#16

If Rapamycin only stopped mtor1 and had no impact on mtor2, should it be taken every day or continue with once a week? Is turning mtor1 back on just as important?

2 Likes
#17

No, every day administration would cause the on-label effect of immunosuppression, evidently mTOR in the immune system is very sensible to Rapamycin; the intermittent administration is at the base of the seminal experiment of Joan Mannick, who had this intuition and observed in the clinical trial an immuno activation subsequent to the intermittent inhibition of mTOR.

Returning to the natural activity of mTOR is vital, we cannot live in a permanent state of prevailing autophagy and catabolism.

The fast mimicking diet of Valter Longo is an example of intermittent inhibition of mTOR, and the reactivation of this complex by proper refeeding is a necessary phase of the technique.

It would be interesting to open a thread to discuss the analogies and differences between Rapamycin and Longo’s FMD, they hit mTOR in similar, but not identical ways.

5 Likes
#18

This clip is very relevant to the original question posed, the answer is given by the discoverer of mTOR himself, David Sabatini, who compares mTOR to the Central Processing Unit of a computer. He also clarifies the role of mTOR in some cancers, where this protein is chronically and pathologically turned on regardless of the input signals.

In the CPU comparison, I would perhaps add that the CPU controls all growth processes and maybe rapamycin would be a program which turns the processor off, blocking growth and proliferation and leaving the system into a default troubleshooting and cleanup mode.

5 Likes
#19

this is another very interesting image of the protein structure of the whole kinase. The Tor dimer, is in green.

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Another structural image with the mTOR complex and the FKBP protein bound by RApamycin. Apparently, direct binding by Rapa alone does not inhibit Tor

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Last, the two complexes #1 and # 2

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#20

I need that on a T-shirt

8 Likes
#21

Here’s a pretty good basic summary of how rapamycin works.

https://mmabrasil.localizer.co/t/former-whole-foods-execs-open-love-life-a-longevity-medical-club/15644/17?u=ng0rge

1 Like
#22

It’s interesting to know that Rapamycin cannot inhibit mTOR by itself but it must first bind a protein called FKBP12. The result is the so-called FRB complex (FKBP-Rapamycin Binding domain of mTOR). When part of this complex, mTOR is switched off.

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4 Likes
#23

FKBPs are involved in diverse cellular functions including protein folding, cellular signaling, apoptosis and transcription. They elicit their function through direct binding and altering conformation of their target proteins, hence acting as molecular switches.

2.1.1. FKBP12 as an Immunophilin

FKBP12 was originally identified as the target of FK506 and rapamycin [1]. Both drugs bind noncovalently to FKBP12 and inhibit its PPIase activity [3]. However, the inhibition of FKBP12 per se does not contribute to their immunosuppressive activity. Instead, the binding with FKBP12 allows the drugs to subsequently interact with the mechanistic targets of their action in immunosuppression. The FK506-FKBP12 complex specifically interacts with calcineurin (CaN), a Ca2±dependent serine-threonine phosphatase [11–14], whereas the rapamycin-FKBP12 complex targets mammalian target of rapamycin (mTOR) [15–17].

FK506-Binding Proteins and Their Diverse Functions - PMC (nih.gov)

1 Like
#24

We don’t fully understand. At best we have hints, but there’s always info coming out that seems hard to fit into the prevailing hypothesis. Here’s an example, where aging in different organs happens at different rates. It is the rapid turnover tissue that ages slower, while the slow turnover tissue is the one that ages faster. Example of rapid turnover, youthful tissues: intestines, skin - rapa slows cell division, yet seems to have good impact on skin and intestines. Meawhile the liver is a rapidly aging organ, because the cell turnover is slower - yet rapa slows cell division, which in this scenario should lead to senescence and error accumulation… made worse by rapa further slowing down cell turnover? How does all of this fit together?

The paper:

https://www.cell.com/cell/fulltext/S0092-8674(24)00963-2

A pop sci writeup:

3 Likes
#25

@CronosTempi Interesting. I wonder if it’s a triage effect as the body has to prioritize the fast turnover cells. In a resource constrained situation, the slow turnover cells don’t get enough resources to age more slowly. The resource constraints could be in energy, minerals, vitamins, amino acids…

1 Like
#26

Possibly. But the whole growth vs antiproliferation axis is highly confusing. There are a number of very slowly, possibly not at all aging molluscs and crustacean species, lobsters and the like, surprisingly long lived for their size - and one thing that these animals do is they never stop growing, as they age, they just become bigger and bigger, and could go on for who knows how long (eventually they get eaten by predators, die accidentally etc.). You wonder - how… but think of it this way, you start aging/decline when you reach maturity, a developing baby/toddler has not yet reached maturity so it is not in aging decline. Now, what if you could prolong that state indefinitely, always growing, never reaching the “end state” from which a decline can start, so like that lobster, you just keep growing. A very different model of aging/antiaging than the mtor/rapa/CR pathway of “let’s hunker down, not grow or proliferate” - note how the IGF-1 inhibited specimens age slower, and in fact grow much smaller as seen in mice etc. (in humans the Laron dwarves) - so the opposite of the lobster, i.e. grow as little as possible and stop as soon as possible.

These two models are opposites, which tells us that there are different ways to skin the cat of aging. This, btw., we see over and over again - example are the slow aging because of slow metabolism, low core temperature, low heart rate, seen often in very long lived reptiles (which btw. often keep growing as they age, like crocks and giant turtles!), but at the other end you have the close relatives of reptiles, birds, which have extremely high metabolism and core body temperature and can be super long lived, especially for their size (parrot species that live longer than humans, being much smaller, or tiny hummingbirds living astonishing 8-10 years with a thermonuclear metabolism turnover, heartbeat and energy output of the sun!), high energy output birds in general don’t display overt signs of aging - what a contrast to the low energy output of the also slow aging reptiles, or mammals subject to CR, where energy output is diminished and conserved.

Bottom line, the proliferation/growth vs nonproliferation/non growth axis vs aging is very complicated.

6 Likes
#27

This is me exactly. The absence of illness and hay fever takes time to notice, but 2 years is enough time to convince me even with n=1.

4 Likes
#28

:rofl: :rofl: :rofl: :rofl: :rofl: :rofl: :rofl: :rofl: :rofl: Yes very simple. :rofl: :rofl: :rofl: :rofl: :rofl: :rofl: :rofl:

#29

The same is true for me. I user to get down once or twice a year with someyhing nasty.

After rapa, I either don’t catch anything (or have discernible symptoms) or have a very mild case, despite having 3 kids at school age.

Shitty imunossupressor…

1 Like
#30

Take it everyday and get back to us on that one.

1 Like
#31

What about this?

Is the liver resilient to the process of ageing?

https://www.sciencedirect.com/science/article/pii/S1665268124003636

The liver’s unique regenerative capacity, immunotolerant feature, and polyploidy status distinguish it as a metabolic organ unlike any other in the body. Despite aging, the liver generally exhibits fewer pathological abnormalities than other organs (such as the kidney), maintaining its functions near-normal balanced manner.

Notably, a recent report suggests that the liver is a youthful organ, with hepatocytes averaging an age of only 3 years.

Despite the liver’s impressive regenerative capabilities and cellular reserve, a lingering question persists: how does the liver maintain its youthful characteristic amidst the chronological aging of the entire organism?

#32

SLC13A5 - that I think is the answer.

#33

The SLC13A5 gene codes for a sodium dependent citrate transporter (NaCT) that brings citrate, a key substrate involved in energy production, into the cell.

High-affinity sodium/citrate cotransporter that mediates the entry of citrate into cells, which is a critical participant of biochemical pathways.
May function in various metabolic processes in which citrate has a critical role such as energy production (Krebs cycle), fatty acid synthesis, cholesterol synthesis, glycolysis, and gluconeogenesis.
Involved in the regulation of citrate levels in the brain (By similarity).

About SLC13A5, a gene responsible for Citrate Transport

Citrate is a small molecule that is found in many types of food and throughout a person’s body. It is an important part of how a cell makes energy. The protein that moves citrate from outside a cell into the inner part of the cell is called a citrate transporter.

In people with seizures and neurologic problems related to the functioning of the citrate transporter, there are changes in the amino acids that make up the transporter protein. The changes in the amino acids are likely to decrease the amount of citrate that is transported into the cell.

Reduced expression of this gene is associated with longer lifespan in many organisms, including some non-human primates. Increased expression is associated with type 2 diabetes and non-alcoholic fatty liver disease. A sugary diet upregulates the expression of the gene, and so does Interleukin 6 signaling.

SLC13A5 (solute carrier family 13, member 5) encodes sodium/citrate cotransporter, which mainly localizes in cellular plasma membranes in the frontal cortex, retina, and liver.

The transporter is widely expressed in neurons, localized in the plasma membrane of various cell types, including hepatocytes in the liver, spermatozoa in the testis, and mostly astrocytes and neurons in the brain (3). Citrate is vital in cellular metabolism and neurotransmitter biogenesis (3). It is known to have an important role in the tricarboxylic acid cycle, where the molecule represents the starting point for generating reducing equivalents nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (reduced form) (FADH2), which in turn enter the electron transport chain to generate ATP (4). The brain cannot produce citrate independently; hence, it depends on citrate uptake via NaCT. Thus, the carrier has a pivotal role in mediating the uptake of circulating citrate for metabolism (4), preferably in the trivalent form rather than the divalent form.

Relatedly, when citrate transport and metabolism are disrupted, intracellular citrate levels fall, resulting in neuronal energy failure, which is thought to be one of the explanations behind epileptic symptoms (3). In other words, a lack of cellular citrate results in energy deficiency in the brain, thus possibly contributing to the pathogenesis of epilepsy and delayed brain development.

Just a brief collection of explanatory info.

1 Like
#34

Yes, this is the problem, when using terms like “youthful organ” - it depends on what you measure. Like in that notorious paper that claimed brain antiaging/youthful profile of 6 years in monkeys based on a handful of markers. Well, all that says is what it says about those specific markers, it doesn’t say that about the whole organ (brain), as other markets may differ. If I administer a drug that turns gray hair back to its original color, have I made that person younger? Gray hair is one marker of aging, but if my drug does nothing for anything else, have I made an anti-aging drug? What if the intervention gives you a result as measured by a marker, but it means nothing, like my intervention is to simply color your hair at the hairdresser? Have I made you younger? Don’t laugh - a ton of drugs and interventions, even FDA approved, work on the marker but do nothing for the disease - like that notorious Alzheimer’s drug that was approved by the FDA despite widespread opposition from scientists, the drug focused on lowering a marker amyloid beta, while doing nothing tangible for AD, and having dangerous side effects to boot.

And that’s the other side of the coin, where I might reverse gray hair, but destroy your heart and shorten your life.

So showing a handful of markers and claiming 6 years age difference in the whole monkey brain, I find highly suspicious.

Back to youthful vs rapidly aging liver - by carefully picking your markers you could argue either case. One way to test would be to say “never mind if it looks/measures as young or old - how does it function, like a young output, or old output?” If as you age, the liver function deteriorates faster than other organs, I say it’s a rapidly aging organ. That would be my criterion. Hearing and vision is an example of rapidly aging organs - you could be firing on all cylinders, but your eyesight deteriorates much more than for example kidney function (comparatively, eyesight is worse compared to its peak sooner than the same for kidneys), or the case of hearing where you lose the very high frequencies already past teenage years, while your brain still keeps getting better until your mid twenties etc. So that’s MY way of judging youthfulness of organs, through function, but others may have different criteria for what a rapidly aging organ is. YMMV.

2 Likes
#35

I was joking about it OFC. But I am not sure a low daily dose would be detrimental.