The Longest-Lived Bats Have Unusual Telomere Biology
Researchers here find that the longest lived bats have unusual telomere biochemistry, and in fact unusual enough that the new knowledge may turn out to be of little relevance to the understanding of telomeres, telomerase, and aging in other mammals. It appears that they rely upon alternative lengthening of telomeres (ALT) to maintain telomere length, a process that doesn't operate in any normal adult human cell. Given that loss of telomere length appears to be a marker of aging rather than a cause, and a fairly loosely coupled marker at that, the real relevance of this area of biochemistry probably lies in the relationship between telomerase and important cellular activities, such as ability and willingness of somatic cells to replicate, or stem cells to support tissue function.
Bats exhibit cellular biochemistry that is somewhat different from that of ground-based species in a number of other ways. The metabolic demands of flight have led to, for example, greater resilience to stress and damage arising from the normal operation of cellular metabolism. When charting life span against metabolic rate, where high metabolic rates usually imply short life spans, some small bat species are noteworthy outliers. Brandt's bat, for example, has a life span of four decades despite being the same size as ground-dwelling mammals that live for only a couple of years.
One of the principal caveats at the present stage of research into telomeres and the use of telomerase gene therapies - or other means of enhancing telomerase activity - as a treatment for aspects of aging is that mice and humans have quite different telomere dynamics and patterns of natural telomerase activity. The balance between cancer risk and beneficially increased stem cell activity resulting from telomerase therapies may turn out to be significantly different in different species. That these bats have their own unique evolved dynamics, ones that are much further removed, suggests that this portion of the comparative biology might not be as useful to the practical science of aging as hoped. The fastest path to understanding is probably to extend present work on telomerase therapies to species more like humans in their telomere biology, such as dogs and pigs perhaps. Or, as some advocate, running human trials immediately.
We urgently need to better understand the mechanisms of the aging process, with a view to improving the future quality of life of our aging populations. Most aging studies have been carried out in shorter-lived laboratory model species, given the ease of manipulation, housing, and length of life span. Although they are excellent study species, it is difficult to extrapolate experimental findings in these short-lived laboratory species to long-lived, outbred species such as humans. Therefore, it has been argued that long-lived, outbred species such as bats may be better models to investigate the aging processes of relevance to people.
Only 19 species of mammal are longer-lived than humans in proportion to their body size, and 18 of these species are bats. Bats are the longest-lived mammals relative to their body size, with the oldest bat recaptured (Myotis brandtii) being more than 41 years old, weighing ~7 g, and living ~9.8 times longer than predicted for its size. Although an excellent model species to study extended healthspan, logistically, it is difficult to study aging in bats because they are not easily maintained in captivity. Here, uniquely drawing on more than 60 years of cumulative long-term, mark-recapture studies from four wild populations of long-lived bats, we determine whether telomeres, a driving factor of the aging process, shorten with age in Myotis myotis (n = 239; age, 0 to 6+ years), Rhinolophus ferrumequinum (n = 160; age, 0 to 24 years), Myotis bechsteinii (n = 49; age, 1 to 16 years), and Miniopterus schreibersii (n = 45; age, 0 to 17 years).
We show that telomeres shorten with age in Rhinolophus ferrumequinum and Miniopterus schreibersii, but not in the bat genus with greatest longevity, Myotis. As in humans, telomerase is not expressed in Myotis myotis blood or fibroblasts. Selection tests on telomere maintenance genes show that ATM and SETX, which repair and prevent DNA damage, potentially mediate telomere dynamics in Myotis bats. Twenty-one telomere maintenance genes are differentially expressed in Myotis, of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. These results, coupled with differential expression of ATM, SETX, MRE11a, RAD50, and WRN across all tissues in the genus Myotis compared to other mammals, suggest a potential role for alternative lengthening of telomeres (ALT) mechanisms in the maintenance of telomeres in these species. If telomeres are maintained by ALT mechanisms in Myotis species, then these genes may represent excellent therapeutic targets given that cancer incidence in bats is rare.
"Given that loss of telomere length appears to be a marker of aging rather than a cause"
And here we go again....
Cue the alternative medicine practitioners' recommendations that we all spend a few hours a day hanging upside down from the ceiling.
Like the long-lived bat, humans have 2 genes that may express some telomerase and lengthen lymphocyte telomere length, thus probably extending lifespan. One is the ADA gene, the SNP rs73598347 CC, the other is the gene OBFC1 SNP rs9419958 CC allele. I checked my genome raw data and found I am homozygous for the good alleles of both genes.
Im happy today because some have donated around 500$ to cryoprize.info and they have got a new mark that shows progress.
Although it is good to see researchers looking at different species and working out why and how evolution has selected a longer or shorter lifespan, I am not sure how useful it is to compare genetic mechanisms a species might be born with to extend or maintain telomeres, with a potential treatment for humans. A potential treatment for human (short) telomeres would certainly not be to adjust various SNPs - atleast not until we know what all the tradeoffs might be. A treatment for humans would involve a short lived plasmid injected into cells, or maybe an even shorter lived RNA. That way telomeres could be restored to a youthful length without altering the underlying genes. This would be a SENS-like therapy, as it would allow aging to continue but from a reset younger age point (along with other therapies of course).
Or in the shorter term, you could use CRISPR technology to get the good alleles with a crisp snip if you did not inherit the longevity alleles and were nearly immunosenesence.
@Mark, agree. When you wish to go to Mars you should build a rocket -- that's all. We know the damage, we know -- in principle -- how to build therapies. Unfortunately, the majority of researchers are curiosity-oriented and not goal-directed.
@Ariel: Investor's Business Daily had an article a week ago titled, "Can these 3 Biotechs Cure 10,000 diseases?" I think I would consider that before trying to go to Mars.
PS: Those 3 Biotechs are CRISPR companies!!! Cure the diseases!!!
Don't trust everything reporters tell you.
(Actually, don't trust 99.99% of what they tell you XD)
Hi Biotechy, you definitely wouldn't want to mess with your genome using SNPs that could be used by cancers to generate telomerase. I am sure humans have short telomeres for that very reason, otherwise evolution would have solved that problem for us already. But it needn't stop us extending our telomeres ectopically; that way we'd restore our telomeres to a youthful length, but without the potential danger of a permanent genomic change.
Maybe long term we can do as you suggest, but we'd probably have to make a host of other changes too, and we don't have the knowledge for that at the moment.
I am sure we should not play with telomeres or telomerase in vivo at all. And, of course, not introduce foreign genes! All It (may) uses the same mechanism like cancer so there is no by now any safe methods to letghen telomeres in live human. Moover, cells with very short telomeres are already defective cells, just old, senescent or damaged in some way. It is much safer to replace these cells with new fresh ones groving from iPSCs. Cell therapy such as RepleniSENS is already a solution for that problem.
All I'm saying is it is enormously exciting to know that we may be able to solve thousands and thousands of genetic disease problems that plague literally millions of people in the World at present. I don't need the CRISPR therapy solution for myself, because I, like the long-lived bats, already have the necessary gene SNP alleles that express telomerase and extend our telomeres. Maybe that is part of the reason I have 6 Centenarians in my family tree, and 24 over 90.
Lots of guessing here and assumptions. Wait for the human data then we will see. Anything else is worthless guessing. If it works it works. Transient expression is looking to the way to do this as it is for oskm too. So lets see what the data is and drop the dogma.
You're right, of course we have to wait for the results. In the meantime, I just discovered another OBFC! gene SNP, perhaps similar to the one I cited above about halfway thru the comments. This SNP rs 3814219 GG allele, occurs in the blood vessel endothelium, and I am thinking it may also express telomerase and lengthen the telomeres of endothelium cell throughout the blood vessel vasculature, much like the intestinal lining has cell replacement mechanisms. This again in speculative, but I feel I may have had a Eureka moment this evening. Again, I am homozygous for the beneficial allele.
Biotechy is not talking about introducing foreign genes Ariel, only changing a patient's genes to the SNPs associated with longer telomeres. But I don't think we should do this. I agree with Aubrey that restricting cells' access to telomerase is a good idea. Where I differ with him at this point is that I think in vivo rather than ex vivo is the way to go to rejuvenate cells. There are pros and cons with either method, but the fact is that we are much closer to extending telomeres (or even a partial de differentiation if that proves necessary) in vivo than we are to being able to infuse every stem cell niche in the body with geneticaly engineered stem cells. As Steve says, we'll know in a few years how effective in vivo telomere therapies are in humans (hopefully), and perhaps induced tissue rejuvenation (which includes telomere lengthening) isn't too far behind that. Eventually RepleniSENS will be available of course, and that will be great.
Senescent cells have been rejuvenated fully in many different ways now, so I think the jury is out on how 'damaged' they really are in any permanent sense.
Hi there! Just a 2 c.
This is a great study and demonstrates, the important roles telomeres play. In my mind telomeres, because the many pathways are dependent and independent of telomeres, it means telomeres have a partial causative weight in aging; not just correlative.
This study is One More study showing that you cannot underestimate telomeres - they are the chromosomal end termini DNA after all, and this DNA has very specific purposes; which are linked to aging; and, partially, causal; and of course, correlative too.
When the telomeres shorten, the methylation level drop. Likewise, the sub-telomeres and centromere see changes, demethylation. Same thing in epegenetic clock cpG-rich islands whom see changes in methylation, either hypomethylation or hypermethylation dependings if they are cpG rich or poor islands. Short telomeres are unstable, uncapped and demthylated, they compromise telomere and genome stability, which lead to mutations and SCE (sister chromatid exchange); and ALT (alternate lenghtening of telomeres) as in the case of these long-lived bats.
In humans, these telomeres rearrangments and chunks extension, are only made by cancers who highjack ALT instead of telomerase. And ALT in normal cells creates SCE in humans - not in these bats, this means bats may have better genes towards telomere maintenance.
We share the same such RAD, Werner Helicase, K67, Shelterin POT, ...which the bat employs to make ALT in its cells' telomeres. As such, it is possible that we Also have ALT, it has not been demonstrated yet; but because we share the same make-up needed to make ALT; then it means it may already be feasible. Since telomeres shrink and telomerase is absent (or not enough) in many cells, telomeres shrink anyway; thus we would think ALT is non-existent in humans, except in their cancerous cells (and what is sure is if cancer cells highjack ALT - in humans, then humans have the necessary for it to be possible, Even in healthy cells. You just need the 'RAD/Helicases' machinery for telomeres and you can make ALT/SCEs (and humans have it))).
But, studies showed that some humans (rare) have telomere *Lenghtening* later in their life, akin to what happens in Albatros bird whom have Lenghtening TElomeres - with age. Just like in human testicular sperm telomere whom Rise with age (sperm maturation by telomerase creating longer telomeres in sperm; and is why the 'old father effect' of children living longer if born to an 'older father' (matured sperm/longer telomeres chunk transfer during conception of new born (older donor sperm has more DNA defect (from age) but telomerase assuages much of this and the telomeres get longer - with age (because telomerase 'has time' to lengten them over the years in the aging testicule/sertoli/leydig cells)).
If certain (rare) humans have Telomere Lengthening With Age, like an albatros, then it means one of two things:
- Either they have More Telomerase activity or they activated it through exogenous ways (such Astragalus, Gingko Biloba, and many other ways that boost telomerase activity; like, simply improving the redox - Boosts telomerase activity. Because telomerase and redox speak to each other. One study demonstrated a 80% reduction of telomerase activity once teh redox lost GSH thiol pool)
- Or, these humans they have functional and active ALT in healthy non-cancerous cells - just like in little Brown bats myotis genus cells. These bats, and certain humans, foudn a way to ReHiJack from cancer cells what they have been doing (using ALT). Since these bats have little cancer, then it means ALT can be made so that SCEs do not happen and that integrity/stability of the genome and chromosomal structure be preserved; so that chromosomal fusion, homologuous recombination and (re)attach/detachments do not happen with genome instability consequeneces (as seen in SCEs; and in ALT/homologuous recombination lengthening too).
I think we still have more to discover from telomere/epigenetic clock saga, we thought we foudn it all but 'it keeps on giving' like 'that gift'.
I agree though, that scientists should work towards Action/Acting on the discoveries...rather then be passive and just 'inform' with new research that leads to nowhere and 'no acting' on it...sometimes it feels like it is only Aubrey de Grey is doing Anything worthwile/tangible, like a 'plan' to 'end aging' and build the therapies; while the other researches just 'study for study' and do Nothing about it; it shows you both their brilliance and (not/less) brilliance at the same time.
I mean you could study all this bs forever...so what, if you're dead it's pointless (let us remeber the example of the Dead Rich person too greedy to give a penny and dies one day...they are Rich.
and, now, dead (if only they had 'connected teh dots in their light-bright' but no, dying rich more important than Acting by Giving some of it to like...build rejuvenation...to like not die).
Well, analoguously, these scientists must 'get it', and 'act on it'; rather than regurgitate what has been studied 1 trillion times and findind a 'new (useless, mostly) discovery of info'.
Meanwhile, 1 million die every month...(and soon, that contingent of scientist will join them, once they get too old 'to study for study and do nothign about it *they are not getting any younger*'.
Just a 2 cent.
@Mark, the issue is that cells become senescent for a reason. For example, critical mutations. In fact you cannot know a priori why some particular cell become senescent. And 'reviving' them is highly dangerous. Then senescent cells even in old people are presented in small numbers, and it much simpler and safer to just remove them than 'revive' them and guess what will go on.
Yeah, I am aware of ITR if you mean research in AgeX. Hovewer, I am slighly skeptical about in vivo methods like that or OSKM. When you work ex vivo you know what is going on with your cells, you can apply any therapy and then screen final cells and use only good ones. When you apply therapy in vivo you work with 1000 billions of various cells with very different biology and biological age. Imagine what will happen if you apply OSKM to just old somatic cell? Probaly, you will 'rejuvenate' such a cell. Now imagine what will happen if you apply OSKM to stem cell which is biologicaly 'young'? You can completely dedifferentiate such a cell to iPSC which may become cancer! So you need very precise targeting and checking based on the cell's internal biological state which will work with each cell.
Finally, all cells in an organism accumulate some mutations and just 'reviving' them will not solve the problem. Here is a piece from my popular essay:
Most cells with critical mutations in nuclear DNA (a) undergo apoptosis, (b) become senescent or (c) become cancerous (and we have already discussed how to address each of these problems). But if the mutations are not critical, the cells will live, divide and accumulate them. Over time, these cells will increase in numbers. One wrong protein here, another one there. Finally, there will be too many of them, and they will lead to the malfunctioning of the body.
Fortunately, experiments done by Dr. Jan Vijg at the Albert Einstein College of Medicine and others on mutations (changes in base sequence in DNA) and additional studies commissioned by SENS Research Foundation on epimutations (changes in the arrangement of methyl groups) suggest that these latter kinds of alterations - the kind that accumulate in cells without triggering apoptosis or senescence or contributing to cancer - accumulate too slowly to make a difference with the current lifespan. Apparently, most (epi)mutations in the cell are recognized as critical and trigger the apoptosis program, or make the cell senescent - and the rest, unfortunately, do contribute to cancer.
But what if the scientists in SENS RF are wrong, and the accumulation of small mutations plays a role now? And in the future we still have to solve this problem. It will be very unpleasant to live three hundred years and die because of brain failure, because we did not take into account the accumulation of small mutations. Houston, it looks like we have a problem! And because each cell has its own unique set of mutations, we cannot solve them with the methods of gene therapy in the adult organism either today or tomorrow.
Of course, in three hundreds (and even fifty) years, we will have completely different technologies (and other problems), but our goal is to show you that even with current technologies the problem of accumulating small mutations is completely solvable.
The point at which these become a problem can also be delayed by the RepleniSENS and OncoSENS programs. As we know, some of the tissues are regularly updated, and a regimen of regularly destroying old, mutated stem cell populations and reseed them with new and healthy ones will slow the rate of accumulation of cells bearing these disabling mutations.
With slowly updated or not renewing at all tissues which do not have their own pools of specialized stem cells, everything is a little more complicated and at the same time easier. On the one hand, the less often the cell divides, the less mutations it accumulates, because most of them are formed in the process of DNA replication. On the other hand, such cells usually accumulate physical and chemical damage in the DNA - chain breaks, oxidized or otherwise modified bases. Over time, the repair system in the cell works worse, and much of this damage either is not corrected at all, disrupting the expression of genes, or converted into mutations. And since such cells usually live for a long time, the accumulated damage and mutations in DNA can exceed the critical level.
To our happiness (I would never have thought that brain degradation would play a good role!) these cells still die, and, as we said above, some long-lived tissues lose about 30% of their cells in 80 years of life. We can replace these dying cells with new healthy cells, and thus dilute the overall level of damage and mutations. However, due to the lack of stem cells in these tissues, we will have to tinker a bit and grow the proper amount of the progenitors or mature cells and integrate them into the tissue. But this is a solvable problem. Recently, scientists have grown mature neurons and transplanted them into the brain of a rat. New neurons successfully integrated into the rat brain and generally behave very well. Similar experiments with the heart muscle also showed good results in restoring it after a heart attack.
Moreover, some tissues (for example, skeletal muscles and skin) will soon be easier to print or grow in a bioreactor than to mess with their cell therapy. Of course, non-invasive methods are always better, so their rejuvenation will still need to be done.
While these rejuvenation biotechnologies give us much reassurance even about the hypothetical dysfunctional mutations,someone should ask the question: where will we take these new healthy cells that we plan to use in cell therapy? In the chapter on RepleniSENS, we discussed in detail the preparation of pluripotent stem and adult cells by reprogramming and transdifferentiation, but ignored the accumulation of small mutations. Now it's time to take them into account.
For example, we took skin cells or more convenient mesenchymal stem cells and sowed them on a nutrient medium. A colony will grow from each cell. We will choose from them the best by their phenotype, sequencing their genomes and discover that they all differ slightly in unique sets of mutations! Which of them we should take as a basis for future cell therapy? Well, probably, the one whose genome is closer to the original, and therefore accumulated fewer mutations. But we do not have the original! The original is a fertilized egg, and it has long grown and turned into 100 trillion cells of an adult human, each of which has its own unique set of mutations. Houston, it seems, we have a problem again and now is much more serious. We have nothing to compare our cells!
But do not panic! If we do not have the original, we will recreate it! How? In the same way in which scientists recreate the original versions of the ancient books, having only a number of slightly different copies. Differences in them, as mutations in cells, arose because of the inevitable mistakes in copying. But scientists have found a way out! The probability of the same error in the same phrase in several books at once is small, and it decreases with the number of copies. In other words, the more times a certain phrase occurs, the more likely it is that it was in the original. With such a simple method, scientists can restore the version of the book closest to the original. And of course, computer programs have been written already, automating the comparison of copies and recreating the original.
Similarly, comparing the sequenced genomes of different cell lines, we can recreate the most closest genome to the original one by using computer. And then we will choose the most genetically close cell line to it and, consistently applying methods of modern genetic engineering, we will correct all found mutations, recreating the cell closest to the original. In the first round, we can not pay attention to the non-coding regions of DNA (which is more than half of the entire genome) and, thus, we will make our work much easier. Cloning the cell, we will get a master line, which we put in the freezer and will use in the cell therapy of our patient. In principle, it is enough to conduct such a procedure only once, but no one forbids us from iteratively improving our master line with the advances of new technologies, using more cells for comparison, better algorithms and methods of genetic engineering.
"Yeah, I am aware of ITR if you mean research in AgeX. Hovewer, I am slighly skeptical about in vivo methods like that or OSKM."
But you work for a company developing OSKM induction in vivo :)
"In 2006, in a Nobel prize winning work, Shinya Yamanaka has shown that a cell can be returned back to a pluripotent state using OSKM transcription factors. Moreover, old cells also experienced considerable rejuvenation while undergoing this transition. Luckily, this turned out to be a gradual process, and in December 2016, Belmonte et al. demonstrated that we can use these factors to rejuvenate not just cells but entire organisms: using weekly OSKM induction, they managed to prolong lifespan of progeric mice by up to 50%.
These results underlie our working hypothesis that aging can be rolled back by periodic induction of certain transcription factors (e.g. OSKM). Our project is aimed at validating this hypothesis and then translating it into a safe therapy that produces sizable, noticeable rejuvenation. In short, we strive to develop an epigenetic rejuvenation gene therapy of aging."
So you are skeptical but you are still working for a company developing things you don't think will work? Makes sense.
Mission statement is here:
http://www.youthereum.io/#rec33441386
See Ariel is on the team here:
http://www.youthereum.io/#rec32405908
"As the most optimal strategy for going forward we see a step-by-step, iterative improvement of the already proven approach (induction of OSKM factors with doxycycline; such OSKM cassette can be delivered into the body using a lentiviral carrier available on the market today) and parallel development of an ideal therapy (maximally safe and effective rejuvenating factors activated by a unique, inert, patentable agent)."
So your company is following on from the Belmonte et al. work with OSKM induction in living animals via the activation of doxycycline. This does not suggest the level of selection you talk about in your comments above, this is the systemic transient induction of OSKM ala Belmonte which resets various aging markers in cells and makes them functionally younger.
If you really think SENS is 100% correct about aging then why on Earth are you working for a company who has a CEO who strongly believes that aging is at least in part caused by epigenetic alterations? You seem to have some seriously mixed priorities here. This makes zero sense.
Oh and in the Belmonte paper the animals did not erupt into balls of cancer, they lived longer than the strain usually lives (around ~35%) and we functionally younger in a number of ways. Blasco also followed this up in January 2017 and showed that OSKM induction in vivo also resets telomeres, this strongly suggests that telomeres are closely linked with epigenetic changes and visa versa as pulling on one influences the other.
But please keep preaching and guessing before all data is in. You also ignore that in biology, there is often more than one way to skin a cat. Don't assume one method is the only method.
Yeah I think the idea of epimutations is much too simplistic a concept. The DNA is coiled up around histones in a very complicated and changeable way, both on short timescales related to environmental stimuli and longer timescales associated with aging. Telomere shortening has also been shown to alter how the DNA is wrapped up too. We know this completely changes gene expression between young and old and senescent cells, and this can and has been reset in numerous ways, including OSKM induction, which results in a cell that is young again. Belmonte just published a paper (Elixir of Life Thwarting Aging With Regenerative Reprogramming) that reviews the work in this space.
If I had to guess how aging will be solved I would expect that SENS' greatest contributions will be in the GlycoSens and LysoSENS areas, and not in MitoSENS or RepleniSENS as the idea of permanently damaged and 'must be replaced cells' is not quite right.
I agree Mark and touting SENS like it is the one and the only solution is dogma pure and simple. I have nothing but admiration for Aubrey and I know him well, I also help SENS raise lots of money, but quite simply, we do not know enough yet to make such conclusions about these things, despite what Ariel is suggesting above. So, let's do science here and leave dogma at the door where it belongs.
Bats and birds have a number of interesting genome features which are thought to be adaptations to the metabolic demands of flight.
viz.
The bat genome: GC-biased small chromosomes associated with reduction in genome size.
https://www.ncbi.nlm.nih.gov/pubmed/23881029?log$=activity
@Steve Hill, I do not like personal questions like why and where I work. You begin name calling instead of answering my engineering questions or arguing my engineering position. Funny? All this is very pity. By the way, I feel no any shame for what I do, so here we go.
I have never said that SENS 1.0 is 100% perfect -- hovewer, Aubrey de Grey says the same, it is merely perfect enough -- in principle -- to give people 20 - 30 young years by fixing all known damage. I think that nuclear mutations and epigenetic shift may play a role. For example, if epigenetic shift is not primary cause of ageing, that does not imply that all changes will be reverted when we restore the cell environment. Easy to imagine that we will need to fix that secondary type of damage. That is the reason why I propose Original Genome Restoration Procedure and why I work as a consultant in Youthereum -- our goal is research because we even do not know how OSKM works, we need much more research. And my small goal is make OSKM more safe. Hovewer, as I said above it is very difficult.
@Mark, do you know another solution for cells that already lost all normal mitochondria excepting than MitoSENS? Again that is ridiculos to say that RepleniSENS 'is not quite right' when all stem / cell therapies, tissue and organ engineering -- the most advanced areas of rejuvenation biotechnology -- are RepleniSENS! Maybe you believe that cancer cell no 'permanently damaged' and can be revived as well? When cell accumulated one critical or many non critical mutations -- game over.
@Ariel, where you work, is relevant to the discussion. It is also public knowledge who you work for. Sorry if that makes you uncomfortable but that is factual information. If you think contradicting yourself and being called out on it is petty then you sure have a strange understanding of the word.
Also, had you been paying attention to the work I do you would also know I advocate for a repair and engineering approach. The difference between you and I is that I am open to other approaches and I do not assume one approach is the only approach before there is enough data to support it.
I don't think RepliniSENS is not quite right, I welcome the day when it is ready - I'm not so sure how important allotropic expression of mitochondrial genes will be, but time will tell on that one. My words were 'the idea of permanently damaged and 'must be replaced cells' is not quite right'.
I also think Aubrey is great, but I don't agree that a plan put together in 2002 or so can remain unchanged; yes - repair damage, but I think much of the damage we are talking about can be reverted by gene expression changes (not all in a mature organism, and not for 100s years of life, hence why I think AGE breakers and more enzymes for lysosomes is a very good idea).
We are all on the same side so let's just agree to disagree on some of the finer details of how to fix aging, we all want to fix it.