
Senescent cells stop producing nucleotides: new research - LinuxBender
https://www.sciencedaily.com/releases/2019/07/190725151018.htm
======
dekhn
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](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.

~~~
cgiles
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these books are often way out of date and only cover topics that have been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.

~~~
dekhn
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.

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

We are agreed on that. I shouldn't have said "out of date", which suggests
what is in those books is invalid. What I should have said is "they don't
really cover topics that are new or controversial and mostly only cover
fundamentals".

In reality as you know each new edition of those books is 95% or more
identical to the previous edition.

The only downside to this approach is that if people are interested in a
particular topic like cell senescence, it's a bit harsh to say "go read these
5 textbooks that may have 2 pages on the subject before you even start looking
into the topic you're interested in". And the Biology of Cancer? I'm published
on several cell senescence papers and don't know jack about cancer. I own the
book and skimmed it though. I think Hallmarks of Cancer review is a much
better introduction than this tome. The other two are good fundamentals books
though. For aging I recommend Handbook of the Biology of Aging.

FWIW, I do not know a single PhD student that read those books cover-to-cover.
In most of my grad school classes you weren't even required to buy the
textbook and they were barely used. Actually in grad school I never bought a
single textbook for classes, although I did get some for personal use.

~~~
pgeorgi
> and mostly only cover fundamentals

I consider that a feature when entering a new field. Once I have the
fundamentals, it's much easier to read a paper and have at least a rough idea
if it's a crackpot theory or the real deal. Without the fundamentals? No clue.

~~~
cgiles
The easy way around this is to find out what journal the article was published
in and look at its impact factor. If the impact factor is below 2, ignore it.
If it is between 3 and 10, it is probably legit although it may not be the
majority viewpoint in the field. If it is above 10, then either the article is
written by a very important person in the field, or it is considered to be
potentially high-impact but may be wrong. Alternatively very massive
consortium experiments are published in high-impact journals as a matter of
course.

It is best to stick to the 3 to 10 range though until you know the ins and
outs. Lots of Nature papers look exciting and turn out to be wrong. This is a
rough guideline that varies by field.

PLoS One is a journal that publishes anything but has a decent impact factor
so it is an exception to this rule. There are a few others but it generally
holds true.

------
pkilgore
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?

~~~
gpm
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.

~~~
rsync
"... 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.

------
beefman
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](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.)

~~~
sfink
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.

------
oppositelock
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.

~~~
gnode
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).

------
AstralStorm
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...

~~~
telotortium
(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?

------
rrwright
"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?

~~~
cgiles
> 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.

~~~
sfink
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.

------
0815test
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.

------
holoduke
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.

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

~~~
LinuxBender
In addition to Aubrey, also Dr. David Sinclair.

~~~
vibrio
...and GSK who payed >$700 MM for Sinclair's company Sirtris (and closed it 5
years later.)

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

------
hellofunk
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
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...](https://lifeapps.io/fasting/a-beginners-guide-to-
intermittent-fasting/)

~~~
jandrese
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.

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

~~~
crimsonalucard
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.

------
ergothus
> 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?"

~~~
jerf
"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.)

~~~
cgiles
> 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.

~~~
jerf
"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."

Yes, but not all at the same ratios; it is not the case that literally
everything is correlated to everything else to 99.9%. When people say
"everything is correlated with everything" they mean that 60%s and 70% and
80%s show up in a large number of places, it does not literally mean that for
every two possible processes the correlation is 99.9%. It's not practical to
set up a large correlation net with that strong a correlation everywhere
unless it really is all the same thing. (It might be mathematically possible,
but it's not something you're going to encounter naturally.)

You're still better off choosing something that is very strongly correlated,
because you have still shaved off huge swathes of the possibility space to
start with which is much less likely to be directly involved. Yes, you still
have a decent chance of being wrong, _but_ you also have to remember that _in
the process of being wrong, you will gather more data_. (Well... assuming that
you actually _listen_ to the data and don't hide behind some scientific dogma,
but that's another discussion.) You're better off choosing something and
probing than sitting there, agog at the net of correlations, and being
paralyzed by the possibilities. Get in there and start shaving them off, and
start with your best guesses, even if they're only your best guesses by a
little bit.

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

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

~~~
jimbokun
"Friends don't let friends P-hack."

"This is your research on P-hacking."

"Just say no to P-hacking!"

~~~
hundreddaysoff
Ha. The sad reality in our system is that if you choose science as a career,
you publish or you perish. P-hacking allows you to publish. Most biologists
know they need to publish or perish, but very few know what P-hacking is,
although many of them do it implicitly.

Once you are aware of the problem, you have three choices that I could see:
(1) roll the dice and legitimately win the lottery of objective truth
discovery, (2) consciously be evil in order to feed your family, or (3) escape
and go find another flawed system to feed yourself.

So I chose (3) and went to med school.

