What do you think about Intermittent Caloric Suppression?

[manuel5]

Intermittent Caloric Suppression (Prolonged Fasting) could have similar results to CR.

What do you think about this topic?

[mccoy]

I have experimented Valter Longo's fast-mimicking diet and it is excellent beyond CR. It is not caloric suppression, rather very low-caloric and avoids the drawbacks that some people like me suffer with total fast. If done once a month, the FMD is all but the same as about 15% CR. With some added benefits, probably.

[Tabastopher]

On 6/3/2023 at 6:00 PM, manuel5 said:

Intermittent Caloric Suppression (Prolonged Fasting) could have similar results to CR.

What do you think about this topic?

Do you mind elaborating the topic further? Either by providing a link to some websites or just explaining it yourself. I am not very familiar with this exact phrase as a topic myself,

Tnx

[InquilineKea]

Or also intermittent isoleucine suppression. Even intermittent veganism would do something (not as much)

Easiest way to do this is semaglutide

Edited November 16, 2023 by InquilineKea

[corybroo]

New research finds that 14-hour fasting improves hunger, mood and sleep

Eating in a ten-hour window is associated with higher energy and mood and lower hunger levels

Despite some IF advocates commonly promoting restrictive eating windows as low as six hours, findings detailed in the abstract show even eating within a less restrictive window of ten hours still has positive health benefits, such as changes in mood, energy and hunger.

Dr. Sarah Berry, from King's College London and chief scientist at ZOE, said, "This is the largest study outside of a tightly controlled clinic to show that intermittent fasting can improve your health in a real world setting. What's really exciting is that the findings show that you don't have to be very restrictive to see positive results: a ten-hour eating window, which was manageable for most people, and improved mood, energy levels and hunger. We found for the first time that those who practiced time-restricted eating, but were not consistent day to day, did not have the same positive health effects as those who were dedicated every day. "

[manuel5]

I am referring to eating a nutrient-optimal normocaloric diet but doing periods of total fasting (water only), for 3 consecutive days or more throughout the year, to mimic the benefits of CR while avoiding the risks associated with CR. In addition, in this way, deeper autophagy would be achieved in all tissues. This idea is striking to me because it has nothing to do with the type of diet...

This would be done in the following way: For example, you eat normally for 3 weeks (without being in deficit or surplus) and the last week of the month, you stop eating for 3 days or more, and the following month the process is repeated. similar to Longo's FMD but without eating anything, just water. (There are many ways to incorporate it and I think it is a very interesting strategy and I think in some ways it could be superior to CR.

I would like to know what you think :)

[IgorF]

Hm, I never had a time to dive deeper into the topic but I had some doubts about let's say "autophagy optimism" basically due to intuition - I had seen this copy-pasted from one motivation and/or health-and-wellness text to another but never with some strong ground references. A quick look on it discovers a wide plethora of different areas thus I tried to just narrow it into an intuitively curious thing from the let's say desired "fundamentals" angle - what about dealing with damaged mitochondria?

So the question is - can starvation-induced autophagy be helpful with those mitochondria which are in a worse shape?

A quick answer from 2018 - seems "no".

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168274/

Quote

No studies show that starvation-induced macroautophagy is selective, and mitochondria and other organelles are not degraded acutely upon starvation (Kristensen et al., 2008; Gomes et al., 2011; Rambold et al., 2011).

(macroautophagy is the most studied type of autophagy, at least it is thought of like that)

Maybe this answer is wrong because it looks like the area to be investigated will itself require many decades to have the first most interesting let's say 10 answers but right now it seems like it is.

Thinking about it intuitively - starvation is nothing less than a cellular emergency, both at the the cell level and at it's mitochondria influx level - it seems electron transfer chain has no idle cycles, thus no time for any "smart selection", anything that could be used as a fuel will be used and these molecules in the closest proximity will be selected first. So actually degradation of unwanted things inside the cell due to starvation will be rather stochastic process than some beneficial outcome of the starvation regimen (besides some small statistical benefit which will be higher in the cells full of relatively benign debris).

Maybe this is a wrong way to think but I have no idea how to assess quantitatevely if starvation-induced autophagy is beneficial to longevity and what percentage it adds in total (especially in humans and in the real life).

Br,

Igor

 

Edited November 18, 2023 by IgorF

[IgorF]

Some more on mitos and starvation:

 

Quote

Under certain starvation conditions (e.g., amino acid depletion) mitochondria may escape
autophagosomal degradation through extensive fusion. Such mitochondrial fusion under
starvation conditions provides enough ATP necessary for cell survival. Downregulation
of the mitochondrial fission protein Drpl is considered to be responsible for the fusion
(Rambold et al., 2011a). The process of fusion tends to result in the interconnected mitochon-
drial network through their elongation. As expected, pharmacological and genetic inhibition
of mTOR leads to increased mitochondrial fusion. It is known that mTOR controls mitochon-
drial fusion. However, other signaling pathways (e.g., AMPK and PKA) may also be involved
in starvation-induced mitochondrial fusion (Rambold et al., 2011b).

 

This is from a book (a part of several on the autophagy topic)

https://books.google.com/books?id=ZOyWCwAAQBAJ&pg=PA52

 

The study refferred is https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327623/

There are several other places in the volume 6 that I serched where it is mentioned that induced aminoacids depletion has this effect. Also an interesting thing:

Quote

The role of mTOR is also relevant in ALR. It has been found that the starvation-induced
autophagy process is transient. During starvation, intracellular mTOR is inhibited before
autophagy can occur, but it is reactivated after prolonged starvation, and the timing of this
reactivation is correlated with the initiation of ALR and termination of autophagy (Chen
and Yu, 2012). Thus, mTOR reactivation is required for ALR. ALR is blocked when mTOR is
inhibited, and mTOR reactivation is linked to lysosomal degradation.

Actually, these are just 2 aspects of an enormous "spaghetti" of different interconnected and interrelated things with multiple backup routes and feedback controls (multiple volume set of publications is just a scratch of it) that makes a person from the outside of research unable to draw any conclusion on the question - is it beneficial per se to induce it via shortterm starvation or the positive effects (if any) come from another areas?

I tried to find if https://en.wikipedia.org/wiki/Roberta_Gottlieb (one of the researchers of the topic in an area of heart+ and the author of some nice poetry on the topic %)) had a public talk with an opinion if starvation-induced autophagy could be beneficial but I failed to find any. I suspect she will use very careful wording as true experts usually do in such cases %).

 

Br,

Igor

 

Edited November 20, 2023 by IgorF

[IgorF]

And another quote, on timing:

 

Quote

Interplay between Autophagy Pathways
Despite sharing an ultimate endpoint of lysosomal degradation, the three autophagy
pathways differ in their kinetics, selectivity and regulatory mechanisms. Interestingly,
while micro- and macroautophagy appear to be evolutionary conserved, CMA has only
been noted in higher organisms. Coupled with the fact that CMA is the only pathway that
is entirely selective suggests that this mechanism evolved to cope with the complex cellular
homeostasis mechanisms required to meet sufficient energy demands.
The coordinated activation of macroautophagy and CMA has been noted in response to
environmental stimuli such as starvation. The kinetics of each pathway, however, differs in
response to the same stimulus. Macroautophagy, for example, reaches a maximum level of
activation after six hours of starvation before slowly declining even where the stimulus per-
sists. This decline in activity is likely to be the result of a feed-forward mechanism whereby
the catabolites released from autophagosome-lysosome fusion reach sufficient cytoplasmic
concentrations to “re-active” mTOR signaling. It has been suggested that there is a mutual
inhibition between macroautophagy and CMA as concomitant to the observed decline in
macroautophagy there is an activation of CMA. CMA activity peaks after 24 hours of nutri-
ent deprivation but can remain elevated for extended periods of time during starvation.
These temporal differences in activation may be due to the higher selectivity CMA has for
its substrates; it is therefore able to have tighter control over the choice of proteins being
degraded. Maintaining high levels of the less selective macroautophagy could quickly tip
the balance and become detrimental to cell growth and survival.
Despite apparent coordination between the two autophagy pathways they cannot fully
compensate for each other; CMA cannot degrade organelles while, as mentioned previously,
macroautophagy does not have the high selectivity of CMA. Indeed, inactivation of CMA
in cultured cells results in increased macroautophagy, but not to sufficient levels to allevi-
ate the increased sensitivity of CMA-deficient cells to stress (Massey et al., 2006). The ability,
however, of the two pathways to seemingly interact suggests that there are indeed under-
lying molecular mechanisms coordinating their action. It has been suggested, for example,
that macroautophagy may degrade endogenous CMA inhibitors, or that macro autophagy
machinery could become CMA substrates, which would explain the transition from
the early activation of macroautophagy to later onset of CMA.

https://books.google.com/books?id=Wh4tBAAAQBAJ&pg=PA110

Thus, if doing water fasts to induce autophagy it probably could be enough to do it less than 2 days to get the most effect, at least according to the 2 decades old data.

 

Br,

Igor

[IgorF]

And another angle - proteins degradation. Generally speaking - it happens constantly and in highly orchestrated manner, via different pathways for the sake of reliability (there seems a crosstalk however which is not surprising https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0569-y). Most of the things eukaryotic cells are doing all the time from the energy cost perspective is proteine lifecycle-related. The half-life of the proteins varies from tens of seconds to many days (up to cell lifetime itself but usually rbcs with their 110-120 days are mentioned as an example, I did not tried to find longlived proteins examples yet). Early starvation induces some increase in proteolysis but I doubt it is selective in the sense coined in simplistic definitions coming from health and longevity books, I think this was a kind of hypothesising that now travels from source to source when it is needed to say something on the topic for different reasons. But some rationale (stochastic perhaps) should exist also.

When starvation goes further, behind 3 days as a usual landmark the things are definitely not selective and muscles (and later organs) will be sacrifised to create glucose and give rbcs and brain a chance to keep the body running.  A brief slide from USMLE textbook summarizing the views on the topic is available here:

https://www.coursehero.com/file/p6p330ib/NB-Acetyl-CoA-from-FA-cant-form-glucose-by-gluconeogenesis-as-its-2-carbons/

(p.231 in)

 

Here is an older study that is useful to see the things from the perspective of home practitioner (need to fetch the pdf e.g. via scihub):

https://pubmed.ncbi.nlm.nih.gov/2593832/

they run a similar protocol on healthy volunteers, measuring simple things like total urea and methylhistidine excretion (also doing biopsies for muscle tissues) to see what happens on the exit of a "blackbox" of a body, from their conclusion I could derive the following - 3 days fasting will definitely break down a lot of proteins unselectively, I can not imagine the tissue that holds so much disfunctional proteins and do not cause serious troubles for a living organism. Another thing - tissue source. It is well known that muscles will come first, so some minuscule addition of bad proteins (e.g. from brain cells, that we could potentially want from neurodegenerative deseases perspective and so on) could be broken or could not be touched at all, from the perspective of body survival it makes zero difference, so no selective pressure, so very unlikely to be developed in the longterm.

Thus, getting into day 3 of fast will probably come at the cost of muscles for most of the people and perhaps it is an unwanted thing.

That is all IMHO off course but looking on the study and given that quantitative 3-MH and urea in blood and urine tests are widely available and quite inexpensive I think a person could finetune own fasting protocol relatively easy.

Br,

Igor

Edited November 28, 2023 by IgorF