I fear that we won't get to find out promptly (read: while I could benefit) because of the FDA's stubborn insistance that aging itself isn't a disease (making it harder to meet ethical critera are a were).
More generally, I'm furious at the many bio-ethicists who are complicit in the game where something bothers ppl in the population but it doesn't seem like a coherent worry so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously.
I'm a fan of exploring these ideas but it's not cool when bio-ethicists work to justify our emotional impulses rather than working to correct them when they disagree with our best rational reconstructions of morals.
I have a lot to respond here, but don't have time to write a full response tonight, so here's a shorter one. I might revisit this later.
David Sinclair is definitely a hype machine, but some of what he's hyping might actually work. Resveratrol is not one of those things (pharmacologically it sucks), but partial epigenetic reprogramming (with OCT4/SOX2/KLF4 or other transcription factors) is. In particular there was a very cool paper recently about restoring vision in aged mice: https://www.nature.com/articles/s41586-020-2975-4
Anyway, I'll believe he can reverse aging when he shows me a 5 year old mouse.
I believe in the book when Sinclair was talking about the Yamanaka factors, he asked the reader to imagine that you start getting into your 40s or 50s and are diagnosed with age. You go in to a clinic for treatment and they use the Yamanaka factors until you become 20 again and you do this over and over. I'm not sure that is possible but that idea got me really excited when reading this book.
I'm interested in taking resveratrol and NMN but I don't really know about this stuff and it seems so speculative. How badly can you hurt yourself with these?
> And finally, what’s the worst that could happen? An overly literal friend has a habit of always answering that question with “everyone in the world dies horribly”. But in this case, that’s what happens if we don’t do it. Seems like we have nowhere to go but up!
I am always surprised that there isn't much, much more support for anti-aging research. I'd figure that everyone expects to age and no one wants to. So the government/billionaires/whatever should be showering the research with money. Yet that doesn't seem to be the case.
The simplest answer to "Why doesn't the body already do this?" is anti-aging isn't free: it costs resources the body can use on other things, like manufacturing sperm or cogitation or even burning for warmth. Animal lifespan varies based on a lot of things but it tends to be shorter in animals that can expect to die by accident or predators because in those animals there is no evolutionary benefit to adaptations for increased lifespan beyond a certain point. Meanwhile, birds that are the same size as mammals that can be expected to live 3-5 years will live 80 years, because flight and their relative intelligence means birds are much less vulnerable to predators and accidents and local food shortages.
Personally I think Algernon's law is absurd and betrays a lack of attention to the natural world and the constraints of evolution.
Only ~1/2 way through. But you haven't mentioned my fav. aging idea. Aging is the response of a multi-cellular organism to cancer. (One cell going crazy and dividing forever.) There is a limit on the number of cell divisions for non-reproductive cells. (most of your body.) When you reach the limit, cells stop dividing and repairing and you get older. The limit stops cancer at least to first order...
I'm going to be so, so, so upset if aging is conquered a few years after I die, or when I'm in my 80s and it's too late for me, or some such thing.
The cosmic unfairness of it! — I want to live forever (or at least "way longer than current human lifespans", and the same for those I love) more than *anyone else I've ever met*; and I live in a time when the spiritual sort of immortality looks more unlikely than it did when "I dunno; magic?" was the best answer available for "how does any of this work?", but the physical sort looks absolutely possible and likely to happen *someday*...
... and I end up one of the poor bastards trapped without the comfort of an eternal heaven waiting after death, *or* the exhilarating freedom of endless experience stretching out to the cosmic horizon? And the latter could possibly be mine, except we spend our time and resources on frivolities that don't matter at all if you don't have *time*? (— whereas solve aging, and you can have all the frivolity you want... literally! you *can't* have all of anything you want, now, because you're going to become decrepit and die!)
I forgot if I had a point. I think it's just that I'm upset. Interesting book review and I want more like it, though.
My favourite human biology fact, the most mind blowing to me, is the fact that if you live to be 100, your odds of surviving to 110 are 0.1% (source https://en.wikipedia.org/wiki/Supercentenarian) . Human bodies just disintegrate at that point. It's also amazing, when you think about, that the world's oldest woman only lived 1.5x as a long as the average woman in a developed country. Whatever one thinks about Sinclair, it's amazing how strong the barrier is to exceptionally long life and more people need to be studying this.
The basic concept of Algernon's law has always bothered me. I don't think it actually holds much water, at least, not in the way that it's commonly used. The human body may well be perfectly optimized for our hunter gatherer lifestyles of the past, but that has very little bearing on how well optimized it is for today. We used to have very real energy input constraints, and that meant the availability of food was a major factor in the objective function our bodies were optimizing for. That constraint is effectively gone today. There may be quite a few biochemical switches that are tuned for energy scarcity that we could easily dial way up/down without harm, and without any real contradiction to Algernon's law.
Similarly, aging and decay are potentially epiphenomena of gene progression. Nature isn't optimizing for immortality of individuals, its optimizing for immortality *of genes*, which it achieves just fine by killing you after you've had your kids. There is no reason to think evolution tried and failed to make us immortal, and therefore no strong a priori reason to think that there shouldn't be low hanging fruit in that domain.
"Can you take rapamycin? Probably a bad idea, it’s a potent immunosuppressant."
This seem incorrect, due to dosage effects. The doses that organ-transplant recipients use are much higher than those used for longevity purpose. There is even some evidence that rapamycin enhances immunity at lower doses. Here's some further discussion with references: https://peterattiamd.com/rapamycin-risks/
The other thing going on which kicks in after the 30-40% improvement is telomere shortening, making more and more cells senescent. This is also something which might have an easy fix once you solve the “all kinds of cancers” problem.
I want nanobots that go around removing senescent cells, cancer cells, arterial plaques, aggregates, unfriendly bacteria, etc. Like an artificial immune system that is way better than the natural one. That could extend lifespan by a lot, even before you program it to mess with Yamanaka factors.
"Cure aging, and the whole concept of life expectancy goes out the window" I am surprised at this comment - I would've thought it's obvious it doesn't. At 70, the probability of dying in the next year is slightly under 2% (albeit substantially higher for men than women). If you could stop aging at 70, then you'd have a 50-50 chance of living until 104. (0.98^34 is about 0.5) What if we could roll back aging to 21? 21 year olds have around a 0.08% chance of dying in a given year. That means you'd have a 50-50 chance of living to about 850 years old. (0.999167^950 is about 0.5) That's barely into the biblical lifespan territory. (Source of actuarial info: https://www.ssa.gov/oact/STATS/table4c6.html)
To clarify, senescent cells are not exactly an unwelcome process in our body. Cells can become senescent to avoid malignant transformation into cancer cells - one of the characteristics of senescent cells is their lack of proliferation. It fits into a broader theme where aging and cancer are two sides of the same tradeoff, biologically speaking. Keep the cancer at bay, and you age faster. Suppress aging and you suffer from cancer. So in this paradigm aging is an in-built protection from cancer, and messing with it (injecting Yamanaka factors, extending telomeres) has a price.
From the publicity standpoint I think the easiest application of anti-aging research is improving the lifespan of our pets, turning cats and dogs into life-long companions. I can think of very few people who would object to that. The regulation in this area is probably much more lax, allowing biohackers to experiment with next-generation treatments and report the results.
However, I'm skeptical that the same anti-aging treatments that work on mice, cats and dogs would make a strong impact on humans. We still don't know why, mechanistically speaking, mouse tissues have a shorter "expiry date" than human tissues. Extending lifespan in animals could be as easy as identifying the mechanisms that keep humans from dying in their 20s and transferring these mechanisms to animals. To extend lifespan in humans we would need to either identify biological mechanisms that keep whales alive for 200+ years and steal those, or come up with the novel ideas ourselves.
Re: stem cells: Do stem cells always know what sort of cell to differentiate into? Would stem cells in the kidney always turn into kidney cells and not lung cells?
I would be very interested in seeing a post on the relationship between cancer and ageing at a cellular mechanism level.
Cancer is a return to the unicellular world. Differentiated cells of multi-cellular organisms such as lung, liver, brain etc becomes dedifferentiated as cancer progresses. Cancer cells also use the significantly more inefficient pathway of anaerobic respiration, as opposed to aerobic or mitochondrial respiration, because the latter pathway was developed for an environment where efficient production of energy was desirable. Who else uses anaerobic respiration? Prokaryotes.
This has implications for us because when glucose is abundant, why care that aerobic respiration is 18x more efficient? Simply use anaerobic respiration, which is much faster and has the byproduct of generating lactic acid which can be used to kill neighboring cells for resources, just like bacteria and other unicellular organisms do. Rapamycin that Scott mentions, is a toxin secreted by a bacteria for this purpose. This is why obese people are significantly more likely to die of cancer. This is also where mTOR comes into the picture.
The other common way to get cancer is for cells to be exposed to chronic stress. If all your lung cells are abused by toxins in cigarettes, eventually they stop hoping that order will be restored, forget about the fact that they're supposed to be lung cells since it's getting impossible to function as one anyway, and revert back to their underlying programming of being a unicellular cell alone in this world, where cooperation no longer matters and survival must come at whatever cost.
At first glance, ageing and cancer seem to be two sides of the same coin. Cancers keep multiplying, just like bacteria, and are remarkable at survival because they are simply unicellular organisms that care only about their survival, to hell with everyone else. Most stay contained because our immune system is incredibly well suited to kill cells it doesn't recognize. But the war on cancer shows slow progress because we keep trying to find targeted ways to kill an organism that has undergone billions of years of evolution to survive. The organism simply evolves another way. Survival of the fittest.
Senescent cells help prevent cancer in a way, by dying off after their telomere cap is hit. Cancer cells aren't constrained by the telomere cap and can keep dividing. Increasing telomere length would reduce senescent cells, but that would increase the likelihood of cancer via cells gone rogue. But perhaps not, if the immune system could be kept healthy.
Jason Fung's The Cancer Code is a great intro to this paradigm.
Thank you, this is a great review and I'm glad you touch upon what "people who are not sinclair" think because some of the stuff in the book is hyped.
"Can you take rapamycin? Probably a bad idea, it’s a potent immunosuppressant. Organ recipients take it sometime to quiet their immune system down to the point where it stops rejecting the transplant, but it’s not a lot of fun."
^That point is not entirely correct. Rapamcycin gets a bad rep due to its history of being used as an organ transplant drug. But low dosage and once a week rapamycin may not be dangerous! In fact, it is one of the drugs that has consistently shown lifespan & healthspan benefits in mice. People in the industry like Matt Kaeberlein and Peter Attia take Rapamycin. I asked Matt about it in my podcast with him if people want to learn more on Rapamycin: https://youtu.be/BL67DhNepfg
"But when David Sinclair says that reservatrol or exercise or intermittent fasting or saunas act by “mimicking calorie restriction”, is he suggesting that they will make you weak and constantly tired? If not, why not? This sounds a denial of the fundamental mTOR tradeoff: less energy expenditure in exchange for worse performance. The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me."
^Yes there is a tradeoff because these activities like exercise & sauna are hormetic stressors. That means that a little bit of stress causes your cells to hunker down and extend lifespan. However, there is a limit where overdoing these hormetic stressors can lead to chronic stress. For example, if you are perpetually fasting, you will obviously die!
Similarly, exercise is in fact a stress to the body and causes low-level inflammation. But that's "good type of stress" where your cells learn to become resistant. Overdo exercise and you might be stressing your body more than what's good life lifespan and healthspan.
In other words, there is a sweet spot for these stressors!
Maybe I just see the most dystopian perspective on everything, but I have a bad feeling about the societal effects we would see from the development of immortality serum.
I don't imagine anyone being forced into immortality, but I can absolutely imagine life becoming impractical otherwise.
For example, increased lifespan means increased potential for labor extraction. More possible working years means greater debts could be repaid. Maybe the 100-year home mortgage becomes a thing, contingent on your compliance with anti-aging treatments, of course. Maybe then the price of houses scales to match what people can finance, just like we see with student loan availability and tuition fees rising.
Or on the other hand, suppose that people who are getting this serum are primarily those who have retired on their investments. How large of an ownership class can society bear?
Im not going to address the entire review for the sake of brevity. But to the core of your question, I will try to argue for the anti-aging efforts and validity.
So, what could be an almost insurmountable problem for cells in a mature animal, but trivially vanishes when you clone a cell into an embryo?
In a few words; the consistency of unmethylated/methylated DNA. Meaning, the cells that grow from the clone are free of DNA methylation, because they have been pre-selected for healthy nucleuses, and therefore the complimentary DNA (cDNA) will be true to original form. The cDNA then goes through its regular processes in transcription then the many forms of RNA and respective processes of translation follow resulting in properly expressed proteins. So, not all cells or cell types are prone to DNA methylation at the same rate or even the same rates from the same hazards and it is because of this that cells progressively fail to transcribe and translate original DNA into proper proteins at high fidelity. As the cell health of the organism dwindles during senescence, proteins and growth factors alike are not being coded for at the rate needed and we see organ failure, cancer, etc. It only takes one serious break in the chain and we have big problems. That's what makes the biology so astonishingly robust and delicate at the same time.
Furthermore, as DNA is progressively compromised, cell division ceases to produce intact differentiated cells and those unsuccessful cells are destroyed by immune functions like those of macrophages. This is very similar to the destruction of an unviable fertilized egg in the blastocyst stage. Still there is no ultimate atavististic feature built into genetics... so once stem cell types have differentiated, that's the end form for potentiality. Although potentiality is limited by the number of viable daughter cells it is also governed by the expression of those cells.
Enter epigenetics. In epigenetics, this revision to a previous state is the goal of upregulating the sirtuins to a degree that all of the methylated DNA will be successfully cleaved back to its original unmethylated code. Not to be confused with changing or reversing cell type (genetics), but to keep the multipotent cells functioning efficiently. Granted I, too, have my doubts about the limit of sirtuin capabilities but remain optimistic about stem cell therapies and gene therapies.
Sirtuins are not the only way to regain optimal cell health from the DNA up. There are ways to shuttle in specific growth factors (to address your point about kidney cells or differentiated cell types more broadly) like engineered stem cells transfected with lentiviral vectors programmed to overexpress carefully selected growth factors that are specific to the target area. This is the area that I am focused on now, but the more communal-power focus on anti-aging the longer we may live to see our loved ones grow and the longer we may not weigh on them like a shadow of ourselves. Or better yet, the longer we will have to think of good solutions to difficult problems. Maybe we'll even get to relax after everything is patched up.
Anyway, I have applied for the ACX grant because a friend pointed me here. This is my first time on the board. I am currently a grad student in a related field but I need funding to complete my next course and hopefully do a PhD in neuroscience... support is warmly welcomed. So, too, would be an understanding PhD mentor, but alas.
If we eliminate disease and aging, the only remaining causes of death are accidents, suicide, and murder. The chances of meeting a violent end become higher as those who favor suicide gradually eliminate themselves.
"In Jonathan Swift's 1726 satirical novel Gulliver's Travels, the name struldbrugg (sometimes spelled struldbrug)is given to those humans in the nation of Luggnagg who are born seemingly normal, but are in fact immortal. Although struldbruggs do not die, they do continue aging. Swift's work depicts the evil of immortality without eternal youth.
They are easily recognized by a red dot above their left eyebrow. They are normal human beings until they reach the age of eighty, at which time they become dejected. Upon reaching the age of eighty they become legally dead, and suffer from many ailments including the loss of eyesight and the loss of hair.
Struldbruggs were forbidden to own property:
"As soon as they have completed the term of eighty years, they are looked on as dead in law; their heirs immediately succeed to their estates; only a small pittance is reserved for their support; and the poor ones are maintained at the public charge. After that period, they are held incapable of any employment of trust or profit; they cannot purchase lands, or take leases; neither are they allowed to be witnesses in any cause, either civil or criminal or economic, not even for the decision of meers (metes) and bounds."
Because:
"Otherwise, as avarice is the necessary consequence of old age, those immortals would in time become proprietors of the whole nation, and engross the civil power, which, for want of abilities to manage, must end in the ruin of the public."
There is an origination called the Gerontology Research Group. one of their activities is tracking the oldest people in the world. Supercentenarians who are 110 years old and older. They take pains to validate their ages via government and private records. Here is a link to their table of living supercentenarians
There are 17 of them out of the ~7 billion living humans today. The oldest is will be 119 years on 2 Jan. 2022. She is older than any person they have tracked since Jean Calment of France who died 1997 at 122 years and 164 days. https://grg.org/SC/SCindex.html
I would posit that 125 years is a hard upper limit on human life spans. Some creatures, such a Galapagos tortoises and some whales live much longer than that. But, all living things grow old and die in their time.
Gen.47
[7] Then Joseph brought in Jacob his father, and set him before Pharaoh, and Jacob blessed Pharaoh.
[8] And Pharaoh said to Jacob, "How many are the days of the years of your life?"
[9] And Jacob said to Pharaoh, "The days of the years of my sojourning are a hundred and thirty years; few and evil have been the days of the years of my life, and they have not attained to the days of the years of the life of my fathers in the days of their sojourning."
"pterostilbene, a more bioavailable resveratrol relative. The other pill is nicotinamide riboside.
Those are the two ingredients in a product called "Basis" that I have been taking for many years. It's only a sample size of one but my biological age, as defined by whatever genetic markers Elysium, the company that makes Basis, uses, was measured a year or two back as about a decade lower than my chronological age.
But then my mother, who didn't take Basis, died at about a hundred and her brother at older than that, so I may just be lucky in my genes.
"you’d have to correct the DNA in every cell in the body (using what template? even if you’d saved a copy of your DNA from childhood, how do you get it into all 30 trillion cells?)"
The template problem is easy; you just take a majority vote of fifty cells. Unless they tend to all have the same mutations, that should get you back to the original.
The distribution problem is harder. In principle you do it with nanotech cell repair machines, but that is going to be quite a while. Possibly a tailored virus?
“Algernon’s Law says there shouldn’t be easy gains in biology. Your body is the product of millions of years of evolution - it would be weird if some drug could make you stronger, faster, and smarter. Why didn’t the body just evolve to secrete that drug itself?”
The reason this argument fails is that immortality isn’t actually evolutionary beneficial. Take two people, one of whom is immortal for biochemical reasons, and a regular human. The human, knowing their clock is ticking, is likely to have children quickly, stick around to help with the grandchildren, and then die. Whereas the immortal person seems like they wouldn’t in such a hurry to have kids, meaning they would be unlikely to pass on their genes as quickly. Consider how birth rates fall as life expectancy goes up, and you can understand why evolution would want to sabotage the body in some way, so that it doesn’t outlive its usefulness or waste time doing things besides copying its genes.
Brett Weinstein's argument seems to be that senescence isn't a bad outcome but a trade off. Immortality always converges on cancer (or IS cancer), so a universal max replication count (however fuzzy) avoids cancer (for the cancers that don't escape the mechanism), but guarantees aging and death. Aging is the body's answer to cancer.
Lab mice accidentally and systemically have been selected for long telomeres and are good at healing and live a long time, but tend to die a lot from cancer (even when we're not guaranteeing it).
I think the best argument against making most of the population immortal today is that in a couple centuries, we will have engineered the entire population to be vastly more intelligent and fitter than they are today.
That said, even if we did achieve biological immortality, at present rates of accidental death, you'd probably make it to roughly 600 or so on average.
Has anyone ever looked at aging through the lens of a human/chimp comparison? We live decades longer than our closest relatives, which are themselves a long-lived mammal. What are the biological differences that makes that difference? If you figured that out, maybe you could crank up those differences.
Going to mention Kim Stanley Robinson's Mars trilogy (and his earlier novel Icehenge) here in case people are inclined to ctrl-F for his name like I was. As an exploration of the consequences of 500-plus-year lifespans I actually don't find the Mars books that interesting. That part of the science fiction is mostly a way to keep the same characters around through a several-hundred-year terraforming project. Robinson also exaggerates the Malthusian / environmental-risk / social-upheaval aspects of longevity, which is typical for him.
Icehenge mentions an interesting idea, though, which is that people seem to "peak" pretty young (physically in particular, but mentally too-- the example Robinson uses is chess champions), as in: soon after they mature. So even with strong anti-aging tech it seems likely that experience of the added years of life would be more like being 50 or 60 or 70 than, say, 30. There might be a feeling of decline and/or stagnation the whole time.
There was a post eight months ago on LessWrong where John S. Wentsworth, an "independent AI researcher" according to LinkedIn, gave a summary of his understanding of how aging worked:
A summary (by me, a complete non-expert) would be:
The symptoms of aging (atherosclerosis, sarcopenia, etc.) are basically caused by too much inflammatory factors (SASP) and reactive oxygen species (ROS). Senescent cells release both.
SASP is released normally by senescent cells in order to tell the immune system to kill them.
ROS is generated by the normal action of mitochondria, and causes DNA damage. ROS goes up when the cell is in a DNA-repairing state - mitochondria become less efficient, producing less energy as part of the repair process, and therefore more ROS, which can in turn cause more damage.
Normally, cells have low levels of DNA damage and low levels of ROS. But after passing some threshold after enough stress has happened to the cell, the ROS damages the DNA faster than it can be repaired, and the cell becomes senescent.
The core cause of aging is suggested by the author to primarily be because of transposon proliferation. Transposons are genes that copy themselves; when they do this, they cause DNA damage. Most transposons in the genome are dead - no longer able to proliferate due to evolutionary accident; they make up about 50% of the genome.
Maybe 100 or so active transposons remain, and these are tightly controlled by epigenetics to prevent them from being expressed. However, as part of the DNA repair process, the epigenetic mechanisms (e.g. sirtuins) are drawn away from repressing them to go help fix the DNA. When that happens, they'll manage to copy themselves. These make future DNA repair attempts more inefficient, and a certain level of transposon proliferation represents the threshold beyond which DNA repair fails and the cell becomes overwhelmed by ROS damage. Transposons also make senescence permanent; once they've been given free reign to copy themselves due to the failure of the DNA repair system, they will proliferate and damage DNA until the genome is beyond recovery, even if the excess ROS were to be cleared away.
One particular thing about transposon proliferation is that it occurs in stem cells too; a stem cell that has a high level of transposon proliferation, but not enough to render it senescent, will cause the cells it forms to quickly become senescent themselves. So the ultimate cause might be said to be an overall increase in the rate of cells senescing, causing body-wide overexpression of SASP and ROS, due to more and more stem cells getting overloaded with transposons at sub-senescent levels.
As to why organisms don't get overloaded with transposons with each successive generation - someone in the comments mentioned that the gonads have very high levels of epigenetic control against the areas with active transposons; this has the side effect of hindering DNA expression overall (which maybe explains why fertility is so hard, and requires so many attempts to succeed).
I think it foolish for us to think we will live on past our time. We are not made out of incorruptible gold and adamant. We are dynamic balances between energy and entropy made out of water, sugar, oil, and protein, in an intricate pattern. We should appreciate the miracle of life and know that it is brief.
Thornton Wilder's novel The Bridge of San Luis Rey is a meditation on the meaning of life and random death. In it the Friar Brother Juniper witnesses the collapse of a bridge and the death of five travelers who were on it. He minutely investigates their lives and searches for the reason, if any, behind their deaths. The novel ends with the Abbess' observation: "There is a land of the living and a land of the dead and the bridge is love, the only survival, the only meaning."
Shakespeare The Tempest Act IV Prospero
Our revels now are ended. These our actors,
As I foretold you, were all spirits and
Are melted into air, into thin air:
And, like the baseless fabric of this vision,
The cloud-capp'd towers, the gorgeous palaces,
The solemn temples, the great globe itself,
Ye all which it inherit, shall dissolve
And, like this insubstantial pageant faded,
Leave not a rack behind. We are such stuff
As dreams are made on, and our little life
Is rounded with a sleep.
Gen. 3:
[17] And to Adam he said, ...
[19] In the sweat of your face you shall eat bread till you return to the ground, for out of it you were taken;
you are dust, and to dust you shall return."...
[22] Then the LORD God said, "Behold, the man has become like one of us, knowing good and evil; and now, lest he put forth his hand and take also of the tree of life, and eat, and live for ever"
[23] therefore the LORD God sent him forth from the garden of Eden, to till the ground from which he was taken.
[24] He drove out the man; and at the east of the garden of Eden he placed the cherubim, and a flaming sword which turned every way, to guard the way to the tree of life.
The more I read about humans wanting to live longer the less I like humans. The sooner the humans die off the better. I want bees or ants to be the future of this planet not ugly primates.
Disclaimer that I haven't read the book even if I read some of Sinclair's scientific output earlier, but to be absolutely clear resveratrol is absolutely not even close to bioavaliable enough in humans. We're talking about taking literal tons of tomatoes or wine or whatever for a biologically significant effect, whatever it is.
This paper https://pubmed.ncbi.nlm.nih.gov/27552971/ by Sinclair did a good work explaining how the mechanism for Sirtuin activating was elucidated and entablished to be related to a resveratrol-in vitro like mechanism against the skepticism of losers and haters (this is a narrow claim, I'm not saying his wider output always replicates). And it takes for granted we need synthetic sirtuin activating compounds for any significant effect. Does Sinclair mention this sort of stuff on the book? This is from 2016 and my quick check is that a lot of the late phase clinical trials in humans with these compounds are not done yet.
>It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
If I may add one anecdata point, in italy most resources are gobbled up by the state pension fund and we are suffering from quite bad youth unemployment rate so I would claim that this scenario is in fact happening nowadays - albeit without the dictatorship part.
Probably a good time to remember the Adversarial Collaboration Contest entry from 2 years ago that looked at aging and concluded the evidence for calorie restriction in humans results in longer lifespan was less strong than e.g. animal studies would suggest: https://slatestarcodex.com/2019/12/12/acc-does-calorie-restriction-slow-aging/
Hi Scott! Great review! And, as the author of another book on aging biology (Ageless: The new science of getting older without getting old), I agree with both you and David on different things. In agreement with you, I think that solving aging is going to take more than just reversing epigenetic changes. In Ageless, I break things down into ten ‘hallmarks’ of the aging process of which I think we’ll need to solve a decent subset in order to make *really* significant progress against aging (though results from tackling individual hallmarks like cellular senescence and epigenetic reprogramming make it seem encouragingly as though we could get some decent gains without solving everything). Where I agree with David is that I’m nonetheless optimistic that if we did plow a decent amount of money into aging biology, we could make huge advances, and it might well be easier than curing cancer (cancer cells are constantly evolving to maximize replication; the changes that cause aging are largely accidental side-effects of evolution and aren’t actively trying to outwit your treatments).
And I’m going to be releasing a free, bonus chapter on the ethics of treating aging next month, so sign up here to be the first to hear about it! https://andrewsteele.substack.com/
> It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
You might want to look around.
But bitter jokes aside, I'm 100% on board with your train of thought. Unfortunately I lean towards the SENS model more than the Sinclair model, but if Sinclair is right, that's _such_ a low hanging fruit we need to exhaust that research direction anyway.
Anectodally, intermittent fasting makes you feel fantastic, actually heals muscle injuries (by downregulating inflammation, I guess?), keeps the weight off. Highly recommended even if it does not, in fact, make you an immortal space murine.
« Algernon’s Law says there shouldn’t be easy gains in biology. Your body is the product of millions of years of evolution - it would be weird if some drug could make you stronger, faster, and smarter. Why didn’t the body just evolve to secrete that drug itself? Or more to the point, since most drugs act by flipping biological “switches”, why does your body have a switch set to the “be weak, slow, and dumb” position? »
Algernon's Law seems very real to me, but for aging, there is something that works strongly in our favor: natural selection heavily discount what happens at older ages, because in our evolutionary past, we were statistically dead after, say, 40 years. This means that a genetic variant producing a very small advantage in youth at a huge cost in later life was usually very advantageous and retained by natural selection. So it seems possible that, conversely, the cost of not aging could actually be very small. And besides, a relatively small number of organisms, some trees and turtles for example, do not seem to age, or at least we are not able to detect a decrease in capacity over time. So it seems possible for biology to make organisms that do not age, or at least age very very slowly.
I find the issue with many of these longevity arguments is in conflating lifespan vs healthspan (the duration of one's life in which you are healthy and disease-free). You could argue that many efforts of medical science over the past 100 years have focussed exclusively on lifespan, and this has caused a number of societal challenges with people who live longer, but are highly dependent upon support to carry out their activities of daily living.
So too with the summary of this book; if these theories bear out, then sure we can prevent cancer, or dementia, or any number of the other "Geriatric Giants", but this isn't (to my mind) going to prevent us losing muscle strength (which happens after age 50 despite exercise, even in retired olympic athletes), or to repair our knee cartilage, worn out from too much running. Without fixing these millions of tiny insults (as Scott says), we might be left with a retired generation who are biochemically healthy, and yet utterly unable to live independently.
> But when David Sinclair says that reservatrol or exercise or intermittent fasting or saunas act by “mimicking calorie restriction”, is he suggesting that they will make you weak and constantly tired? If not, why not? This sounds a denial of the fundamental mTOR tradeoff: less energy expenditure in exchange for worse performance. The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me.
We evolved and are tuned to lifestyle involving massive amount of exercise and much wilder swings of temperature and far less plentiful food.
It seems plausible to me that modern lifestyle is a massive health problem. We life longer because it was outweighed by reduction of diseases and starvation, but still sitting still in front of screen is extremely unhealthy.
It is not surprising that our body gets out of whack if we sit still, look at colored plate 50cm away and eat piles of food.
> But if you transfer the skin cell DNA to an egg, inseminate the egg, and turn it into a baby, that baby is just as young as all the other babies. So DNA damage can’t be the whole story.
Is it possible that this process filters out any damaged cells? As in, more damaged cells will not succeed and we just look at successful ones?
So one mostly end with failed growth or (usually) healthy new organism?
Lets say that growing baby is a tricky process where any unhealthy/damaged cells will die. Would it be consistent with success rate of cloning?
Still, reproduction requires producing less burdened cells so likely there is some repair - but maybe it is for some reason of another very costly to do or rarely successful?
"Second, life expectancy at age 10 (ie excluding infant mortality) went up from about 45 in medieval Europe to about 85 in modern Europe. What bad things happened because of this?"
I am surprised anyone would make this kind of argument. There were quite a lot of other changes in health and nutrition and everything confounding the life expectancy changes. For example, industrial revolution kicked off an extreme population growth event, and until recently there (in general) was more kids and young people than old people (discounting mortality effects from world wars).
Immortality is also different than extended lifespan. Extended lifespan for one individual still ends, which obviously results in kids and grandkids of the said individual getting the inheritance. (Maybe it could be good for economy that people have time to collect more net worth and then pass it around.) It is quite different from true immortality (it is no longer making sense to save money for retirement, instead it makes sense to build continuous equally immortal income streams to fund on-going immortality treatments and all the fun stuff you want to do).
Also greatly expanded lifespan is different than slightly expanded lifespan. The first change was that lifespans were more equal: more people had a chance of live into so old age where they could be grandparents and maybe great-grandparent, but there were such people even before. The future where the super rich / all 1st world people / everyone gets to live until they are 120 or 200 with young person's body (if not immortal) would be more drastic change.
"One unambitious - but still potentially true - counterargument to this is that a world where we conquered aging, then euthanized everyone when they hit 80, would still be infinitely better than the current world where we age to 80 the normal way"
Is it really? I think it is quite ambitious argument to make that it doesn't matter that in the universe A (current) we don't do anything we are not currently doing and in universe B (aging stops and people are euthanized) lots of people are killed. Sounds like an argument against universe B, because in universe B we are euthanizing a lot of healthy people.
"Second, life expectancy at age 10 (ie excluding infant mortality) went up from about 45 in medieval Europe to about 85 in modern Europe. What bad things happened because of this?"
Thomas Malthus would like to have a word here.
One of the arguments from the school of economics at the time of the Great Famine was precisely this - there were just Too Damn Many Irish, so the famine was in fact a great opportunity in disguise to clear out the surplus excess population (by emigration to Canada and the USA) and put agricultural practices on a profitable basis.
The previous explanation I've encountered for aging clashes with this. The way I've heard aging explained before is that genes do a bunch of different stuff (assumedly due to compression) and some of those things will be good/bad early/later in life (where early is before passing on genes via having children).
So a gene that's bad early gets evolution'd out of existence; leaving genes that are good early and good/bad later. The probability space of negative mutations is larger than positive mutations so most genes end up being beneficial early in life and bad later in life.
This logic feels compelling to me and precludes the idea that aging is simple enough to be easily cured. I admit to not really knowing much about the topic though.
Is part of the answer to the “algernon’s law” objection “because we aren’t evolved to be in this environment of plenty all the time?”
The people who are big on fasting argue you’ll feel more mentally alert and sharper when you’re hungry. This matches my experience as well: I have less energy after I’ve eaten a meal. My guess would be that we may be evolved for a specific long term average rate of mTOR activity, and most of us have it on too often, just like most of us are overweight.
He also argues in the book that there wouldn’t have been some evolutionary benefit for living for arbitrary periods of time in an environment that was chaotic and dangerous. So maybe there’s the answer: yes, you might take longer to heal from physical injuries with lower mTOR activation but this cost is outweight by having fewer senescent cells.
Also, maybe he looks super young in part because he’s so optimistic? Maybe it’s a mix of drugs and positive attitude.
Isn't Algernon's law reconciliation well established for aging? Aging and dieing are good for evolution. We mature we reproduce we care for our offspring and when they are mature we age and die. In the malthusian environment all species evolved in, not competing with our young for resources makes the species more fit. So the trade off to solving aging is that our species is less fit 100000 years out. This could make the toggle easy, but it could also be hard, not because evolution couldn't figure out how not to age but it explicitly made it hard to avoid.
I gave up on true anti-aging when I read an ophthalmology textbook. It was *filled* with explanations of the changes to the eye that take place as you get older, and reversing/stopping those changes would require technology unrecognizable to us. Even if you found some way to get the rest of your body to live forever, you will eventually go blind.
It's straightforward to do epigenetic mapping of cells, even down to the single-cell level. So: take an elderly mouse and a baby mouse, do the epigenetic mapping, see if there are systematic differences. Has he done this?
Agree with the distinction between lifespan and healthspan. Also skeptical that extending lifespan will be as simple as taking a pill and/or intermittent fasting. I think it's likely that average lifespan will continue to increase. But there is likely a natural limit (I've seen ~150 yrs mentioned before, but don't recall exactly what that's based on). Haven't read Sinclair's book yet. So not sure if he addresses it, but mitochondrial dysfunction plays a key role in aging. Mitochondria acquire mutations as we age due to ROS, etc. which leads to cellular malfunction. One potential therapy I haven't seen mentioned in this thread yet is mitochondrial transfer from healthy (young) cells to damaged cells. This has been shown to occur in vitro and in vivo. Nobody has quite figured out a way to harness this phenomenon for therapeutic use yet (lots of people claim they have, but evidence is lacking). The appeal of somatic cell nuclear transfer (SCNT) is that you can create genetically-matched cells for cell-based therapy that have young, healthy mitochondria from a donor oocyte/egg. This is also an advantage of embryonic stem cells over iPS-based cell therapies because those cells originate from an adult with already acquired mtDNA mutations (we've published on this). The challenges with therapeutic cloning of course is that donor oocytes are scarce (although maybe not for long if we can mass produce them in vitro) and delivery is an issue as with any form somatic gene therapy. Anyway, if you're a VC or philanthropist reading this post and want to support our research in this area (as the NIH currently does not fund human embryo research), hit me up. Paula Amato, MD at amatop@ohsu.edu.
> it would be weird if some drug could make you stronger, faster, and smarter.
Isn't that methamphetamine? Perhaps it has some negative side effects.
Regarding embryo's resetting the clock to zero . . .. Years ago, I watched one of those science shows (could have been NOVA), and the topic was cancer. The showed some results with chimeric mice. Start with a blastocyst from a white mouse, then inject a few cells from a black mouse. When the mouse pup is born, and grows, you can see where the black cells ended up -- all the black patches on the mouse.
Now the interesting bit. Now inject black cancer cells into a white blastocyst. In the experiment presented, they injected particularly nasty cancer cells, known to create a tumor wherever they land. The mouse pup is born, grows . . . and is cancer free. You can see where the black cancer cells ended up -- the black patches on the mouse -- but they are not cancerous.
Aging seems like an area where we might not expect Algernon's Law to apply. In my opinion, the evolutionary biology of aging is pretty solid:
From an evolutionary standpoint, organisms (probably) face tradeoffs between survival and reproduction--any given resource can either be invested in maintaining your current condition, or producing offspring, but not both.
Having offspring now is better than having offspring later, even if you have the same total number of offspring, because that means that your lineage fits more generations into the same time period as your competitors, and is thus more fit. Depending on the numbers, it will often be better to have fewer offspring quickly than more offspring over an extended period of time.
Put this together, and it means that basically all organisms should want to shorten their lifespan in order to reproduce more and more quickly. Even going from "infinite lifespan" to "finite lifespan" is going to be worth it for surprisingly small gains in reproductive rate.
"Aging" is just the molecular consequences of making that tradeoff. Stopping aging isn't about breaking a tradeoff (in which case Algernon's Rule would kick in), but just moving the tradeoff to an evolutionarily disadvantageous solution. This seems easier.
Chiming in as well to add my take on rapamycin: out of all of the longevity agents I am interested in and/or take myself, it is likely to be the one that I have the highest hope for in humans. We have a decent understanding of the mechanism (compared to many other things, at least), it works very consistently and strongly in several other organisms, and the mechanism of action is strongly evolutionarily conserved. As for safety concerns, it seems like if taken in a low dosage and infrequently enough, the safety profile improves significantly and it may be a net-plus in many areas (this may be related to mtorc1 vs mtorc2 activation depending on the dosage and timing (it does have a pretty long half-life!), which also makes it seem like it can be taken without actually suppressing one's immune system or causing some other undesirable effect categories).
Although I do know of many others that take rapamycin, I still don't suggest it to anyone myself, firstly because I don't offer medical advice of that nature regardless of my cost/benefit analysis (are there risks of potentially bad unknown side-effects with long-term usage? sure, but the risk of *not* taking longevity agents is also pretty large, and results in a much earlier likely death), and secondly because it is still likely to be higher risk than a lot of other simple things that I do often suggest to others, like glycine supplementation, which I see as close to zero risk (a few others on https://nearcyan.com/supplements/ if interested). I'd hope that anyone that takes it themselves has blood panels done (if not much more) to ensure they're not doing easily-observable harm to themselves as well. It's definitely a very interesting area of research either way; I can't stop myself from paying attention to stuff like this due to how large the potential impact on humanity is.
A few rapamycin links for those interested (more if you just search on pubmed!):
I enjoyed David Sinclair's book and some videos, but he is too good at hyping whatever he wants to. I trust his results published in good magazines, but he hasn't so far done anything in humans. He is a mouse guy.
Meanwhile, Greg Fahy has succeeded in reducing epigenetic age in humans by rejuvenation of the thymus (by a combination of HGH which rejuvenates the thymus + metformin and DHEA that prevent some bad side effects of HGH on insulin regulation). The trial was called TRIIM. He is now running an extended trial in humans again, called TRIIM-X, to find out how many measurable qualities improve as well. (Because we do not know how tight or loose the connection between epigenetic age and real state of the organism is). There was a recent interview in which he claimed that intermediate results are fairly good so far - for example, kidney function has improved, inflammation markers and PSA went down.
But Fahy is an unassuming kind of guy, almost shy, so he gets almost zero attention.
>Modern Europe is currently in crisis because it has too *few* people and has to import immigrants from elsewhere in the world.
It's not hard to imagine that in a society where people live to be 200, the fertility rate would plummet, particularly if you measured fertility based on the number of children women have for each year of their life, which might be a sensibility way to measure it if that denominator changes dramatically. And if the problem is not too few people, but too few workers, you could end up with a lot of old rich people living off many decades of capital gains. A shortage of workers could really become a problem in such a society.
But that's just speculation, and I agree with the point you make in the next paragraph:
>Would Europe be better off if the government killed every European the day they turned 45? If not, it seems like the experiment with extending life expectancy from 45 to 85 went pretty well. Why not try the experiment of extending life expectancy from 85 to 125, and see if that goes well too?
My favorite aging theory is the gradual dysfunction of proteosomes. Cells make a crapton of proteins all the time, and they really need to get rid of all the broken and dysfunctional ones, so my theory is the increasingly failure to do so as cells age is what makes them senescent. It also fits nicely with the starvation effect: presumably when your cells aren't getting enough fuel and nutrients they have some ways of boosting the efficiency of recycling.
> calorie restriction hasn’t been around the hundred years it would take to see results in humans. A few very committed biohackers having been trying it for a few decades now, so I guess we’ll know if it works by the mid-21st century.
We should see results in reduced mortality rate soon.
> Why didn’t the body just evolve to secrete that drug itself?
Since only traits that are beneficial or neutral would have persisted, presumably keeping old people around beyond a certain point is not particularly beneficial. Older proto-humans had incentives to crush younger and healthier challengers to their power, which would inevitably weaken a species. Older genetics may also be more poorly adapted to changed environments.
Humans are now pretty adaptable to a wide range of different environments, and we have some cultural adaptations that could possibly mitigate the "threat" of immortal old people.
> The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me.
It's common sense that you would want a strong immune system, unless you get lupus. So maybe mTOR gets *overactive* as we age, and these compounds suppress it only where it's not really needed.
People in this thread keep saying that NMN is "cheap", but I don't see it. Sinclair recommends 15mg/kg/day, so that's 1g/day for me. Most capsules I see on Amazon look to have 150mg and a bottle of 120 capsules is over $100 (CAD). That's $5.50 per dose, per day. That's not really that cheap given its speculative benefits.
Even the bulk supplier I'm aware of sell 500mg bags for over $1,600 (CAD), which is at least cheaper at $3.20 per dose, but still not cheap. If the benefits were more certain then maybe it'd be worth it.
I'd love if we could make some progress against aging, but I'm highly skeptical of nearly every claim made about its underlying causes and how to control it. Call me part of the camp that believes the problem is a death by a thousand cuts issue, where aging isn't just one or two problems that can be solved by 'fixing' DNA damage or epigenetic drift.
Speaking of DNA damage: it just doesn't fit. If accumulating mutations naturally caused aging, then why don't successive generations live shorter and shorter lives? We shouldn't have a situation where lifespan (controlled for infant/infectious disease mortality) is LONGER today than at any time in the past. Presumably the gametes are still dividing, just not as much as the kidney cells, so the same mechanism is at play there. So the same mechanism of DNA damage accumulation will happen, just more slowly over generations instead of over a single lifespan. In other words, this mechanism seems to suggest humans would have died of old age long before they ever evolved as a species.
Same argument for mtDNA damage accumulations.
Same argument for epigenetic drift. Why aren't we seeing epigenetic drift in the gametes? Are egg cells special in that they don't have epigenetic drift? Shouldn't we expect that there will be none left in a few generations - same as other cell types? Why not?
Meanwhile, there are all the normal mechanisms of aging that just don't feel like they're adequately explained by these ideas. They feel like a lot of hand-waving about how a general mechanism will lead to downstream effects, without ever having to connect the dots. For example, why does this accumulation of genetic/epigenetic changes lead specifically to memory B-cell depletion? And why is that mechanism both consistent, and gradual? If this were random drift, we'd expect to see more variation among individuals. A natural mechanistic explanation would better explain a phenomenon that is consistent and gradual.
For example, not everyone gets malignant cancers, and yet we all accumulate stochastic mutations over our lives. And even among those who get cancer, there's massive variation in which cell types are most affected, and how that manifests. Yet for aging, we always see arterial wall hardening, skin changes, etc. Why such consistency if we're working from a random mechanism? It doesn't fit our other experiences with stochastic biological mechanisms.
I feel like a lot of the signaling pathways game misses the complexity of the system. We talk about "mTOR" as if it were a hormone like insulin that we can track, or that your body turns on and off. But mTOR is an intracellular signaling molecule. And intracellular signaling molecules don't work in PATHWAYS so much as they work as parts of NETWORKS. The complicated-looking diagram Scott showed is probably right for some cells, where other cells might have a different set of signaling molecules expressed. Thus activation (or suppression) of mTOR will have a different effect, depending on what else is being expressed in the cell at the time.
To say cell signaling is complex doesn't begin to describe the situation. I remember learning about promiscuous signaling molecules back in undergrad, and thinking, "Okay, now I know how NFkappaB works", or "so that's what ras is doing." Then I'd learn that NFkB wasn't just a single protein, it was made up of subunits, and each of those subunits had different splice variants which would do different things, and some scaffolding proteins changed which subunits came together in the protein complex, and post-translational modifications could also alter each protein subunit, and all the same were true of ras, and ... eventually I gave up.
I realized that the easiest thing in the world is to say that "signaling molecule X is the key to this whole operation". That's like telling a patient, "The reason you're having difficulty breathing is because of your lungs." Great. That's not really interesting or helpful.
It's the illusion of knowledge about the root cause of the situation without any actual understanding of time, place, and manner. Saying things like "we just need to turn off mTOR" is about as useful as saying, "you wouldn't have these breathing problems if we just shut off your lungs. No more breathing, no more problems." Or the seemingly more sophisticated, "we can solve your aging problems through better regulation of mTOR" which is functionally equivalent to, "we can solve your breathing problems through better regulation of your lungs."
What we should really be saying is, "It looks like mTOR is involved in this process, but we honestly don't know how or why. We're unclear how we might use the mTOR information to solve the problem. We're looking into it, but don't get too excited because until we understand the root cause of the issue we won't even begin to know how to solve it." Not as much hype that way, though.
> And the increase didn’t cause some kind of stagnation where older people prevented society from ever changing. It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
Didn't most of the life expectancy increase between medieval and modern occur in the 20th century? And aren't most developed nations right now trying to cope with an abnormally large wave of increasingly long-lived people (e.g. boomers). And isn't the current zeitgeist that millennials have nothing while their parents/grandparents have everything? Saturday Night Live did a music video sketch about boomers not that long ago that contains this sentiment (paraphrasing) "they took all the money and they took all the jobs and they won't ever die!".
It's not a good reason to ban immortality, of course. And perhaps in the long-run steady-state, this would just work out OK, but people don't live in the long-run steady state - the first "old" generation to get the immortality pill is going to receive some truly vicious hate from the younger generations of the time.
Here's a somewhat plausible modest goal. There are people who live into their 90s in good health and then die fairly quickly. It runs in families, so presumably hereditary. The best news I've heard is that these people don't lack deleterious genes, they have more (better?) protective genes, so there might be something which can be bottled.
The massive challenge for any sort of longevity is that we might not have the tools we need yet. More math! But which math? Better tools! But which tools?
"Finally, a friend wasn’t impressed with Sinclair’s clone argument. They point out: suppose aging is DNA damage, and it happens to every tenth cell. Having a tenth of your cells damaged is pretty bad, especially if they become senescent. “Senescent cells”, common in elderly people, have sustained so much damage that they can’t even die properly, and just sort of sit around being hopelessly confused and secreting random chemicals which freak out all the other cells around them. Everyone agrees these are an important part of aging, even if they’re not sure about the specifics. But if 1/10 of your cells are like this, then you have a 90% chance of grabbing a healthy cell for cloning. And even if you get a bad cell, no cloning process works every time, so you’ll just shrug and try again."
Couldn't you decipher an old person's original, undamaged genome by sequencing the genomes of ten of their cells, and the creating a composite genome that excluded any base pairs that were different in a minority of the ten?
For example, assume there's a gene made of six nucleotides. I extract ten cells from the same person, and the sequences for that particular gene are:
Cell A genome: AGGCTA
Cell B genome: AGGCTC
Cell C genome: AGGCTA
Cell D genome: AGGCTA
Cell E genome: AGGCTA
Cell F genome: AGGCTA
Cell G genome: AGGCTA
Cell H genome: AGGCTA
Cell I genome: AGGCTA
Cell J genome: AGGCTA
Cell B is the senescent cell, and so is the only one that is different. I throw out its results and conclude that the correct sequence for the gene is AGGCTA.
One part of the definition of biological life, I think, is that it dies. Another implicit part of the definition, I think, is that it is unique, an individual entity. Are there cases where biological life as "an individual entity" are blurred?
Us fellow humans tend to view a bee hive as a composite entity, not life itself but composed of many individual biological entities. Part of the reason is the physical separation between one bee and another. Another part of the bigotry I mean bias I mean logical reasoning is that a particularly bee hive could last forever and not die like an individual primate is destined to in under 120 years.
Is it not a central reason that life can't become immortal because we define life as mortal?
Does anyone seriously think that any anti-aging intervention we are likely to make in the next 10 years will be remotely applicable to people who are 70+ right now? Seems to me like preservation is the only way to help these people.
I didn't know that cloning works well, I remember being said that clones have shorter lifespans. So cloning works ok? Why can't we have hundreds of clones of Neumann then?
Will we be able to grow human skin tissue in vitro indefinitely soon?
So... I guess in the end this supposed "cure for aging" would really only be a significant-but-not-orders-of-magnitude slowing of aging? If so, surely none of the usual arguments against preventing aging/death apply?
My first thought is that aging isn't just about DNA or generalized metabolism. There are all sorts of structural things going on. The body can repair itself, but the repairs rarely leave the body in the same shape as its original structure. There are all sorts of scarring, restructuring, and work arounds. You can reduce to damage by providing better medical care. You can induce repairs. You just can't eliminate the structural changes.
For example, there is work on inducing heart cells to reproduce to repair heart attack damage. It might even work, but how much growth can be induced and how much scarring endured without compromise.
Still, I'm optimistic. Every time scientists agree that we've reached some maximum age limit, new ideas and treatments come up and we move past it.
> The increase didn’t cause some kind of stagnation where older people prevented society from ever changing. It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps
Except it actually does -feel- that way. (Sorry I don't have any resources to back this up but my own experience). If you grow up in Italy you're definitely confronted with a political and economic system where older and powerful actors hoard resources and prevent younger dynamic forces to destabilise them. No wonder Italian researchers/workers/entrepreneurs do so well when they emigrate: the latent potential is there (they're educated in a modern, beautiful, powerful country) but they lack the opportunity to express their talents.
So yeah, maybe reversing again does have negative consequences to the economy.
I finished this book 1 or 2 days ago. The end has a lot of discussion of political issues and I felt like it was a lot less enjoyable to read his analysis of the political issues related to aging and his progressive viewpoint on certain things.
On the off chance that anyone will ever read this, I want to comment on Scott’s skepticism that sirtuins (or some other protein) can figure out the “correct” epigenetic state of a gene, esp because it differs for the same gene in different cell types.
One epigenetic modification is cytosine methylation when it is followed by a guanine, called CpG, to distinguish it from the CG base pair. One might notice that if one strand has 5’CpG3’ then the complementary strand also has CpG at that point (read the opposite direction - the strands are antiparallel. When CpG cytosines are methylated, they are methylated on both strands.
So, if somehow the methylation is lost in one strand, a hemimethylase could check the other strand. If it’s methylated, then methylate the first strand. Incidentally, methylation tells the cell which strand is old when DNA is replicated. If there is a mismatch, the unmethylated strand is wrong. It’s imaginable that breaking methylation ups the mutation rate, though probably only slightly.
There is also a possibility that the transcription factor(s) for being one cell type can suppress transcription from other sorts of promoters. Maybe that’s how a muscle cell knows to be muscular? Maybe that process breaks down when an animal is well-fed?
That said, I think epigenetic dysregulation is an interesting theory of aging. Probably wrong, but very interesting.
Bats would be super-interesting to study for aging research. There are lots of species, so cross-species comparisons are more reasonable than mouse <--> man. If two bats species have similar size, diet, and metabolic rate, but much different lifespans in captivity, then physiological differences might be causing slower aging. Some bats are roughly mouse-sized but live a lot longer.
On cancer and telomerase, the protein p53 checks for DNA damage and arrests the cell cycle/leads to apoptosis (cell death). It’s mutated or missing in half of cancers. Elephants have many more copies of the gene and much lower cancer rates. Upping p53 in all a person’s cells through germline or currently magical somatic cell genetic engineering would give them a lot more headroom for other changes that would increase cellular regeneration but increase cancer risk,
Then, it could well be possible to reverse this process quite easily by giving cells the signal(s) opposite to the pro-aging one(s). Katcher has essentially done it even more impressively than Sinclair in rats.
Also, are you aware that Sinclair's lab managed to make old mice regrow their optic nerves using Yamanaka factors? That's just one tissue but it's an amazing boost. And the cancer problem was solved because they removed one of the five factors which turned out to be cancerogenic.
There have recently been controversies about Sinclair's work on resveratrol and sirtuins; video summary, from Lifespan News, here: https://www.youtube.com/watch?v=eBxw6_8PivA.
My favourite pop science book on aging is Andrew Steele's "Ageless" (2019); it's broader and less focused on one guy's theories. My goodreads review of it is here: https://www.goodreads.com/book/show/52954648-ageless
I fear that we won't get to find out promptly (read: while I could benefit) because of the FDA's stubborn insistance that aging itself isn't a disease (making it harder to meet ethical critera are a were).
More generally, I'm furious at the many bio-ethicists who are complicit in the game where something bothers ppl in the population but it doesn't seem like a coherent worry so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously.
I'm a fan of exploring these ideas but it's not cool when bio-ethicists work to justify our emotional impulses rather than working to correct them when they disagree with our best rational reconstructions of morals.
I think it's spelled "resveratrol."
> using what template?
Show me a hundred copies of a string with a random error and I tell you the original.
I have a lot to respond here, but don't have time to write a full response tonight, so here's a shorter one. I might revisit this later.
David Sinclair is definitely a hype machine, but some of what he's hyping might actually work. Resveratrol is not one of those things (pharmacologically it sucks), but partial epigenetic reprogramming (with OCT4/SOX2/KLF4 or other transcription factors) is. In particular there was a very cool paper recently about restoring vision in aged mice: https://www.nature.com/articles/s41586-020-2975-4
Anyway, I'll believe he can reverse aging when he shows me a 5 year old mouse.
Why did you use 40 and 70 in "If a 70 year old man marries a 40 year old woman.."? I think I'm missing the point and would like to understand.
I believe in the book when Sinclair was talking about the Yamanaka factors, he asked the reader to imagine that you start getting into your 40s or 50s and are diagnosed with age. You go in to a clinic for treatment and they use the Yamanaka factors until you become 20 again and you do this over and over. I'm not sure that is possible but that idea got me really excited when reading this book.
I'm interested in taking resveratrol and NMN but I don't really know about this stuff and it seems so speculative. How badly can you hurt yourself with these?
> And finally, what’s the worst that could happen? An overly literal friend has a habit of always answering that question with “everyone in the world dies horribly”. But in this case, that’s what happens if we don’t do it. Seems like we have nowhere to go but up!
I am always surprised that there isn't much, much more support for anti-aging research. I'd figure that everyone expects to age and no one wants to. So the government/billionaires/whatever should be showering the research with money. Yet that doesn't seem to be the case.
The simplest answer to "Why doesn't the body already do this?" is anti-aging isn't free: it costs resources the body can use on other things, like manufacturing sperm or cogitation or even burning for warmth. Animal lifespan varies based on a lot of things but it tends to be shorter in animals that can expect to die by accident or predators because in those animals there is no evolutionary benefit to adaptations for increased lifespan beyond a certain point. Meanwhile, birds that are the same size as mammals that can be expected to live 3-5 years will live 80 years, because flight and their relative intelligence means birds are much less vulnerable to predators and accidents and local food shortages.
Personally I think Algernon's law is absurd and betrays a lack of attention to the natural world and the constraints of evolution.
Only ~1/2 way through. But you haven't mentioned my fav. aging idea. Aging is the response of a multi-cellular organism to cancer. (One cell going crazy and dividing forever.) There is a limit on the number of cell divisions for non-reproductive cells. (most of your body.) When you reach the limit, cells stop dividing and repairing and you get older. The limit stops cancer at least to first order...
I'm going to be so, so, so upset if aging is conquered a few years after I die, or when I'm in my 80s and it's too late for me, or some such thing.
The cosmic unfairness of it! — I want to live forever (or at least "way longer than current human lifespans", and the same for those I love) more than *anyone else I've ever met*; and I live in a time when the spiritual sort of immortality looks more unlikely than it did when "I dunno; magic?" was the best answer available for "how does any of this work?", but the physical sort looks absolutely possible and likely to happen *someday*...
... and I end up one of the poor bastards trapped without the comfort of an eternal heaven waiting after death, *or* the exhilarating freedom of endless experience stretching out to the cosmic horizon? And the latter could possibly be mine, except we spend our time and resources on frivolities that don't matter at all if you don't have *time*? (— whereas solve aging, and you can have all the frivolity you want... literally! you *can't* have all of anything you want, now, because you're going to become decrepit and die!)
I forgot if I had a point. I think it's just that I'm upset. Interesting book review and I want more like it, though.
My favourite human biology fact, the most mind blowing to me, is the fact that if you live to be 100, your odds of surviving to 110 are 0.1% (source https://en.wikipedia.org/wiki/Supercentenarian) . Human bodies just disintegrate at that point. It's also amazing, when you think about, that the world's oldest woman only lived 1.5x as a long as the average woman in a developed country. Whatever one thinks about Sinclair, it's amazing how strong the barrier is to exceptionally long life and more people need to be studying this.
The basic concept of Algernon's law has always bothered me. I don't think it actually holds much water, at least, not in the way that it's commonly used. The human body may well be perfectly optimized for our hunter gatherer lifestyles of the past, but that has very little bearing on how well optimized it is for today. We used to have very real energy input constraints, and that meant the availability of food was a major factor in the objective function our bodies were optimizing for. That constraint is effectively gone today. There may be quite a few biochemical switches that are tuned for energy scarcity that we could easily dial way up/down without harm, and without any real contradiction to Algernon's law.
Similarly, aging and decay are potentially epiphenomena of gene progression. Nature isn't optimizing for immortality of individuals, its optimizing for immortality *of genes*, which it achieves just fine by killing you after you've had your kids. There is no reason to think evolution tried and failed to make us immortal, and therefore no strong a priori reason to think that there shouldn't be low hanging fruit in that domain.
This was entertaining. But can we please get Mantic Mondays back?
"Can you take rapamycin? Probably a bad idea, it’s a potent immunosuppressant."
This seem incorrect, due to dosage effects. The doses that organ-transplant recipients use are much higher than those used for longevity purpose. There is even some evidence that rapamycin enhances immunity at lower doses. Here's some further discussion with references: https://peterattiamd.com/rapamycin-risks/
The other thing going on which kicks in after the 30-40% improvement is telomere shortening, making more and more cells senescent. This is also something which might have an easy fix once you solve the “all kinds of cancers” problem.
I want nanobots that go around removing senescent cells, cancer cells, arterial plaques, aggregates, unfriendly bacteria, etc. Like an artificial immune system that is way better than the natural one. That could extend lifespan by a lot, even before you program it to mess with Yamanaka factors.
"Cure aging, and the whole concept of life expectancy goes out the window" I am surprised at this comment - I would've thought it's obvious it doesn't. At 70, the probability of dying in the next year is slightly under 2% (albeit substantially higher for men than women). If you could stop aging at 70, then you'd have a 50-50 chance of living until 104. (0.98^34 is about 0.5) What if we could roll back aging to 21? 21 year olds have around a 0.08% chance of dying in a given year. That means you'd have a 50-50 chance of living to about 850 years old. (0.999167^950 is about 0.5) That's barely into the biblical lifespan territory. (Source of actuarial info: https://www.ssa.gov/oact/STATS/table4c6.html)
> babies are very young [citation needed]
You are hella funny guy at times.
To clarify, senescent cells are not exactly an unwelcome process in our body. Cells can become senescent to avoid malignant transformation into cancer cells - one of the characteristics of senescent cells is their lack of proliferation. It fits into a broader theme where aging and cancer are two sides of the same tradeoff, biologically speaking. Keep the cancer at bay, and you age faster. Suppress aging and you suffer from cancer. So in this paradigm aging is an in-built protection from cancer, and messing with it (injecting Yamanaka factors, extending telomeres) has a price.
From the publicity standpoint I think the easiest application of anti-aging research is improving the lifespan of our pets, turning cats and dogs into life-long companions. I can think of very few people who would object to that. The regulation in this area is probably much more lax, allowing biohackers to experiment with next-generation treatments and report the results.
However, I'm skeptical that the same anti-aging treatments that work on mice, cats and dogs would make a strong impact on humans. We still don't know why, mechanistically speaking, mouse tissues have a shorter "expiry date" than human tissues. Extending lifespan in animals could be as easy as identifying the mechanisms that keep humans from dying in their 20s and transferring these mechanisms to animals. To extend lifespan in humans we would need to either identify biological mechanisms that keep whales alive for 200+ years and steal those, or come up with the novel ideas ourselves.
Re: stem cells: Do stem cells always know what sort of cell to differentiate into? Would stem cells in the kidney always turn into kidney cells and not lung cells?
I would be very interested in seeing a post on the relationship between cancer and ageing at a cellular mechanism level.
Cancer is a return to the unicellular world. Differentiated cells of multi-cellular organisms such as lung, liver, brain etc becomes dedifferentiated as cancer progresses. Cancer cells also use the significantly more inefficient pathway of anaerobic respiration, as opposed to aerobic or mitochondrial respiration, because the latter pathway was developed for an environment where efficient production of energy was desirable. Who else uses anaerobic respiration? Prokaryotes.
This has implications for us because when glucose is abundant, why care that aerobic respiration is 18x more efficient? Simply use anaerobic respiration, which is much faster and has the byproduct of generating lactic acid which can be used to kill neighboring cells for resources, just like bacteria and other unicellular organisms do. Rapamycin that Scott mentions, is a toxin secreted by a bacteria for this purpose. This is why obese people are significantly more likely to die of cancer. This is also where mTOR comes into the picture.
The other common way to get cancer is for cells to be exposed to chronic stress. If all your lung cells are abused by toxins in cigarettes, eventually they stop hoping that order will be restored, forget about the fact that they're supposed to be lung cells since it's getting impossible to function as one anyway, and revert back to their underlying programming of being a unicellular cell alone in this world, where cooperation no longer matters and survival must come at whatever cost.
At first glance, ageing and cancer seem to be two sides of the same coin. Cancers keep multiplying, just like bacteria, and are remarkable at survival because they are simply unicellular organisms that care only about their survival, to hell with everyone else. Most stay contained because our immune system is incredibly well suited to kill cells it doesn't recognize. But the war on cancer shows slow progress because we keep trying to find targeted ways to kill an organism that has undergone billions of years of evolution to survive. The organism simply evolves another way. Survival of the fittest.
Senescent cells help prevent cancer in a way, by dying off after their telomere cap is hit. Cancer cells aren't constrained by the telomere cap and can keep dividing. Increasing telomere length would reduce senescent cells, but that would increase the likelihood of cancer via cells gone rogue. But perhaps not, if the immune system could be kept healthy.
Jason Fung's The Cancer Code is a great intro to this paradigm.
Thank you, this is a great review and I'm glad you touch upon what "people who are not sinclair" think because some of the stuff in the book is hyped.
"Can you take rapamycin? Probably a bad idea, it’s a potent immunosuppressant. Organ recipients take it sometime to quiet their immune system down to the point where it stops rejecting the transplant, but it’s not a lot of fun."
^That point is not entirely correct. Rapamcycin gets a bad rep due to its history of being used as an organ transplant drug. But low dosage and once a week rapamycin may not be dangerous! In fact, it is one of the drugs that has consistently shown lifespan & healthspan benefits in mice. People in the industry like Matt Kaeberlein and Peter Attia take Rapamycin. I asked Matt about it in my podcast with him if people want to learn more on Rapamycin: https://youtu.be/BL67DhNepfg
Thread on the history & benefits of Rapamycin here: https://twitter.com/livelongerworld/status/1462538431091953668
"But when David Sinclair says that reservatrol or exercise or intermittent fasting or saunas act by “mimicking calorie restriction”, is he suggesting that they will make you weak and constantly tired? If not, why not? This sounds a denial of the fundamental mTOR tradeoff: less energy expenditure in exchange for worse performance. The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me."
^Yes there is a tradeoff because these activities like exercise & sauna are hormetic stressors. That means that a little bit of stress causes your cells to hunker down and extend lifespan. However, there is a limit where overdoing these hormetic stressors can lead to chronic stress. For example, if you are perpetually fasting, you will obviously die!
Similarly, exercise is in fact a stress to the body and causes low-level inflammation. But that's "good type of stress" where your cells learn to become resistant. Overdo exercise and you might be stressing your body more than what's good life lifespan and healthspan.
In other words, there is a sweet spot for these stressors!
Maybe I just see the most dystopian perspective on everything, but I have a bad feeling about the societal effects we would see from the development of immortality serum.
I don't imagine anyone being forced into immortality, but I can absolutely imagine life becoming impractical otherwise.
For example, increased lifespan means increased potential for labor extraction. More possible working years means greater debts could be repaid. Maybe the 100-year home mortgage becomes a thing, contingent on your compliance with anti-aging treatments, of course. Maybe then the price of houses scales to match what people can finance, just like we see with student loan availability and tuition fees rising.
Or on the other hand, suppose that people who are getting this serum are primarily those who have retired on their investments. How large of an ownership class can society bear?
So does the insanity wolf perspective suggest I go buy 60 500mg pills of NMN for 27 bucks?
Im not going to address the entire review for the sake of brevity. But to the core of your question, I will try to argue for the anti-aging efforts and validity.
So, what could be an almost insurmountable problem for cells in a mature animal, but trivially vanishes when you clone a cell into an embryo?
In a few words; the consistency of unmethylated/methylated DNA. Meaning, the cells that grow from the clone are free of DNA methylation, because they have been pre-selected for healthy nucleuses, and therefore the complimentary DNA (cDNA) will be true to original form. The cDNA then goes through its regular processes in transcription then the many forms of RNA and respective processes of translation follow resulting in properly expressed proteins. So, not all cells or cell types are prone to DNA methylation at the same rate or even the same rates from the same hazards and it is because of this that cells progressively fail to transcribe and translate original DNA into proper proteins at high fidelity. As the cell health of the organism dwindles during senescence, proteins and growth factors alike are not being coded for at the rate needed and we see organ failure, cancer, etc. It only takes one serious break in the chain and we have big problems. That's what makes the biology so astonishingly robust and delicate at the same time.
Furthermore, as DNA is progressively compromised, cell division ceases to produce intact differentiated cells and those unsuccessful cells are destroyed by immune functions like those of macrophages. This is very similar to the destruction of an unviable fertilized egg in the blastocyst stage. Still there is no ultimate atavististic feature built into genetics... so once stem cell types have differentiated, that's the end form for potentiality. Although potentiality is limited by the number of viable daughter cells it is also governed by the expression of those cells.
Enter epigenetics. In epigenetics, this revision to a previous state is the goal of upregulating the sirtuins to a degree that all of the methylated DNA will be successfully cleaved back to its original unmethylated code. Not to be confused with changing or reversing cell type (genetics), but to keep the multipotent cells functioning efficiently. Granted I, too, have my doubts about the limit of sirtuin capabilities but remain optimistic about stem cell therapies and gene therapies.
Sirtuins are not the only way to regain optimal cell health from the DNA up. There are ways to shuttle in specific growth factors (to address your point about kidney cells or differentiated cell types more broadly) like engineered stem cells transfected with lentiviral vectors programmed to overexpress carefully selected growth factors that are specific to the target area. This is the area that I am focused on now, but the more communal-power focus on anti-aging the longer we may live to see our loved ones grow and the longer we may not weigh on them like a shadow of ourselves. Or better yet, the longer we will have to think of good solutions to difficult problems. Maybe we'll even get to relax after everything is patched up.
Anyway, I have applied for the ACX grant because a friend pointed me here. This is my first time on the board. I am currently a grad student in a related field but I need funding to complete my next course and hopefully do a PhD in neuroscience... support is warmly welcomed. So, too, would be an understanding PhD mentor, but alas.
If we eliminate disease and aging, the only remaining causes of death are accidents, suicide, and murder. The chances of meeting a violent end become higher as those who favor suicide gradually eliminate themselves.
https://en.wikipedia.org/wiki/Struldbrugg
"In Jonathan Swift's 1726 satirical novel Gulliver's Travels, the name struldbrugg (sometimes spelled struldbrug)is given to those humans in the nation of Luggnagg who are born seemingly normal, but are in fact immortal. Although struldbruggs do not die, they do continue aging. Swift's work depicts the evil of immortality without eternal youth.
They are easily recognized by a red dot above their left eyebrow. They are normal human beings until they reach the age of eighty, at which time they become dejected. Upon reaching the age of eighty they become legally dead, and suffer from many ailments including the loss of eyesight and the loss of hair.
Struldbruggs were forbidden to own property:
"As soon as they have completed the term of eighty years, they are looked on as dead in law; their heirs immediately succeed to their estates; only a small pittance is reserved for their support; and the poor ones are maintained at the public charge. After that period, they are held incapable of any employment of trust or profit; they cannot purchase lands, or take leases; neither are they allowed to be witnesses in any cause, either civil or criminal or economic, not even for the decision of meers (metes) and bounds."
Because:
"Otherwise, as avarice is the necessary consequence of old age, those immortals would in time become proprietors of the whole nation, and engross the civil power, which, for want of abilities to manage, must end in the ruin of the public."
There is an origination called the Gerontology Research Group. one of their activities is tracking the oldest people in the world. Supercentenarians who are 110 years old and older. They take pains to validate their ages via government and private records. Here is a link to their table of living supercentenarians
https://grg.org/WSRL/TableE.aspx
There are 17 of them out of the ~7 billion living humans today. The oldest is will be 119 years on 2 Jan. 2022. She is older than any person they have tracked since Jean Calment of France who died 1997 at 122 years and 164 days. https://grg.org/SC/SCindex.html
I would posit that 125 years is a hard upper limit on human life spans. Some creatures, such a Galapagos tortoises and some whales live much longer than that. But, all living things grow old and die in their time.
Gen.47
[7] Then Joseph brought in Jacob his father, and set him before Pharaoh, and Jacob blessed Pharaoh.
[8] And Pharaoh said to Jacob, "How many are the days of the years of your life?"
[9] And Jacob said to Pharaoh, "The days of the years of my sojourning are a hundred and thirty years; few and evil have been the days of the years of my life, and they have not attained to the days of the years of the life of my fathers in the days of their sojourning."
"pterostilbene, a more bioavailable resveratrol relative. The other pill is nicotinamide riboside.
Those are the two ingredients in a product called "Basis" that I have been taking for many years. It's only a sample size of one but my biological age, as defined by whatever genetic markers Elysium, the company that makes Basis, uses, was measured a year or two back as about a decade lower than my chronological age.
But then my mother, who didn't take Basis, died at about a hundred and her brother at older than that, so I may just be lucky in my genes.
"you’d have to correct the DNA in every cell in the body (using what template? even if you’d saved a copy of your DNA from childhood, how do you get it into all 30 trillion cells?)"
The template problem is easy; you just take a majority vote of fifty cells. Unless they tend to all have the same mutations, that should get you back to the original.
The distribution problem is harder. In principle you do it with nanotech cell repair machines, but that is going to be quite a while. Possibly a tailored virus?
“Algernon’s Law says there shouldn’t be easy gains in biology. Your body is the product of millions of years of evolution - it would be weird if some drug could make you stronger, faster, and smarter. Why didn’t the body just evolve to secrete that drug itself?”
The reason this argument fails is that immortality isn’t actually evolutionary beneficial. Take two people, one of whom is immortal for biochemical reasons, and a regular human. The human, knowing their clock is ticking, is likely to have children quickly, stick around to help with the grandchildren, and then die. Whereas the immortal person seems like they wouldn’t in such a hurry to have kids, meaning they would be unlikely to pass on their genes as quickly. Consider how birth rates fall as life expectancy goes up, and you can understand why evolution would want to sabotage the body in some way, so that it doesn’t outlive its usefulness or waste time doing things besides copying its genes.
Brett Weinstein's argument seems to be that senescence isn't a bad outcome but a trade off. Immortality always converges on cancer (or IS cancer), so a universal max replication count (however fuzzy) avoids cancer (for the cancers that don't escape the mechanism), but guarantees aging and death. Aging is the body's answer to cancer.
Lab mice accidentally and systemically have been selected for long telomeres and are good at healing and live a long time, but tend to die a lot from cancer (even when we're not guaranteeing it).
I think the best argument against making most of the population immortal today is that in a couple centuries, we will have engineered the entire population to be vastly more intelligent and fitter than they are today.
That said, even if we did achieve biological immortality, at present rates of accidental death, you'd probably make it to roughly 600 or so on average.
"Infinitely" seems obviously wrong. Not all the ills of the world consist of the aging process up to exactly the age of 80.
Has anyone ever looked at aging through the lens of a human/chimp comparison? We live decades longer than our closest relatives, which are themselves a long-lived mammal. What are the biological differences that makes that difference? If you figured that out, maybe you could crank up those differences.
Going to mention Kim Stanley Robinson's Mars trilogy (and his earlier novel Icehenge) here in case people are inclined to ctrl-F for his name like I was. As an exploration of the consequences of 500-plus-year lifespans I actually don't find the Mars books that interesting. That part of the science fiction is mostly a way to keep the same characters around through a several-hundred-year terraforming project. Robinson also exaggerates the Malthusian / environmental-risk / social-upheaval aspects of longevity, which is typical for him.
Icehenge mentions an interesting idea, though, which is that people seem to "peak" pretty young (physically in particular, but mentally too-- the example Robinson uses is chess champions), as in: soon after they mature. So even with strong anti-aging tech it seems likely that experience of the added years of life would be more like being 50 or 60 or 70 than, say, 30. There might be a feeling of decline and/or stagnation the whole time.
We're never, ever going to colonize space.
There was a post eight months ago on LessWrong where John S. Wentsworth, an "independent AI researcher" according to LinkedIn, gave a summary of his understanding of how aging worked:
https://www.lesswrong.com/posts/ui6mDLdqXkaXiDMJ5/core-pathways-of-aging
A summary (by me, a complete non-expert) would be:
The symptoms of aging (atherosclerosis, sarcopenia, etc.) are basically caused by too much inflammatory factors (SASP) and reactive oxygen species (ROS). Senescent cells release both.
SASP is released normally by senescent cells in order to tell the immune system to kill them.
ROS is generated by the normal action of mitochondria, and causes DNA damage. ROS goes up when the cell is in a DNA-repairing state - mitochondria become less efficient, producing less energy as part of the repair process, and therefore more ROS, which can in turn cause more damage.
Normally, cells have low levels of DNA damage and low levels of ROS. But after passing some threshold after enough stress has happened to the cell, the ROS damages the DNA faster than it can be repaired, and the cell becomes senescent.
The core cause of aging is suggested by the author to primarily be because of transposon proliferation. Transposons are genes that copy themselves; when they do this, they cause DNA damage. Most transposons in the genome are dead - no longer able to proliferate due to evolutionary accident; they make up about 50% of the genome.
Maybe 100 or so active transposons remain, and these are tightly controlled by epigenetics to prevent them from being expressed. However, as part of the DNA repair process, the epigenetic mechanisms (e.g. sirtuins) are drawn away from repressing them to go help fix the DNA. When that happens, they'll manage to copy themselves. These make future DNA repair attempts more inefficient, and a certain level of transposon proliferation represents the threshold beyond which DNA repair fails and the cell becomes overwhelmed by ROS damage. Transposons also make senescence permanent; once they've been given free reign to copy themselves due to the failure of the DNA repair system, they will proliferate and damage DNA until the genome is beyond recovery, even if the excess ROS were to be cleared away.
One particular thing about transposon proliferation is that it occurs in stem cells too; a stem cell that has a high level of transposon proliferation, but not enough to render it senescent, will cause the cells it forms to quickly become senescent themselves. So the ultimate cause might be said to be an overall increase in the rate of cells senescing, causing body-wide overexpression of SASP and ROS, due to more and more stem cells getting overloaded with transposons at sub-senescent levels.
As to why organisms don't get overloaded with transposons with each successive generation - someone in the comments mentioned that the gonads have very high levels of epigenetic control against the areas with active transposons; this has the side effect of hindering DNA expression overall (which maybe explains why fertility is so hard, and requires so many attempts to succeed).
I think it foolish for us to think we will live on past our time. We are not made out of incorruptible gold and adamant. We are dynamic balances between energy and entropy made out of water, sugar, oil, and protein, in an intricate pattern. We should appreciate the miracle of life and know that it is brief.
Thornton Wilder's novel The Bridge of San Luis Rey is a meditation on the meaning of life and random death. In it the Friar Brother Juniper witnesses the collapse of a bridge and the death of five travelers who were on it. He minutely investigates their lives and searches for the reason, if any, behind their deaths. The novel ends with the Abbess' observation: "There is a land of the living and a land of the dead and the bridge is love, the only survival, the only meaning."
Shakespeare The Tempest Act IV Prospero
Our revels now are ended. These our actors,
As I foretold you, were all spirits and
Are melted into air, into thin air:
And, like the baseless fabric of this vision,
The cloud-capp'd towers, the gorgeous palaces,
The solemn temples, the great globe itself,
Ye all which it inherit, shall dissolve
And, like this insubstantial pageant faded,
Leave not a rack behind. We are such stuff
As dreams are made on, and our little life
Is rounded with a sleep.
Gen. 3:
[17] And to Adam he said, ...
[19] In the sweat of your face you shall eat bread till you return to the ground, for out of it you were taken;
you are dust, and to dust you shall return."...
[22] Then the LORD God said, "Behold, the man has become like one of us, knowing good and evil; and now, lest he put forth his hand and take also of the tree of life, and eat, and live for ever"
[23] therefore the LORD God sent him forth from the garden of Eden, to till the ground from which he was taken.
[24] He drove out the man; and at the east of the garden of Eden he placed the cherubim, and a flaming sword which turned every way, to guard the way to the tree of life.
The more I read about humans wanting to live longer the less I like humans. The sooner the humans die off the better. I want bees or ants to be the future of this planet not ugly primates.
Disclaimer that I haven't read the book even if I read some of Sinclair's scientific output earlier, but to be absolutely clear resveratrol is absolutely not even close to bioavaliable enough in humans. We're talking about taking literal tons of tomatoes or wine or whatever for a biologically significant effect, whatever it is.
This paper https://pubmed.ncbi.nlm.nih.gov/27552971/ by Sinclair did a good work explaining how the mechanism for Sirtuin activating was elucidated and entablished to be related to a resveratrol-in vitro like mechanism against the skepticism of losers and haters (this is a narrow claim, I'm not saying his wider output always replicates). And it takes for granted we need synthetic sirtuin activating compounds for any significant effect. Does Sinclair mention this sort of stuff on the book? This is from 2016 and my quick check is that a lot of the late phase clinical trials in humans with these compounds are not done yet.
>It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
If I may add one anecdata point, in italy most resources are gobbled up by the state pension fund and we are suffering from quite bad youth unemployment rate so I would claim that this scenario is in fact happening nowadays - albeit without the dictatorship part.
Probably a good time to remember the Adversarial Collaboration Contest entry from 2 years ago that looked at aging and concluded the evidence for calorie restriction in humans results in longer lifespan was less strong than e.g. animal studies would suggest: https://slatestarcodex.com/2019/12/12/acc-does-calorie-restriction-slow-aging/
Hi Scott! Great review! And, as the author of another book on aging biology (Ageless: The new science of getting older without getting old), I agree with both you and David on different things. In agreement with you, I think that solving aging is going to take more than just reversing epigenetic changes. In Ageless, I break things down into ten ‘hallmarks’ of the aging process of which I think we’ll need to solve a decent subset in order to make *really* significant progress against aging (though results from tackling individual hallmarks like cellular senescence and epigenetic reprogramming make it seem encouragingly as though we could get some decent gains without solving everything). Where I agree with David is that I’m nonetheless optimistic that if we did plow a decent amount of money into aging biology, we could make huge advances, and it might well be easier than curing cancer (cancer cells are constantly evolving to maximize replication; the changes that cause aging are largely accidental side-effects of evolution and aren’t actively trying to outwit your treatments).
If you’d like to find out more, check out https://ageless.link/
And I’m going to be releasing a free, bonus chapter on the ethics of treating aging next month, so sign up here to be the first to hear about it! https://andrewsteele.substack.com/
> It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
You might want to look around.
But bitter jokes aside, I'm 100% on board with your train of thought. Unfortunately I lean towards the SENS model more than the Sinclair model, but if Sinclair is right, that's _such_ a low hanging fruit we need to exhaust that research direction anyway.
Anectodally, intermittent fasting makes you feel fantastic, actually heals muscle injuries (by downregulating inflammation, I guess?), keeps the weight off. Highly recommended even if it does not, in fact, make you an immortal space murine.
« Algernon’s Law says there shouldn’t be easy gains in biology. Your body is the product of millions of years of evolution - it would be weird if some drug could make you stronger, faster, and smarter. Why didn’t the body just evolve to secrete that drug itself? Or more to the point, since most drugs act by flipping biological “switches”, why does your body have a switch set to the “be weak, slow, and dumb” position? »
Algernon's Law seems very real to me, but for aging, there is something that works strongly in our favor: natural selection heavily discount what happens at older ages, because in our evolutionary past, we were statistically dead after, say, 40 years. This means that a genetic variant producing a very small advantage in youth at a huge cost in later life was usually very advantageous and retained by natural selection. So it seems possible that, conversely, the cost of not aging could actually be very small. And besides, a relatively small number of organisms, some trees and turtles for example, do not seem to age, or at least we are not able to detect a decrease in capacity over time. So it seems possible for biology to make organisms that do not age, or at least age very very slowly.
I find the issue with many of these longevity arguments is in conflating lifespan vs healthspan (the duration of one's life in which you are healthy and disease-free). You could argue that many efforts of medical science over the past 100 years have focussed exclusively on lifespan, and this has caused a number of societal challenges with people who live longer, but are highly dependent upon support to carry out their activities of daily living.
So too with the summary of this book; if these theories bear out, then sure we can prevent cancer, or dementia, or any number of the other "Geriatric Giants", but this isn't (to my mind) going to prevent us losing muscle strength (which happens after age 50 despite exercise, even in retired olympic athletes), or to repair our knee cartilage, worn out from too much running. Without fixing these millions of tiny insults (as Scott says), we might be left with a retired generation who are biochemically healthy, and yet utterly unable to live independently.
Is it just me or is 'expand full comment' broken for others too (fails both in mobile Firefox and mobile Edge for me)?
> But when David Sinclair says that reservatrol or exercise or intermittent fasting or saunas act by “mimicking calorie restriction”, is he suggesting that they will make you weak and constantly tired? If not, why not? This sounds a denial of the fundamental mTOR tradeoff: less energy expenditure in exchange for worse performance. The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me.
We evolved and are tuned to lifestyle involving massive amount of exercise and much wilder swings of temperature and far less plentiful food.
It seems plausible to me that modern lifestyle is a massive health problem. We life longer because it was outweighed by reduction of diseases and starvation, but still sitting still in front of screen is extremely unhealthy.
It is not surprising that our body gets out of whack if we sit still, look at colored plate 50cm away and eat piles of food.
> But if you transfer the skin cell DNA to an egg, inseminate the egg, and turn it into a baby, that baby is just as young as all the other babies. So DNA damage can’t be the whole story.
Is it possible that this process filters out any damaged cells? As in, more damaged cells will not succeed and we just look at successful ones?
So one mostly end with failed growth or (usually) healthy new organism?
Lets say that growing baby is a tricky process where any unhealthy/damaged cells will die. Would it be consistent with success rate of cloning?
Still, reproduction requires producing less burdened cells so likely there is some repair - but maybe it is for some reason of another very costly to do or rarely successful?
"Second, life expectancy at age 10 (ie excluding infant mortality) went up from about 45 in medieval Europe to about 85 in modern Europe. What bad things happened because of this?"
I am surprised anyone would make this kind of argument. There were quite a lot of other changes in health and nutrition and everything confounding the life expectancy changes. For example, industrial revolution kicked off an extreme population growth event, and until recently there (in general) was more kids and young people than old people (discounting mortality effects from world wars).
Immortality is also different than extended lifespan. Extended lifespan for one individual still ends, which obviously results in kids and grandkids of the said individual getting the inheritance. (Maybe it could be good for economy that people have time to collect more net worth and then pass it around.) It is quite different from true immortality (it is no longer making sense to save money for retirement, instead it makes sense to build continuous equally immortal income streams to fund on-going immortality treatments and all the fun stuff you want to do).
Also greatly expanded lifespan is different than slightly expanded lifespan. The first change was that lifespans were more equal: more people had a chance of live into so old age where they could be grandparents and maybe great-grandparent, but there were such people even before. The future where the super rich / all 1st world people / everyone gets to live until they are 120 or 200 with young person's body (if not immortal) would be more drastic change.
"One unambitious - but still potentially true - counterargument to this is that a world where we conquered aging, then euthanized everyone when they hit 80, would still be infinitely better than the current world where we age to 80 the normal way"
Is it really? I think it is quite ambitious argument to make that it doesn't matter that in the universe A (current) we don't do anything we are not currently doing and in universe B (aging stops and people are euthanized) lots of people are killed. Sounds like an argument against universe B, because in universe B we are euthanizing a lot of healthy people.
"Second, life expectancy at age 10 (ie excluding infant mortality) went up from about 45 in medieval Europe to about 85 in modern Europe. What bad things happened because of this?"
Thomas Malthus would like to have a word here.
One of the arguments from the school of economics at the time of the Great Famine was precisely this - there were just Too Damn Many Irish, so the famine was in fact a great opportunity in disguise to clear out the surplus excess population (by emigration to Canada and the USA) and put agricultural practices on a profitable basis.
https://www.jstor.org/stable/2120439
https://www.jstor.org/stable/23040822
https://www.youtube.com/watch?v=7ai5sPkSDI8
The previous explanation I've encountered for aging clashes with this. The way I've heard aging explained before is that genes do a bunch of different stuff (assumedly due to compression) and some of those things will be good/bad early/later in life (where early is before passing on genes via having children).
So a gene that's bad early gets evolution'd out of existence; leaving genes that are good early and good/bad later. The probability space of negative mutations is larger than positive mutations so most genes end up being beneficial early in life and bad later in life.
This logic feels compelling to me and precludes the idea that aging is simple enough to be easily cured. I admit to not really knowing much about the topic though.
I read about this in this book. https://en.wikipedia.org/wiki/Other_Minds:_The_Octopus,_the_Sea,_and_the_Deep_Origins_of_Consciousness
I'm amazed by people who long for eternity, when they don't know what to do on a rainy Sunday afternoon
"David Sinclair - ... celebrity biologist" Harsh!
"David Sinclair - Harvard professor" Harsher!
Reading this, and I cannot not make a connection to Robert Heinlein's Time Enough for Love. Read it in my 20s, a few decades back . . .
Is part of the answer to the “algernon’s law” objection “because we aren’t evolved to be in this environment of plenty all the time?”
The people who are big on fasting argue you’ll feel more mentally alert and sharper when you’re hungry. This matches my experience as well: I have less energy after I’ve eaten a meal. My guess would be that we may be evolved for a specific long term average rate of mTOR activity, and most of us have it on too often, just like most of us are overweight.
He also argues in the book that there wouldn’t have been some evolutionary benefit for living for arbitrary periods of time in an environment that was chaotic and dangerous. So maybe there’s the answer: yes, you might take longer to heal from physical injuries with lower mTOR activation but this cost is outweight by having fewer senescent cells.
Also, maybe he looks super young in part because he’s so optimistic? Maybe it’s a mix of drugs and positive attitude.
Against Algernon's Law: Evolution shaped us in a certain way under severe energy constraints.
Meaning, the most likely consequence of any improvement to intelligence or any other desirable trait is that you'd have to eat more to stay alive.
Which was catastrophic a couple hundred years ago, and a boon today.
Is that taken into account?
Isn't Algernon's law reconciliation well established for aging? Aging and dieing are good for evolution. We mature we reproduce we care for our offspring and when they are mature we age and die. In the malthusian environment all species evolved in, not competing with our young for resources makes the species more fit. So the trade off to solving aging is that our species is less fit 100000 years out. This could make the toggle easy, but it could also be hard, not because evolution couldn't figure out how not to age but it explicitly made it hard to avoid.
> (using what template? even if you’d saved a copy of your DNA from childhood, how do you get it into all 30 trillion cells?)
One could just take the DNA from 100 or 1000 random cells and average it out. It'd be probably free of mutations... I think.
As for getting it into 30 trillion cells... yeah, that's an issue.
I gave up on true anti-aging when I read an ophthalmology textbook. It was *filled* with explanations of the changes to the eye that take place as you get older, and reversing/stopping those changes would require technology unrecognizable to us. Even if you found some way to get the rest of your body to live forever, you will eventually go blind.
It's straightforward to do epigenetic mapping of cells, even down to the single-cell level. So: take an elderly mouse and a baby mouse, do the epigenetic mapping, see if there are systematic differences. Has he done this?
Sort of but not really, in a still un-peer-reviewed 2019 paper on biorxiv: https://www.biorxiv.org/content/biorxiv/early/2019/10/19/808642.full.pdf
Agree with the distinction between lifespan and healthspan. Also skeptical that extending lifespan will be as simple as taking a pill and/or intermittent fasting. I think it's likely that average lifespan will continue to increase. But there is likely a natural limit (I've seen ~150 yrs mentioned before, but don't recall exactly what that's based on). Haven't read Sinclair's book yet. So not sure if he addresses it, but mitochondrial dysfunction plays a key role in aging. Mitochondria acquire mutations as we age due to ROS, etc. which leads to cellular malfunction. One potential therapy I haven't seen mentioned in this thread yet is mitochondrial transfer from healthy (young) cells to damaged cells. This has been shown to occur in vitro and in vivo. Nobody has quite figured out a way to harness this phenomenon for therapeutic use yet (lots of people claim they have, but evidence is lacking). The appeal of somatic cell nuclear transfer (SCNT) is that you can create genetically-matched cells for cell-based therapy that have young, healthy mitochondria from a donor oocyte/egg. This is also an advantage of embryonic stem cells over iPS-based cell therapies because those cells originate from an adult with already acquired mtDNA mutations (we've published on this). The challenges with therapeutic cloning of course is that donor oocytes are scarce (although maybe not for long if we can mass produce them in vitro) and delivery is an issue as with any form somatic gene therapy. Anyway, if you're a VC or philanthropist reading this post and want to support our research in this area (as the NIH currently does not fund human embryo research), hit me up. Paula Amato, MD at amatop@ohsu.edu.
> it would be weird if some drug could make you stronger, faster, and smarter.
Isn't that methamphetamine? Perhaps it has some negative side effects.
Regarding embryo's resetting the clock to zero . . .. Years ago, I watched one of those science shows (could have been NOVA), and the topic was cancer. The showed some results with chimeric mice. Start with a blastocyst from a white mouse, then inject a few cells from a black mouse. When the mouse pup is born, and grows, you can see where the black cells ended up -- all the black patches on the mouse.
Now the interesting bit. Now inject black cancer cells into a white blastocyst. In the experiment presented, they injected particularly nasty cancer cells, known to create a tumor wherever they land. The mouse pup is born, grows . . . and is cancer free. You can see where the black cancer cells ended up -- the black patches on the mouse -- but they are not cancerous.
Aging seems like an area where we might not expect Algernon's Law to apply. In my opinion, the evolutionary biology of aging is pretty solid:
From an evolutionary standpoint, organisms (probably) face tradeoffs between survival and reproduction--any given resource can either be invested in maintaining your current condition, or producing offspring, but not both.
Having offspring now is better than having offspring later, even if you have the same total number of offspring, because that means that your lineage fits more generations into the same time period as your competitors, and is thus more fit. Depending on the numbers, it will often be better to have fewer offspring quickly than more offspring over an extended period of time.
Put this together, and it means that basically all organisms should want to shorten their lifespan in order to reproduce more and more quickly. Even going from "infinite lifespan" to "finite lifespan" is going to be worth it for surprisingly small gains in reproductive rate.
"Aging" is just the molecular consequences of making that tradeoff. Stopping aging isn't about breaking a tradeoff (in which case Algernon's Rule would kick in), but just moving the tradeoff to an evolutionarily disadvantageous solution. This seems easier.
Chiming in as well to add my take on rapamycin: out of all of the longevity agents I am interested in and/or take myself, it is likely to be the one that I have the highest hope for in humans. We have a decent understanding of the mechanism (compared to many other things, at least), it works very consistently and strongly in several other organisms, and the mechanism of action is strongly evolutionarily conserved. As for safety concerns, it seems like if taken in a low dosage and infrequently enough, the safety profile improves significantly and it may be a net-plus in many areas (this may be related to mtorc1 vs mtorc2 activation depending on the dosage and timing (it does have a pretty long half-life!), which also makes it seem like it can be taken without actually suppressing one's immune system or causing some other undesirable effect categories).
Although I do know of many others that take rapamycin, I still don't suggest it to anyone myself, firstly because I don't offer medical advice of that nature regardless of my cost/benefit analysis (are there risks of potentially bad unknown side-effects with long-term usage? sure, but the risk of *not* taking longevity agents is also pretty large, and results in a much earlier likely death), and secondly because it is still likely to be higher risk than a lot of other simple things that I do often suggest to others, like glycine supplementation, which I see as close to zero risk (a few others on https://nearcyan.com/supplements/ if interested). I'd hope that anyone that takes it themselves has blood panels done (if not much more) to ensure they're not doing easily-observable harm to themselves as well. It's definitely a very interesting area of research either way; I can't stop myself from paying attention to stuff like this due to how large the potential impact on humanity is.
A few rapamycin links for those interested (more if you just search on pubmed!):
Rapamycin and aging: When, for how long, and how much: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401992/
Longevity, aging and rapamycin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207939/
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786175/
Rapamycin slows aging in mice: https://www.ncbi.nlm.nih.gov/pubmed/22587563
Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032600/
I enjoyed David Sinclair's book and some videos, but he is too good at hyping whatever he wants to. I trust his results published in good magazines, but he hasn't so far done anything in humans. He is a mouse guy.
Meanwhile, Greg Fahy has succeeded in reducing epigenetic age in humans by rejuvenation of the thymus (by a combination of HGH which rejuvenates the thymus + metformin and DHEA that prevent some bad side effects of HGH on insulin regulation). The trial was called TRIIM. He is now running an extended trial in humans again, called TRIIM-X, to find out how many measurable qualities improve as well. (Because we do not know how tight or loose the connection between epigenetic age and real state of the organism is). There was a recent interview in which he claimed that intermediate results are fairly good so far - for example, kidney function has improved, inflammation markers and PSA went down.
But Fahy is an unassuming kind of guy, almost shy, so he gets almost zero attention.
>Modern Europe is currently in crisis because it has too *few* people and has to import immigrants from elsewhere in the world.
It's not hard to imagine that in a society where people live to be 200, the fertility rate would plummet, particularly if you measured fertility based on the number of children women have for each year of their life, which might be a sensibility way to measure it if that denominator changes dramatically. And if the problem is not too few people, but too few workers, you could end up with a lot of old rich people living off many decades of capital gains. A shortage of workers could really become a problem in such a society.
But that's just speculation, and I agree with the point you make in the next paragraph:
>Would Europe be better off if the government killed every European the day they turned 45? If not, it seems like the experiment with extending life expectancy from 45 to 85 went pretty well. Why not try the experiment of extending life expectancy from 85 to 125, and see if that goes well too?
My favorite aging theory is the gradual dysfunction of proteosomes. Cells make a crapton of proteins all the time, and they really need to get rid of all the broken and dysfunctional ones, so my theory is the increasingly failure to do so as cells age is what makes them senescent. It also fits nicely with the starvation effect: presumably when your cells aren't getting enough fuel and nutrients they have some ways of boosting the efficiency of recycling.
"Modern Europe is currently in crisis because it has too few people and has to import immigrants from elsewhere in the world."
Much of Modern Europe is currently desperately trying to prevent immigration.
> Kidney cells go from definitely-kidney-cells to mostly kidney cells but also a little lung cell and maybe some heart cell in there too.
I'm not a biologist... but isn't this a testable claim?
The "expand full comment" link isn't working for me. Anyone else have this problem?
> calorie restriction hasn’t been around the hundred years it would take to see results in humans. A few very committed biohackers having been trying it for a few decades now, so I guess we’ll know if it works by the mid-21st century.
We should see results in reduced mortality rate soon.
> Why didn’t the body just evolve to secrete that drug itself?
Since only traits that are beneficial or neutral would have persisted, presumably keeping old people around beyond a certain point is not particularly beneficial. Older proto-humans had incentives to crush younger and healthier challengers to their power, which would inevitably weaken a species. Older genetics may also be more poorly adapted to changed environments.
Humans are now pretty adaptable to a wide range of different environments, and we have some cultural adaptations that could possibly mitigate the "threat" of immortal old people.
> The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me.
It's common sense that you would want a strong immune system, unless you get lupus. So maybe mTOR gets *overactive* as we age, and these compounds suppress it only where it's not really needed.
People in this thread keep saying that NMN is "cheap", but I don't see it. Sinclair recommends 15mg/kg/day, so that's 1g/day for me. Most capsules I see on Amazon look to have 150mg and a bottle of 120 capsules is over $100 (CAD). That's $5.50 per dose, per day. That's not really that cheap given its speculative benefits.
Even the bulk supplier I'm aware of sell 500mg bags for over $1,600 (CAD), which is at least cheaper at $3.20 per dose, but still not cheap. If the benefits were more certain then maybe it'd be worth it.
I'd love if we could make some progress against aging, but I'm highly skeptical of nearly every claim made about its underlying causes and how to control it. Call me part of the camp that believes the problem is a death by a thousand cuts issue, where aging isn't just one or two problems that can be solved by 'fixing' DNA damage or epigenetic drift.
Speaking of DNA damage: it just doesn't fit. If accumulating mutations naturally caused aging, then why don't successive generations live shorter and shorter lives? We shouldn't have a situation where lifespan (controlled for infant/infectious disease mortality) is LONGER today than at any time in the past. Presumably the gametes are still dividing, just not as much as the kidney cells, so the same mechanism is at play there. So the same mechanism of DNA damage accumulation will happen, just more slowly over generations instead of over a single lifespan. In other words, this mechanism seems to suggest humans would have died of old age long before they ever evolved as a species.
Same argument for mtDNA damage accumulations.
Same argument for epigenetic drift. Why aren't we seeing epigenetic drift in the gametes? Are egg cells special in that they don't have epigenetic drift? Shouldn't we expect that there will be none left in a few generations - same as other cell types? Why not?
Meanwhile, there are all the normal mechanisms of aging that just don't feel like they're adequately explained by these ideas. They feel like a lot of hand-waving about how a general mechanism will lead to downstream effects, without ever having to connect the dots. For example, why does this accumulation of genetic/epigenetic changes lead specifically to memory B-cell depletion? And why is that mechanism both consistent, and gradual? If this were random drift, we'd expect to see more variation among individuals. A natural mechanistic explanation would better explain a phenomenon that is consistent and gradual.
For example, not everyone gets malignant cancers, and yet we all accumulate stochastic mutations over our lives. And even among those who get cancer, there's massive variation in which cell types are most affected, and how that manifests. Yet for aging, we always see arterial wall hardening, skin changes, etc. Why such consistency if we're working from a random mechanism? It doesn't fit our other experiences with stochastic biological mechanisms.
Here's an interview with Aubrey de Grey from 10 years ago about his own book on the same subject of human immortality, "Ending Aging":
https://hplusmagazine.com/2011/07/19/starting-to-make-sens/
I feel like a lot of the signaling pathways game misses the complexity of the system. We talk about "mTOR" as if it were a hormone like insulin that we can track, or that your body turns on and off. But mTOR is an intracellular signaling molecule. And intracellular signaling molecules don't work in PATHWAYS so much as they work as parts of NETWORKS. The complicated-looking diagram Scott showed is probably right for some cells, where other cells might have a different set of signaling molecules expressed. Thus activation (or suppression) of mTOR will have a different effect, depending on what else is being expressed in the cell at the time.
To say cell signaling is complex doesn't begin to describe the situation. I remember learning about promiscuous signaling molecules back in undergrad, and thinking, "Okay, now I know how NFkappaB works", or "so that's what ras is doing." Then I'd learn that NFkB wasn't just a single protein, it was made up of subunits, and each of those subunits had different splice variants which would do different things, and some scaffolding proteins changed which subunits came together in the protein complex, and post-translational modifications could also alter each protein subunit, and all the same were true of ras, and ... eventually I gave up.
I realized that the easiest thing in the world is to say that "signaling molecule X is the key to this whole operation". That's like telling a patient, "The reason you're having difficulty breathing is because of your lungs." Great. That's not really interesting or helpful.
It's the illusion of knowledge about the root cause of the situation without any actual understanding of time, place, and manner. Saying things like "we just need to turn off mTOR" is about as useful as saying, "you wouldn't have these breathing problems if we just shut off your lungs. No more breathing, no more problems." Or the seemingly more sophisticated, "we can solve your aging problems through better regulation of mTOR" which is functionally equivalent to, "we can solve your breathing problems through better regulation of your lungs."
What we should really be saying is, "It looks like mTOR is involved in this process, but we honestly don't know how or why. We're unclear how we might use the mTOR information to solve the problem. We're looking into it, but don't get too excited because until we understand the root cause of the issue we won't even begin to know how to solve it." Not as much hype that way, though.
> And the increase didn’t cause some kind of stagnation where older people prevented society from ever changing. It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
Didn't most of the life expectancy increase between medieval and modern occur in the 20th century? And aren't most developed nations right now trying to cope with an abnormally large wave of increasingly long-lived people (e.g. boomers). And isn't the current zeitgeist that millennials have nothing while their parents/grandparents have everything? Saturday Night Live did a music video sketch about boomers not that long ago that contains this sentiment (paraphrasing) "they took all the money and they took all the jobs and they won't ever die!".
It's not a good reason to ban immortality, of course. And perhaps in the long-run steady-state, this would just work out OK, but people don't live in the long-run steady state - the first "old" generation to get the immortality pill is going to receive some truly vicious hate from the younger generations of the time.
Here's a somewhat plausible modest goal. There are people who live into their 90s in good health and then die fairly quickly. It runs in families, so presumably hereditary. The best news I've heard is that these people don't lack deleterious genes, they have more (better?) protective genes, so there might be something which can be bottled.
The massive challenge for any sort of longevity is that we might not have the tools we need yet. More math! But which math? Better tools! But which tools?
"Finally, a friend wasn’t impressed with Sinclair’s clone argument. They point out: suppose aging is DNA damage, and it happens to every tenth cell. Having a tenth of your cells damaged is pretty bad, especially if they become senescent. “Senescent cells”, common in elderly people, have sustained so much damage that they can’t even die properly, and just sort of sit around being hopelessly confused and secreting random chemicals which freak out all the other cells around them. Everyone agrees these are an important part of aging, even if they’re not sure about the specifics. But if 1/10 of your cells are like this, then you have a 90% chance of grabbing a healthy cell for cloning. And even if you get a bad cell, no cloning process works every time, so you’ll just shrug and try again."
Couldn't you decipher an old person's original, undamaged genome by sequencing the genomes of ten of their cells, and the creating a composite genome that excluded any base pairs that were different in a minority of the ten?
For example, assume there's a gene made of six nucleotides. I extract ten cells from the same person, and the sequences for that particular gene are:
Cell A genome: AGGCTA
Cell B genome: AGGCTC
Cell C genome: AGGCTA
Cell D genome: AGGCTA
Cell E genome: AGGCTA
Cell F genome: AGGCTA
Cell G genome: AGGCTA
Cell H genome: AGGCTA
Cell I genome: AGGCTA
Cell J genome: AGGCTA
Cell B is the senescent cell, and so is the only one that is different. I throw out its results and conclude that the correct sequence for the gene is AGGCTA.
Correction for Scott: Rapamycin is made by a bacterium, not a fungus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561035/
One part of the definition of biological life, I think, is that it dies. Another implicit part of the definition, I think, is that it is unique, an individual entity. Are there cases where biological life as "an individual entity" are blurred?
Us fellow humans tend to view a bee hive as a composite entity, not life itself but composed of many individual biological entities. Part of the reason is the physical separation between one bee and another. Another part of the bigotry I mean bias I mean logical reasoning is that a particularly bee hive could last forever and not die like an individual primate is destined to in under 120 years.
Is it not a central reason that life can't become immortal because we define life as mortal?
Does anyone seriously think that any anti-aging intervention we are likely to make in the next 10 years will be remotely applicable to people who are 70+ right now? Seems to me like preservation is the only way to help these people.
I didn't know that cloning works well, I remember being said that clones have shorter lifespans. So cloning works ok? Why can't we have hundreds of clones of Neumann then?
Will we be able to grow human skin tissue in vitro indefinitely soon?
Sorry for stupid questions.
So... I guess in the end this supposed "cure for aging" would really only be a significant-but-not-orders-of-magnitude slowing of aging? If so, surely none of the usual arguments against preventing aging/death apply?
My first thought is that aging isn't just about DNA or generalized metabolism. There are all sorts of structural things going on. The body can repair itself, but the repairs rarely leave the body in the same shape as its original structure. There are all sorts of scarring, restructuring, and work arounds. You can reduce to damage by providing better medical care. You can induce repairs. You just can't eliminate the structural changes.
For example, there is work on inducing heart cells to reproduce to repair heart attack damage. It might even work, but how much growth can be induced and how much scarring endured without compromise.
Still, I'm optimistic. Every time scientists agree that we've reached some maximum age limit, new ideas and treatments come up and we move past it.
> The increase didn’t cause some kind of stagnation where older people prevented society from ever changing. It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps
Except it actually does -feel- that way. (Sorry I don't have any resources to back this up but my own experience). If you grow up in Italy you're definitely confronted with a political and economic system where older and powerful actors hoard resources and prevent younger dynamic forces to destabilise them. No wonder Italian researchers/workers/entrepreneurs do so well when they emigrate: the latent potential is there (they're educated in a modern, beautiful, powerful country) but they lack the opportunity to express their talents.
So yeah, maybe reversing again does have negative consequences to the economy.
I finished this book 1 or 2 days ago. The end has a lot of discussion of political issues and I felt like it was a lot less enjoyable to read his analysis of the political issues related to aging and his progressive viewpoint on certain things.
his name appears to me to correspond to malkuth...
On the off chance that anyone will ever read this, I want to comment on Scott’s skepticism that sirtuins (or some other protein) can figure out the “correct” epigenetic state of a gene, esp because it differs for the same gene in different cell types.
One epigenetic modification is cytosine methylation when it is followed by a guanine, called CpG, to distinguish it from the CG base pair. One might notice that if one strand has 5’CpG3’ then the complementary strand also has CpG at that point (read the opposite direction - the strands are antiparallel. When CpG cytosines are methylated, they are methylated on both strands.
So, if somehow the methylation is lost in one strand, a hemimethylase could check the other strand. If it’s methylated, then methylate the first strand. Incidentally, methylation tells the cell which strand is old when DNA is replicated. If there is a mismatch, the unmethylated strand is wrong. It’s imaginable that breaking methylation ups the mutation rate, though probably only slightly.
There is also a possibility that the transcription factor(s) for being one cell type can suppress transcription from other sorts of promoters. Maybe that’s how a muscle cell knows to be muscular? Maybe that process breaks down when an animal is well-fed?
That said, I think epigenetic dysregulation is an interesting theory of aging. Probably wrong, but very interesting.
Bats would be super-interesting to study for aging research. There are lots of species, so cross-species comparisons are more reasonable than mouse <--> man. If two bats species have similar size, diet, and metabolic rate, but much different lifespans in captivity, then physiological differences might be causing slower aging. Some bats are roughly mouse-sized but live a lot longer.
On cancer and telomerase, the protein p53 checks for DNA damage and arrests the cell cycle/leads to apoptosis (cell death). It’s mutated or missing in half of cancers. Elephants have many more copies of the gene and much lower cancer rates. Upping p53 in all a person’s cells through germline or currently magical somatic cell genetic engineering would give them a lot more headroom for other changes that would increase cellular regeneration but increase cancer risk,
This would be a good point if aging were some kind of a random process. But what if it's biologically programmed as Harold Katcher rather convincingly argues here? https://www.amazon.com/Illusion-Knowledge-paradigm-research-rejuvenation-ebook/dp/B09C7JNB64
Then, it could well be possible to reverse this process quite easily by giving cells the signal(s) opposite to the pro-aging one(s). Katcher has essentially done it even more impressively than Sinclair in rats.
Also, are you aware that Sinclair's lab managed to make old mice regrow their optic nerves using Yamanaka factors? That's just one tissue but it's an amazing boost. And the cancer problem was solved because they removed one of the five factors which turned out to be cancerogenic.
There have recently been controversies about Sinclair's work on resveratrol and sirtuins; video summary, from Lifespan News, here: https://www.youtube.com/watch?v=eBxw6_8PivA.
My favourite pop science book on aging is Andrew Steele's "Ageless" (2019); it's broader and less focused on one guy's theories. My goodreads review of it is here: https://www.goodreads.com/book/show/52954648-ageless