Fasting Reverses Age-Related Decline in Regenerative Capacity of Intestinal Stem Cells
Today I'll point out a demonstration of one of the many ways in which calorie restriction and fasting improve matters in our biology, in this case via improved stem cell function. As always it is worth bearing in mind that while forms of calorie restriction produce useful short term and long term healthy benefits in humans, they don't have anywhere near the same size of effect on life span as occurs in short-lived species such as mice. We didn't evolve to react as strongly to famines, as famines are typically a much shorter fraction of our life span in comparison to that of a mouse.
Stem cell populations, of different types for each variety of tissue in the body, support surrounding tissue by providing a supply of daughter somatic cells. As aging progresses, stem cell populations become ever less active, and this supply diminishes. Tissue function falters and eventually fails as a consequence. The evidence to date suggests that this decline is at least as much an evolved reaction to the state of damage in the body as it is dysfunction in the stem cells themselves. Numerous demonstrations show that, placed into a less damaged environment, old stem cells are just as active as young stem cells. Other lines of research have delivered signal molecules to induce old stem cells into greater activity in situ.
Is this safe? The consensus on why stem cell activity declines with age is that it balances mortality due to cancer versus mortality due to failing tissue function. Stem cells in old individuals do accumulate mutations and other forms of damage, while at the same time rising levels of inflammation and incapacity of the immune system lead to an environment that favors the development of cancer. Thus unrestricted cellular replication should have a higher risk of cancer. Evolutionary pressures have led our species to a long life span among mammals, but at the cost of a slow functional decline in later life.
Conversely, consider what has been discovered and achieved in the field of regenerative medicine: all sorts of methodologies to achieve enhanced stem cell activity. Consider the mice genetically engineered for greater levels of telomerase, in which their enhanced life span is probably mediated by increased levels of stem cell activity and tissue maintenance. The evolutionary balance appears to have a fair degree of wiggle room in which it is possible to build therapies to increase tissue maintenance without also needing to first repair the stem cells involved. The research community should still be aiming to repair and replace stem cell populations, of course - diminished numbers and cell damage become significant and problematic in very late life. This is a part of the SENS rejuvenation research agenda that, despite the high levels of funding and activity in the stem cell research community, hasn't yet made anywhere near enough material progress.
Fasting boosts stem cells' regenerative capacity
As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine. This age-related loss of stem cell function can be reversed by a 24-hour fast, according to a new study. The researchers found that fasting dramatically improves stem cells' ability to regenerate, in both aged and young mice.
Intestinal stem cells are responsible for maintaining the lining of the intestine, which typically renews itself every five days. When an injury or infection occurs, stem cells are key to repairing any damage. As people age, the regenerative abilities of these intestinal stem cells decline, so it takes longer for the intestine to recover. After mice fasted for 24 hours, the researchers removed intestinal stem cells and grew them in a culture dish, allowing them to determine whether the cells can give rise to "mini-intestines" known as organoids. The researchers found that stem cells from the fasting mice doubled their regenerative capacity.
Further studies, including sequencing the messenger RNA of stem cells from the mice that fasted, revealed that fasting induces cells to switch from their usual metabolism, which burns carbohydrates such as sugars, to metabolizing fatty acids. This switch occurs through the activation of transcription factors called PPARs, which turn on many genes that are involved in metabolizing fatty acids. The researchers found that if they turned off this pathway, fasting could no longer boost regeneration. They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities. They also found that they could reproduce the beneficial effects of fasting by treating mice with a molecule that mimics the effects of PPARs.
Acute fasting regimens have pro-longevity and regenerative effects in diverse species, and they may represent a dietary approach to enhance aged stem cell activity in tissues. Aging in lower organisms and mammals results in the attrition of stem cell numbers, function, or both in a myriad of tissues. Such age-related changes in stem cells are proposed to underlie some of the untoward consequences of organismal aging.
It has long been appreciated that fasting has a profound impact on aging and tissue homeostasis. Our data illustrate that a 24-hr fast augments intestinal stem cell (ISC) function through the activation of fatty acid oxidation (FAO), which subsequently improves ISC activity in young and aged mice. Fasting increases FAO in ISCs by driving both a robust PPAR-mediated FAO program in ISCs and by increasing circulating levels of triglycerides and free fatty acids (FFAs) that can be then used by cells to generate acetyl-CoA for energy. Although FAO is critical for tissues with high-energy needs like skeletal and cardiac muscle, little is known about the role of FAO in ISC biology. An important question is how does increased FAO boost ISC function.
Our data indicate that aged ISCs have a reduced capacity to utilize lipids for FAO. Consistent with this notion, aging has been associated with impaired mitochondrial metabolism and FAO in a number of tissues. Because the addition of palmitic acid (PA) or induction of FAO with PPAR-delta agonists largely restores aged ISC function in our organoid assay, one possibility is that ISCs rely on FAO and a shortage in cellular energy hampers old ISC activity.
This implies that fasting is beneficial. A recommendation as to frequency and duration of fasting would be helpful.
Fasting as an extreme calorie restriction for sure has benefits. It is where the autophagy should be boosted, junk accumulation reduced, weak cells removed. From evolutionary point of view our predecessors had to fast for many days on regular basis. So, this downtime is quite natural. Probably not having to fast a single day for duration of one's life is not what our bodies were planned/optimized for.
Is there a downside? Could fasting be dangerous if the cleanup processes are too aggressive and destroy crucial cells and tissues while not doing enough to junk/senescent cells removal? (one obvious victim of the fasting is the muscle mass ). And malnutrition is proven to damage our bodies in various ways.
Could fasting be beneficial ? For sure, it is applied with and without medical supervision all over the world.
So what could be the best human protocol from SENS point of view ?
And how can we translate mouse studies to humans? How can we compare one day of mouse fasting to humans? What multiplier should we use ? We live at least 20 times longer than a mouse. Is one mouse fasting day equal to 20 days in humans or more like it is 1 to 1?
@cuberat
currently we have no idea HOW MANY DAYS it takes to induce autophagy. we know it happen but when ? according to my knowledge not sure also take home note is every human is different the human biology also work differently with different races. because of genes they have. I do 16/8 eating window Intermittent fasting with metformin I am 25 and happy with current progress because I look 19-20.
I am surprised that nobody knows. After all , medically supervised fasting had been practiced for many decades with good results. Fasting miss are wired different between species. For example, the vampire bars will day after a couple of days since they have virtually no energy stored. Hibernating animals are a whole different story. Humans are/were opportunists feeders with feast followed by many lean days.
And the most practiced fasting is the one what is easiest to adhere to. We need more studies . Especially on how to combine find with senolitics and other supplements. One might cancel our compound the bridal effects.
Kinda a low hanging fruit...
to Salman
I recall few studies that show some association between metformin and neurodegenerative diseases. Basically diabetes patients that were treated by metformin have greater odds of NDDs over T2D patients that were treated with other drugs.
Judy Campisi has suggested four days:
https://www.youtube.com/watch?v=adg3vUez3EU&t=2135s
Over the holidays I fasted for four days; on the fifth day I ate half my normal caloric intake to ease back in. I'm heterozygous for MCAD deficiency with some (relatively speaking) mild symptoms that only seem to be a problem if I consume medium chain triglycerides. If I had felt lethargic, confused, or hypoglycemic I would have broken the fast. I'm sure a doctor would advise me not to fast, but I was fine - in fact, it felt great and I hope to do it again.
Posted by: CD at May 6th, 2018 1:52 PM: :
Judy Campisi has suggested four days:
https://www.youtube.com/watch?v=adg3vUez3EU&t=2135s
If you wind back a couple of minutes and listen to this quote in context, it's reasonably clear that she isn't asserting this. Campisi first explains that innate immune clearance of senescent cells declines with age, and mentions that unlike with adaptive immunity, there is not a grossly obvious decline in innate immunity with age. Starting at 30:30, Patrick that this brings to mind Valter Longo's fasting work, which showed a rebalancing of the populations of haematopoietic stem cells in mice fasted for 48 h - which she says "translates to four days in humans" - "clears away senescent cells, and presumably senescent cells," and misremembers it showing a rebalancing of the innate and adaptive immune systems. Note that the idea of a 4-day fast is introduced by Patrick, and likewise it is she that introduces the idea that fasting might clear out senescent cells, not Campisi - nor Longo (this is not touched on in the study she references, nor in any of Longo's other work). Campisi then speaks hypothetically, extending Patrick's statements and hypotheses - she's not specifically endorsing a 4-day fast for this or any other purpose.
I can give my two anecdotal cents. Up to 24 hours it is just peculiar feeding habits like eating once a day. Fasting above 24h to 3 days reduces the blood sugar, so can be bring short term benefits which could be emulated with metformin and TOR pathway hacking. It can soften some acute inflammatory conditions but nothing special. For me probably the biggest benefit is that I just sleep more.
For me anything less than 3 days I consider it a mild detox nothing special unless you combine it rigorous phisical activity or some strong supplement.
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From 4 to 7 days your mileage will vary. Some chronic inflammatory conditions might feel worse. Or better. Some people have endorphin spikes. I personally, lack energy and feel most of the times like crap. But a few days are the fast I start feeling bête than before.
There is also a self experimentation program suggested by some German guy however you need to translate this first
http://lang-leben.xobor.de/t372f35-Senolysis-Program.html
The idea is almost same as josh mitteldorf 4 day fast on third day 2-3 gram quercetin and 4th day 2-3 gram quercetin but this guy also added some arginine and curcumim for autophagy he also have some suggestions for thymus and other stuff
Will fasting have any greater effect on longevity than taking an aspirin everyday?
Massive amounts of current fasting science is based on rats and mice.
It is often, even in Longevity circles translated hour for hour to humans without any hesitation.
But metabolic rate of small rodents is absurdly fast compared to humans.
As I recall from one study, ~50 % of mice die of starvation after 72 hours of fasting.
There are some Youtube Vloggers who water fast for Jesus and so on, they will do it for up to 30 days and log every day. You can then look at their other videos months later, I note that many of them come out looking very good after the recovery period. Towards the end of the actual fast many of them look like almost dead palliative care corpses though.
I would love for someone to set up a serious trial in humans and see what happens if a group is fasted 5 days once every month for a year. I'm sure they would see great improvements.
>As I recall from one study, ~50 % of mice die of starvation after 72 hours of fasting.
I would expect them to be able to drive much longer. In the whild both mice and rats are facing periods without available food.
As for the humans, even in 19 th century a lot of people routinely had to run on empty for 2-3 days. And that wasn't considered special. No food today? No problem, just tighten your belt a bit...
>There are some Youtube Vloggers who water fast for Jesus and so on, they will do it for up to 30 days and log every day.
Ironically, the most vocal people practicing fasting are mystically oriented. Probably it has to do with motivation and altered state of mind during the fast . So you will hear very weird claims and some of them with very questionable scientific value. However, they have a lot of experience and some "bioenergy" groups at least try to use some scientific explanations. Especially, when trying to cure a disease.
The fasting period humans can tolerate is highly dependant on the starting BMI. One estimate I have seen is that the first few days the body loses about 2 pounds/1kg a day. After that there is an adaptations, which reduces the basic body metabolic rate and until day 17-21 the body burns/loses about a pound. In fact, burning 100 grams of fats should give 900 K calories. Obviously the body loses also some water and proteins. After about day 21 the body has yet more adaptations and switches to keto cycle. Noe that it burns less than a pound a day. Probablyy half a pound but mainly fats. So half a pound fats can easily give enough energy to run the body for a day. Therefore, for extremely long fast the rough capacity is 2 days per pound body fat.
From the shared experience, it seems that everything over 21 days induces strong autophagy and cenecent cell removal. Of course YMMV.
@Michael
I did not suppose that Campisi was advocating fasting. I should not have used 'suggested' since I realize now that that could connote a recommendation. You are correct, Patrick was the one to introduce the idea that four days of fasting would be equivalent to the time period of extended fasting used in many mouse studies, but apparently Campisi (who has conducted studies using mice and is presumably quite familiar with their biology) thought the time period to be a reasonable estimate, also.
~
@Cuberat
Four days was pretty much the limit for me as I have a low BMI; I doubt I would survive a 21 day fast. The effective minimum duration might vary among individuals depending on starting BMI.
As far as senescent cell clearance goes, I would expect fasting to be a more widespread practice if it had such a profound effect (but as you say, more studies are needed). OTOH, fasting has a lot of other well-documented physiological effects. Four days of fasting did seem to be quite beneficial to me, though as I mentioned above I have a mild form of a fatty acid oxidation disorder.
It certainly was a lot easier than I thought it would be* - far easier than some other interventions such as maintaining a regular exercise schedule (still doing it) or contrast showers (given up).
*{ and no dishes for four days! }
@CD
>*{ and no dishes for four days! }
And also no time spent cooking, eating and you save on toilet paper :)
> I have a low BMI; I doubt I would survive a 21 day fast. The effective minimum duration might vary among individuals depending on starting BMI.
of course it varies. I think there were people fasting over a year but those weighted over 400 LBS.
As of how much could you survive, the general recommendation is to stop fasting when you reach BMI of 18. Probably can go 1 or 2 BMI units below if you consult a doctor.
On the other hand, having a low BMI suggest a low calorie intake, so you have a mini CR ongoing anyway
Yup! :)
If 18 is the threshold, I could have gone another day. In college, though, my BMI was 17.6 and I got by; I had health issues, but I don't think low BMI was the problem (more likely it was eating oreo cookies). 17.6 looked a lot better on me then than it would now, though, due to changes in fat distribution (I wish someone would figure out that problem... ).
Out of curiosity, I looked up death by starvation and was surprised to find it typically occurs at a BMI of around 12. So I figure I could go up to 35 days - good to know in case of famine / collapse of civilization.
@CD
BMI of 12 might mean that the body had destroyed and cannibalized important tissues and probably cause irreversible damage. On the other hand you have a very hight chance that the autophagy and cenecent cells removal were performed out of necessity. I can imagine an experiment were old mice are starved to MD 50 and the remaining are checked for improvements. However have to be careful about the selection bias. The ones that have survived might have better clearing mechanisms to start.
from Josh
>I wrote to Valter yesterday, asking this question. Does he have evidence from people suggesting how long it takes for the immune reset? Is it different for people who start with a lot of fat on their bodies compared to people who have nothing in reserve? His answer was short and to the point:
"3 days is optimal for mice. For humans 4-5 minimum, depending on what you are trying to achieve"<<<
@Jeffrey Lewis
The mice for after 2 to 4 days of starving. That would be far from optimal, though...
For the humans even short fasting provides noticable, albeit temporary , benefits. But for a long lasting change humans will have to go 14 to 20 days or use some intermittent or cascading protocol.
There is an interesting interview of dr. Ed Group interviewed by dr. Jockers on youtube.
Dr. Group says that a clean water fast (so no bullet proof coffee, etc.) of 6 days is required to have a significant degree of autophagy and stem cell regeneration.
He mentions a case of a 40 year old man who did a 14 days water fast and experienced a rejuvenation of all his vital organs with roughly 25 years. Amazing.