A Review of Lifespan, the Book, and Some Confusion About Aging
David Sinclair works on areas of mitochondrial metabolism relevant to aging, sirtuins and NAD, and of late is involved in research into a novel understanding of the relationship between DNA repair and age-related epigenetic change, as well as the use of in vivo reprogramming as a way to reverse age-related epigenetic change. He is first and foremost an excellent self-promoter, however, a job that has come to includes authoring books such as Lifespan.
On balance, self-promotion seems a useful trait for people who work on projects of merit. It is a tough job to raise funds and build the necessary networks of allies to push forward the bounds of any field; every advantage helps. It is not such a good trait when the projects themselves are not useful. Self-promoters have a way of cluttering the road to clear debate and understanding, and Sinclair's work is a mixed bag when it comes to utility as the basis for treatments for aging. That said, I think it unlikely that Altos Labs would exist in its present form, devoting a sizable budget - hundreds of millions initially - towards in vivo reprogramming as an approach to the treatment of aging, absent Sinclair spending the last few years aggressively publicizing his work on reprogramming to everyone who would listen. Fortunately, and unlike everything else Sinclair has worked on and relentlessly publicized to date, in vivo reprogramming is an area of research that might turn out to produce a meaningful degree of rejuvenation in old people.
Unfortunately, this still means that one should take everything Sinclair says outside a peer reviewed scientific paper as propaganda, a matter of talking up his position and enabling the companies he is involved in to raise funds and find exits. Self-promotion is a game in which one can win every battle and still lose the war, as people come to filter everything one says through the lens of self-interest and then disregard it. Perhaps Sinclair believes in the position he puts forward in the book Lifespan, perhaps not, but to present epigenetic change as the whole of aging - which it is most certainly not, and may not even be that close to the root causes - is just too convenient given his portfolio of interests. Maybe he is a true believer in his own work, and that explains it all, but this is also the person who talked up the dead end of sirtuins and resveratrol in exactly the same way fifteen years ago. He overhypes everything that he is earnestly involved in.
I have no horse in this race, beyond a desire to see meaningful progress towards rejuvenation in my lifetime. I've never met the man. It is good that Sinclair is now putting earnest effort into a potential road to therapies - in vivo reprogramming - that might actually have some promise when it comes to human rejuvenation, and has persuaded others with significant resources to do the same. I do wish he would temper the way in which he publicizes and promotes his work, however. It think that it harms long-term prospects for the field more than it helps.
Separately, and to the content of the review here, it is always interesting to see people coming in from the outside the field and describing their confusion on encountering the various competing views of aging and possible paths to the treatment of aging. The confusion is only exacerbated by the degree to which various parties present narrow views of aging, or present their narrow view of aging as the whole of the picture, or leave out inconvenient points that undermine their position. This sort of thing is rife in the scientific literature, and worse in popular science materials.
David Sinclair - Harvard professor, celebrity biologist, and author of Lifespan - thinks solving aging will be easy. "Aging is going to be remarkably easy to tackle. Easier than cancer" are his exact words, which is maybe less encouraging than he thinks. Sinclair thinks aging is epigenetic damage. As time goes on, cells lose or garble the epigenetic markers telling them what cells to be. 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. It's hard to run a kidney off of cells that aren't entirely sure whether they're supposed to be kidney cells or something else, and so your kidneys (and all your other organs) break down as you age. He doesn't come out and say this is literally 100% of aging. But everyone else thinks aging is probably a combination of many complicated processes, and I think Sinclair thinks it's mostly epigenetic damage and then a few other odds and ends that matter much less.
Epigenetic damage could potentially still be unfixable: how do you convince the thousands of different intermixed cell types in the body to all be the right type again? But Sinclair thinks the body already has a mechanism for doing this: epigenetic repair proteins called sirtuins. Sirtuin activity seems to be regulated by a protein called mTOR, which can be influenced by treatments such as rapamycin, an mTOR inhibitor. The other pill is nicotinamide riboside aka NR (and its close cousin nicotinamide mononucleotide aka NMN). The reactions catalyzed by sirtuins involve nicotinamides, and the more nicotinamides you have, the more effective sirtuins are.
People who are not David Sinclair generally don't expect conquering aging to be this easy. The anti-aging SENS Research Foundation has a list of seven different programs to address what they consider to be seven different causes of age-related damage. This seems more like the "humans are like cars" scenario where you have to fix every part individually and it's really hard. People who are not David Sinclair don't think that nicotinamides are a miracle drug. A well-regarded research center ran a big study on nicotinamides in mice and found that they lived no longer than usual, although they did seem to be healthier in various ways. And people who are not David Sinclair are less enthusiastic about sirtuins, mTOR, and calorie restriction.
My impression of the consensus in anti-aging research is that many people are excited for the same reasons Sinclair is excited, that people are much more optimistic than they were five or ten years ago - but that their level of optimism hasn't quite caught up to Sinclair's level yet.
If we put the self promotion and deliberate disinformation aside. It seems that he believes that aging is simply a metialtion issue. If you reprogram the cells to the uthful state you have solved it. By this narrow definition it is solvable. However, useful will that be if taken alone..
It won't be solved even if we reprogram all cells to a youthful state, because there are still other forms of damage such as extracellular damage we need to address. And who knows if reprogramming cells to a youthful state fixes all types of damage within the cell or not.
I'm cautiously optimistic but I think its more complicated than what Sinclair implies
Hi there! Just a 2 cents.
Though at first view, it may seem/look (like) he is overhyping it...I think is, at least, a bit more 'hypeable' than most anything else..and I understand people are wary of other 'overhyping' people...false hopes/snake oil/fraud. Not inherently fraudulent, of course, it's people immediately 'brand' the person fraud/charlatan - even if - they are Recognized Scientist...'delusion/deluded'..
It's also a bit of combination of hopes that were dashed in the past (failing on and on...makes you think that it will be a failure - next, too; you become good at predicting failure - it always happens..when you say it will; confirming and Reaffirming what you knew already (that it would fail- again (and again..))); and pessimism...while Mr. St-Clair is full of (hype(r)(over)optimism...
But, it's not without reason; Mr. St-Clair basically invented -The- clock (epigenetic clock) that measure the Aging process...yeah, you have Hannum, GrimAge clocks...and a few other epiclocks; but , The- clock..is His Clock. He believes in it because it'S been tested and came out quite solid; over thousands of animal types/species and their organs...etc...
It may not predict health or certain disease as well as the GrimAge clock...but on the Max. Aging/Longevity (not just healthiness threshold maintenance), specifically, -point..it is one of the best and Thoroughly tested. IT measures CpG and Non-CpG methyland islands/pockets solidly and compares it to chronological life (age) vs (epi) biological life (bodily/organ age).
Epigenetic reversal must be accompanied with DNA repair..if that does not happen then the DNA damage was not repaired and can cause health maintenance to not linger; because DNA DSBs (double strand breaks) in nucleus were not repaired (via his sirtuins/SIR/DAF/FOXO/mTOR pathway...and other helicases/exonuclease that 'cleave' and repair chromosome/telomeric DNA damage; but, specifically, nDNA Double-Strand Breaks which are Causal to Maximal Longevity of any animal. Not just correlative.
With that said, as others said, the damage Already accumulated will make it hard to make it Stronger Rejuvenation and Epiclock Reversion...and on top of that, it is Only Partial Epiclock Reprogramming - meaning it can return the clock approx. 30 years behind (in epiclock/bioage); but this needs to be Continuous affair. as it was shown that epiclock reversal is Short/Temporary..once the reversal is done...after a while, the senescence comes back;;;kind of like stopping to take your pills/supplements...if you stop...well the effects of it wane...until back to 'square 1' (when you started, at the start, when took first pill); thus, it is something that needs to be done - nearly - daily; like daily maintenance to Keep the clock 30 years behind...and not accelerate Back to 30 years later...in a few days. That's the bigger problematic, is this daily maintenance to keep the effect of partial epiclock reversal/reprogramming. As I said before, the genome/nucleus is not 'made' for that - it is like a fortress - you can't open it; if you do, it's like havoc...genome/epimethylome tinkering is not something that is suppose to happen; and is Why the genome/methylome is Refractory (about it); this is was Shown in Naked Mole Rats;;they tried to epireprogrammed NMRs cells...but saw that their methylome/epigenome is Very refractory and Disallows that. And, for reason...that's because epigenetic reprogrammic is Very Volatile and Hazardous -> Mutation/Chromosomal Havoc; the genome does not allow tinkering/opening it like a can of sardines -> Stability Compromising. It demonstrated something; Humans and NMRs live extremely long lifespans - because - their epigenome is Very Stable and Very Refractory to External Intervention in it. This means genomic Stability/Protection. -> Lifespan/Longevity Assurance. -> No mutations/Less DNA deletions/damage/Less Cancer....etc...
So, of course, us tring to 'open the pandora's box'...are seeing that..(that, it is not meant to be/for that); but, I think we can ccrack this (box) code (box); and we have to be careful because we know the hazards/dangers of that -> Terratoma Formation if Exceeding Reprogramming Window.
Cancer everywhere in our body.
It's why I am optimizing but also veryy caustious(ly) about it; I mean, we have to do something to stop aging..and live for however long we wish (reach LEV and all - LEV-EL-UP); instead of continuously leveling down...enough people died already (COVID killed thousands upon...)
The fact that you put your trust in the science...but it's scary none the less...a small error and you could end up cancer-ladden...they might reprogrammed you to 20 years old...but if cancer takes over (and it will because Full epigenomic reprogramming in mouse - is deadly/fatal as they because metastatic-tumorfull; Partial reprograming avoids that - but that is in mouse..not humans yet..and we don't know the effects in human - it's VERY possible the epigenetic reprogramming will Kill Many people -> many unforeseen side effects; because, Genome/Clock Tinkering)..it's game over. Thus, I think epigenetic reprogramming - though- would Need to be done earliest possible to reap more benefit..the Cost/Weight; Risk vs Benefit...will mean that people will feel 50-60 years old seems the best in between (since you are mid-life) and thus if you die after doing the therapy; you at least lived half your life - and Tried to stop aging/reverse it;; but if you Are Young..like 20-30...it'S almost suicide to do a reprogramming intervention IF it carries such a Huge Life/Fatal risk ('Bad Reprogramming/The Reprogrammation Turned (out) Bad')...with it.
AT 20,30,, you are too young..to die this early...of trying to stop your aging. That'S the compromise I think.
IF you are 90 years old...well it can seem 'useless'..you are 90 and lived you whole life already..you got nothing to lose..whether it kills you or not...you lived already (whole life);thus, should not be so scare - by late then; but may think :' it's useless I'm 90 I'll probably get like 10 year reversal that's it..why even bother..I'm too old to reap much any benefits...too damaged..too close to the end of life'.
Because, normally, epigenetic would work Best on Older/Oldest people - they would Get Maximal Reversal and it would not be useless/very much Useful..as they might get 30 years reversal (90 back to 60...); but that is only speculative...we know So much damage as accumulated by then that the rejuvenation/reprogramming's 'efficiency/results' become weaker...because too old/too late. So..
It means 'in between' -> 50 years, sounds about right/center/middle. Neither too old (not too much damage), neither too young (not to young, to die suddenly as youngster if reprogramming kills you); this way we mitigate problems and halve the risks...to a life.
It's a gamble....longevity vs cancer risks vs any other potential reprogramming fatal hazards...it's scary yet it's probably 1 of truly only way to beat aging/get eternal longevity (especially, if we can't repair DNA DSBs and DNA repair therapies have been lackluster (always in the 20% life boost ballpark thing; so, far away from LEV).
Just a 2 cents.
Dr. Sinclair is an above-average scientist who has to date:
- failed in translational drug development (the Sirtirs / GSK fiasco);
- is trying to suck as much $$$ as possible from the dietary supplement domain until those dubious wells run dry;
- clearly wants to replace Aubrey de Grey as the field's next "guru", all while stepping on the shoulders of giants who did the real work (Yamanaka et al.)
He is a dangerous person to put as the "face" of the longevity industry
I agree that Lifespan gives much too narrow a view of aging and misses multiple things that will not be fixed by epigenetic reprogramming alone and which are at least as important if not more. If I had my wish, he would have given the root classes of damage coverage as well. However, his book is very well written and has succeeded in bringing many new people into believing that rejuvenation is possible and, therefore, improved the advocacy climate. Additionally, although epigenetic reprograming may not be a root cause, it still appears that it might have a sufficiently significant effect that it is worth earnestly pursuing and so it is one of the few non-SENS categories that I am excited about.
In that book D. Sinclair basically wrote that improving artificially damaged (pinched) optic nerves of mice with yamanaka factors equals anti aging. A bit nerve regeneration? Probably. But anti-aging?
Yep - that's an example of something he is hyping to the extreme
Yamanaka factors are not "youth factors" and on their own are not the fountain of youth.
They are purely factors which allow for cells to freely explore cell lineage "state space".
During development, when locked down, cells are guided down select lineage pathways to help guide proper morphogenesis
Unlocking them, per such de-differentiation experiments, allows terminally differentiated cells to re-explore lineage possibilities
Hence, in Dr. Sinclair's acute optic nerve damage model, he is "loosening up" the potential lineage flexibility to allow new neurogenesis to occur, versus say scar tissue formation.
This is potentially useful for stimulating certain very targeted regeneration events in-vivo - but must be balanced with appropriate re-differentiation signaling to avoid establishing inappropriate lineages, or uncontrolled proliferation
But this is far from a technology which on it's own can make your body younger
The optic nerve is very unique tissue micro-environment, especially this animal model
But in say an aged, chronically damaged human heart, made up of cardiomyocytes, fibroblasts, endothelial cells, peri-vascular cells, pacemaker cells, etc. etc., things are quite more complicated and unlocking cells to explore the wealth of lineage "state space" with a blast of Yamanaka factors on their own, is potentially a recipe for disaster
Also, Yamanaka factor de-differentiation efficiency in the petri dish is extremely low (< 0.01%) demonstrating again why this technology on it's own is a very limited tool...
On balance, I disagree with you, Reason.
I don't disagree because I think you're wrong and that Sinclair is right, but because I think the evidence out there is insufficient to warrant your conclusions-- for example, that sirtuins are a dead end. You have pointed out that there just isn't enough being done-- not enough money in the field, not enough knowledge in the public mind, and too many regulatory obstacles such as the FDA's refusal to recognize aging as a disease. With all of that I agree, of course. But it seems strange that you both say that and at the same time feel confident in conclusions which require a degree of certainty that to my mind we just don't have yet-- as a direct result of not enough being done.
The processes of aging are many, but they seem to encourage one another so much that it is not crazy to think that there might be a single upstream cause, and I see solid reasons why it might, and no reasons why it could not, be the loss of epigenetic information, for which there might be a "backup copy" somewhere (Sinclair's theory) that gets read when organisms reproduce to result in a baby starting at age zero. The truth of the matter is that there seem to be remarkably few experiments going on out there that combine phenomena-- heterochronic parabiosis using old organisms that have had their senescent cells removed, for example-- that would enable any of us to be able to make many statements with confidence about which hallmarks of aging are further upstream and which further downstream.
"Hype" is one of those words that describes the interpretation of the speaker as much as it does the subject. Where is the line between "hype" and enthusiastic promotion of firmly held beliefs? Setting aside the speaker's interpretation, and in the absence of any serious argument (for which I see no basis) that he does not actually hold those beliefs, it seems like a distinction without a difference. True, at some point people will be cloyed by overpromotion, but the serious science is still so obscure that I don't see that he has crossed that line yet.
If nothing else, Sinclair's work has been invaluable in educating people not only in details of biology and of his area of geroscience in particular, but also in the fact, which you have done excellent work yourself in making known, that anti-aging is a serious field which is being hindered by lack of funds and FDA stodginess. The weight of public opinion may be what forces the reversal of that situation, and that probably won't come about without energy and promotion, and even occasional hyperbole. Certainly most people I talk with these days (and recommend Sinclair's work to, just as I recommend yours) still have no idea that any of this is going on.
Too many people caring about "educating the public"
If he educates the public with nonsense and half-science truths we go nowhere
Although they are competitors in the NAD market, Dr. Charles Brenner shreds most of what Sinclair is pitching in this 30 minutes -
There is another person in the geroscience community who fits this description. Hint: You met this man in person.