. The gene called SERPINE1, encoding PAI-1, is mutated and non-functional in these families. The result is longer telomeres, better insulin sensitivity, protection from cardiovascular disease, and longer life expectancy. Conversely, the SERPINE1 must be regarded as an aging gene, having no purpose (we know of) except to hasten the demise of its owner.
What do the authors say about the evolutionary implications of their finding? Exactly nothing.
In Japan, the life-shortening effects of PAI-1 have been known for several years, and there is already a drug in development that blocks its effect. The drug is called TM5441, and a quick Google search located two lab houses [one, two] that sell it for the same exorbitant price.
In Defense of Pleiotropy
To be fair, I should point out that these genes that have no other purpose than to cause early death really are the exception. Almost all genes are pleiotropic in one way or another. Much more common than pure aging genes like SERPINE1 is the situation where genes are dialed up or dialed down late in life in a way that is detrimental (or fatal). The canonical example is mTOR, the target of rapamycin gene. This gene plays an essential role programming the development of a young animal. But when it is turned on late in life, it promotes aging and shortens lifespan.
My position is that this doesn’t let the theory of antagonistic pleiotropy off the hook. Epigenetic programming is every bit as much under the control of evolution as gene sequences. Many genes are turned on and off as needed, and this is a matter of course. A matter of life and death, in fact. If mTOR is turned on late in life, I presume that natural selection has deemed it so.
Pleiotropy is real. Most genes have several functions. But for the pleiotropic theory of aging to be valid, it must be true that tradeoffs are unavoidable. In fact, when the theory was put forth by George Williams , epigenetics had not yet been discovered, and there was yet no notion of turning genes on and off. We now know that this process of gene regulation is an essential part of life in all eukaryotes, and that the timing of gene expression is exquisitely regulated. It makes no sense to imagine (as Williams did) that once you have a gene you’re stuck with it, even if it kills you. In fact, there are many genes that are turned on in youth and turned off in old age, and the effect is almost always to pro-aging. In other words, aging is programmed for the most part not through aging genes like SERPINE1, and certainly not through pleiotropy, but rather through epigenetics. Essential body systems like inflammation and apoptosis are re-purposed later in life as a means of self-destruction.
This opens onto a larger story, the subject of my book.
My understanding is that the serpine1 variant would make you more likely to bleed to death as it makes your blood effectively thinner. And other things, such as fibrosis of the heart (if you have 2 copies).
It appears to come from Switzerland, my suspicion is that it is a high altitude (thin air) advantage in addition to the longevity benefit. I’ve already checked, there is a native plants there (yarrow) that can help with coagulation, which the Swiss drink tea of (I have used it myself for that same reason) and surely knew the benefit. My ancestors are from that same area.
Your comment about high altitude very interesting. At high altitude would expect inhabitants to develop higher Hematocrit making spontaneous thrombosis more of a risk. Then increased anti-coagulation activity would be protective, aside from risk of bleeding.
Excellent article! and as usual some great new facts..Thanks Josh! And if any of your readers haven’t read Josh’s book on aging!! Do your self a favor and get it I loved it…>>>
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sorry for this next shameless plug josh but I dont know where to find an audience that is interested in this topic other than here!>>>>
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The Unselfish Genome- How Darwin & Dawkins Missed The 2nd Half Of The Theory Of Evolution: New Research Identifies The Hormone Changes That Control Human Aging Jeff T. Bowles
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Sex and aging have never had any satisfactory explanation within the Selfish Gene paradigm begun by Darwin and his disciples, and popularized by Dawkins in his famous book-“The Selfish Gene”.
Aging and Sex are shown to be evolution’s evolved defenses to evolving predation, and in the absence of predation, they will eventually become undone-leading to a strange world where humans eventually will evolve immortal lifepsans, and become 100% female who reproduce solely through parthenogenesis (female self-cloning)!
As odd as it sounds, examples of many types of animals where this type of reproduction already occurs are provided. Including animals as complicated as turkeys, sharks, and lizards!
Homosexuality, usally ignored by evolutionary biologists, is examined and shown to also be a defense agasint evolving predation that acts as birth control for what evolution perceives as less fit (predator-stressed) mothers.
Even human religion as an evolved defense to famine and drought is explored and explained with a special emphasis on the high rate of religious suicide associated with various religions and cults.
Sex and Aging are examined and shown to be a species-selected defense to evolving predation that is being selected for at the local ecosystem level virtually everywhere and all the time.
It turns out that species selection, which is a higher level of selection than individual selection will be the
NEXT BIG THING in evolutionary theory. SPECIES SELECTION, almost unknown to today’s mainstream theorists, is the only path through which all of modern evolutionary theory’s exceptions and discrepencies like sex and aging can be resolved.
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There is a ‘gang of one’ (maybe two if you include Leonard Hayflick) that is on the editorial board of many journals dealing with aging, to whit; Tom Kirkwood, who is there to insure that no one ever breaks the rules and suggests that aging might be ‘programmed’. I find it particularly interesting that Leonard Hayflick was the first to discover that cells were mortal. His own explanation (as given in a PLOS Biology editorial in 2006 (I believe)), was that the bonds holding complex biological macromolecules together wore out over time, with no evidence to support this. Later, the phenomena of ‘telomere attrition’ was recognized as the mechanism behind “replicative senescence”, that is, cells are programmed to die after a number of divisions. In spite of that, Hayflick equates aging and death as an aspect of entropy, in direct contradiction to his own findings of programmed senescence.
Tom Kirkwood, on the other hand stipulates that the organism sacrifice their soma for the evolutionarily more important germline – ignoring entropy as the cause of aging, and stipulating a ‘choice’ of living things to expend their limited energy on reproduction rather than extended lifespan; in essence, itself a programmed aging theory! That no, or contradictory evidence has been found supporting this ‘theory’ (hypothesis) has had no effect on his convictions that programmed aging is impossible; if you dare to doubt this and try to publish an article doubting this, he will ensure that it will not be published. He has many acolytes in positions of power supporting this ban on programmed aging. The more exciting investigations as to the nature of aging, like the work of the Conboys, of Saul Villeda, of Cai (Dongsheng), no longer come from journals devoted to aging.
Excellent installment. Incredibly up to date and beautifully stated. I feel your frustration with the mentality you document. To your examples of epigenetic aging I would add also that of lin-4 mentioned briefly in section 188.8.131.52 of my chapter in The Future of Aging ( Boehm and Slack 2005, 2006) and the ELT-1 through ELT-6 story (section 184.108.40.206), about which I provide commentary about mentality similar to yours.
I think PAI, though, is pretty important for normal control of PA, so how the Amish mutants do without it may be a more interesting story than it seems at first glance.
In my opinion, prior to 2006 and Blagosklonny paper, “Aging and Immortality, Quasi-programmed senescence And its Parmacologic Inhibition”; there was no understanding of aging. After this paper and understanding of role of mTOR everything changed. It was like 1859 and Darwin published Origin of Species. mTOR is perfect example of antagonistic pleiotrophy.
Purpose of mTOR is to promote growth and development. Just unplanned happenstance that mTOR drives aging. All this theory explained in various Blagosklonny papers. Modern aging theory starts in 2006.
I think Blagosklonny gets a lot of things right, and I’m grateful for all I have learned from him, especially about mTOR. The only place I part company with his story is that he thinks evolution has not been able to figure out how to turn off mTOR, and I don’t find that credible.
So the fact that a gene can be beneficial for reproduction and development then later becomes an agent for programmed death, because reproduction cannot or does not continue for the whole life of an organism. If it did there would be very long lasting or immortal individuals in a population explosion with unlimited natural or artificial resources. Yes antagonistic pleiotropy unfortunately makes sense. This means the only way humans can gain immortality is to free themselves from the limited resources of this planet or curtail reproduction and don’t use up the resources and/or use them wisely. Something I find hard to see that we are progressing in that direction. Maybe we have curtailed reproduction ie birth control but now we have a problem of limited resources to support aging populations against the needs of young.
Everyone has their favourite theory of why aging happens. Most of them seem to be amiable to intervention, in theory at least. But the crux of the matter is that if we get the theory wrong, our interventions may be inefficient, or worse ineffective. So we need to use interventions that look likely to work, regardless of the underlying theory.
For example, telomere attrition and cellular senescence. We get DNA damage all the time, either from ROS or errors during copying. The cell then gets arrested and there follows a race against time to repair it before MTOR overcomes Autophagy and the cell becomes irreversibly senescent.
In mice MTOR and ROS is so high this leads to death rather quickly, regardless of telomere length. In humans this process is much slower. But then telomeres start getting shorter because of cellular proliferation and the equation changes. More and more cells turn senescent.
So what can we do to intervene? Lower MTOR, check. Rev up Autophagy, check. Lengthen telomeres, check.
Doesn’t really matter whether this process is programmed or accidental, it will work, and give us time to solve this riddle once and for all.
Mark – I agree with your assessment and your priorities. The reason that theory is important, however, is that many people are still using “no free lunch” arguments to say that it’s dangerous to lengthen telomeres and it’s dangerous to block mTOR. These things “must have been optimized” by natural selection and we tinker with them at our peril.
You make a very good point about the no free lunch bunch who believe that natural selection has everything just about perfect, and if you interfere with it you do so at great peril. This is probably correct to some degree, for instance one wouldn’t want to totally inhibit mTOR, just dial it down some. The same with telomeres where the body has a very natural way of giving out of control long ones a “haircut”, and we don’t want to prevent that, but we do want to intervene and elongate the critically short ones. Again, not a total makeover, just a modification based on benefit/risk.
Even in the case of PAI-1, those with two mutated genes have bleeding and fibrosis risk, but not so in those with only one mutated allele , they live 14 years longer and without the risks, so that modification will be the target of drug trials.
Tweaking the system may be enough to reap great rewards with minimal risks.
I think that once we get to the point of safe senolytics, that may also be a real turning point, and we seem to be getting closer. P.D.Mangan points out that senescent cells increase gene expression for PAI-1. They’re everywhere and the risks seem to outweigh the benefits.
I don’t know why the ‘no free lunch’ argument still gets used, given how simple interventions can have such profound effects on the lifespan of other animals.
I guess some still cling to the argument that humans are different, but advances such as PCSK9 inhibition whereby LDL is literally sucked out of the bloodstream, and hopefully soon senolytics and telomerase treatment, should show that the human organism can have its defences considerably improved upon .
SERPINE1 is not a pure aging gene. PAI-1 makes sure that blood clots don’t dissolve prematurely. The Amish with two copies of that mutation have bleeding problems and can develop spontaneous heart fibrosis (though less fibrosis in other parts of the body).
In your analysis, you should consider errors of omission and errors of commission; the difference between action. And lack of action.
In regard to mTOR, it is acting since conception, during growth and development and in old age. What you are talking about is failure for evolution to turn mTOR down in old age to perhaps an ideal 25% of activity during active growth. Perhaps evolution could have done this; but for what purpose. In the battle for survival, the old animals with low mTOR would probably have been inferior to young animals and would have been killed. It did not take action to kill off old animals. Preserving old animals would have taken acts and new programs and preserving old animals was not a good plan for evolution.
Evolution struggled with a way to keep animals alive long enough to reproduce. Death doesn’t need a plan; it is too easy.
>> In the battle for survival, the old animals with low mTOR would probably have been inferior to young animals and would have been killed.
This is Weismann’s argument from 1889. His was the first theory of aging, and he said animals wear out over time, and aging-to-death is a way to get them out of the way to make room for younger animals.
Later in life, he realized that the argument was flawed. Why should animals “wear out” over time? Isn’t this aging? Isn’t it what you were trying to explain in the first place.
Seventy years later, Peter Medawar said, “Weismann canters twice round the perimeter of a vicious circle. By assuming that the elders of his race are decrepit and worn out, he assumes all but a fraction of what he has set himself to prove.”
At age 74 I feel extremely healthy; but as regards strength and speed, I am lucky if about 25% of a twenty something. Federer, Nadal, Djokovic, Murray are four of greatest tennis players ever, now all in their 30s, only Federer was still standing at season end and he lost in semi-finals of year end championship. Even without aging, injuries takes its toll.
I fully agree with your insightful position that death is very good and necessary for evolution and each species. Just what you see as acts of commission, I see as acts of omission.
Let me use a car as an analogy. Even a Honda Odyssey at 150,000 miles is starting to break down. Did Honda build the car to affirmatively break down with things designed to break; or did they build a car as reasonably good as they could. Granted car is not living thing with ability to repair and regenerate itself. But I don’t think Honda builds a car to break down; but they also see no commercial reason to build car that could drive 500,000 miles.
I agree that evolution could have made immortal animals;but that would have taken very major modifications. There was just no good reason to do that and a lot of very bad reasons.
We both agree that good for animals to get old and die. We disagree over whether matter of intentional design or just failure to do something,
It has very practical implications. In your system, there is a “kill switch” that could be disabled. In my system, you have a human organism just not built to go much past 100; before everything starts to naturally go bad.
I am very happy that by reducing activity of mTOR now appears good chance to make it to 100 as the walking wounded; but I see that as the end of the line.
I think you should use a different analogy. A living organism is more like a car plus a mechanic. The mechanic can keep the car running as long as he wants–as long as he keeps doing all the required maintenance.
So, how does the car finally die? The mechanic stops working on it, and lets it fall into disrepair. Why would the mechanic do such a thing? That is the interesting question, and according to the programmed aging view, evolution via group selection has caused this to make room for newer more innovative models.
Josh has argued that programmed death also helps to prevent extinction, by smoothing out death rates, so that the entire population doesn’t all die in a disaster/famine. It turns up aging program when times are good and dramatically slows aging when times are bad. (Josh, correct me if I mis-stated)
The life cycle of salmon also seem to better fit a programmed explanation, but I suppose you could always say they trade fertility for longevity. But the natural wear theory is harder to maintain. Personally, Josh has swayed me over to the programmed aging camp, and the world makes more sense (to me at least).
Hi is this Vince Guilliano? I fully agree that a car and a mechanic is a better analogy. Programmed progressive loss of repair efficiency leads to death. Barring mutations at birth if we could repair damage as it occurs we could live forever (Dr. Rosedale). mTOR over activation can also be one of the dysfunctions caused by unrepaired damage. Also agree with Josh on the potential of epigenetics in aging.
Making it too 100 as the walking wounded is certainly a big improvement on dying of atherosclerosis or cancer, or god forbid, getting Alzheimer’s. But I think we can, and will do a lot better than that. The only question in my mind is how long will it take?
Oh and god knows what Federer, Nadal, Djokovic, Murray are on to keep going like they do.
Their systems benefit from regular boost to repair and renewal provided by their training and game – high intensity intermittent excercise activating hormetic response.
You make the statement that the human organism isn’t built to go past 100 because that is how you see it based on what we have at the present moment, but you must admit that just 3 years ago you may have said that we aren’t meant to go much past 90. There may be a new and improved version of rapamycin in the future, or other types of synergies and modifications that are completely unknown at the present time, but may get us easily to 120 or so and would not contradict your overall theory of things.
Yes, we only have to live long enough to make it to the next big break through. There are many of these on the horizon.
Josh, reading the report I thought that excessive bleeding was the consequence of a double knock out of SERPINE1. Similar to sickle cell and malaria resistance the benefit accrues to the heterozygous individual. It still raises the question of why evolution hasn’t figured out how to epigenetically imprint one of the copies.
Yes, we could be evolved to just lower the dosage of SERPINE1.
I’ve been thinking about this article a great deal over the last couple of days. I’ve also been reading this paper, ‘Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging’. It discusses how HSR is effectively lost when worms reach sexual maturity, but that mild mitochondrial stress promoted by the partial knockdown of F29C4.2 (analogous to the human COX6C nuclear encoded gene) restores the HSR response, as well as proteostasis and extends lifespan.
I don’t want to go into the paper too much, anyone that wants to can read it, but what made me think was that although the Pleiotropy argument probably holds with messing with the electron transport chain from birth, why is epigenetic regulation not possible later in life? Why can the worm not run the ETC at max to produce the biggest brood of eggs, and then epigenetically downregulate it?
Let us suppose a worm evolves with a new gene that can regulate the genes of the ETC, and does so later in life. Even if such an adaption resulted in only 0.1% more eggs, this would be enough for evolution to select for and given enough time this adaptation would dominate the gene pool.
I call this the ‘have your cake and eat it’ evolutionary strategy. The same would apply to short lived animals like rats. Why not grow up fast, have lots of young, and then downregulate MTOR, MtROS, etc.? This doesn’t seem to be happening. Why not? I can think of only two explanations.
1. This strategy is possible, and does happen, but is selected against by evolution. This is essentially Josh’s group selection, whereby more robust individuals are selected against because of changes in the environment favours quick turnover.
2. This fine epigenetic regulation or transcriptional control later in life simply is not possible.
It might be possible to find some evidence for 1 in the fossil record.
Proving 2 would be much more conclusive, if it can be done. The only way I can see this being true is if mitochondrially encoded genes cannot be epigenetically regulated (but note COX6C is a nuclear encoded gene).
Can anyone point out a flaw I my logic, or help with proving or disproving 1 or 2?
Evolution has no problem greatly extending lifespan when has a compelling reason. Consider long lifespan of Queen bee. Likely most lifespans work out best for species survival. For evolution, no concern for individual and aging and dying is neither good or bad, just what is better for fitness.
Consider humans, 100,000 years ago had same lifespan as other great apes @55-60 years. They complex societies happened and better have some people live to 80. Very quickly maximum human lifespan jumped 20 years to present length. This jump from 60 to 80 happened about 50,000 to 100,000 years ago.
You’ll get no argument from me on that score Alan. But it appears that there is significant scope for lifespan extension without genetic alteration, purely from gene regulation (epigenetics). And you’ve picked a great example in the Queen Bee, who as far as I am aware does not differ genetically from a worker bee.
We may only be scratching the surface of these possibilities with calorie restriction, rapamycin, etc.
C elegans worms are exquisitely adapted for population regulation. They have to be able to live through long periods of famine, and then make hay while the sun shines. Aging and the way aging works is part of that. They reproduce, age and die when times are good; but they have marvelous stress adaptations to hang in there when times are tough.
Some further reading on mitochondrial methylation, ‘Experimental mitochondrial targeted DNA methylation identifies GpC methylation, not CpG methylation, as potential regulator of mitochondrial gene expression’.
This has been a controversial areas, with much of the work done very recently, but it does appear now that mitochondrial DNA can be methylated, although at very low levels compared to that in the nucleus. Interestingly, according to the above paper mitochondrial methylation can disable heat shock proteins, which links in well with the worm paper I referenced previously. The fact that the heat shock response could be re-established in worms through slight inhibition of the ETC shows that this stress response is under epigenetic control. It also, to my mind at least, explains much of the benefits of exercise and calorie restriction in humans.
I agree. I also believe that in the natural world without all of our modern creature comforts, stressors tended to be seasonal in many parts of our planet, and we are well adapted to respond to them in a manner that is very beneficial, especially in the long term. Two that immediately come to mind are UV light through sun exposure and cold temperatures in the winter.These both evoke heat shock protein responses, as well as the development of brown fat deposits ( cold exposure) and vitamin D (sun). We ignore natural stressors for the sake of comfort at great peril to our health and longevity.
As an aside, It’s Thanksgiving over here, and I do want to give thanks for this site and Josh as well as all of the commentors for teaching me more over the past year than I can put in words. It has been both great fun and a fantastic learning experience and I’m confident that it will continue.
Happy Thanksgiving! A nice poem I would like to share by Florence Earle Coates:
I thank Thee for the unexplained,
The hope that lies before,
The victory that is not gained,—
O Father, more and more
I thank Thee for the unattained,
The good we hunger for!
I thank Thee for the voice that sings
To inner depths of being;
For all the spread and sweep of wings,
From earthly bondage freeing;
For mystery—the dream of things
Beyond our power of seeing!
Josh, do you happen to know why nobody does ipsc generation with C. elegans?
Epigenetic reprogramming could be tested much easier on the worm with 2 week lifespan.
I apologize in advance for my lack of technical knowledge about this paper https://bmccellbiol.biomedcentral.com/articles/10.1186/s12860-017-0147-7
Your conclusions are hards “This is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies”.
Any specialist can give some opinion on this work?
Thank you very much in advance. Angel
The following paper just came out from Calico labs ans looks quite interesting but unfortunately, it is not open access:
“A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage”.
They have identified a switch in C.Elegans to acidify lysosomes and stimulate the degradation of protein aggregates. This switch is activated by sperm and allow to restore proteostasis in the oocytes just before fertilization. They have also identified a similar switch in a frog species, which could indicate that it is universal.
An obvious short term goal is to find out if mammals have a similar switch.
Assuming that this is the case, a few questions come to my mind.
Is this switch naturally activated during IPSC generation?
If not, can we improve IPSC generation by activating it?
Is it imaginable to activate this switch in vivo to clear-up, at least partially, lipofuscin?
Does this discovery somehow limits the importance of the lysosens project which goal is to augment lysosomal capabilities with the addition of extra genes?
I’m very impressed Calico have been looking into the difference between the immortal germ line and normal somatic cells. I expect when we look into the mechanism behind iPSC generation we’ll find that the lysomal acidification and mitochondrial fission-fusion process elucidated here is part of dedifferentiation.
Unfortunately I doubt worms suffer from lipofuscin like us, and I’m guessing the human germ line deals with indigestible waste by dilution when the embryo rapidly divides but has not yet differentiated. So unless we can cycle all our old quiescent cells, I expect we’ll probably need some sort of assistance from exogenous enzymes, as envisaged by SENS. I’d be happy to be proven wrong however, and the way to do that would be to generate iPSCs from old or senescent human cells and then hold them quiescent and check for lipofuscin. That way dilution will not be able to come to the rescue.
I like your suggestion. It would be good to find out if lipofuscin accumulates with age because it contains truly indigestible stuff or because the stuff is produced faster than it can be degraded. I guess the proponents of programmed aging will tend to think that we do have enzymes to degrade lipofuscin under the right conditions.
In any case, lysosomal enzymes function optimally over a narrow range of acidic PH (around 4.5) and raising the PH to a value as low as 5.2 significantly reduces their activity.
In particular, the following paper suggest that the acidification of RPE cells’s lysosomes can be an effective strategy to prevent AMD.
“Rescue of compromised lysosomes enhances degradation of photoreceptor outer segments and reduce lipofuscin-like autofluorescence”
Interestingly, some stress hormones such as adrenalin, that we tend to view as pro-aging, can acidify lysosomes.
Lipofuscin removal fell out of fashion. In ancient times (~1970s), DMAE etc. were used to reduce lipfuscin… anyone know whether there is anything recent on this?
Also, SERPINE1 pretty much proves Josh’s programmed-aging thesis. Now to spread the meme 😉
Interesting read. Thanks.
I am not aware of any recent major progress about lipofuscin clearance. As long as cells divide, this is probably not a major issue since lipofuscin is continuously diluted but we’ll need a plan to clear it in post-mitotic cells.
I really resonated with this comment in the concord monitor linked article you provided.
From the article:
[[[[ “The future of our health spans has little to do with the current “health care system.” Real change is being driven by these disruptive researchers and small startup companies that are attacking the underlying biology of aging and cancer.” ]]]]
IMO, This is so true. I only use the traditional healthcare system for preventive screening and bloodwork monitoring.
Most of the time, I avoid the traditional medical care system.
Each time I go for preventive testing or bloodwork the kindly doctor gently suggests that I should stop taking nutrients or herbs or anything else I take that lives outside of mainstream medicine, or traditional standard of care.
He/she ALWAYS totally ignores the fact that my blood work has always been normal, that I rarely get viral or bacterial infections that need treatment. If I do. I self medicate and symptoms last only a few days at most.
One substitute doctor who had never seen me prior, thought I was using my mothers health care card to get medical coverage for bloodwork because he insisted I could not be as old as my healthcare provider records showed.
That one really made me laugh.
I have never had plastic surgery or fillers. Plastic surgeons scare me, particularly after seeing friends with infections and failed cosmetic procedures.
I use Retin A and European sunscreens that contain Tinosorb S, Tinosorb M, Mexoryl SX and Mexoryl XL, all of which appear to be more effective than avobenzone.
IMO, those topical products as well as the oral products really help with photo aging of the skin. Both inside and out.
I think I and my husband are healthier than our peers because we rarely avail ourselves of the present healthcare system.
We actually avoid the traditional medical care system.
I married my husband when we were both in our 30s. He never took nutrients or herbs until a few years after we married.
Before that, he used to get sick quite frequently. He started taking the cupful of nutrients and herbs and alternative meds that I take mainly because he noticed that I never got seriously ill, while he frequently did.
He would often get bronchial infections, colds and the flu and would be ill for weeks.
His health improved when he finally stopped laughing at me for taking so many pills and started taking a cupful of nutrients herbs and alternative therapies, daily, for himself.
I do not foolishly think that people can stave off ALL genetic based illness, but they can create a healthier internal environment, where the degenerative process may start later in life, thereby increasing healthspan.
This is the closest:”Ameliorative Action of Mn-Salen Derivatives on CCl4-Induced Destructive Effects and Lipofuscin-Like Pigment Formation in Rats’ Liver and Brain:Post-Treatment of Young Rats with EUKs”, 2014, http://www.scirp.org/journal/ijcm/ and full http://file.scirp.org/pdf/CellBio_2014091115152642.pdf.
“The protective effect of Mn-salen derivatives may be due to both their free radical scavenging properties and the indirect effects on the defense systems. As a result, they may be applicable in inhibiting LFPs accumulation and the therapy of age-related diseases”.
This is an in vivo and in vitro study of an edible fungus:”Structural analysis of water-soluble polysaccharides in the fruiting body of Dictyophora indusiata polysaccharides (DIP) and their in vivo antioxidant activities”, 2011, Hua Yanglin
“The results showed that treatment group with DIP at medium and high doses both significantly (P < 0.05) reduced lipofuscin level in rats liver tissue compared with the model group. Moreover, lipofuscin level of Ve positive group were significantly (P < 0.05) lower than that of model control group. This result indicated DIP extracts had good antioxidant activity in vivo."
This is interesting but my understanding is that it is not about lipofuscin clearance but rather about prevention of lipofuscin accumulation.
Will you please explain your preference for pparg neutral Candesartan with respect to pparg+ Telmisartan. The studies I see suggest more weight loss and increased metabolic benefit for Telmisartan with respect to Candesartan .
Also I haven’t seen much in the way of life extension in humans from recent studies of treatment with the typical cardiovascular drugs. A typical value might be say .5 days per month of treatment. Unfortunately it doesn’t seem the rodent studies are supported by these recent human studies.
Hi, great question,
Candesartan, (pparg neutral) vs Telmisartan (pparg +).
I like rapamycin and don’t like mTOR. mTOR friends with PPARG.
See paper, “Major involvement of mTOR in the PPARG-induced stimulation of adipose tissue lipid uptake and fat accretion”, Blanchard, 2012
mTOR major regulator of adiposity through positive action PPARG. PPARG master regulator of adipose tissue. PPARG stimulates lipid uptake and glucose uptake into fat cells.
PPARG actions are hypolipidemic and lipogenic and adipocyte differentiation.
People who like PPARG think good to help clear lipids and glucose into fat cells; ie on blood tests lowers glucose and lipids. (looks nice in blood test results)
So PPARG doing everything in regard to fat tissue that rapamycin is blocking.
Question is do you like lipidemia or do you like being fat?
Rapamycin prevents lipids from going into fat cells; but also not going into vascular tissues and rapamycin prevents atherosclerosis plaque destabilization by blocking nF-kB–MMP9 pathway.
“Chronic mTOR inhibition attenuated the upregulation of lipid uptake, LPL (lipoprotein lipase) expression/activity,and fat accretion induced by PPRG activation in both subcutaneous WAT and BAT, which resulted in hyperlipidemia…Together these finding demonstrate that mTOR is a major regulator of adipose tssue LPL-mediated lipid uptake and a critical mediator of the hypolipidemic and lipogenic actions of PPARG activation.”
So people who like action PPARG think hypolipidemic and lipogenic is GOOD.
“PPARG agonist Rosiglitazone stimulated adipose tissue mTOR complex 1 and induced lipid uptake and LPL activity 2-6 fold and fat accretion.
Rosiglitazone is “Avandia” and brand name med promoted as great stuff. So medical world seems to think stimulation of PPARG way to go.
So who is the bad guy, rapamycin or Avandia in this paper ? I only saw abstract; but my guess is they like Avandia, not rapamycin.
Just a matter if want a 32 inch waist or not.
But specifically for telmisartan I see studies such as the following that suggest decreased adiposity-
Diab Vasc Dis Res. 2013 Jan;10(1):93-6. doi: 10.1177/1479164112444640. Epub 2012 May 4.
The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO). I need to consider these studies further in light of your comments.
Based on my personal experience I agree with you completely for mtor and rapamycin but less so about the beneficial effects and the spectrum of effects of the ARB’s. For my genotype/phenotype at least rapamycin has had a substantial positive impact. Statistical studies thus far have suggested minuscule life extension impact in humans for statins, ARB’s, etc and I personally have no positive results that would suggest material LE impact.
This is not my area of expertise and so like others here constantly trying to improve my LE regimen based on the latest research as I understand it. This has been my approach for the last 30 years and looking back I wouldn’t have done anything differently since based on my understanding of the research at that time. However my regimen was often not well supported by later research so always looking for both positive and negative research results to improve efficacy. Common for me to modify my regimen based on studies in short lived species and then to modify later when evidence mounts one way or the other in humans. In the case of ARB’s it seems plausible to me that there would be a beneficial impact on human LE but the data thus far doesn’t support that plausibility.
As regards ARBs and LE , agree so far only seen in rats. If effect human lifespan, would only see in people who reached super old age. I see main anti-aging effect on mitochondria.
1. Instead of “antagonistic pleiotrophy theory” you may read as “insert your favourite theory HERE”, then everything still makes sense.
2. Making up a theory and then making the facts fitting is definitely not science, only in case anyone has missed that one.
3. I see no reason why antagonistic pleiotrophy theory, or any theory for that matter, could deny the advantages of assuring a constant population turnover by using “killer-genes”. As pointed out, without there will be no development and improvement, and one can read improvement also as genetic adaption to changing circumstances. Without a new start ( read: life) there is only so much improvement (adaption, development … ) one life can have.
So “killer-genes” would actually help “survival” i all its forms (and i am not sure that survival is nature’s most important agenda, by the way).
4. There is no reason not to have a lot of antagonistic pleiotrophy genes and killer-genes too ( just to be sure), and both can support each other quite nicely – or sometimes even be the same.
5. Either/ Or thinking or better put: thinking in black and white patterns is generally not a good thing.
6.There are actually a lot more theories worth mentioned, e-g. the work of Gladyshev ( https://www.ncbi.nlm.nih.gov/pubmed/23769208 ).
This is a really convincing theory, which theoretically puts down everything else, were it not for 2 small facts:
1 ) Theories are often not mutually exclusive but can coexist. (general reasoning)
2 ) Does the body really has to be in possession of a special programme for every possible biochemical combination, or could not more general programmes being able to deal with classes of substances, e.g. like chelating substances with metals regardless of the kind of metal ( simplified spoken) ?
This is a special argumentation which deals directly with the most basic premise of the theorie.
It is certainly true that shorter lives favour quicker natural selection if an environment is changing rapidly. But this does not mean there is a program to shorten life, it could just be that evolution has not bothered to work against aging, unless it is worthwhile to do so.
As an example of plieotrophy one might consider the life of a rat vs that of a squirrel. The rat general dies quickly even in the absence of aging, it has many predators and an uncertain food supply. So evolution favours a rapid gestation and development. But this high metabolism leads to an early grave. Still having many babies early means this is the optimal strategy. But for a squirrel life is easier. They are safer living in trees. So evolution has found longer lived individuals produce more babies. By this argument there is no need for aging genes, as external causes of death need to be reduced below a certain level before evolution will act to make a species longer lived. This is probably why we love so much longer than apes, as our society massively reduced death rates due to predation and starvation. Even now we are likely to be evolving longer lifespans, though too slowly for my taste!
To demonstrate a killing gene one would have to find a gene and show that it has no possible benefit early in life. The recent SERPINE gene is no exception, and unfortunately for Josh’s theory it has been shown to be beneficial to those living at altitude.
Nevertheless I can certainly support a weak form of Josh’s argument, in that an excessively long lived species would be likely to become extinct eventually due to changes in the environment. But short of a planet wide extinction event, humans are unlikely to be subject to those restrictions anymore.
I have found it is very easy to get lost in theorizing about whether aging is programmed or not. So in my books an articles I just avoid the question with regards to gradual aging seen in humans as it is too easy for many to get lost . It is much easier to see what you are dealing with if you consider how did female menopause evolve? It is obviously programmed, and it does exactly the same thing that aging and death do from an evolutionary perspective>>>prevents further reproduction by the female. (So form the simple selfish gene perspective it should not exist) So I challenge all those dabbling in the evolutionary purpose of gradual aging (or the lack of purpose) to first explain human female menopause before attempting to tackle the evolution of gradual aging. Training wheels before the ten speed, Learn to walk before trying to run
If you read anything by Blagosklonny you would find paper that explains menopause in exquisite detail and why not programmed. Again since Blagosklonny is one of greatest Biologist of past 150 years probable worth reading his paper
People talk about the pituitary ovary axis and menopause as if something simple and obvious. The interactions between hypothalamus pituitary FSH ovary corpus Luteum and estrogen are a very complex feedback system.
If you read anything by Blagosklonny you would find paper that explains menopause in exquisite detail and why not programmed. Again since Blagosklonny is one of greatest Biologist of past 150 years probable worth reading his paper
Jeff says “after just a brief review…I’m sorry to say he seems to be just another variant of a mainstream non-programmed aging theory hack. Like Aubrey,, Kirkwood, and so many others…Sorry”
Unlike a lot of people here, I am not real smart. I have no original ideas in evolution, aging or medicine. The best I can ever hope for is to find a super genius who explains it all for me.
So all I can do is repeat what Blagosklonny wrote. After that, I have reached as far as I can go.
I’m glad you like him..oddly I have never heard of him…
How about you Josh?
Do you believe that menopause is not selected for and just an accident of nature…that is a pretty big stretch even Dawkins says menopause is programmed…. It is driven by changes in the reproductive hormones and steroid hormones I am hoping you would agree??
I never heard of him which is odd if he is the top evol biologist of the last 150 years…How about you josh??
Anyway I ran across his theory of hyperfunction and cell aging and that aging is just a continuation of development that has wandered off course kind of like walking with your eyes closed….the further along you go the more off target you are…I dont buy it sorry…Looking at aging like this just as other mainstream aging theories require…to place the rpaidly aging pacific salmon in a special category called semalparous aging which can then be ignored…Programmed aging i the Salmon is so obvious and in your face-0it only takes 3 days to kill the fish off after spawning….If you cant explain aging in the pacific salmon as being non programmed then everything else must be thrown out (unless you define a different form of aging that does not count and can be ignored )
My theory of aging has no glaring exceptions like this..im sure if I finr his menopause arguments i can rip it to shreds
Since I consider Blagosklonny the greatest scientist/biologist since Charles Darwin; but he doesn’t post comments on blogs ,I will offer this quote from 2006 paper:
“Why are we mortal? No law of physics precludes immortality… In a natural environment, an animal has little chance to survive above a certain age, because of high risk of death from external causes such as predators, competition…Even a potentially immortal animal would die at the same time…When animals die from external causes, immortality is useless…When longevity is necessary, nature easily finds a way to extend lifespan…”Queen honeybee have life spans that are 100-fold longer…So it is not that an organism cannot maintain what already exists. Simply an organism does not need to maintain what already exist for too long.”
“Programmed aging is questionable on theoretical grounds…From evolutionary point of view, there can be no special program that is intended to impair animal functions. There is no selective advantage in altruistic senescence, as well as no genes are known to have evolved specifically to cause damage or aging.”
Oh but there are genes that cause aging…just ask Josh for a list…..
I have worked out a simple model that suggests how and why evolution limits life span of individuals>>to keep them from reproducing too much and reducing a local species diversity which wold make the local species ,more vulnerable to extinction caused by evolving predation wiping them out completely..It is actually very simple and elegant if you think about it for awhile
.Read the short article here>>>>
Abstract of the previously mentioned article
Abstract: The last two major areas of evolution that continue to be shrouded in confusion and suffer from unsatisfactory explanation, are sex and aging. A new higher level order of selection is defined as a special form of species selection termed “predator selection” which allows for a simple solution to the question of the evolutionary purpose of sex and aging. Sex exists to generate and capture beneficial genetic and phenotypic diversity that helps a species survive when confronted with evolving predation. Aging exists to prevent the loss of this beneficial diversity. In the prolonged absence of predation, sex and aging will be lost in a species which will ultimately consist of all clonally reproducing females such as the all-female walking stick insect, whiptail lizards, Brahminy blind snakes, and cave crickets, to name a few. In the absence of predation, programmed aging will be lost and longevity will gradually evolve which can explain all species with exceptionally long lives based on their body size, such as arctic clams 500 years, mouse sized bats 41 years, humans 120 years, box tortoises 130 years, all cave animals, etc. These long-lived examples all have one thing in common: an excellent defense to predation, full body armor, isolation, flight, and extreme intelligence. This article basically summarizes the missing half of Darwin’s theory of evolution.
I’ve nothing against a programmed theory, but there needs to be evidence that it is in fact programmed and not just inadequate repair. For example you talk about programmed aging being lost gradually in species with low predation. I explained the exact same thing without any need for genes that kill you.
As far as menopause is concerned, it is tempting to attribute that to programmed aging. But again I think it is probably just an intricate system that senesces quickly because of high mTOR and not enough replacement cells. Just look at the link between age of a girls first period and her later menopause, even her death. They are all linked in a clear case of plieotrophy.
Now epigenetics clearly does have the ability to switch genes on and off. If there is hope for programmed aging, it is there. But it is a case of proving a negative; why do animals not control their rate of aging better? It might just be that they can’t for some reason. For example telomeres; it is dangerous to have too many beneficial SNPs because it makes it easier for cancer to appear of an when any telomeres do get short. But the good news for us is that we can lengthen telomeres exogenously without adding anything perilous to our genome. And it may be a similar story for full epigenetic cellular reprogramming, maybe there is a reason it can’t be done endogeneously by nature. We’ll have to wait and see.
Sex and aging aren’t the only flies in the ointment. The origin of life is a huge mystery, telling us that there’s something we really don’t understand. The evolution of evolvability is another deep question that present evolutionary theory can’t address.
Rather than say “sex and aging are the last two major areas”, I’d say sex and aging are doors that lead us to the larger problems in evolutionary understanding.
It’s also interesting to note that some studies have shown that people who are infertile live linger than their fertile peers.
From the article:
The findings fit in with a theory of Darwinian survival, which says that some animals are genetically programmed to die young and have many offspring whereas others are less fertile and so live longer. …
Professor Kirkwood, a biological gerontologist, was testing his “disposable soma theory”, which predicts that any investment the body – or soma – makes in ensuring fertility and reproduction is diverted away from repairing the continual damage caused by the ageing process.
This “trade off” has already been established by experiments on fruit-flies, which show that individual animals who are genetically programmed to have a long life are less fertile than those destined to die young.
“Aging exists because no one in nature lives long enough for aging to matter.”
This idea was articulated by Medawar in 1952, starting the modern understanding of aging. But already in 1957, Williams was saying “I’m not so sure that this can work.”
Take this general statement and translate it into quantitative terms. Ask, “what is the impact on fitness of aging in the wild?” Answer: usually 20 to 30%. Ask, “what usually happens to traits that cause a 20 to 30% deficit in fitness?” Answer: Such traits don’t last more than a few generations before natural selection gets rid of them.
This is the reason that Medawar’s idea is not an explanation for aging. The best we can say for it is that “the fitness cost of dying old is not so great as the cost would have been from dying young.” There’s still a hefty cost, and pleiotropy doesn’t supply a consistent enough benefit to cover it. Hence we need group selection to explain aging.
In response to your assertion that we need group selection to explain aging..
.I once believed that too until I could not get past the cheater problem and the interbreeding between groups problem.
The cheater problem occurs within a group where a individual mutates away the aging genes and is able to reproduce forever and her genes take over the gene pool and aging is lost.
The interbreeding problem is say one group evolves and retains aging, but then an individual from a distant group that does not age wanders by and breeds within the aging group..boom grpoup differences are lost, aging is lost and non- aging spreads throughout the group.
Why don’t you give it some thought Josh and explain why these aren’t problems for your model of the evolution of aging.
I solved the interbreeding problem by moving it up one level to the species level….Basically group selection at the species level solves the interbreeding problem…AND having a local evolving predator that causes non-aging local groups to go extinct solves the cheater problem. You can see the argument in more detail at>>>>>
here I found something by him on menopause////see below
He says menopause is not a program just a wandering of the female reproductive system!!! What a leap! If that were true why is the age of menopause so tightly controlled in women to occur age 45-50??? And why do all women have dramatic rises in LH FSH and a crash of estrogen and progesterone and melatonin…. Shouldn’t the age of manopause be wandering around all over with its eyes closed??/HAHAHA!! This guy has barely scratched the surface and should spend about 20 more years in the library before giving us these highly superficial theories….I doubt there is any meat on his menopause theory bones..does he address hormones, menopause reversal, menoapause , similar hormone changes in men, menopause in other animals like bats and killer whales etc…And the increasing fertilility with age of some other female animals until they die!! like the tortoise and I think the alpine swift, crocodile ,etc…why dont their reproductive systems wander off…It’s hard to do a puzzle when you barely have half the pieces! That’s where the library comes in….
Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives.
Women live longer than men. Yet, it is believed that men do not age faster than women but simply are weaker at every age. In contrast, I discuss that men age faster. From evolutionary perspective, high accidental death rate in young males is compatible with fast aging. Mechanistically, hyper-activated mTOR (Target of Rapamycin) may render young males robust at the cost of accelerated aging. But if women age slower, why then is it women who have menopause? Some believe that menopause is programmed and purposeful (grandmother theory). In contrast, I discuss how menopause is not programmed but rather is an aimless continuation of the same program that initially starts reproduction at puberty. This quasi-program causes over-activation of female reproductive system, which is very vulnerable to over-activation. Mechanisms of aging and menopause are discussed.
Excellent job. You found paper I had in mind.
In some other paper he mentioned the pacific salmon you talked about. Sorry, can’t say which paper.
As you certainly know, two important features of a theory is to be able to make new predictions and to be refutable. In his 2006 paper, Blagosklonny predicted that mTOR inhibitors would increase life span of mammals. This was brilliantly demonstrated in 2010 with rapamycin. Note that if rapamycin had failed to impact life span of mice, his theory would have been in serious trouble.
If truly aging genes do exist (by that I mean genes that have no other purpose than accelerate aging), then it should be easy to test. Just produce KO mice for these genes and check that they live significantly longer than their peers without any other side effects (menopause of females should be delayed as well). This would brilliantly demonstrate that aging is indeed programmed. Note that PAI-1 is not a truly aging gene according to that definition since its complete absence has serious consequences on coagulation and cardiac fibrosis.
I am not aware of any truly aging gene but I certainly wish they do exist. Regardless, I find your paper interesting and informative.
As you certainly know, two important features of a theory is to be able to make new predictions and to be refutable. In his 2006 paper, Blagosklonny predicted that mTOR inhibitors would increase life span of mammals. This was brilliantly demonstrated in 2010 with rapamycin. Note that if rapamycin had failed to impact life span of mice, his theory would have been in serious trouble.
>>>Well isn;t that amazing??Now if you refer back to my 1998 puiblished paper on which all my subsequent work relies…You will see that i was the first to predict that huge LH and FSH increases after age 50 drive menopause AND the subsequent gradual aging process in humans (a higher level than cellular transcription factors) . It predicted that suppressing the LH rise wold be found to be an effective treatment for Alzheimers disease…adn this was indeed found t be the case in women after a $50 million see study by Voyager Pharmaceuticals- or read all about it in my book on alzheimers>> wild guess?? only problem it did not work in men..(I know why) That paper also predicted that aging was controlled by epigenetics which 10 years alter became a mainstream idea when Rando and Josh publijsed their papers on this idea…Thisb later led to my prediciton oin a boo about ALS that progesteone might be a good treatment for ALS why? because men get ALS at 4:1 ratio to wmoen except at age 60 when the ratio becomes 1:1>>what happened ? female progesterone crashes to 0 at menopause>>>I published ebook and what happened? a few years later some Korean researches extended the lives of ALS mice form the human equivalent of 3-5 years to 17 years….with what?? progesterone injections…anyway My theory has made many predictions which turned out true mor ethan I want to list here…check my youtube video for oldest rat in the world on record via water restriction
aldebaran>>I am not aware of any truly aging gene but I certainly wish they do exist. Regardless, I find your paper interesting and informative.
response I always thought this one wa a good candidate>>Genetic ablation of the p66 – Nature
by R Derungs – 2016 – Cited by 1 – Related articles
Jul 19, 2016 – Moreover, p66Shc is involved in mammalian longevity and lifespan determination as revealed in the p66Shc knockout mice, which are characterized by a 30% prolonged lifespan, lower ROS levels and protection from age-related impairment of physical and cognitive performance. In this study, we …
You seem to have many novel ideas Jeff (to me), and I consider myself widely read on the subject! I will certainly read up on the links you’ve provided. I dearly wish aging were programmed and we could simply overwrite the program. And I regard Josh and yourself as brilliant. But many brilliant people have been mislead by what they wished to be true.
I am a dreamer, but I am also pragmatic. I must see and understand the mechanism before I will really believe.
Thanks for your quick response and providing reference about p66Shc paper. Looks indeed quite interesting.
After a bit of research on p66Sch, it looks like we cannot rule out its pleiotropic nature, which question that it is a truly aging gene. In particular, it seems to provide a fitness advantage in the wild, according to the following paper:
“Deletion of p66Shc in mice increases the frequency of size-change mutations in the lacZ transgene”
“Finally, p66Shc deletion protects from stress and degenerative diseases but may affect robustness of some tissues allowing the accumulation of particularly mutated cells. To what extent these cells guarantee tissue function is questionable. Recently, we have found that p66Shc deletion is counter-selected when mice are maintained in harsh conditions (open field under cold and competition for food) that mimic wild, indicating that p66Shc is essential for fitness under naturally stressful conditions but redundant in protected environments (Giorgio et al., 2012). So, p66KO mice can survive to accumulate a peculiar spectrum of mutations only in laboratory conditions.”
Oh no you got me! well then take a crack at 238 more genes that when removed increase the lifespn of yeast…(notice how mainstrream theorists are so blinded by their biases they call them “longevity genes” HAHAA!!>>>
summary form Science Daily>>>
Mapping the genes that increase lifespan
Comprehensive study finds 238 genes that affect aging in yeast cells
October 8, 2015
Buck Institute for Research on Aging
Researchers aiming to slow the aging process have new targets to explore. Following an exhaustive, 10-year effort, scientists have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health.
Saccharomyces cerevisiae cells in DIC microscopy.
Credit: By Masur (Own work) [Public domain], via Wikimedia Commons
Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. The research was published online on October 8th in the journal Cell Metabolism.
“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”
The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.
“We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.”
These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.
“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”
Thanks. Let me digest all this information. Just to be clear, I am just trying to understand aging and don’t have any strong opinion about which theory is correct. You have made certainly good points.
I am just not convinced that certain genes are there just to make an individual age faster. There is always some trade off. But certainly having the youthful pattern of gene expression rather than an aged/deregulated pattern is an intriguing avenue for longevity research. I used to think that epigenetic changes was just the body’s way of adapting to rising damage, but having seen how telomere changes and epigenetic reprogramming has such as profound effect, I am now inclined to think this is causal as well as adaptive in some situations. Whether this is programmed or cells genuinely making the best of their situation, I don’t know.
If look at p66Shc on Wikipedia see more than 20 ifunctions.
Also see receptor for Insulin growth factor 1. iGF1 lowering increases lifespan.
Known for 100 years caloric restriction increases lifespan. Tons of genes feed into mTOR and IGF1 pathway. Lowering them increases lifespan.
finding genes don’t knowing their exact benefit and jumping to idea they are their to promote death is pure nonsense.
Ah yes the aging gene conundrum.!!!…it always rears its ugly head….If anyone reads my book they will see my answer for this. Here I have to use thought experiments which I don’t like doing if facts are available so forgive me……YES it is true that no genes that I know of or expect to see initially evolve for the purpose of causing aging and death…That is the big problem that most mainstream theorists cant get past..And it is at this point that their minds shut down and they just repeat like a mantra..:”no such thing as aging genes” and that’s the end of the discussion..Just talk to Aubrey de Grey and you will see what I mean..HAHA
But if you think a little harder and consider the idea of late acting genes that get turned on after say age 40 for some reason…some of these will eventually mutate in an individual and become detrimental>>we now have created an “aging gene” by chance….(This is just one possible scenario-there are others like say a promoter site getting spliced into some some random DNA…etc…) Anyway , as far as I can imagine, any aging gene arises by chance.
..is NEVER created for the purpose of causing harm and aging, but once it does arise, Evolution has found a way to capture it and protect it from being selected against, via timing mechanisms like DNA methylation or telomere supression etc. , covering it up with proteins until the right time etc…. So while these “aging genes” are popping up at a steady state, they can be mutating back to good genes or neutral as well….If there is no interference from evolution these beneficial and negative late acting (after ,most reproduction) mutations should achieve a stand off with an edge towards good mutations to the point where longevity will evolve over time.
Introduce a predator that causes non diverse local populations to go extinct..you have the selection force that somehow selects for retaining these formerly good genes as “aging genes”. A good example to ponder is the disease of Huntington’s disease which doesn’t kick in until one is 40+ and how it has spread throughout a small Venezuelan town….It is not exactly a gene but it is caused by aberrant DNA that has not been selected out of the population due to its late acting effects and it spreads via reproduction..even though having no apparent benefit. Please visit my website and check out the 50+ articles on the blog site…you surely will find something you like…..
He eis a challenge for those promoting non programmed aging theories..spend at least a year in the med school library studying nothing but progeria, and Werner’s syndrome and then tell us how they do not represent examples of the acceleration of the various aging programs. embedded in our genomes…..
mainstream theorists have to ignore these cases as well ..calling them ” not real” forms of aging….HAHAHA!!!…Aubrey de Grey suggests progeria is aused by DNA damage!! When it is clear with a little study that proeria is an epigenetic disease caused by loss of gene silencing by a defective lamin a protein
If you is laughing at Aubrey de Gray, I’ll jump on that bus.
But in that case, shouldn’t we expect the Horvath clock to be accelerated in progeric patients? Yet it is not the case.
Here is a link to an NIH abstract that indicates that the combination of a germ free environment and calorie restriction extends the life span of mice.
He is trying to defeat aging. Whether or not his approach is right, I can not help but applaud his audacity. We should respect that at least.
I certainly agree. Aubrey is both smart and courageous. He has generated lot of momentum around the problem of aging.
The main controversy about him is, I think, that he has made extraordinary claims about curing aging which rely on technology not currently available and controversial hypothesis. Because of that, he might be viewed more as a Guru than a scientist, specifically because the field of anti-aging is already full of charlatans.
It probably does not help that he dismisses all the work around tuning metabolism (rapamycin, CR mimetics, sirtuin activators, …).
However, some might argue that the momentum he has created around anti-aging will ultimately have a positive impact on funding anti-aging science (whether it is directed to SENS or not). I guess we’ll have to wait to have a better idea about his contribution.
There currently is excellent anti-aging meds and excellent understanding of aging based upon Blagosklonny theory. However, Aubrey contributes to general belief that aging is quacks and nut cases. Aubrey and other nut cases block anti-aging from being consider science or medicine
You might be right about that part. But Aubrey is also editor in chief of “Rejuvenation Research”, which publish some serious scientific work as far as I can tell.
The reason there is still controversy is because we still do not fully understand the mechanism of aging. If it is just a matter of resetting epigenetics to a correct pattern of expression for us to remain eternally youthful, then Aubrey will ultimately be proven wrong. If metabolism is always producing some level of damage beyond the ability of any but a theoretical system to repair, then his approach will be right. As far as I can tell scientific opinion is starting to move in Aubrey’s direction. But it may be that the answer is some combination of both viewpoints, both accumulating unrepaired damage and altered and harmful patterns of gene expression, both causal and a consequence of one another. Many things that are talked about seem fanciful, human-level or higher artificial intelligence, cities on Mars, and ending aging. But we live in remarkable times, and such things may not remain fanciful.
Yes, but I would even be more specific before crediting Aubrey. Certainly, if one of his original SENS proposal turn out to be the right approach, than yes, I will say that he was right.
However, if for example mitochondrial damage is an important factor to aging but the right way to address it turn out to be different than inserting some mito genes into the nucleus, then I would not give any credit to Aubrey for that.
To be fair SENS was envisaged in 2002, so I would not expect it all to be spot on in terms of approach. Epigenetics was not yet understood. Allotopic expression of mitochondrial DNA in particular looks to be unnecessary now, although I think glucosepane and lipofuscin clearance will be needed to clear out post mitotic cells, unless we can safely cycle them.
Yes good point. Let’s see how Aubrey and the SENS platform evolve in light of the recent discoveries.
Aubrey is a visionary who saw the possibilities for a science of anti-aging medicine at a time when most scientists were not yet ready to consider it. His charisma and leadership skills and years of dedication have paved the way to create public support and even public demand for anti-aging science. Scientifically, he got some things right very early. He foresaw the potential good of removing senescent cells and was an early advocate for stem cell therapies.
It is only because of the influence he has earned that his mistakes have power to move research in the wrong directions. I think he is on the wrong side of telomere science, and his conception of aging as “accumulated damage” has discouraged research that I consider most promising. All in all, Aubrey has done a great deal more good than harm.
In 2005 EMBO in article including following I recognize as leading scientists, S Austad, L. Guarente, L. Harrison, T. Kirkwood, R. Miller, Olshansky, A. Richardson, J. Wei.
Entitled: Pseudoscience and the SENS Plan.
The report concluded none of de Grey’s therapies has ever been shown to extend the lifespan of any organism, let alone human.”
Basically, if you like junk science, then de Grey is your man.
As somebody who works in anti-aging field, I would like the face of anti-aging to be EMBO, not SENS and de Grey who famously proclaimed in 2008 broadcast that first human to live to 1000 years was probably already alive, and might be between 50 and 60 years old already. That means people now between 60 and 70 may live to 1000 years. Well, if you think that is true, God bless your heart.
I suspect that many of those scientists would now be embarrassed of their declaration that SENS was pseudoscience.
Has someone already posted link of this article “Towards natural mimetics of metformin and rapamycin” http://www.aging-us.com/article/101319/text
The natural mimetics they mentioned include:
Allantoin, glucosamine, withaferin-A, ginsenoside…..
Life extension organization, has been discussing these compounds for awhile.
They are all certainly easier to buy then both off label use Metformin and Rapamycin and certainly more cost effective than Rapamycin.
Mark has already posted it a few weeks back. Interesting paper.