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

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