
Drugs that kill off old cells may limit a body’s aging - rbanffy
https://arstechnica.com/science/2018/07/drugs-that-kill-off-old-cells-may-limit-a-bodys-aging/
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Symmetry
Humans live a lot longer than other animals of our size and have a lot of
adaptions to let us live longer that mice don't. Seemingly for this reason
lots of aging reduction techniques that work for mice don't work in us. So
don't get too optimistic about this result.

~~~
danieltillett
This increase in lifespan is relatively recent in evolutionary history too so
it can't involve too many genes, but yes it appears likely that the low
hanging fruit may have been picked already by evolution.

On the positive side we live a lot less than animals like the bowhead whale or
the Greenland shark. There is a lot (in theory) that can be done.

~~~
olliej
The vast majority of the increase in average life expectancy is the massive
reduction in childhood and childbirth mortality. All of which is a direct
result of the massive improvement in the quality of medical care in the 20th
century. Not very much genetic impact (such a massive genetic shift would have
had to happen in 2-3 generations globally. A genetic source of such a massive
change would be incredibly geographically biased: while there has been more
more migration in the last hundred year than at any prior point in history, a
genetic change would require a complete spread through the source population)

~~~
danieltillett
The genetic change I am referring to is since we split from our common
ancestors the chimps and gorillas. Our ageing rate has more than halved since
this split. This has been so rapid and so recent that it can't involve that
many genes.

~~~
olliej
We diverged from apes around 7 million years ago, so assuming a way higher
than reasonable average generation time of 50 years gives you 140k
generations. If we assume a more reasonable turn around (based on 15 being a
marriage worthy age in Romeo and Juliet) we easily get around 300k
generations. That’s actually quite a lot for evolution to play with.

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felipemnoa
The part that really called my attention is this one:

>>Cells pick up damage all the time, either through environmental exposures or
simply as a byproduct of their normal metabolism. If the damage is
sufficiently critical, the cell will respond by committing an orderly sort of
suicide called apoptosis, which keeps it from causing any further problems.
For lesser damage, there's a less drastic alternative called senescence, in
which the cell remains active and contributes its normal functions to the
organism's health, but it commits to no longer dividing.<<

Old people, lots of senescence cells no longer dividing, young people, lots of
young cells still dividing. Aging kind of makes sense when looked at it this
way. As long as cells are able to keep dividing you may be able to stay
relatively young.

Knowing nothing else it seems that you must keep the number of senescence
cells low to keep the effects of aging at bay. Of course, it is probably much
more complicated than this. At a minimum this may be a piece of the puzzle to
figure out long life.

~~~
DenisM
The key aging problem is that DNA damage is accumulating over the lifetime.
Some cells reach apoptosis, some reach senescence, some reach cancer, some
keep on being normal for a while.

Culling senescent cells does not undo the accumulated damage. You are making
room both for cancerous and normal cells. Normal cells are still damaged
though. I'm guessing the net contribution is still positive, but the specter
of cancer is still looming.

On the bright side, I hope that cancer can be managed purely mechanically.
Imagine dropping by for your weekly ultra-targeted radiation therapy to kill
this week's tumors before going for lunch.

~~~
mettamage
Silly question: how difficult would it be to extract your DNA code into
digital format and then create cells based on that digital formatted DNA and
put them into your body?

Note: not at all a biologist as you can probably see from the way I phrase
things :)

~~~
derefr
I imagine it'd be far easier to just extract existing stem cells from the
body, freeze them, and then every once in a while wake them up, culture some,
and re-seed the body with them.

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SketchySeaBeast
What the evolutionary purpose of the senescence cells inhibiting other cells?
I feel like it may be a "let's slow down until we heal" type thing, which
would indicate there's other mechanisms at play that explains why they aren't
being replaced as they should. I could be totally off the mark though.

Also, I just looked up how they test grip strength on mice. It's equal parts
funny and sad.

~~~
reasonattlm
Senescence is a tool of embryonic development repurposed to wound healing and
cancer suppression. Cells need to be suppressed once the finger is done being
built at the end and the edges, and senescent cells do that job. Cancerous
tissue needs to be suppressed, and senescent cells are there to do that job.

The problem is not that senescent cells exist, it is that there is not 100%
coverage of their removal after they do whatever the short-term job at hand
happens to be. It is the lingering ones that cause the harm.

~~~
SketchySeaBeast
So it's their inability to be replaced that's the issue - some other mechanism
is failing us. I suppose in the short term removing the cells "manually" would
help.

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reasonattlm
The paper:
[https://doi.org/10.1038/s41591-018-0092-9](https://doi.org/10.1038/s41591-018-0092-9)
The usual sources for bypassing journal paywalls will work.

The lifespan curves in the paper are very nice: same slope, shifted to the
right all the way down to 100% cohort mortality. The 36% increase in remaining
life span refers to the difference between 140 days and 190 days to 50% cohort
mortality in the control and treated group respectively.

Senolytic approaches that clear some fraction of senescent cells are highly
reliable when it comes to extending life span and reversing aspects of aging
in mice. The drug combination used here, dasatinib and quercetin, is cheap:
$100-200/dose if you are shopping carefully. It is being trialed by the non-
profit Betterhumans at the moment in a 65+ year old human group. Dasatinib is
a generic, so there is absolutely zero interest in anyone taking this into a
development program, which is a shame. None of the later pharmaceuticals have
yet demonstrated any better results in terms of percentage of senescent cells
killed off, but FOXO4-DRI has essentially no side effects.

(If you are interested, dasatinib pharmacokinetics and side-effects are pretty
well described. E.g.
[https://doi.org/10.1124/dmd.107.018267](https://doi.org/10.1124/dmd.107.018267)
)

Based on reporting from the self-experimentation community, and first
principles arguments, senolytics are something to take once every few years,
and don't expect to see noteworthy effects unless you are into high cancer
risk years or have something like obesity or early arthritis going on, in
which more than the usual count of senescent cells will be in place. Senescent
cell contribution to aging most likely scales in the same way as cancer risk
and for the same reason, loss of immunosurveillance.

Or you could wait for the human trial results to be published. Those will
start to emerge next year for various senolytic candidates.

An interesting thought: compelling evidence for senescent cells to be an
important contribution to aging has existed for 30+ years. The research
community deliberately avoided engagement with treatment of aging as a medical
condition from the 1970s to a decade or so ago. It took a lot of advocacy and
people coming in from outside the research community to make that change. If
that cultural black hole for development had not happened, how much sooner
could simple pharmaceuticals have been discovered that significantly addressed
aspects of aging in humans through selective destruction of senescent cells?

Another thought: there has been the usual foaming at the mouth over the past
decade among those who decry rejuvenation therapies as the purview of the
ultra-wealthy. Dasatinib and quercetin at $100-200/dose, at one dose every two
years or so? That is much closer to the future of longevity science that this
wild tale of massively expensive approaches hoarded by the rich.

~~~
delbel
Turmeric contains quercetin and it is cheap. Certified organic for $13/lb.
Sorry I don't have time to go through the paper and figure out the dosage vs
tumeric and consider the absorption rate/ability. I take it daily with
Japanese Knotweed. I really appreciate your comment.

~~~
reasonattlm
Quercetin on its own is not significantly senolytic. Only in combination with
dasatinib. See:

[https://doi.org/10.1371/journal.pone.0190374](https://doi.org/10.1371/journal.pone.0190374)

Another argument against quercetin on its own having any significant effect is
that it is widely used in large enough amounts. It would be well known by now
if it had significant senolytic effects, because everyone with arthritis would
have found their conditions meaningfully improved. That sort of thing doesn't
escape notice for long.

~~~
jessaustin
How does a non-cancerous person obtain a chemo drug on a regular basis?

~~~
devereaux
With money I suppose. Lots of.

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baccheion
Vitamin D causes autophagy.

------
cies
There is another way that recently gets a lot of attention, and it is drug-
free. It's called "fasting". The practice is very old (holy books speak of
it). Only recently one of fasting's method has been understood as "autophagy",
which means "self-eating". When your body is starved for nutrients it turns to
it's own tissues, and eats the weak/unhealthy cells first.

[https://en.wikipedia.org/wiki/Autophagy](https://en.wikipedia.org/wiki/Autophagy)

The 2016 Nobel Prize for Physiology or Medicine was awarded to Japan’s Dr.
Yoshinori Ohsumi for his discoveries of the underlying mechanisms of
autophagy.

I found a lot of interest on YT for this topic, and related "fasting" topics.
With alternative "healers" gaining huge following with treatments that include
fasting. Note worthy are Dr Morse (mostly juice fasts) and the Master Fast
System (mostly intermittent fasts). Also I see a lot of people doing long
water-fasts in combination with strength training for rapid weight loss.

Its a very interesting subject to me, and I have done some experiments with it
myself, not without results.

~~~
madeuptempacct
I hear so much of this fasting hype lately. People seem to conveniently forget
that you:

1\. Lose all your muscle mass.

2\. Suffer malnutrition.

3\. Destroy your stomach lining due to too much acid building up.

All for zero proven benefit.

But hey, people like TDD too, so I don't hold it against you.

~~~
CyberDildonics
I think you will need to source all those claims, all the evidence I've seen
is to the contrary.

For 1. you can see MMA fighters cut weight and not 'lose all their muscle
mass' so that one seems to have some pretty stark evidence against it. Not to
mention that body builders routinely go on bulking and cutting cycles
specifically to put on more muscle.

~~~
bitwize
MMA fighters and bodybuilders do lose significant muscle mass during their
cutting phase, not to mention dehydrating the shit out of themselves. It's not
a healthy way to live, and it's not undertaken by these athletes unless
strictly necesssry.

~~~
CyberDildonics
Fat goes first. Saying that a theoretical body builder who isn't even trying
to make a certain weight loses 'significant' muscle is not something that's
backed up by even common sense. If that were true, how does anyone end up with
more muscle after they lose weight?

> It's not a healthy way to live, and it's not undertaken by these athletes
> unless strictly necesssry

That's not the discussion, this has nothing to do with whether fasting
destroys muscle mass.

Do you have anything to back up your claim?

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XalvinX
Some people theorize that alcohol works in a similar way for the brain.

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MayeulC
Ethical issues aside (which is essentially the _biggest_ issue to be solved),
I could see great value in applying some software methods to biology, among
which something akin to unit testing.

What would be needed is a way to reliably test drugs in conditions as close to
in vivo as possible (if going full SF, we can imagine full warehouses of human
bodies that would be bred, preferably without brains for those aforementioned
ethical issues -- unless you are creating a dystopia universe -- for the
purpose of testing drugs, and harvesting organs). I cannot imagine how big an
impact it would have on healthcare, biology and more general human body-
related issues.

SF technologies like prosthetics, cryo-preservation/life support, stem cell
regeneration, embryology and in vitro fetus development, cloning for "body
parts", and countless others would suddenly seem a lot closer.

I don't think that kind of thing will happen any time soon, though. It may
happen in the future if alternative technologies can't replace it (simulation,
nanoscale engineering).

Such topics can quickly become extremely philosophical. I initially wrote a
paragraph on what dying means to me (maybe fine with it), etc; on which I
think I could go on for pages, but I think it would be better to stop here :)

