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Cellular Senescence as a Cause of Aging: from Wishful Thinking to Case Closed

Today's open access review covers what is known of cellular senescence as a cause of aging, and is a very readable example of the type. It is always pleasant to find a well-written paper that can serve as an introduction for people outside the scientific community, those with an interest in the topic but only a little knowledge of the relevant biology. If you have friends who fit that description, and who are not all that familiar with the science, then you might send this over as a more gentle introduction than some of the other reviews of cellular senescence published in recent years. In particular, you might point out the middle section from which I borrowed the title for this post.

Senescent cells are those that have entered an altered state in which replication is shut down, and a range of signals and other molecules are secreted. These provoke inflammation, attract immune cells, remodel the nearby extracellular matrix, and increase the likelihood of nearby cells also becoming senescent. Senescence has several forms, occurring in response to cell damage, a toxic environment, radiation, or in the vast majority of cases as the end state of a somatic cell that has reached the Hayflick limit on cell divisions. Most species have a two-tier hierarchy of cells: a small number of stem cells that can replicate indefinitely, and the limited somatic cells that make up the vast majority of any tissue. Stem cells produce a supply of somatic cells to make up those lost to the Hayflick limit. In such a system something like senescence has to exist if somatic cells are in fact to be limited in the number of times they can replicate. Why does this two-tier system exist? Probably because it is the most accessible way to suppress the risk of cancer sufficiently well for higher animal life to evolve at all: if any more of our cells were normally capable of unlimited replication, and thus easily subverted by cancerous mutations, then our lineage could not survive over evolutionary time.

Beyond the necessity of being a full stop at the end of a somatic cell's life span, cellular senescence appears to have evolved other uses along the way. Reuse is very common in biology. Thus cellular senescence acts to set limits to growth in embryonic development, coordinates with the immune system in wound healing, and acts to suppress cancer, at least when the number of senescent cells is still low, by shutting down replication in cells that are most at risk of becoming cancerous. Senescent cells so far appear to be best as short-lived entities that self-destruct or are destroyed by the immune system quite quickly after they appear. The contribution of senescent cells to aging is produced by the tiny minority of such cells that somehow linger instead. The signals they secrete, used in the short term to carry out their evolved tasks, become destructive when issued over the long-term, and in ever increasing volume. The solution to this problem is likely very simple: destroy these cells, clearing up the remnant population that natural processes fail to eliminate. Doing so will reverse this one portion of the aging process.

Senescence in the aging process

From its initial discovery, it was postulated that senescence, on some level, was linked with organismal ageing. Modern forms of this hypothesis propose that senescent cells are produced gradually throughout life. These then begin to accumulate in mitotic tissues and act as causal agents of the ageing process through the disruption of tissue function. This conceptual model carries three underlying assumptions: firstly that senescent cells are present in vivo, secondly that they accumulate with age, and finally that an accumulation of senescent cells can have a negative impact. Each is worthy of examination.

A steady production of senescent cells is quite plausible if the kinetics whereby populations of normal cells become senescent in vitro are assumed to be similar in vivo. Many early reports evaluated findings with the mistaken underlying assumption that cell cultures become senescent because all of the cells divide synchronously for a fixed number of times and then stop. In fact, it has been known since the early 1970s that each time a cell goes through the cell cycle (i) it has a finite chance of entering the senescent state and (ii) this chance increases with each subsequent division. Thus, senescent cells appear early on if a cell population is required to divide. Indirect demonstrations that senescent cells occur in vivo, accumulate with ageing, and do so at reduced rates in organisms where ageing is slowed (for example, by dietary restriction) were occasionally published from the 1970s onwards. However, they were technically difficult to perform and correspondingly hard to interpret.

Senescence triggers changes in gene expression. A central component of this shift is the secretion of biologically active proteins (for example, growth factors, proteases, and cytokines) that have potent autocrine and paracrine activities, a process termed the senescence-associated secretory phenotype (SASP). This results in cells that overproduce a wide variety of pro-inflammatory cytokines, typically through the induction of nuclear factor kappa B (NF-κB) and matrix-degrading proteins such as collagenase. Other radical phenotypic changes, such as calcification, have also been shown to occur in some cell types with the onset of replicative senescence. The individual components of the SASP vary from tissue to tissue and, within a given cell type, can differ depending upon the stimulus used to induce senescence (for example, in fibroblasts rendered senescent by oncogene activation compared with telomere attrition or mitochondrial dysfunction). Such studies demonstrated that senescent cells could, at least potentially, produce significant and diverse degenerative pathology.

However, the observation that something can produce pathology does not mean that it must produce pathology, and a historic weakness of the cell senescence literature was that the in vivo studies essential to testing the causal relationship between ageing and cellular senescence (induced by any mechanism) were lacking. However, the production of transgenic mouse models in which it was possible to eliminate senescent cells has finally made such tests experimentally feasible. Initial studies demonstrated first that senescent cells appeared to play a causal role in a variety of age-associated pathologies in the BubR1 mutant mouse and subsequently that either life-long removal of senescent cells or their clearance late in life significantly attenuated the development of such pathologies in these progeroid animals. This clearly demonstrated that senescent cells can have significant, deleterious effects in vivo. Interestingly, the removal of senescent cells in this system was not associated with increased lifespan (an observation that demonstrated that it is possible to achieve classic 'compression of morbidity' by deleting senescent cells). However, on more conventional genetic backgrounds, attenuated age-related organ deterioration was accompanied by increases in lifespan of the order of 25%.

A justifiable claim can be made to consider these studies 'landmarks' in the field in that (i) they demonstrate a causal relationship between senescent cells and 'ageing' and (ii) the same mechanism can cause changes associated with 'ageing' as well as those associated with 'age-related disease'. These results have unusually profound philosophical implications for a scientific paper and challenge a fundamental ontological distinction that has been drawn for almost two thousand years between 'natural' ageing and 'unnatural' disease.

Whether an enhanced emphasis on basic human studies is a useful parallel-track approach to the pioneering work now taking place in rodent models or an essential next step is a matter of perspective. Many fundamental mechanisms of ageing are conserved between species, but there are often important species-specific differences. Those inclined to stress the cross-species similarities will be inclined to deprioritise human studies and vice versa. Regardless of the species of origin, the extent of variation in the phenotype of senescent cells derived from the same tissue in different individuals is not well characterised. It would be surprising if important intra-individual variation did not exist within the general population as well as 'outliers' (for example, centenarians and those with accelerated ageing diseases such as Werner's syndrome). Although data on differential SASP profiles in response to a senescence stimulus are beginning to enter the literature, they remain fragmentary concerning the senescent cell phenotype in different tissues.

Despite these gaps, progress is being made towards the development of 'senolytic' drugs that can destroy senescent cells - with the goal of duplicating the effects of the transgenic mouse models first in normal animals and eventually in human patients. Initial results seem promising.

Comments

"It is always pleasant to find a well-written paper that can serve as an introduction for people outside the scientific community, those with an interest in the topic but only a little knowledge of the relevant biology. If you have friends who fit that description, and who are not all that familiar with the science, then you might send this over as a more gentle introduction than some of the other reviews of cellular senescence published in recent years."

Well I can tell you that exactly zero of my friends would bother to click on that link. Not being negative, but a new way is needed to inform these people. Or we need to accept that they will never be convinced.

Posted by: Jim at August 9th, 2017 11:17 PM

"(i) they demonstrate a causal relationship between senescent cells and 'ageing' and (ii) the same mechanism can cause changes associated with 'ageing' as well as those associated with 'age-related disease'"

2-0 for Aubrey, even if he and SENS aren't mentioned in the article.

Posted by: Antonio at August 10th, 2017 12:37 AM

@ Jim : Worldwide TV spot campaigns might help change this situation. But we'd need a hefty sum to finance that.

Posted by: Spede at August 10th, 2017 4:55 AM

@Jim so you mean something like this but presented in an engaging kind of way that people would be interested in? I wonder who could do something like that?

Posted by: Steve Hill at August 10th, 2017 7:29 AM

Jeez Louise.....the headline seems definite while the final sentence seems "maybe". The key is whether we see any marked effect in (long lived, as opposed to mice) humans.

Posted by: chriszell at August 10th, 2017 8:58 AM

I still remember Dr Richard Faragher having a very ill tempered debate with Aubrey de Grey and accusing him of saying that he was a Cambridge Don st the end.

His basic argument against SENS was that technologies to repair damage in all seven categories would have to be developed, and if even one category took much longer than expected then the whole concept was sunk. Well if Unity or Oisin or any of the other companies are successful in safely removing senescent cells that will be one category down and only six to go.

Expect a paper from skeptical grerontologists like this group in around 3-5 years on how glucosepane cross links have long been a part of aging. Don't expect them to apologise for rubbishing the idea that anything could be done about it in a reasonable timeframe only a few years back.

Posted by: Jim at August 10th, 2017 10:27 AM

I've never quite understood what it is about SENS that provokes the level of hostility and ridicule expressed in that letter to MIT Tech Review or in the Oxford debate between Faragher and de Grey - or that "SENS is so wrong that it is not worthy of learned debate" debate.

People like Faragher have a strangle hold on the establishment in gerontology - he's a past Chair of both the British Society for Research on Ageing and the International Association of Biomedical Gerontology, and a current director in the American Federation for Aging Research. Yet many academics like him go well out of their way to rubbish SENS. If I were as convinced as they seem to be that it is peddling a fantasy I wouldn't lower myself to even pass comment.

Posted by: TheRage at August 10th, 2017 1:05 PM

This is beyond introduction level.

Posted by: JohnD at August 10th, 2017 6:51 PM

@TheRage - I wish scientists would at least talk about the possible benefits of individual types damage repair, even if they don't think it will lead to some grand prize of ending aging as we know it. I guess it's the whole circular logjam again - scientists can't explain damage repair proposals to the public, and and afraid of going out on a limb, as their funders, the politicians, are super afraid of being accused of spending money on boondoggles by their rivals. Politicians can't explain the risk reward ratio as the public don't understand the rewards.

Also, I think we tend to forget how much of a brutal day in day out fight for funding is involved in being a scientist. Unfortunately this viscous fight has an ultra conservative survivor bias. It also means that the scientists left standing are the ones who most like the endless disparaging of others and backbiting. Most of the more reasonable ones will have left for other careers with less fighting involved.

One of the things that has always impressed me about the SENS RF is how patient, calm, and nice its members seem to be. Other aging scientists that I have met tend to be nearer in personality to psychotic hedge fund bros.

Posted by: Jim at August 11th, 2017 3:29 AM

Today I was rereading the interchange of articles in EMBO Reports back in July 2005 (they are now open access). The lack of knowledge of SENS critics about SENS was amazing. They were dismissing it out of hand without barely knowing it. I saw a similarly furious and ignorant attack on cryonics on the recent cryonics and life extension conference in Spain this year (by one of the chairmen of the conference!) https://www.youtube.com/watch?v=b0QhRtpvTU8

Many scientists are equally prone to knee-jerk reactions against technological proposals than laypersons. A good deal of outreach is still needed.

Posted by: Antonio at August 11th, 2017 4:36 AM

Dear all,

This thread was brought to my attention by a colleague. It is not my normal practice to post in online fora but some of the comments are sufficiently intriguing that I decided to take some time off from my 'stranglehold on the field' to provide a little background and hopefully some utile advice.

Firstly, thank you for posting my article. It is not, as has been observed. written for the general reader, rather it is for biologists lacking an easy reading introduction to cellular senescence. They are, I am afraid, numerous.

Since much of the comment concerns the debate Aubrey and I held some years ago I will provide some background (I believe it can be found on YouTube).

I was persuaded to undertake it because it became clear that some ill informed individuals (both Academic and non Academic) appeared to be attacking the field under the guise of attacking Aubrey. Thus a debate presented an opportunity publicly to showcase those points on which we were, and I believe still are, in accord.

It also presented an opportunity to clearly identify points of possible agreement and those were there was definite disagreement. The two of us collaborated closely on this (although we kept our disagreement slides confidential beyond agreeing the points to be covered- this was because it WAS a debate and we needed that bit to be fresh). I trust that explains why the debate occurred in the way and at the time it did.

I should also point out that those of us in 'mainstream' dealing with the 'fringe' are beaten up with one of two sticks. Refrain from debate and you are accused of 'not daring to discuss' or 'having no arguments'. Enter a debate and you get the 'if I were as convinced as they...I wouldn't bother discussing it'! Ho-hum.

On a personal note I think Aubrey was fortunate in the Tech Review matter (ie 'SENS is so off the wall it is unworthy of academic debate'). If the judges were fair in my view he had to draw or win. But then, so did anyone else. Academics debate the will of made up deities, UFOs, the virtues of homeopathy, magicians as practitioners of 'alternative truth' and the value of cryptozoology (aka the Loch Ness Monster). Being 'worthy of Academic debate' is a staggeringly low bar.

Thus the event provided, in our eyes at least, an excellent opportunity to set out the major points of disagreement between Aubrey and at least one 'mainstream' gerontologist. Given our hopes it is a shame that 'Jim' appears to remember nothing of Academic consequence from it (including the fact that my proper form of academic address is 'Professor', not 'Dr'. All I can say in response to 'Jim's account of my opposition to SENS is that he has failed on any meaningful level to understand what I said on the day. Since what I did say on the day is a matter of public record I would advise those interested to watch the debate. Perhaps he was shocked that I took some of the gilt off his gingerbread saint?

My 'calling out' Aubrey on his 'equivocation' on his status at Cambridge (BTW Aubrey's 'economy with the truth' concerning his Academic position was disclosed to the British Public on a Channel 4 documentary- just the image the ageing field needed!) was warranted because it was indicative of the mind that has ascribed the 'will to lie' to an entire discipline. He claimed that the distinction between ageing and disease was a recent, fiscally motivated, invention. This is profoundly ahistorical. Worse, it ignores THE major barrier to progress in funding and translating the science of ageing. The catagorisation of ageing as a 'natural process'. This has been around for about 1700 years and is a real disincentive to action. This, combined with a lack of understanding of the values motivations of humans, has led to the situation we currently experience- ageing as a high visibility but low salience issue (as a marketing guy would say). Unless proper values based engagement is undertaken 'worldwide TV spot campaigns' will no more produce improvements in public engagement than will ritualised incantation. Though I greatly applaud the sentiment. For those with an interest at its best the UK spent less than 0.25% of the annual cost of ageing badly to the NHS on ALL aspects of ageing research (including social gerontology). Enhanced funding would be exceptionally welcome.

Lastly, the '2-0 for Aubrey' should more properly be '2-0 for Hippocrates or possibly Aristotle' if understood in terms of 'who first proposed a conceptual unity between 'ageing' and 'disease' mechanisms. Antecedents of that idea also appear in the 1950s. In the same view, Fritz Vezar (1886-1979) is generally reckoned the individual who first proposed protein cross-linking as an ageing mechanism and Bjorkstein (1967) as the first person to propose that bacteria might contain enzymes capable of degrading cross linked moieties. I'm afraid the solitary genius only really exists in science fiction.

Richard Faragher

Posted by: Richard Faragher at August 12th, 2017 9:16 AM

Well that was a very enlightening response, thank you Professor Faragher for taking the time to give you side of the story here.

Posted by: Steve Hill at August 12th, 2017 11:36 AM

Professor Faragher: I'm sure that Jim neither meant any disrespect nor was he acting outside of norms for North America. For future reference, the UK convention of systematically referring to Professors as such (outside of a specific reason to highlight their post) rather than by their degree does not exist here, in part because "Professor" is not as high a rank in the academic system as it is across the pond:
http://www.theexclusive.org/2013/08/academic-ranks-in-us-and-uk.html
... and also because Americans aren't as hung up on titles as the British are in the first place (we don't even use "Mr." as much as the Brits, for instance).

Posted by: Kent at August 12th, 2017 12:28 PM

@Richard Faragher

Thanks for your reply. My personal impression about your replies when I saw the debate was that, apart from the part were you both agreed, they consisted of:

- A defense of mainstream gerontologists (they don't make a distinction between aging itself and age-related diseases, etc.).

- Personal attacks against Aubrey de Grey.

I didn't see any specific counterargument against SENS itself, and that was quite disturbing. I'll rewatch the debate, but I don't remember any critique of SENS itself.

"My 'calling out' Aubrey on his 'equivocation' on his status at Cambridge (BTW Aubrey's 'economy with the truth' concerning his Academic position was disclosed to the British Public on a Channel 4 documentary- just the image the ageing field needed!) was warranted because it was indicative of the mind that has ascribed the 'will to lie' to an entire discipline."

Sorry, but if you can't point out the lies or faults in the SENS arguments or experimental data and have to point out the lies in the job career of his proponent, then that is a personal attack, unworthy of appearing in a scientific debate.

Posted by: Antonio at August 12th, 2017 12:59 PM

Has anyone got any popcorn? :)

Posted by: Steve Hill at August 12th, 2017 2:16 PM

I rewatched the debate, searching for arguments against SENS. This is what I found (I will write my own replies/comments in square braquets):

First, I found an argument against LEV: LEV assumes linear progress in technology. [The rebuttal is easy: it doesn't assume it, and AdG has said that many times; maintaining LEV becomes exponentially easier with every passing year, once you achieve it, because you get more and more time with every iteration to develop new therapies.]

Next there are some ideas that are presented as arguments against SENS but most of them are so vague that can be applied to anything. Anyway, here they are:

- Visions of the future are no guide to the future, since some people in the past were wrong when predicting the future. [And some were right, so what?]

- The judges of the MIT Tech Review challege said that "SENS has many unsupported claims and is certainly not scientifically proven". [Somebody dissagrees with idea X, so X is wrong. Not really an argument.]

- The same judges said that "de Grey had not convincingly defended SENS". [Apart from having the same problem than above, a defense of SENS wasn't the purpose of the challenge. AdG simply replied to the arguments of the challengers for the claim that "SENS is not worthy of serious consideration". For a defense of SENS he already wrote a book and many papers.]

- I'm not sure if this is presented as an argument against the correctness of SENS or against spending money on it, but here it goes: SENS is closed, it assumes we know what aging is and how to intervene in it. Mainstream biogerontology is open, it assumes we don't know yet what aging is and how to intervene in it. So the latter is better and more practical. [WTF? How can not having an intervention be more practical than having an intervention?]

- SENS has no research proof. [Around 16:20 in part III. Nothing more specific is said. Maybe this is the usual confusion of science and technology.]

- Some aging theories of the past have been proven wrong, so SENS is wrong, or at least there are more damages than the SENS damages. [Again, not really an argument, and Faragher fails to show any of those new damages.]

And that's all. I couldn't find anything more against SENS in the debate. There is really nothing that can be replied to with SENS details since there are no SENS details in Faragher's arguments.

Posted by: Antonio at August 12th, 2017 4:37 PM

So Gerontologists find it worthy to academically debate "...the will of made up deities, UFOs, the virtues of homeopathy, magicians as practitioners of 'alternative truth' and the value of cryptozoology (aka the Loch Ness Monster)."??? Wow, no wonder they haven't made much progress on aging! :-/

Posted by: Florin Clapa at August 12th, 2017 8:01 PM

Well I think I was being a bit harsh in my criticisms of "mainstream gerontologists".

Re-watching that debate I can see that Aubrey must be frustrating if you are a researcher in the aging field and you don't think new technologies and treatments are going to lead to life extension in the medium, short, or even long term. As a researcher you've got to deliver on your research promises to your political funders more or less, but then the aging field has had Aubrey de Grey swoop in and highjack it and promise the moon on a stick, which puts the funding of everyone in the field at risk.

The question of whether or not something like the strategies for negligible senescence is possible is a steam engine time question. No one can actually prove it either way, so everyone uses analogies like car repair and the advances in aeroplane speeds. I wish the third part of the debate hadn't descended into some ad hominen attacks, but then I guess scientific debate is a bare knuckle sport.

Aubrey kicking over apple carts may be amusing to those of us watching from the sidelines, but if, as many researchers expect, his promises don't pan out, then funding for aging research overall could be reduced resulting in ruined careers and lives for people.

Posted by: Jim at August 13th, 2017 7:34 AM

Internet comments can have more 'bite' than are perhaps intended and if I had an expectation that Prof. Faragher (and I did know he's a professor at Brighton University not a doctor!) would read let alone engage BTL on a post on FA! I may have phrased my remark differently. So I did want to thank Prof. Faragher for taking the time to write his comments and engage with this community - even if he remains deeply skeptical about SENS and LEV.

Posted by: TheRage at August 13th, 2017 7:43 AM

Dear all,

Thank you for your generally courteous responses. As I have said, I am uncomfortable posting on internet fora but a situation has occurred which has the potential to interest you.

I have been asked to discuss a variety of questions with Aubrey and others at a debate to be held on the 7th November. These take place under the rather provocative heading of 'Should science help us to live forever?' Perhaps unsurprisingly I have been asked to speak on the 'no' side.

I intend to present some arguments that have not, I believe, been heard before and go beyond the tired and tiresome "overpopulation" (as though people were yeast) and "boredom" (only boring people are bored)tropes. Some of them, and the failure to address them or realise they exist, are directly linked to the ~70 year failure to adequately fund the field. Therefore, whether ones agrees or disagrees with them they must be faced.

It is therefore important that the views of the lifespan extension community are presented fairly and objectively. Amusingly, there is a relative paucity of data in the peer reviewed literature on these (Partridge et al (2009)Am. J. Bioethics 9:68-76). This site has been, I think, overlooked as an academic resource. More bluntly, if you want to know what people think, you have to ask them.

Reading the site I have found ethical arguments asserting that, in addition to good health through the current life course (maximal currently ~125-130 years)an additional 60-100 years of life in good health would be as desirable, and a further 100 years equally so.

Arguments commonly used to support this contention include both notions of personal growth and primacy of freedom and choice as foundational human rights (https://www.fightaging.org/archives/2017/10/why-pursue-the-development-of-rejuvenation-therapies/). Are there any others? If so please let me know.

Arguments around the societal benefits of health are common between those primarily interested in improving health in later life and those primarily interested in extending lifespan (this is an attitudinal rather than a technical or experimental distinction. The distinction, in essence, is between researchers who are seeking to improve health and accept an extension of lifespan as a side-effect and those seeking to increase lifespan for whom the improvement of health is a pre-requisite. The experimental approaches employed by scientists pursuing either goal are substantially the same). There is a chance that I will publish the arguments and would like to quote any responses, I will of course acknowledge appropriately.

Since I'm here I'll pick up a couple of things from earlier posts. There are important from the point of view of structuring an argument. I don't expect them to change minds.

[1] Antonio appears to consider some of my arguments 'vague' and 'so general they can be applied to anything'. This is to mistake the point. A general argument can be used to rebut a specific case if that case relies on the general argument. By way of analogy, if dogs can't talk I do not, at least initially, need to engage in a detailed and specific argument about why your dog doesn't talk when you think it does. In this instance the underlying general argument is that an individual is making specific predictions about the future development of science and technology. Saying 'some were wrong and some were right' demonstrates a failure to understand the argument, which is that virtually EVERYONE who has tried to do this has failed. To succeed Aubrey would not simply be right he would be UNIQUELY right. In the words of the current 'Kingsman' film "That dog don't hunt".

[2] The MIT business. I have said this before and say it again. It would have been deeply unfair to Aubrey if his ideas had been ruled 'unworthy of serious consideration' (note the wording- not 'implausible' or 'unlikely to be executable within the next decade' but flat out 'unworthy'). Given that academics (NOT biogerontologists) recently held a conference on 'My little pony' "serious consideration" is a low bar. This matters because Aubrey in 'Ending Aging' appears to treat the verdict as a validation of his ideas. It is not.

[3] 'Faragher fails to show any of these new damages (sic)'. Faragher didn't have to. He simply had to postulate that our scientific knowledge about the mechanisms of ageing was incomplete. Hardly a gamble. However I draw your attention to:

Harries et al (2011) Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell. 10(5):868-78

Lee et al (2016) Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans. Aging Cell. 15(5):903-13

Latorre et al (2017) Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biol. 18(1):31

These papers describe alterations in RNA splicing capacity with ageing in humans and rodents probably resulting in key features of the underlying frailty of older organisms. This is independent of cell senescence but occurs in parallel with it. I did not expect to be involved in this work but it has caused my to reconsider some key aspects of my own ideas about ageing mechanisms. Splicing factor restriction does not fit any aspect of the SENS damage classes. This is a statement of fact rather than a criticism (qv). In terms of potential interventions I draw your attention to the new classes of molecules we have developed to reverse these changes which I hope could one day form the basis of drug development. Since only one of out ~5000 lead compounds ever becomes a drug I use the word 'hope' advisedly. Anyone thinking that the mainstream research community is not interested in the development of interventions is misinformed, to put it mildly.

[4]'SENS details'. This kind of thing tends to frustrate researchers because it is not clear which is being asked for (i.e. 'what argument would convince you SENS was wrong?' If none then there is nothing I can say to change your mind, so why say anything?). I will explain my 'take' on the problem:

'SENS' appear to combine the following features:
[a] It is asserted as being cognitively distinct from 'mainstream' gerontology (if it isn't then it IS gerontology). How is never foregrounded except in terms which misrepresent either what gerontologists do (e.g.work on metabolism'- I work of cell senescence, does that mean I am not 'mainstream')or why they do it 'just curiosity'. Sorry, I'm into fixing things.
(b) It is an ontology. It takes pre-existing data which we generated and organises it.
This is fine, ontologies are useful and the SENS ontology is quite good for the time in which it was written. I might personally have raised objections to the 'death resistant cells' strand but they wouldn't have been major. A key feature of ontologies (Linnean classification being a case in point) is that they are descriptive and regularly revised. They are problematic if they are used proscriptively and new findings are 'shoehorned' into them. Anyone holding that an ontology is valid for all time and not a simply a tool is riding for a fall.
(c) It has elements of a strategy (in 'Ending Aging'). The strategic elements of SENS are thus susceptible to the same critiques as other strategies (e.g. plausibility of assumptions). That is 'that dog don't hunt'.
(d) It has experimental and interventional elements. These fall into three classes. (A) interventions and approaches pre-existing in the literature (such as senescent cell clearance) which formed part of the general discussion within the community about what could be done to improve later life health. (B)ideas proposed before which Aubrey thought of again- here I am thinking of what became LYSOSENS in essence the idea that soil bacteria contain enzymes capable of degrading substrates refractory to ordinary lysosome action. This was first proposed by Bjorkstein in the late 1960s. (C) Ideas which Aubrey thought up himself such as WILT or moving the mitochondrial genome into the nucleus. At the time these were proposed they were not technically feasible. The longer one waits the more feasible in principle they might become.

In general, researchers are cautious around condemning experimental approaches out of hand. This is based on practical experience- things that should work in a lab frequently don't and things that shouldn't work occasionally do. This is because of two general features (I) technical difficulty- something that works really well in one system performs poorly in another (a trivial example being stable transfection of cell lines compared to human primary cell strains) and (ii) because of knowledge of the world is partial and may never be complete (for example the gene silencing experiments with anti sense in the 1980s in petunias- conducted in complete ignorance of the existence of miRNAs etc). Such ignorance is a perpetual, not transient state. Thus, the approach taken by most working scientists to an experimental approach is a probabilistic one- is it LIKELY to work? The answer to category (C) elements, by and large, was and is 'no'.

I trust that provides some clarification and look forward to hearing from you.

All best wishes
Richard Faragher

Posted by: Richard Faragher at October 20th, 2017 5:41 AM

Thanks for your reply, Mr. Faragher. I will try to answer all your points.

"Arguments commonly used to support this contention include both notions of personal growth and primacy of freedom and choice as foundational human rights. Are there any others?"

IMO, it's the decision to die what needs arguments, not the decision to continue living. Very very very very few people decide to die. For example, in my country, suicide rate is around 1 per 10,000 people per year. And even the people that decide to kill themselves, wait many years to do that (or to get in the mood of doing that). We even have many public services (some by the government, some by NGO) to prevent suicides. So to continue living is the common sense decision. It's the people who argue in favour of death who need to provide arguments (and very strong ones), not the other way around.

Even more so for medical researchers/doctors, since the goal of medicine is to cure people, not to let them get sick and die. Again, almost all sick people seek for a cure to their disease, if there is one (probably more than 9,999 per 10,000 but I have no accurate data).

"The distinction, in essence, is between researchers who are seeking to improve health and accept an extension of lifespan as a side-effect and those seeking to increase lifespan for whom the improvement of health is a pre-requisite."

I would be highly surprised if there were a significant part of the general population (not bioethicists population!) that thinks that the goal of medicine is not to prevent people from dying, but only to prevent people from being sick, and die anyway.

Now for the specific replies to my comments:

[1] "Saying 'some were wrong and some were right' demonstrates a failure to understand the argument, which is that virtually EVERYONE who has tried to do this has failed."

Yeah, that's one of the vague "arguments" in the debate, and thus not really worth considering. I called them arguments but I didn't really consider them real arguments, I mean, correct arguments. Simply I was referring to them that way because they were what you proposed as your arguments, so I called them 'your arguments'.

There are some general arguments that work in many situations (for example, you don't need to see a design of a perpetual motion machine to know that it won't work) but your "arguments" weren't of that type, they were so general, vague, undefined... that their premises apply to anything but, since they aren't real arguments, they don't work for anything. That's why I said in different parts of my comments that they can be applied to anything and nothing. They can be used in any situation, because they are so vague and general, but they aren't correct arguments in any situation, because they are logically faulty.

Everybody failed at heavier than air flying machines until the Wright brothers succeeded. Everybody failed at leaving Earth until Gagarin succeeded. Everybody failed at rabies until Pasteur and Roux succeeded. And so on. SENS is not a vague assertion that someday, somehow, aging can be cured. It's a detailed treatment strategy based on detailed medical and biological data. And there are very detailed and rational reasons why it should work where others failed (for a proper justification, see de Grey's book). It can't be simply dismissed with vague "arguments" like "everybody failed before". If you want to disprove it, you have to enter into details. And I didn't see any details in your speech at the debate.

[2] I think you are missinterpreting what I said. I was not saying that the MIT contest result validated SENS, what I said is that your "argument" using that result doesn't invalidate SENS.

[3] "Faragher didn't have to. He simply had to postulate that our scientific knowledge about the mechanisms of ageing was incomplete."

"Our scientific knowledge about the mechanisms of ageing is incomplete" and "there are damage types outside the seven SENS categories" are VERY different assertions. And anyway, SENS doesn't claim to list all the aging damages, only the damages that matter for current lifespans.

"Harries et al (2011) Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell. 10(5):868-78"

Good to see details.

(Epi)genetic mutations are considered by SENS only relevant to aging as a cause of cancer, cellular senescence or apoptosis, for current lifespans. And those problems are already covered by OncoSENS, ApoptoSENS and RepleniSENS. This is based on theoretical arguments (anticancer mechanisms in the cell are so huge that noncancerous (epi)mutations can't do real harm on current lifespans, apart from increasing senescent cells or deplete important cells) and on some research results that quantify the rate of (epi)mutation in human cells along the lifespan, both from SRF-funded research and from others. See for example:

http://www.sens.org/research/publications/protagonistic-pleiotropy-why-cancer-may-be-only-pathogenic-effect-accumulating-nuclear-mutations-and

http://www.sens.org/research/research-blog/2013-research-report-part-6-12-epimutations

The same theoretical argument can be applied to splicing "mutations". I don't know to what extent the burden of those spli-mutations is experimentally quantified, though.

[4] "This kind of thing tends to frustrate researchers because it is not clear which is being asked for"

Something in the line of [3] above would be good, i.e., some really medical/biological arguments. Again, in your speech you didn't comment about any of the seven damages or therapy types, only vague "arguments" about people failing before in totally different endeavours, discussions about Aubrey's position in Cambridge, discussions about gerontology history/advocacy/politics, etc.

About (a), (b), (c) and (c), I will try to reply to all together:

SENS is based on previous research. Both the damages and the treatments (except WILT, I think) have been discovered/proposed by previous researchers. What is original from Aubrey de Grey is:

(1) The compilation of all the damages that cause aging in a comprehensive categorization. All those damages are known from at least 1985, but nobody tried (or claimed) to elaborate a comprehensive list.

(2) A treatment type is proposed for every damage type. Indeed, the damage categories were created based on the treatments that can address each damage. Again, those treatments were proposed before by others (not all of them being gerontologists), except WILT.

The two points above constitute a detailed research strategy to completely cure aging (instead of simply slowing it, like most biogerontologists did when SENS was proposed), the novelty being it's completeness, its focus on removing damage (instead of slowind accumulation), and its short-term feasibility (no need for highly advanced nanotechnology and the like).

There have been similar attempts (the Hallmarks of Aging paper) but SENS predate it by more than a decade, and anyway the Hallmarks is not completely based on damage-repair but mixes repair and slowing, and AFAIK doesn't aim at completely curing aging.

(To be clear, when I say "completeness" I mean for current lifespans, SENS doesn't claim to know what damages will be important for 500 year olds. Those damages, if they exist, will need to be investigated and adequate cures found.)

Posted by: Antonio at October 20th, 2017 2:35 PM

Richard, you're wrong about the mito stuff. No, Aubrey didn't invent the idea of "moving the mitochondrial genome into the nucleus." Nagley's group first proposed the idea back in 1986. And no, the allotopic expression approach he is advocating isn't all that improbable. It seems to be starting to work in multiple clinical trials for LHON patients for the ND4 mito gene. Yes, in human LHON patients. Right now. Allotopic expression is also starting to work for getting the ATP6 and ATP8 mito genes to work at the same time in the same cell in vitro.

https://web.archive.org/web/20071031105459/www.sens.org/IBGcase.htm#mtmut

https://www.fightaging.org/archives/2016/06/multiple-independent-groups-are-carrying-out-trials-of-allotopic-expression-of-mitochondrial-genes-the-basis-for-a-rejuvenation-therapy/

https://www.fightaging.org/archives/2017/06/gensight-continues-to-forge-ahead-with-the-first-implementation-of-allotopic-expression-of-mitochondrial-genes/

https://www.fightaging.org/archives/2016/09/first-published-paper-for-the-sens-research-foundation-mitochondria-team/

Posted by: Florin Clapa at October 20th, 2017 4:23 PM

Since you seem to have missed my point, I'll say it again too—this time more directly. It seems that Aubrey was looking for "serious consideration" of SENS from gerontologists (or biogerontologists or whatever you want to call them) in the context doing something about aging, but when that wasn't forthcoming, he took what he could from the fairly respectable judges (even though they weren't gerontologists) of the TR thing. Equating that with debating about crackpot ideas seems disingenuous.

Posted by: Florin Clapa at October 20th, 2017 6:32 PM

Dear both,

Thank you for this. It has proved informative.

Antonio, for completeness I will outline some answers regarding the 'providing reasons for dying' business. This is done the way a lawyer might provide suggestions about how a case might go 'in law' before judges from various legal schools. I do not necessarily associate myself with any of there positions.

An ethical relativist would simply not feel obliged to provide you with reasons, strong or otherwise, for not wishing to have a greatly extended lifespan. They can simply assert that the decision is right 'for them'. Relativism gets a rough ride from many philosophers (particularly realists and meta realists with whom I feel an affinity) but in practice many social problems are dealt with (or avoided) by recourse to relativism (I will touch upon a possible explanation for this on the 7th if time allows).

Some individuals (I estimate 10-30% of the population) will probably not view choosing to reject life extension as functionally equivalent to committing suicide (even though it could be argued that is in fact the case). This is because the situation is comparable to the throw switch/don't throw switch component of the 'Trolley problem' and its variants first proposed by Phillipa Foot in the late 1960s. Many actors do not intuitively regard the idea that 'choosing not to make a choice is still a choice' as valid. There are evolutionary reasons for this.

Some communitarians (the essence of communitarian positions being that there are no 'unencumbered selves' and the individual is structured/exists only through the community) would postulate circumstances under which rejecting lifespan extension is a moral obligation. The analogy would be with those who sacrifice themselves for the defence or enhancement of the community in wars. They are willing and highly honoured but do not necessarily wish to die. Those who give themselves up to act as food in a famine are similarly honoured, though no-one wishes to be lunch.

The essence of this position is that right action is dictated by the needs of the many who constitute the community, not the needs of the individual. It is worth noting in passing that a moral actor who regards human lives as ethically incommensurable would not find this line of reasoning compelling.

An individual from an honour-based culture would not extend their life if it required an act that was viewed as dishonourable (for example violating an obligation). Under such circumstances passivity would probably result regarding ageing and if a dishonourable act was inadvertently committed suicide would result and would atone for any honour lost. It is important to note that, in contrast to the negative view of suicide held in the Western cultural tradition this individual would be mourned but viewed positively by other members of his or her culture. The Japanese saying 'Death is a feather, duty is a mountain' summarises this perspective. In short, correct behaviour trumps survival. In passing it is worth noting that an individual does not need to believe in an afterlife to hold this position.

Again, one does not have to be convinced by any of these arguments. One simply has to recognise that they are regarded as compelling by those who hold them and are internally consistent. That is, the actor is behaving rationally within their own ethical framework. The more deontological of these positions would regard life extension, under some circumstances as valorising personal survival over other moral needs. A life extensionist might call them 'stupid'. If they bothered to reply at all (and the relativist wouldn't) they might retort that the extensionist was 'selfish' or 'infantile'. This is unhelpful to the extensionist since he/she needs to get them on side. They do not need him and may actively impede him if they regard him as threatening moral norms.

Florin, do you have any ethical component to add? I would just say (again). I am not comparing Aubrey's ideas to the wilder academic fringe. Rather, I assert that a panel of judges ruling his ideas beyond serious discussion would have essentially deemed them of less worth than a meeting on 'My little pony'.

The idea that Aubrey wants his ideas to be 'taken seriously'(and I am indebted to Antonio for explaining what these are held to be by those convinced of their value) appears to constitute a demand that they are seen as having high 'salience' (as a political scientist might say). I am afraid there is nothing in the features identified as unique that persuades me, personally, to accord them prominence, either for good or bad. It would appear most of my colleagues are of like mind. The general attitude to a low salience issue is not hostility so much as 'so what?'.

I must stress this is neither positive or negative, it simply 'is' and it is frustrating if someone views as low salience an issue that another considers the Most Important Problem. However, it can be worked round. By way of example, when Aubrey and I discussed which issues constituted points of disagreement Aubrey assigned a high salience to his view that some gerontologists were, as he put it, 'saying there would be big gains in lifespan from rapamycin when in fact there would be small ones' (Aubrey- if I've misquoted you I'm really sorry). I was quite happy to address this but it wasn't even on the salience radar for me. Vice versa, I ascribe high salience to Aubrey's claim that the early gerontologists essentially invented the 'ageing-disease' divide. I'm not sure Aubrey regarded it as the highest salience issue but he was willing to put it on our debate list as well.

Many thanks
Richard

Posted by: Richard Faragher at October 21st, 2017 10:53 AM

Dear Dr. Faragher,

well, I, and all people I know in the life extension community, don't want to force life extension on anybody. Everybody should be free to use or not use it. The problem is that the debate is 'Should science help us to live forever?', not 'Should I live forever?'. And thus, the other side of the debate, i.e., the people answering NO to the first question, are demanding to force all humanity to not use life extension, thus forcing all people in the world to die, whether they want or not.

Again, you need very strong arguments to defend that position, since 99,99% of people want to live. Even more, life is the most basic human right, first and foremost in any modern legislation and of course in the Universal Declaration of Human Rights and other international treaties.

So, it's that side of the debate who needs a very good explanation of why stopping LE research is not a highly unethical demand.

The fact that some people do want to die, due to depression, honour, religion or whatever, doesn't change that need. So, when you say:

"An ethical relativist would simply not feel obliged to provide you with reasons, strong or otherwise, for not wishing to have a greatly extended lifespan."

"Some communitarians [..] would postulate circumstances under which rejecting lifespan extension is a moral obligation."

"An individual from an honour-based culture would not extend their life if it required an act that was viewed as dishonourable"

"Again, one does not have to be convinced by any of these arguments. One simply has to recognise that they are regarded as compelling by those who hold them and are internally consistent. That is, the actor is behaving rationally within their own ethical framework. The more deontological of these positions would regard life extension, under some circumstances as valorising personal survival over other moral needs."

you are talking about a very different debate.

"Some individuals (I estimate 10-30% of the population) will probably not view choosing to reject life extension as functionally equivalent to committing suicide"

I think what they say in polls and the like, and what they will do when time comes and they need to decide whether to use or not to use the treatments will be very different. I don't know any old people that refuses to use medicine. On the contrary, they usually overuse it, and they are the most afraid people about delinquency, car accidents, etc.

"The general attitude to a low salience issue is not hostility so much as 'so what?'."

Somebody presents a plan that you consider not unscientific, that can be fully implemented in 25-35 years and that, if successful, would prevent 70% of deaths in the world, more than 90% of deaths in the developed countries, and what you have to say is 'so what?'???????

Posted by: Antonio at October 21st, 2017 1:10 PM

Seriously, WTF?????

Posted by: Antonio at October 21st, 2017 1:16 PM

Dear Florin,
Thanks for these, I had missed them, ditto Nagley. As you say, they don't provide ethical framework information but the numbers are useful regardless.
All best wishes
Richard

Posted by: Richard Faragher at October 22nd, 2017 5:20 AM

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