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Does Killing Senescent Cells REALLY Extend Rodent Lifespan?

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Sithra (thanks Sithra!) was the first to alert us of this brand new study [1] out yesterday in Nature, now getting lots of attention in the popular press (e.g. here, here and here). He made relatively casual mention of it, deep in this thread on Intrinsic Aging, so at first I didn't realize its significance. Now that I do, I think it definitely deserves its own thread.


It could be the kind of "out of the blue" breakthrough mentioned here that just might rapidly advance the science of human longevity, or at least put us on the road to longevity escape velocity to give Aubrey and Co. time to solve the plethora of other problems (discussed here and here) which cause aging...


With that build-up, what was the study about, and what did they find?


It was a study in mice, and the effects on health & longevity of killing off of senescent cells - old dysfunctional cells that are no longer dividing, but that refuse to die and as a result spew out reactive oxygen species (ROSs) and inflammatory chemicals into the body. It has long been suspected that senescent cells contribute to aging, but it has been hard to prove it. It seems that the researchers in this study may have done that, and opened up new research directions for anti-aging therapy.


What they actually did is rather complicated. But in a nutshell, as I understand it, here is what they did. It seems that in addition to all other crap that senescent cells spew out, they generate a tumor suppressing protein called p16Ink4a, which I'll abbreviate as p16. From this popular press article:


You can think of [p16] as basically [the senescent cells'] calling card.
By rewriting a tiny portion of the mouse genetic code, Baker and van Deursen's team developed a genetic line of mice with cells that could, under the right circumstances, produce a powerful protein called caspase when they start secreting p16.  Caspase acts essentially as a self-destruct button; when it's manufactured in a cell, that cell rapidly dies [via apoptosis]. 
So what exactly are these circumstances where the p16 secreting cells start to create caspase and self-destruct? Well, only in the presence of a specific medicine the scientists could give the mice. With their highly-specific genetic tweak, the scientists had created a drug-initiated killswitch for senescent cells.


So the researchers took mice genetically modified to carry this senescent cell "kill switch" and started injecting them with the kill switch activator at 12 months of age (around the human equivalent of 45 years old). This resulted in the death of a large fraction of senescent cells in various parts of the mice with the kill switch. As a result, in two strains of mice, both males and females median lifespan was significantly extended by about 25%. Here are the male-only survival curves of controls without the kill switch but treated with the activator (C57 +AP), controls with the kill switch but without activating it (ATTAC -AP) and the treatment group with the kill-switch which was activated (ATTAC +AP) to kill off the senescent cells, for the commonly-employed C57BL/6 strain of mice:




The magenta curve shows administering the activator alone doesn't improve or harm the survival of natural mice without the genetically-engineered kill-switch (C57 +AP). The dark blue (solid) curve shows the genetic modification, without the activator, doesn't improve or harm mice survival either (ATTAC -AP). The light blue (dashed) curve shows that in mice with the kill-switch and treated with the kill-switch activator (ATTAC +AP), lived significantly longer on average, by in this case, a whopping 35%. The "xxx d" numbers associated with each curve represent the different groups' median lifespan.


Now before we jump to any conclusions, we should do as Michael always says, and check the longevity of these mice against other studies of the same strain, and especially compare their longevity with the results of CR. From this study [2], discussed here, the median lifespan of male-only C57BL/6 is 26.3 months for AL fed mice and 32.6 months for CR fed mice. At an average of 30.4 days per month, that is a median lifespan of 800 days for AL mice, and 991 day for CR mice (24% life median life extension for CR). 


Hmmm... That calls these results into question a bit. Why? Because well-cared-for C57BL/6 mice fed ad lib appear to live 800 days in other labs, whereas the equivalent so-called "controls" in this study lived only 626 days. Killing off the senescent cells eliminated this early death effect observed in the so-called controls, boosting the treated mice to a median lifespan of 843 days. But this 843 days is only marginally longer (if at all) than the median lifespan of well-cared-for ad lib controls in this strain (800 days), and nowhere near the median lifespan of male C57BL/6 mice subjected to CR (991 days).


The other important thing to notice is that in the above survival curve, the median lifespan of the treated mice was increased, but not the maximum lifespan. The two blue curves hit zero on the x-axis at the exact same age. This is in contrast with the effect of CR in this strain, where the median and maximum lifespan of CRed mice is greatly extended, as can be seen from the survival curve from [2]:




Whether it was due to poor animal husbandry, or something in the genetic manipulation, treatmetn and/or kill-switch activator compound itself, something was killing off the control animals early in this new study. The treatment appears to restore their median longevity to the natural median lifespan of well-cared-for ad lib-fed controls, but even there the maximum lifespan of well-cared-for ad lib-fed controls was 1042 days (34.3 months), while the treated animals in this study lived to a maximum of only 900 days. So the treated mice didn't even come close to the maximum lifespan of ad lib fed well-cared-for mice, to say nothing of the 1300 day maximum lifespan of the well-cared-for CR C57BL/6 mice.


This may explain several anomalies between the popular press reports of this study and the full text of the study itself. First of all, compare the gushing popular press headlines:

  • In New Anti-Aging Strategy, Clearing Out Old Cells Increases Life Span of Mice by 25 Percent - MIT Technology Review
  • Scientists Can Now Radically Expand the Lifespan of Mice—and Humans May Be Next - Popular Mechanics

with the much more modest title from the Nature paper itself on which they are reporting:

  • Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan - Nature

I've underlined the key difference - "shortens" vs. "increases", "adds up to a third" or "radically expands". With the very title of their paper the authors are conceding that they haven't actually increased the median (to say nothing of maximum) lifespan of mice relative to normal, ad lib controls of the same strain with their treatment for killing off senescent cells. In the discussion section of the full text of the paper, the authors clarify what might be going on with this passage:


It will be useful to optimize senescent cell removal protocols and methods further because the longevity of male C57BL/6 mice seemed negatively affected by repetitive vehicle injection stress, and because clearance was partial and several key tissues were refractory to clearance, including liver and colon.


In short, so far the 'cure' (killing off senescent cells) seems worse (or at least not significantly better) than the 'disease' (living with senescent cells).


Plus, remember the mice had to be genetically engineered so that their p16-expressing senescent cells would be targeted by the apoptosis-activating compound, a genetic modification that a technology like CRISPR might one day be able to pull-off in humans, but that day is a long way off.


So not for the first time, I started off a post with a flourish of enthusiasm, only to discover the popular press has seriously overhyped the significance of the research. I considered going back and curbing the enthusiasm I expressed in the introductory paragraphs of this post. But I figured it was better not to - since this way it serves as a nice case-study in the value and importance of careful reading and analyzing the original source.


Overall, the results are certainly suggestive that senescent cells are bad news for health & longevity, but we pretty much knew that already. Getting rid of senescent cells may indeed extend longevity, at least on average. But true (maximum) human lifespan extension, still seems to remain a long way off... But this hasn't stopped the researchers involved from partnering with the Buck Institute to form a biotech startup called Unity Biotechnology to try to push towards commercializing methods to clear senescent cells. 





[1] Nature. 2016 Feb 3. doi: 10.1038/nature16932. [Epub ahead of print]

Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.

Baker DJ(1), Childs BG(2), Durik M(1), Wijers ME(1), Sieben CJ(2), Zhong J(1), A
Saltness R(1), Jeganathan KB(1), Verzosa GC(3), Pezeshki A(4), Khazaie K(4),
Miller JD(3), van Deursen JM(1,)(2).

Author information:
(1)Department of Pediatric and Adolescent Medicine, Mayo Clinic College of
Medicine, Rochester, Minnesota 55905, USA. (2)Department of Biochemistry and
Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905,
USA. (3)Division of Cardiovascular Surgery, Mayo Clinic College of Medicine,
Rochester, Minnesota 55905, USA. (4)Department of Immunology, Mayo Clinic College
of Medicine, Rochester, Minnesota 55905, USA.


Full text: http://www.nature.com.sci-hub.io/nature/journal/vaop/ncurrent/full/nature16932.html

Cellular senescence, a stress-induced irreversible growth arrest often
characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also
known as Cdkn2a) and a distinctive secretory phenotype, prevents the
proliferation of preneoplastic cells and has beneficial roles in tissue
remodelling during embryogenesis and wound healing. Senescent cells accumulate in
various tissues and organs over time, and have been speculated to have a role in
ageing. To explore the physiological relevance and consequences of naturally
occurring senescent cells, here we use a previously established transgene,
INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice
by injection of AP20187 twice a week starting at one year of age. We show that
compared to vehicle alone, AP20187 treatment extended median lifespan in both
male and female mice of two distinct genetic backgrounds. The clearance of
p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related
deterioration of several organs without apparent side effects, including kidney,
heart and fat, where clearance preserved the functionality of glomeruli,
cardio-protective KATP channels and adipocytes, respectively. Thus,
p16(Ink4a)-positive cells that accumulate during adulthood negatively influence
lifespan and promote age-dependent changes in several organs, and their
therapeutic removal may be an attractive approach to extend healthy lifespan.

PMID: 26840489



[2] Genotype and age influence the effect of caloric intake on mortality in mice.

Forster MJ, Morris P, Sohal RS.
FASEB J. 2003 Apr;17(6):690-2. Epub 2003 Feb 5.
PMID: 12586746 Free PMC Article
Long-term caloric restriction (CR) has been repeatedly shown to increase life span and delay the onset of age-associated pathologies in laboratory mice and rats. The purpose of the current study was to determine whether the CR-associated increase in life span occurs in all strains of mice or only in some genotypes and whether the effects of CR and ad libitum (AL) feeding on mortality accrue gradually or are rapidly inducible and reversible. In one experiment, groups of male C57BL/6, DBA/2, and B6D2F1 mice were fed AL or CR (60% of AL) diets beginning at 4 months of age until death. In the companion study, separate groups of mice were maintained chronically on AL or CR regimens until 7, 17, or 22–24 months of age, after which, half of each AL and CR group was switched to the opposite regimen for 11 wk. This procedure yielded four experimental groups for each genotype, namely AL==>AL, AL==>CR, CR==>CR, and CR==>AL, designated according to long-term and short-term caloric regimen, respectively. Long-term CR resulted in increased median and maximum life span in C57BL/6 and B6D2F1 mice but failed to affect either parameter in the DBA/2 mice. The shift from AL==>CR increased mortality in 17- and 24-month-old mice, whereas the shift from CR==>AL did not significantly affect mortality of any age group. Such increased risk of mortality following implementation of CR at older ages was evident in all three strains but was most dramatic in DBA/2 mice. Results of this study indicate that CR does not have beneficial effects in all strains of mice, and it increases rather than decreases mortality if initiated in advanced age.
Keywords: caloric restriction, aging, C57BL/6, DBA/2, B6D2F1
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Thanks for your writeup, Dean.


What interested me was the idea that only some (60-70%) of the sick cells needed to be cleared in order to show a therapeutic effect (in gen-modified mice)


I posted with regard to your comments about SRF and de Grey because maybe all sick cells need not be cleared out in order for SENS type therapies to be beneficial. A first, more humble step, may be developing drugs to clear only some toxic-spewing cells. Not all, just most. Of course it's still wild crazy dreaming in the over regulated environment of 'merican medicine -- where nothing much will happen without deep political changes. Like, maybe the 21st Century Cures Act, which appears stalled in the senate until now spring 2016 :-(

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Its pretty crazy how much hype this senescent cell therapy study is getting in the popular press, and how ill-informed it is. Even a supposedly scientifically rigorous site like Phys.org is touting this study as the greatest thing since sliced bread, saying:


The results of deleting senescent cells in this manner are impressive. Median lifespan increased by about 25%. This is a similar effect to that of two laboratory interventions already known to extend healthy lifespan in mice – dietary restriction and supplementation with the drug rapamycin.
First of all, the benefits of rapamycin are highly contentious. And as for CR, as the analysis above shows, the treatment group in the senescent cell study barely lived longer than AL-fed controls of this strain, and lived far shorter lives than well-cared-for CRed mice, both in terms of median (-17%) and especially maximum (-40%) lifespan.
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Its pretty crazy how much hype this senescent cell therapy study is getting in the popular press, and how ill-informed it is.

That may be because you -- yes you, Dean Pomerleau! -- are probably more devoted to this stuff than the writers. You more know about the mice used here, and have probably actually read the study and thought coherently about it.


Have you considered becoming a gerontologist, Dean? You have major contributions to make, it seems to me, and it's a shame to see your talents wasted on irreverent hacks like me.


Meanwhile, I still think the mouse study is hopeful and encouraging. In that, you know, mousy kinda way that won't be translatable for more decades. And another new startup company is forming to pursue it; you, Dean Pomerleau, should apply for a job as their chief science writer! But no! Then you'd disappear from us here :-(

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above: Image from AAAS article: "Although these two mice are the same age, the mouse on the right appears younger because researchers removed its senescent cells."


This (same ??) study was also in the Feb. 4 Science magazine (AAAS) podcast (at start of Podcast):






The mice image above seems impressive, but there are aspects of the study more questionable ...


Perhaps the most interesting part of the study describes changes to mice psychology (podcast 02:32) -- the mice were more daring (risk taking)! 


They were more daring and youthful than the control mice. Like middle-aged folks who’d rather watch TV than hit the clubs, the controls were less active and more reluctant to explore new environments.

This is sort of reminiscent of the psychological effects of toxoplasmosis, the human effects of which are documented here:



The noticeable changes in risky behavior, in the application of senescent-cell therapy, is a cautionary reminder -- esp. to anti-senescence advocates -- that Mother Nature is in charge.


BTW, just after the senescent-cells story, listen for the report on flexible wristbands that taste sweat (like a super-duper FitBit). 




No surprise, the paper journal's own podcast (Nature) has a topical segment here [15:42]:


Spring cleaning cells---Mice live up to one-third longer if their old, worn-out cells are removed

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The study used the intervention at 12 months, not 4 months as was done in the study you referenced above. Walfords study in 1982 using C57BL/6 mouse strain also implemented CR at 12 months and here was the result:


Weindruch R, & Walford RL. (1982). Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science, March 12, 215(4538), pages 1415-8.



Also, see: Lifespan of C57BL, though it doesn't mention substrain:

"Mean life-span 800 days in males and 750 days in females according to Rowlatt et al. (1976)"



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Thanks Matt - Nice to see you on these forums again!


Let's ignore comparisons with CR when evaluating the senescent cell therapy study (PMID: 26840489), since you are right that CR's effectiveness depends on when and how CR is initiated, so it is hard to compare with this study.


The real point of my critique above is that something about the animal husbandry and/or senescent cell treatment that is shortening the lives of the mice they are employing, and then the senescent cell therapy is bringing their lifespan back up to around the level it would have been if they had simply fed them ad lib and left them alone. So it seems misleading, or at least premature, to say the treatment is extending the lifespan of the mice, since they are not living any longer than well-cared-for, AL-fed mice of this strain normally do.


Now let's consider this critique in light of lifespan on the control C57BL/6 mice in the W&W (1982) study (PMID: 7063854) which you point to. As is shown by the faint lines in the "B6" graph you posted, the median lifespan for the control mice appears to be just over 24 months. From the full text, "Mean survival was 24.9 ± 0.9 months for all of the B6 controls...". So let's split the difference, and say 24.5 months. At 30.4 days per month, that is 745 days for well-cared-for AL mice from the same strain as the senescent cell therapy study. While 745 days is somewhat short of the "800 days" I indicated in my analysis to be the median lifespan of these mice, it's still a lot longer than the 625 days the "control" mice in the senescent cell therapy study were living. But the 843 day median lifespan of the senescent cell treatment group is looking pretty good relative to this 745 day control mouse lifespan - i.e. a 13% life extension, which isn't the 25% claimed in the paper, but it would seem significant. I certainly wouldn't mind 13% more years!


But let's look at the issue of control longevity in this strain a little more closely. You'll obviously have noticed the W&W study is from 1982. That's a long time ago. Researchers have learned a lot about the proper diet and husbandry of lab mice since then. In particular, in 1991, it was learned that the Purina Lab Chow commonly fed to mice in prior controlled feeding studies (and specifically fed to the mice in the W&W (1982) study as stated in the full text), contained toxic levels of aluminum which was shortening animal lifespans [1]. But even so, animals in [1] fed the Purina chow with excess aluminum lived an average of 852 days, and on the non-toxic chow to 901 days. So using either of these (852 or 901 days) as a benchmark, the 843 day median lifespan of the senescent cell treatment group doesn't look so impressive, and my thesis stands.


Finally, as Michael points to in this helpful post, in reference to this figure from [2]: 



Representative age ranges for mature life history stages in C57BL/6J mice; comparison to human beings. 

(Adapted from Figure 20-3: Flurkey K, Currer JM, Harrison DE. 2007. The Mouse in Aging Research.

In The Mouse in Biomedical Research 2nd Edition. Fox JG, et al, editors. American College Laboratory

Animal Medicine (Elsevier), Burlington, MA. pp. 637–672.) Swiped from Life span as a biomarker, a page

from David Harrison's lab at The Jackson Laboratories.


the  50% survivorship for well cared for C57BL/6 mice is generally accepted to be about 28 months. A lifespan of 28 months is 851 days. So again we see evidence that the senescent cell treatment is simply restoring a shortened lifespan to normal for this strain. 


For anyone who is more visually than numerically inclined, I've made a simple graph to illustrate my point about the real results of the senescent cell therapy paper. Here it is:




As you can see, the Senescent Cell Therapy Controls are living a heck of a lot shorter lives (625 days) than well cared for controls of this strain (851 days). The treatment to kill off the senescent cells is restoring the mices' lifespan to 843 days, about the same as the well cared for controls, which is nice. But until they show median (or better yet, median and maximum) lifespan extension with the therapy relative to well cared for controls, it doesn't seem like it warrants getting all that worked up about. Although this analogy may not be quite fair, it is sort of like subjecting a group of animals to an insult or injury that shortens their lifespan, and then treating them to repair the insult/injury and claiming victory for extending lifespan. A sort of Munchausen Syndrome by Proxy, rodent style.  :)xyz


Don't get me wrong. I don't want to suggest that this sort of treatment won't ever be an important arrow in the quiver of anti-aging techniques. There is clearly something going on, and we know pretty well that senescent cells are bad news, so one would hope that clearing them would/will be beneficial. It's just that they've got a ways to go to refine and demonstrate the effectiveness of their approach before the researchers (via the media) should be shouting from the rooftops about extending lifespan by 25%. 





[1] AGE April 1991, Volume 14, Issue 2, pp 53-56

Comparative survival of C57BL/6J mice on two commonly used mouse diets
Harold R. Massie, Valerie R. Aiello, Syamala M. Sternick
Survival of C57BL/6J male mice was found to improve when fed Old Guilford (OG) mouse food as compared to Purina (P) mouse diet. The median life span increased 3.9%, the longest-lived decile increased 17.3% and the maximum life span by 18.5%. This occurred in spite of the fact that the peak weight attained by mice on the OG diet was 14.7% higher than the maximum weight on the P diet. Mean survival times were 852 days on the P diet and 901 days for the OG diet. The increase in the maximum life span was greater than that for the mean or median, with 933 days for the P diet and 1106 days for OG.
The two different commercially available diets were found to differ in their trace element content. The P diet was higher than the OG diet by 908% for aluminum, 1% for boron, 22.3% for cadmium, 231% for calcium, 29.2% for copper and 100% for iron. In addition to these differences in trace element content, other factors may have been involved in determining life span such as differences in food consumption or in the caloric content of the two diets.
[2] Flurkey K, Currer JM, Harrison DE. 2007. The Mouse in Aging Research. In The Mouse in Biomedical Research 2nd Edition. Fox JG, et al, editors. American College Laboratory Animal Medicine (Elsevier), Burlington, MA. pp. 637–672.
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I do not have so much difficulty if control and experimental treatment subjects are both treated in ways that limit potential lifespan.  You say, Dean, that fixing a problem with husbandry is not increasing longevity, but I doubt that unrelated treatments would exactly counter each other.  What got me wondering about the Nature paper was that I failed to see -- did I miss it -- mention of Calorie/food consumption or even weight of the animals -- although the latter seems to be addressed in the picture of the mice shown above.

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What got me wondering about the Nature paper was that I failed to see -- did I miss it -- mention of Calorie/food consumption or even weight of the animals -- although the latter seems to be addressed in the picture of the mice shown above.


Good point Al. I searched the paper and you are right - they don't report food intake or body weight. But they do report several interesting things in the figures in the "Extended Data" at the bottom of the full text of the paper that I hadn't paid attention to, that are worth noting. First, regarding the anomalous short lifespan of the controls - in extended data figure 4, they address this issue and confirm that their controls are indeed short-lived relative to other studies:




so that remains an issue that even the authors recognize.


The closest they come to your question of weight is extended data Figure 9h:



where they show the total fat mass didn't differ between male mice with the genetic modification but not given the "senescent cell suicide" compound (ATTAC -AP) and male mice without the genetic modification but given the "senescent cell suicide" compound anyway (WT +AP). This sort of suggests that it might not be a "crypto-CR" effect, but only very weakly, since strangely, they don't show the fat mass of the mice in the treatment group, with the ATTAC gene and given the suicide compound (ATTAC +AP). I wonder why...


I also found Figure 6 in the extended data to provide interesting insights, particularly as to what six months of the senescent cell treatment didn't accomplish:



Figure 6a shows that the treated male mice (light blue bar) weren't any more coordinated than the control mice (dark blue bar). 


Figure 6b shows they weren't any better on the rodent equivalent of a declarative memory test.


Figure 6c,d,e show they weren't stronger or more able to exercise than control mice.


Overall, while the treated mice may have lived somewhat longer on average, killing off senescent cells didn't appear to benefit either their physical or cognitive health relative to age-matched controls...



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Regarding the (in)significance of this treatment to remove senescent cells in mice for fighting human aging, Michael has several posts in the comment section discussing this study over on the Fight Aging! website. He seems to generally agree with me, saying (my emphasis):


Right f****ing on!! Thanks, Reason. [in response to a commenter named Reason, who praised the study as an important indicator that researchers are finally pursuing an engineering approach to fighting aging - DP]
To be clear, they're claiming a 25% increase in median LS, not maximum: a substantial decrease in midlife mortality, but still lights out for everyone by their genetic fate. This is as you'd predict, based on the principle of the "weakest link in the chain": to move the needle on maximum lifespan, you have to push back on all of the cellular and molecular damage of aging, not just one form.
One caveat is that actually, the untreated mice lived a little bit shorter than they "should" have by historical precedent, and the treated mice only lived as long as they "should." The authors attribute this, not unreasonably, to the stress of being grabbed and injected with the drug that activates the INK-ATTAC "suicide gene" twice a week from early middle age until the day they die.
In a later comment, Michael clarifies that "lights out for everyone by their genetic fate" means a lifespan of about 82 years on average. So alone this strategy won't "move the needle" wrt real lifespan extension, even if it works in humans as it appears to (maybe) in mice.
I'm really looking forward to Michael's promised response over on this thread (in particular this and this post) on what it is really going to take to get past the "weakest link in the chain" problem he references, and significantly extend human longevity via the SENS strategy.
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The Scientist » News & Opinion » Daily News

Aging Shrinks Chromosomes

A study on human cells reveals how cellular aging affects the 3-D architecture of chromosomes.


By Ruth Williams | February 5, 2016


Still from video showing model of chromosome compaction (right) in aging cells

CRISCIONE ET AL, SCI. ADV. 2016; 2 : e1500882

In cells undergoing senescence, chromosomes tend to become more compact, according to a report published today (February 5) in Science Advances. This and other chromatin rearrangements noted in the report add to a growing understanding of how the physical structure of chromosomes might contribute to altered gene expression in aging cells.


“This is the first study using this model of replicative senescence to define those higher-order three-dimensional chromatin changes,” said epigeneticist Peter Adams of the Cancer Research UK Beatson Institute in Glasgow who was not involved in the work. “It’s something that people have waited for quite a long time to see.”


Although getting older causes our tissues to deteriorate and eventually fail, at a cellular level senescence is an important process for health. Cellular senescence marks the permanent, stable end to a cell’s replicating ability. “It basically puts an upper limit on the number of times that any one cell can divide,” explained Adams and, therefore, “it inherently tends to prevent cancer”—which occurs when cells proliferate uncontrollably. On the other hand, this lack of cell division prevents tissues from indefinitely renewing, so, eventually, muscles weaken, bones fracture, and skin wrinkles.


At the genomic level, “it’s been known for a long time that the chromatin of senescent cells changes radically,” said cell and developmental biologist Jeanne Lawrence of the University of Massachusetts Medical School who also was not involved in the work. Although exactly why “is kind of a mystery,” she said.


Lawrence and colleagues had previously shown, for example, that the normally densely packed heterochromatin at centromeres loosens up as cells age. Others had noted that senescence in some cell types triggers the formation of densely packed heterochromatin foci. Meanwhile, Nicola Neretti of Brown University—who led the present work—and his colleagues had shown that although the chromatin around some genes becomes inaccessible during senescence, other regions seem to open up.


It was time to scale-up, said Neretti. “Instead of just looking at accessibility of different parts of the genome,” he said, “we were wondering how does this happen at the level of the chromosome.”


To examine 3-D genome conformation, Neretti’s team first used a technique called Hi-C, which reveals the proximity of any genomic region to any other in nuclear space. This analysis revealed that as human fibroblast cells became senescent the number of short-range interactions—such as those between neighboring regions on a chromosome—increased, while there was a decrease in long-range interactions—such as those between non-neighboring loci on the same chromosome or between loci on different chromosomes.


This increase in short-range interactions suggested that the chromosomes might be shrinking in volume, said Neretti. To see whether this was the case, the team performed 3-D chromosome painting—a technique whereby fluorescent DNA probes spanning an entire chromosome are used to hybridize, or “paint,” that chromosome in structurally preserved cells. Painting thus reveals the volume of the nucleus occupied by a particular chromosome. Comparing chromosome volumes in proliferating cells with those in senescent cells confirmed the smaller size of those in the latter.


Although there was a global increase in chromatin compaction—that is, a decrease in chromosome volume—associated with senescence, certain regions of the genome behaved in the opposite manner, the researchers found. Hybridization of fluorescent probes to centromeric DNA, for example, revealed that these regions increased in volume, in line with Lawrence’s previous observations. And some heterochromatic regions of the genome became more decondensed too. Furthermore, the expression of genes in these decondensed regions tended to be upregulated, while gene expression in regions that condensed during senescence tended to decrease.


For researchers studying cancer and aging, said Adams, a major goal is to find ways “to maintain the cancer suppressive effects [of senescence] but somehow prevent the ageing [effects]” and thereby help people to maintain healthy tissues for longer.


To that end, the new work “helps us to understand how the epigenome is regulated in senescent cells: how some genes are repressed and how other genes are switched on,” Adams told The Scientist.


Ultimately, added Neretti, “the more we understand about how the senescent state is achieved, the more we will be able to modulate and control it.”


S.W. Criscione et al., “Reorganization of chromosome architecture in replicative cellular senescence,” Science Advances, 2:e1500882, 2016.




senescence, genetics & genomics, epigenetics, disease/medicine, chromatin, cell & molecular biology and aging


Science Advances  05 Feb 2016:

Vol. 2, no. 2, e1500882

DOI: 10.1126/sciadv.1500882




Replicative cellular senescence is a fundamental biological process characterized by an irreversible arrest of proliferation. Senescent cells accumulate a variety of epigenetic changes, but the three-dimensional (3D) organization of their chromatin is not known. We applied a combination of whole-genome chromosome conformation capture (Hi-C), fluorescence in situ hybridization, and in silico modeling methods to characterize the 3D architecture of interphase chromosomes in proliferating, quiescent, and senescent cells. Although the overall organization of the chromatin into active (A) and repressive (B) compartments and topologically associated domains (TADs) is conserved between the three conditions, a subset of TADs switches between compartments. On a global level, the Hi-C interaction matrices of senescent cells are characterized by a relative loss of long-range and gain of short-range interactions within chromosomes. Direct measurements of distances between genetic loci, chromosome volumes, and chromatin accessibility suggest that the Hi-C interaction changes are caused by a significant reduction of the volumes occupied by individual chromosome arms. In contrast, centromeres oppose this overall compaction trend and increase in volume. The structural model arising from our study provides a unique high-resolution view of the complex chromosomal architecture in senescent cells.

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Here is an article from Nature on the Nature paper.


Ageing: Out with the old
Jesús Gil & Dominic J. Withers
See also Article by Baker et al.
Nature 530, 164–165 (11 February 2016) doi:10.1038/nature16875 Published online 03 February 2016

The selective elimination of cells that have adopted an irreversible, senescent state has now been shown to extend the lifespan of mice and to ameliorate some age-related disease processes. See Article p.184

Subject terms:

The ability to fight the ageing process has been a long-held human desire. Although this quest often seems to be driven by vanity, ageing is the major risk factor for many of the diseases that plague modern society. More than 50 years ago, it was suggested that ageing is linked to a state of arrested cell growth known as senescence1, but this link has remained unproven, and the molecular basis for organismal ageing has been elusive. In this issue, Baker et al.2 (page 184) demonstrate that the removal of senescent cells does indeed delay ageing and increase healthy lifespan (healthspan).

Senescence is a cellular state in which cells permanently stop dividing. It is mediated by two signalling pathways — the p53 pathway and the p16Ink4a–Rb pathway. Senescent cells secrete a complex cocktail of factors called the senescence-associated secretory phenotype (SASP), which includes matrix metalloproteinases (enzymes that break down the extracellular matrix) and pro-inflammatory signalling molecules. Such cells have been shown to accumulate during ageing, and their presence has been associated with a broad range of diseases, including diabetes, kidney disease and many cancers3.

The group that performed the current study previously showed that removing senescent cells from a mouse model of accelerated ageing delays the onset of several disease-related processes4. However, the relevance of these observations to the normal ageing process was unclear. Baker et al. have now directly tackled this uncertainty using a genetically engineered mouse model that they had developed previously4, called INK–ATTAC. These mice produce a caspase enzyme specifically in cells that express the p16Ink4a gene. The caspase can be activated by the injection of a drug; the activated caspase then triggers cell death, eliminating senescent cells in which it is expressed.

Baker and colleagues found that the elimination of p16Ink4a-expressing cells increased lifespan, regardless of the sex or strain of mouse examined, and ameliorated a range of age-dependent, disease-related abnormalities, including kidney dysfunction and abnormalities in heart and fat tissue (Fig. 1). The authors observed increased activity and exploratory behaviour and a decrease in the incidence of cataracts (although this improvement was strain-dependent). Senescent-cell removal also delayed the onset of cancer, without affecting the range of observed tumour types. Together, these findings suggest that the accumulation of p16Ink4a-expressing cells during normal ageing shortens healthspan.

Figure 1: Improving healthspan.

Senescent cells, which are in a state of irreversible growth arrest, accumulate in various organs during ageing and are associated with age-related diseases in many tissues. Baker et al.2 selectively eliminated senescent cells in ageing mice. This increased healthy lifespan, reducing many age-related, disease-associated abnormalities.

The INK–ATTAC mouse is a powerful model with which to investigate the physiological relevance of senescence, but it is not without limitations. For instance, the model is assumed to selectively eliminate senescent cells — and although not all p16Ink4a-expressing cells are necessarily senescent, the ATTAC transgene that produces the caspase seems to be expressed only in senescent cells. However, it could be that drug treatment kills only 'late senescence' cells5, which express high levels of p16Ink4a and ATTAC, rather than triggering a more general elimination of senescence. Moreover, drug treatment does not kill some senescent cells, including immune cells called lymphocytes as well as liver and colon cells, which limits the reach of the model. An improved characterization of the cell types that are eliminated is needed to fully understand the basis of the extended healthspan of these animals.

Another caveat is that the inducible elimination of senescent cells requires twice-weekly, long-term injections into the abdomen. Males that were injected with a control solution rather than the drug typically had shorter lifespans than normal mice, perhaps because of this intensive treatment regime. More-sophisticated model animals, in which senescent cells can be ablated in different tissues at different times and without the need for repeated injections, would help to extend the current findings.

Although the ablation of senescent cells ameliorates some age-related defects, it has no effect on others, including declines in motor performance, muscle strength and memory. This could reflect limitations of the ATTAC model. However, it might also suggest that senescent cells are involved in the progression of only some diseases.

Why might eliminating just the few cells that are senescent have beneficial effects in a range of tissues? Baker and colleagues' analysis of the kidney might help to explain this observation and clarify why senescent cells can be so disruptive during ageing. A striking disease-associated change often arises in aged kidneys, in capillary networks called glomeruli. However, the authors observed senescence primarily in another cell type, the epithelial cells of the kidney tubules. This suggests that SASP components secreted by epithelial cells could be responsible for disease in the glomeruli.

A search for compounds that can selectively eliminate senescent cells is under way67, and could be an important step in translating the findings of Baker and colleagues' study to combating diseases of ageing in humans. An alternative therapeutic approach could be to repress the SASP. Indeed, inhibition of JAK proteins, which mediate the actions of some cytokines (a type of signalling molecule), reduces the SASP and alleviates frailty in old mice8. Rapamycin, a drug that is used as an immunosuppressant in humans, also robustly extends mouse lifespan9 and regulates the SASP1011. Thus, common therapeutic mechanisms acting on the SASP might underlie the beneficial effects of both rapamycin and senescent-cell ablation on lifespan and healthspan.

It is worth noting that senescence is a protective response that limits tissue scarring (fibrosis) and cancer. Cells that express senescence markers are also involved in wound healing. Interestingly, the current study suggests that, although ablating senescent cells impairs wound healing, in general it has limited negative effects, and the authors found no evidence for increased fibrosis or cancer development. Nonetheless, any future senescence-based therapies must take care to control for possible detrimental consequences.

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Thanks Al,


The last paragraph is worth emphasizing. There is usually no "free lunch" when it comes to interventions that promote health / longevity - if it were easy nature would already be doing it. Like with telomere lengthening, there is likely to be a downside along with an upside associated with eliminating senescent cells:


It is worth noting that senescence is a protective response that limits tissue scarring (fibrosis) and cancer. Cells that express senescence markers are also involved in wound healing. Interestingly, the current study suggests that, although ablating senescent cells impairs wound healing, in general it has limited negative effects, and the authors found no evidence for increased fibrosis or cancer development. Nonetheless, any future senescence-based therapies must take care to control for possible detrimental consequences.



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I wanted to commend Dean on his assessment of this study. Dean, you picked up on many concerns that would have gone unnoticed by many scientists in this field, including apparently those writing the 'News and Views' section at Nature. I was also impressed that you noticed the discrepancy between the modestness of the article title and what is being reported in the popular press. Unfortunately, I believe that far too often studies are published with extreme/questionable and weakly-supported claims, embedded in a larger body of much better supported claims upon which the publishability of the article is anchored. Whereas the focus should be on the well-supported claims, the questionable claims get the attention.

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  • 1 month later...

Thanks BigB!  - and welcome to the CR Forums. You've apparently been lurking for a while. Please feel free to introduce yourself. 


On the topic of this thread, I previously posted (two posts above) on the likelihood of "no free lunch" when it comes to completely sweeping the body clean of senescent cells. In this review over at the Fight Aging! website, Reason suggests the same thing, and points to this new paper [1], which found (from the press release):


To their surprise, the researchers discovered that during normal aging, p16 and cellular senescence actually improve the primary function of beta cells: the secretion of insulin upon glucose stimulation. Because insulin secretion increases during the normal aging of mice and is driven by elevated p16 activity, some of these cells actually start to function better.


So as usual, it looks like metabolism is more complex than can be captured by simplistic notions like "senescent cells are bad".


It's results like these that make me personally pretty pessimistic about the prospects (at least over the next several decades) for the SENS project to reverse aging by cleaning up the damage wrought by metabolism. Metabolism is just too damn complicated





[1]  Nature Medicine, Advance Online Publication, March 7, 2016, doi:10.1038/nm.4054. 


p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion.


Aharon Helman, Agnes Klochendler, Narmen Azazmeh, Yael Gabai, Elad Horwitz, Shira Anzi, Avital Swisa, Reba Condiotti, Roy Z Granit, Yuval Nevo, Yaakov Fixler, Dorin Shreibman, Amit Zamir, Sharona Tornovsky-Babeay, Chunhua Dai, Benjamin Glaser, Alvin C Powers, A M James Shapiro, Mark A Magnuson, Yuval Dor & Ittai Ben-Porath.


Press release: http://new.huji.ac.il/en/article/29587

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  • 2 weeks later...

Thanks BigB!  - and welcome to the CR Forums. You've apparently been lurking for a while. Please feel free to introduce yourself. 


I’ll be brief in my introduction so as to try to keep the thread on topic: In a former life, I was a mechanical/electrical engineer, computer scientist, entrepreneur, etc. A fascination with biological aging drove me to transition into a career in the life sciences. A significant portion of my efforts for the last 4-6 years have been spent studying the theoretical aspects of biological aging. I am 6 weeks away from completing a PhD in biomedical sciences.
I do not practice caloric restriction myself, but I have an interest in CR since it is the only intervention that has been shown unequivocally to increase longevity in at least some mammals. I believe that any viable theory of aging should reconcile with this fact. Yet, most common theories of aging fail to do this very well.
I agree with the “no free lunch” position regarding the feasibility of longevity interventions such as the one proposed by the study discussed in this thread. I have formulated a theoretical framework that offers an explanation for why this may be the case. A preprint of my manuscript outlining these concepts is available on bioRxiV:
Although I only discuss CR in passing, it should be apparent to the reader how the longevity extension effects of CR are explainable by my model. I also discuss why the results from studies involving “aging-model” organisms do not translate well to more complex organisms.
Studies involving basic manipulations of the aging phenotype have generated numerous false conclusions regarding the culpability of particular factors as causal agents in the aging process and have given rise to simplistic notions like Dean mentions, e.g. the idea that senescent cells or eroding telomeres are simply bad and should be dealt with accordingly. Given the hugely multivariate nature of the aging process and the lack of a central paradigm of biological aging, it is inconceivable to me that it has become accepted practice to draw conclusions in this manner.
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It's results like these that make me personally pretty pessimistic about the prospects (at least over the next several decades) for the SENS project to reverse aging by cleaning up the damage wrought by metabolism. Metabolism is just too damn complicated




I agree with you and with BigB.


BigB, come to CR IX. I'm sure that you'll find it interesting.


-- Saul

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