Drugs that kill off old cells may limit a body’s aging
arstechnica.com
arstechnica.com
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.
Socrates lived to 71. Meanwhile today NPR reported that rubbish pickers in Mumbai live on average to 39.
It could if it was just an epigenetic switch that was flipped to turn back on an old and complex adaptation. (Which presumably saw regular-enough use through the aeons to avoid genetic drift "rusting" it.)
>>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.
Eagerly awaiting reasonattlm's take on this.
At a minimum it seems that we are on the right track. Pretty exciting times.
From what I read, a lot of the things the body does, which have aging as a side effect, are intended to block cells from becoming cancerous.
For example a senescent cell - it might be damaged, and if it dived it might become a cancer, so better stop it from dividing. But we still need it, so don't kill it off.
Now you might think - actually, let's kill it and let some other cell divide and replace it. But that creates more cell division, which are more opportunities for cancer.
Basically, it's a delicate balance.
I suspect a different balance is also possible (there are animals without cancer for example), but the hard part is you must change all the parts at once (into the new balance), and simply stopping one part of the process will cause cancer.
This is going to make the research very hand without truly understanding all the moving parts, and joining all the different treatments into a single working whole.
What's needed is a fast-living animal, that ages, and gets cancer, in the same way humans do. Then you can just experiment without understanding.
A simulated human?
(I know that's A Lot of computing power, but maybe an algorithm like HashLife could make this possible by, say, 2100?)
For the chemical simulation side of things, it would take many centuries of continued Moore's Law progress to make today's most accurate algorithms for fully quantum chemistry run fast enough. And the wild ride of Moore's Law already appears to be closer to its end than its beginning. We'd need fundamental algorithmic breakthroughs to make it feasible without relying on better simulation hardware solving the problem. That might be possible, but I don't when/how/if such algorithms may appear.
On the problem of getting a ground-truth molecular map of a cell in the first place, we know that there are many gaps in current models. We're not sure where all of them are. Even if you had the fast, efficient, vast molecular simulation capacity I sketched above, it would still take a lot of experiment/simulation comparisons to be sure that all the biologically relevant features had been captured in the original model.
Even now I'm probably badly understating all the problems on the biology side. I worked at the interface of chemistry, biology, and chemical physics, but I was more familiar with the software/physics side of things. I learned just about enough biology to be useful in my role and to be grateful that even my most complicated debugging sessions didn't involve 3 billion years' worth of undocumented legacy code running on wet nanotechnology.
And after listening to one sleep-inducing waterfall video for a single long night of sleeping the next day about 2/3 of my Youtube homepage's suggestions are about soothing, meditative, nature videos... what a laugh.
Very rarely are things in biology so simple. Everytime we thought something was useless in the past (junk DNA, appendix, tonsils, ...) it turned out that removing it causes damage somewhere else.
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.
Note: not at all a biologist as you can probably see from the way I phrase things :)
I suspect if we ever reach such a distant future, we'll consider most radiation therapy to be a very blunt and barbaric instrument (even if ultra-targeted) and use some kind of nanotechnology instead. Some engineered virus or bacterium or nanomachine that hunts down the carcinogenic cells.
Damage happens all the time, and unrepaired damage accumulated over the lifetime, hence aging.
You have an interesting point with prevalence of senescent cells can interfere with natural immune response to cancer.
Anyway, I think this is where some lifestyle fads can become interesting. Sure, there are definitely some aspects to aging that are unaffected by this, but I think better chances of reaching current max human age are in our hands somewhat. Balancing IGF1 and frequently giving the body a break to repair, kill, and remove trash, are sound targets IMHO. So for me that is: restriction of certein makros, in particular animal proteins and refined carbs, early and midlife to lower IGF1 (raising it seems beneficial in old people); short term fasting every now and then. Both have shown to increase apoptosis and repair. It's not even hard to do, if you stick to a blue zone typical diet (plantbased diets are associated with double digit reduction in overall cancer risk, which is huge considering lifetime death by cancer risk is 1/5) and have a daily fasting window of 13+ h (eg. Shown to reduce reoccurrence of breast cancer). I focused on cancer here, because intuitively it seems like a good marker for DNA maintenance.
How about a source.
Also, I just looked up how they test grip strength on mice. It's equal parts funny and sad.
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.
https://www.bioseb.com/bioseb/anglais/default/item_id=48_Gri...
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 )
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.
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.
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.
Is it? How does it affect lean body mass and muscle mass?
Same with weak joints, old muscle bruises, etc.
But again, eating properly after the fast is important to let the body rebuild what it destroyed.
IF this is correct, it means keto and fasting both accomplish the same thing in terms of life extension, only with keto you get to eat bacon, steak and cabbage, spinach, brussel sprouts, etc rather than starve and be miserable. :D
You can perfectly use both if you know what you are doing. They don't mutually exclude. Although day to day keto is a lot of fat and meat. You may want to favor the vegetable part of keto after a long fast for some time.
People who do keto do get a majority of their calories from fat, but a majority of long term ketors tend to eat mostly low NET carb vegetables by volume. For example, you could eat a whole small cabbage in a day and not fall outside macros that would allow for a ketogenic state.
>Fasting have other benefits than keto: it activates your immune system, increase you hormone levels, allows many organs to rest and clean themself.
I have seen studies that show many of these as the same benifits of keto. For example, NAFLD resolves within only slightly longer on keto than by fasting. Keto is pretty effective at resolving PCOS for example.
Now, it maybe the case that fasting is more actually effective, but keto unlike fasting is sustainable as a long term lifestyle (conserves LBM etc).
As you pointed out, intermittent fasting and keto are completely compatible.
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.
I have been doing intermittent fasting 3 days a week, each time 24 hours, for 6 months. I've lost 35 pounds thus far.
1.) I am still doing the same weights as 6 months ago, some muscle groups even more. I make sure I have a protein shake after.
2.) I did blood testing for everything with my doctor 3 months ago and last week. My doctor says i'm perfectly healthy
3.) again, if you're eating alot of complex carbohydrates after fasting, or before, your stomach will have more acids. the key is to reduce your complex carbs as well
Plus, light fasting (aka, skipping a couple of meals) actually feels really good!
Given that fasting is always temporary, and that in one week of fasting you only consume 25% more proteins than an entire active day (remember you are supposed to rest while fasting), it's doubtful. Especially since fasting activate the production of growth hormones.
Not that you won't loose a little muscle. Of course you will on long fasts. But "all your muscle mass" is just plain silly.
Also it just doesn't happen with intermittent fasting: you tend to gain muscle.
2. Suffer malnutrition.
Malnutrition is a condition you get on the long run. Not on a few weeks on not eating a year. Besides, the improvement you get on your digestive systems after putting it to rest improve your ability to absorb nutriments after the fact, so if you follow a balanced nutrition after your fast, you should actually be better off.
And any fast minded person will tell you that what you eat after a fast is as much important as the fast itself. Once you empty the body, you gotta fill it with good things to allow it to rebuild clean what the autophagy removed.
3. Destroy your stomach lining due to too much acid building up.
Acid production stops after a few days because there is nothing to digest. The rare cases where people suffered from stomach lining were people with terrible eating habits that had acid problems already and went full throttle on fasting. Nobody knowledgeable about the practice would forget to tell you how important it is to prepare your body days or weeks before you fast. Especially if you are not used to it.
Have you ever read any study about fasting at all ?
https://www.telegraph.co.uk/science/2016/03/12/fasting-for-t...
I have anecdotal evidence that it helps, as I seem to get sick less than I used to.
> This is also a common regimen for cancer patients, fasting before they start a new round of chemo.
Yes, not only fasting has a positive effect on cancer, but it lower the side effects of the chemo.
I also suffer from heartburn that started way before I ever fasted the first time. In contradiction to the poster you were responding to, I find that it goes away, not gets worse, when I'm fasting. As you say, the acid does seem to stop getting produced during fasting.
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.
When fighters cut just before weight in, they do so to make sure that they make their weight class cut off or they can't compete. This has nothing to do with fasting - they are forced to do it to stay in weight class, but at the very top of it (being as heavy as possible is overall a boon in the ring).
The idea that you think 'fasting' loses muscle mass is an idea that is not backed up by any evidence. Fasting isn't a diet, it is about when you eat.
Also, you didn't source anything. Don't you think maybe the dozen people replying to you might be less likely to be 'making stuff up?'
> 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?
They try to rid their body of as much water as possible to lower their weight.
When we say fasting for health it usually means lots of water, but no calories.
It isn't that MMA cutting is healthy, it is that fat is burned first, not muscle. Fasting for a day here and there isn't going to make someone 'lose all their muscle mass'.
Please stop spreading fear and ignorance if you haven't taken the time to do the research.
There is something about taking some salts/electrolites/minerals with your water at some point to counter some things like light-headedness.
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 :)