Senescent cells stop producing nucleotides: new research

https://www.sciencedaily.com/releases/2019/07/190725151018.htm

by LinuxBender • 7 years ago

309 97 7 years ago

Is this sloppy reporting or are these researchers actually confused about senescent cells often having two nuclei? One of the known cause of cellular senescence is G-phase cell division cycle arrest, usually due to damage, which will result in a cell with two nuclei...

debatem1• 7 years ago

Is there a good place to learn about this that doesn't assume a deep bio background?

telotortium• 7 years ago

(No biology training here.)

According to Wikipedia, it looks like G-phase is part of interphase. During interphase, the cell isn't actually in the process of dividing, right? Wouldn't it be more likely that a senescent cell would have two nuclei if there was an error during telophase, right before cytokinesis?

myarr• 7 years ago

Sounds like this supports marketing claims by Elysium? https://www.elysiumhealth.com/en-us/basis

pkilgore5• 7 years ago

Now granted I only have a undergraduate degree in Chemistry, but to me, the statement "the lack of nucleotides causes cells to age" is akin to saying "the lack of steel causes a car factory to stop". Of course if a cell lacks the basic components to divide its DNA it... won't divide? The more interesting question is _why_ are there no nucleotides in cells that are aging.

My sense is that this summary of the underlying article is missing something (not uncommon in scientific journalism), or this really isn't all that revolutionary.

I'd love for a better explanation of why this matters, or a better link?

heymijo2• 7 years ago

Excellent line of inquiry. I'll have to dig but I know I've read that senesence has an important function. Like most things in the body, it happens for a reason but there are often downsides.

It was probably something Dr. Judith Campesi, a pre eminent senesence scholar, wrote.

DenisM• 7 years ago

I've read that senesence has an important function

Unless you're a water bear your DNA accrues continuous and irreversible damage throughout life. End of the road is either cancer or senesence as an attempt to arrest cancer.

thebeefytaco• 7 years ago

Here's the original article: https://viterbischool.usc.edu/news/2019/07/fighting-back-aga...

And the primary source/study: http://www.jbc.org/content/early/2019/05/28/jbc.RA118.005806

pkilgore5• 7 years ago

Thank you.

seanmceligot• 7 years ago

It seems to me that they would now do studies to find out what increases or decreases nucleotide production in cells. If, for example, you found out that capsaicin in chilli peppers increased nucleotide production, then that could be useful.

gpm• 7 years ago

Of course a lack of steel causes the car factory to stop, but it would still be quite the discovery that car factories are regularly stopping because of a lack of steel.

In fact I wouldn't believe you if you told me that was in fact the case.

pkilgore5• 7 years ago

This is an exceptionally insightful point, thank you.

rsync• 7 years ago

"... but it would still be quite the discovery that car factories are regularly stopping because of a lack of steel ..."

What if you dug deeper and found that the steel-lacking factories were the ones which made the worst cars ?

I think that's the default analogy you should be making when you see cells "stopping".

This idea that cells that stop processing, or that undergo apoptosis (cell death) or are incapacitated by free-radical damage / oxidation should be "saved" is probably a mistaken one.

It's probably a much better outcome that they die.

jameshart• 7 years ago

When you go off into analogies it can become difficult to determine whether the paralleled are insightful or worthless.

For what it’s worth though, I think there are plenty of examples of car factories closing down because they are unable to secure a supply of raw materials. The machinery and the workers are all still there, but for whatever reason the owner stops sending steel to the plant and it shuts down.

Make of that analogy what you will.

crimsonalucard2• 7 years ago

A better analogy is, you're given a broken car. The car barely runs. Why? You're also a caveman, you've never seen a car before.

No gas, that's why. How long will it take your cave man brain to figure that out?

felipemnoa• 7 years ago

>Of course if a cell lacks the basic components to divide its DNA it... won't divide?

The big thing here is that now they know that it is a lack of this particular substance causing the problem. Nobody could have guessed that this was the case. It is part of the debugging process. It provides a path for further discovery. Now they know where to focus their efforts.

pkilgore5• 7 years ago

Thanks for a great answer. I suppose it's rather quite like discovering a program isn't entering a code path. Knowing that is the first step to figuring out why it doesn't create a side effect at the end. (Metaphors all suck, but...yeah).

gnulinux• 7 years ago

no steel => factory stops

does not imply

factory stops => no steel

Seeing that the factory has stopped, you need to determine whether it is because factory is lacking steel; or whether the effects of lack of steel consistent with current outage. This study seems to do this.

VeninVidiaVicii• 7 years ago

Going into a PhD in genetics this fall. I think it's a good analogy, but it's more akin to say, "Factories that are closing don't have steel." To which, I think we'd all say, "Of course."

qserasera• 7 years ago

Don't we already have general knowledge about the molecular machinery that can stop cellular replication?

Wouldn't inhibiting nucleotide production already be explored well for cancer targets?

Isnt the only new thing here that they profiled and used senescent HMEC cells?

It seems they already had pharmaceutical and genetic means to target the protein already.

dekhn5• 7 years ago

I love your statement "the lack of steel causes a car factory to stop". You might not realize this but there is a lovely pair of articles comparing the approaches of genetics and biochemistry to understanding how car factories make cars. http://www2.biology.ualberta.ca/locke.hp/dougandbill.htm

The more biology you learn, the cleverer the jokes get:

"""Emboldened by his successes, the next morning the geneticist tied of the hands of an individual dressed in a suit and carrying a briefcase in one hand and a laser pointer in the other (he was a vice president). That evening the geneticist, and Doug (although he would not openly admit it), anxiously awaited to see the effect on the cars. They speculated that the effect might be so great as to prevent the production of the cars entirely. To their surprise, however, that afternoon the cars rolled off the assembly line with no discemible effect.

The two scientists conversed late into the evening about the implications of this result. The geneticist, always having had a dislike for men in suits, concluded that the vice president sat around drinking coffee all day (much like geneticists) and had no role in the production of the automobiles. Doug, however, held the view that there was more than one vice president so that if one was unable to perform, others could take over his duties."""

(in biology, many processes have redundant components)

rexpop• 7 years ago

This joke is only funny if it's taken as fact that authoritarian management hierarchies are necessary for industrial production. You take that notion for granted.

pkilgore5• 7 years ago

Fun link, thanks!

ergothus2• 7 years ago

The research team discovered that the aging, senescent cells stopped producing a class of chemicals called nucleotides, which are the building blocks of DNA. When they took young cells and forced them to stop producing nucleotides, they became senescent, or aged.

^ From the article. Yet, when I check the linked journal entry:

Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells

^ journal article title, which seems somewhat the reverse of the article claim.

To test whether cellular immortalization would reverse these observations, we expressed telomerase in HMECs. In addition to preventing senescence, telomerase expression maintained metabolic flux from glucose into nucleotide synthesis pathways. Finally, we investigated whether inhibition of nucleotide synthesis in proliferating HMECs is sufficient to induce senescence.

^ From the journal article abstract. This states NONE of the "took young cells and..." claims from the article, but rather the opposite.

Taken together, our results suggest that nucleotide synthesis inhibition plays a causative role in the establishment of replicative senescence in HMECs.

Umm...unless I'm missing something, this is literally taking correlation and determining causation.

TL;DR: This looks like an exploratory data point in the "how does the telomere clock actually cause senescence in a cell". While this COULD lead to some "new" treatment, vast issues remain, including both "is this the sole cause", "is this actually relevant", and "if this is the Big Cause, what could we do about it anyway?"

jerf2• 7 years ago

"Umm...unless I'm missing something, this is literally taking correlation and determining causation."

Yes. But when you're in a machine as complex as a cell and trying to figure out how to stop some process, if you can find a correlation, it's at least worth a try to treat that as causation. It's much better than picking a random answer.

Where we go wrong is when the game of telephone gets played and the correlation gets locked in as the official causation answer. But technically, "I see a correlation between A and B, therefore I hypothesize that the cause of the correlation is that A causes B" is at least a good first hypothesis. (The moreso when "B causes A" is not plausible for some reason.)

ergothus2• 7 years ago

All true - my complaint here was that the article went from "Here's a correlation that might indicate causation" to "This is the cause". Science journalism, I know, but still, if we don't call it out, will it ever improve?

I don't think the study was a bad thing at all (from my limited understanding), but the article was...a poor representation of it.

cgiles5• 7 years ago

if you can find a correlation, it's at least worth a try to treat that as causation. It's much better than picking a random answer.

No, it isn't. Or if it is, it's barely better, not much better. See my lengthier reply above.

The reason why this is false is because in biology, there is an enormous correlation structure in which, to a good approximation, everything is correlated with everything. If you take a random gene, its expression will be significantly correlated or anticorrelated with well over half of all other genes. Probably over 80% if I remember correctly. Depends on the number of samples, if you get into 10K+ samples it approaches 100%.

In an area like aging, skin wrinkling is correlated with sarcopenia is correlated with atherosclerosis is correlated with number of senescent cells is correlated with all kinds of gene and metabolite expression levels etc ... you get the idea.

In genetics a SNP will be correlated with hundreds of thousands of other SNPs.

I guess you can go so far as to say correlations can generate hypotheses. People certainly do this all the time. But "a correlation is tentative evidence of direct causation" is just wrong. Technically it is evidence, it's just that in my experience in biology it is such weak evidence as to be useless without other evidence.

vilhelm_s• 7 years ago

Finally, we investigated whether inhibition of nucleotide synthesis in proliferating HMECs is sufficient to induce senescence. In proliferating HMECs, both pharmacological and genetic inhibition of ribonucleotide reductase regulatory subunit M2 (RRM2), a rate-limiting enzyme in dNTP synthesis, induced premature senescence with concomitantly decreased metabolic flux from glucose into nucleotide synthesis.

This is the part where they took young cells and stopped them from producing nucleotides, and it's also what's described in the paper title.

xwdv• 7 years ago

So basically, exercise can help slow the aging of cells in humans through adaption to stress.

0815test• 7 years ago

A "new cause of cell aging" might cause trouble for the somewhat-speculative programme of SENS, the pursuit of long-term "negligible" senescence via regenerative medicine. In this case, if it turns out that telomerase is needed to prevent cellular senescence, it seems you can't use whole-body inhibition of telomerase as a cure for cancer, which is the approach SENS is proposing. It doesn't make all regenerative medicine useless, but it might be a challenge.

oppositelock• 7 years ago

This was the most interesting part to me:

"Scott Fraser and his lab worked with the research team to develop 3D imagery of the results. The images unexpectedly revealed that senescent cells often have two nuclei, and that they do not synthesize DNA."

Huh, the interesting part to me was that the senescent cells have two nuclei. Muscle cells fuse during development and have multiple nuclei, and they can't divide anymore either. I wonder if senescence happens due to mitosis being stopped short by some mechanism, and whether the multiple nuclei are a symptom or one mechanism by which cells enter senescence.

gnode3• 7 years ago

It sounds to me like these senescent cells have reached or completed telophase (construction of nuclear membranes after mitosis), yet cytokinesis (splitting of the cell) has been inhibited. Perhaps during mitosis some kind of genetic integrity check is performed and failure halts cytokinesis (or success enables it).

echelon• 7 years ago

You don't want certain cells to continue to proliferate.

The development lifecycle also ends once a cell has differentiated into its ultimate tissue type. You don't want everything to be forever pluripotent.

Proliferation and pluripotency are classic markers for cancer.

tjpaudio2• 7 years ago

Well, until it has been confirmed by a study, it's not science, obvious or not. A few years ago there was a major study that proved a relationship between multiple concussions and long term brain damage. Anyone could have made the conclusion that repeated blows to the head is bad but it doesn't become science until we apply rigor to test it. That's a good thing. At all points in history we believed foolish things that we thought were obvious.

not_a_cop75• 7 years ago

And sometimes with modern p-hacking and big corp sponsored studies, it's still not technically science. We should all be wary of the "this one study proves everything" attitude. Confirmation studies are both underfunded and the real rubber meets the road science.

misterprime• 7 years ago

I'd really love to see an awareness campaign about this issue.

chrisco2552• 7 years ago

I'm not sure what you mean about it not being "science". Science is a process, and hypotheses are part of that process. And the process never really ends.

tjpaudio2• 7 years ago

Crossing over from thinking something is one way to testing that something really is that way is certainly a line held within the purview of science. I think you are reading my statement too literally.

hellofunk• 7 years ago

It would be great to know if there were obvious lifestyle or diet changes that can help the natural mechanisms at work in possibly removing these cells.

sappapp• 7 years ago

It’s hypothesized that intermittent fasting is a natural mechanism. This article is a good introduction: https://lifeapps.io/fasting/a-beginners-guide-to-intermitten...

jandrese• 7 years ago

I would warn that the studies on that are still preliminary. Even really promising research, like the Vitamin D supplement craze from a couple of years ago, can fizzle out when more data comes in.

asdf21• 7 years ago

There are... autophagy.

Cannibalizes any under-performing cells.

gnode3• 7 years ago

Autophagy is the self-cannibalisation of cells to give up their molecular components. Are senescent cells capable of doing this? They have at least stopped producing nucleotides, and the double nucleus suggests they have broken down toward the end of mitosis.

notadoc• 7 years ago

A lot of research suggests that fasting does exactly that

rrwright• 7 years ago

"This means that the production of nucleotides is essential to keep cells young," Delfarah said. "It also means that if we could prevent cells from losing nucleotide synthesis, the cells might age more slowly."

Am I the only one wondering if this person is confusing cause and effect?

dumbfoundded• 7 years ago

It probably isn't the root cause but it probably isn't the final symptom either. Solving aging seems to resemble working up a complicated tree of causality with multiple roots. Fixing nucleotide synthesis won't make us immortal but it may prevent significant downstream impacts.

cma• 7 years ago

Don't confuse might for definitely

cgiles5• 7 years ago

Am I the only one wondering if this person is confusing cause and effect?

No you are not. I work in this field and confusions of cause and effect are a daily occurrence. It is as dumfoundedd said, the reality is that aging is a complex causal network. I think everyone knows that but can't resist the temptation to pretend like the one edge they are working on in the network is the end-all.

It can get very ridiculous. At this year's aging meeting someone was actually proposing DNN predictions of age based on people's faces as a gold standard for biomarkers of aging. That is, they were suggesting people's faces were a better indicator of their internal biological state of aging than both their actual age and any internal biological marker.

Metagenomics is another one, although more debatable. I personally find it much more plausible that changes in the aging gut cause changes in the microbiome than the reverse (in general).

Horvath's epigenetic clock is another one, he presented a elastic net model that could predict age based on DNA methylation using a few hundred loci. For several years and even now, way too many investigators thought those loci were actually causal in aging because they don't understand how statistics work.

It annoys me. I have long considered writing a review to remind people what causality means. It is far too common for people to observe correlations and just straight to predicting causality without any additional evidence besides the correlation.

The interesting finding of this paper is that inhibition of nucleotide synthesis can induce senescence. But the (simplistic) definition of senescence is inability to replicate. You can't replicate without nucleotides, but this doesn't at all mean that the ordinary cause of senescence is lack of nucleotides. The common understanding is that it is G1 or G2 arrest due to DNA damage of one sort or another. Furthermore, the observation that senescent cells don't produce many nucleotides is kind of a duh. It is useful and important that they quantified it, but still it is hardly surprising.

But there is still hope. I just saw my chair in the hall, told him about this paper, and asked his opinion of the idea that "fixing nucleotide synthesis may help reduce cell senescence or help cells age more slowly". His response was to laugh, pat me on the shoulder, and walk away, if that says anything.

sfink2• 7 years ago

That'd be like giving CPR to dead squirrels. It seems more promising to introduce a mechanism to gradually kill off cells that aren't producing nucleotides. Though there must be easier symptoms of senescence to key off of.

Once the squirrel starts to stink, bury it.

meowface• 7 years ago

I think they probably are, but they could also be right (maybe without realizing the nuances).

It may be true that slowing down loss of nucleotide synthesis, while not fixing the root cause, may still slow down the aging process. Just like giving Parkinson's patients L-DOPA doesn't resolve the root cause of the disease; it's treating the effect and not the cause. But there isn't really anything better out there (AFAIK), and it slows down the brain degeneration process by replenishing one of the important things that gets destroyed in the degeneration, just as fixing nucleotide production may slow down cell degeneration. It's a very imperfect solution, but it still provides some relief for many people. We've got to work with what we've got.

holoduke• 7 years ago

What would happen if there was somekind of treatment where people could reduce aging process, so potentially we could reach the age of 500. Would we still able to handle this mentally wise.

nkozyra• 7 years ago

I don't think most people have the mental energy for our current lifespans

allworknoplay• 7 years ago

There's a whole world of thought on this. Check out some of Aubrey de Grey's work for starters.

LinuxBender2• 7 years ago

In addition to Aubrey, also Dr. David Sinclair.

krferriter• 7 years ago

I think we could easily handle it. Most people want to live longer and do more while they're alive. People who parrot the idea of "the shortness of life is what gives it meaning" are lying to themselves and others, in my view. They use that sort of justification as a coping mechanism, it isn't a truly held belief. If it turned out that humans could now live to 500, they'd just update their baselines to be 500 instead of 80 and adjust to the new situation rapidly.

mr_toad• 7 years ago

What would happen if there was somekind of treatment where people could reduce aging process

Probably the first result would be cancer.

pochamago• 7 years ago

Are Senolytic drugs something new they came up with our something that we've had for a while?

crimsonalucard2• 7 years ago

I've talked to researchers in the bio field dealing with immortal cells. Those cells are apparently dangerous to touch because they will give you cancer.

gnode3• 7 years ago

The wikipedia article ( https://en.wikipedia.org/wiki/Senolytic ) cites https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748967/ from December 2015, so the concept is at least that old.

hundreddaysoff4• 7 years ago

My remembrance is that Campisi and others were thinking about them since at least the early 2000s.

beefman• 7 years ago

As is often the case, simply reading the abstract gives a much better idea of what happened

http://www.jbc.org/content/294/27/10564

It's also faster and easier. It's faster because it's shorter (2k vs 5k). It's easier because 'abstract format' is a tigher constraint than 'popular science story format'. (Much as Wikipedia entries are often easier than random web pages because they're constrained to a standard format.)

sfink2• 7 years ago

Whoa! Thanks for this. The abstract makes so much more sense, and is at the same time more exciting, than the originally posted article.

That article was like saying that geriatric people are observed to never go clubbing, and if you prevent young people from clubbing they mope around the house all day, so maybe if we get people to go clubbing every day they'll never grow old.

The abstract is a lot more reasonable and sensible, and concludes that (lack of) nucleotide synthesis does seem to play an important role in senescence. They were able to kick things back into action with telomerase. Enforced clubbing resources bed sores. No word yet on how many additional injuries it might trigger from ill-advised breakdancing.

dekhn5• 7 years ago

To the computer hackers who read these things: biology is a complex system. So complex that the most complicated system you have ever worked on seems very simple compared to it. WHen you read articles like this, be aware the scientists have extensive training in working with complex systems, and publish exciting sounding coherent narratives that are, at best, incorrect but useful working models (https://en.wikipedia.org/wiki/Not_even_wrong).

It's fun to speculate but to prove your case and make a real dent in human health problems is a lot harder than coming in late and saying "But wait, why don't you just..."

I heartily recommend going back to the great textbooks of these fields and reading them, rather than trying to understand things by dropping into the state of the art research (which is usually wrong, and hard to understand in detail).

Some books I recommend: The Biology of Cancer (Weinberg). After you read this book you'll have a better understanding of why doctors and scientists cringe when people say "cure cancer".

Molecular Biology the Cell (Alberts, etc). After you read this book you'll have a much better understanding of the full complexity that scientists have to deal with in complex cellular systems.

Molecular Biology of the Gene (watson, etc). Can't say much about this book except that's it's a classic reference.

What makes these three books exception is that they support all their factual claims with direct links to the papers that established the facts. And they provide you with the skills to evaluate modern research. But nothing compares to actually going to grad school and participating in the research- once you see how the grants are made, the experiments are, and the papers are written, you'll understand why trying to understand biology by press release is like trying to understand assembly language by watching a Steve Jobs product announcement.

cgiles5• 7 years ago

This is not bad advice, especially for people lacking the fundamentals, but these books are often way out of date and only cover topics that have been solidly established 20 years ago.

I would suggest, especially for people interested in a relatively niche field like aging, that a good compromise is to read review articles. You can go to PubMed and filter by review articles to find them.

But I wholeheartedly concur that for non-experts to read primary research articles will cause much more confusion than clarity. And doubly so for press releases on those articles.

dekhn5• 7 years ago

Biology of Cancer ed 2 is from 2013 and nothing has changed tremendously to the point where the book would be out of date.

Molecular Biology of the Cell ed 6 is from 2014

Molecular Biology fo the Gene is a bit older and I would generally not recommend people read it, but the problem is (IMHO) the alternative, Genetics by Lewin, is genetics-oriented instead of molecular biology, and I find that most CS folks understand MB and find genetics confusing.

Review articles are good, but I still recommend starting with textbooks before moving on to reviews.

vaylian• 7 years ago

Given the considerable size of the books in question I think it is actually good that they do not cover absolutely everything up to the latest research. I have read large fractions of these books but I never fully read any of them. There is simply too much to learn.

It's much better if you read the relevant parts of these books and then ramp up from there with the papers that are actually relevant to your studies/work.

With that being said, the Molecular Biology of the Cell and the Biology of Cancer are also very enjoyable (but challenging) reads just for satisfying your curiousity. But don't expect to finish these within a 3 months.

coldtea• 7 years ago

but these books are often way out of date and only cover topics that have been solidly established 20 years ago.

Those are the best topics to cover, especially for people starting out and wanting something solid. Anything after that is in flux and will end 90% bogus.

aussieguy1234• 7 years ago

Also: The mouse operating system is quite different to the human operating system. Just because it works in a mouse, doesn't mean it will work in a human.

breck3• 7 years ago

To the computer hackers who read these things: biology is a complex system. So complex that the most complicated system you have ever worked on seems very simple compared to it.

I had this exact experience, when I transitioned from working in big tech to working at a cancer research center. The scales are wildly different. In the time it’s taken me to write this comment, my body has generated nearly a billion new cells at 20GB of data per cell, or about 100 google web indexes worth of data. Very humbling. But also very fun!

copperx• 7 years ago

Could you explain how you made that transition? Or any advice for someone in tech interested in getting into working with cancer?

amelius• 7 years ago

To the computer hackers who read these things: biology is a complex system.

Reminds me of: "Can a biologist fix a radio?", http://protein.bio.msu.ru/biokhimiya/contents/v69/pdf/bcm_14...

762236• 7 years ago

I am a computer hacker that has dipped into physiology to perform at athletic extremes to good success. I always rely on data and evidence, and refuse to take advice on physiology from anyone (including doctors), because very few stick to evidence-based strategies (and doctors seem uninterested in sports physiology). Physiology is many orders of magnitude more complicated than any computer system I've worked on. It is easy to create abstractions that try to explain some of the data, but you must always be ready to have them proven wrong when you look at the next layer down. Evidence must rule.

andy_ppp• 7 years ago

I’d also thoroughly recommend Peter Attia’s podcast, it’s a really amazing in depth discussion into how the body works and it never anything but astonishing.

bhouston• 7 years ago

In University I tried to transition into molecular neuroscience. It was very frustrating how slow porgress is and how little a single individual can impact it. Biology feels like a huge spaghetti code project with millions upon millions of lines and much of it interconnected.

Basically biology feels like a working but horribly written program with secret gotchas everywhere.

I left and went back to coding and mathematics. So easy to make progress. I can pretty much understand the whole system. Everyday I get something real done.

Senescent cells stop producing nucleotides: new research

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