How Rapamycin Extends Lifespan (mechanism and implications) Discussion

People here who have read in-depth on this topic and have an opinion;

What is your opinion on the mechanism by which Rapamycin extends lifespan?
And, How does this opinion drive your thoughts and approaches to longevity?

Here are some thoughts from the Nir Barzelai / Joan Mannick podcast with Peter Attia:

Mechanisms by which rapamycin (and rapalogs) might extend lifespan

1—Less protein and lipid synthesis which may decrease proteotoxic stress just by having fewer proteins made that your protein degradation system has to deal with

2—Autophagy , but, rapamycin and rapalogs don’t consistently induce autophagy

  • It’s cell-dependent—so how much of a role autophagy has in the benefits of rapalog is probably tissue-dependent
  • In many cell lines, there’s no induction of autophagy
  • In the few cell lines that do have induction of autophagy, it’s hard to distinguish the tissue of origin (e.g., Is it the liver versus the cells from neurons?)

3—Impact on senescence-associated secretory phenotype(SASP). Regulation of the SASPs (similar to metformin)

  • Senescent cells accumulate as we age resulting in the secretion of inflammatory cytokine

  • Inhibiting mTOR will decrease SASPs, which will decrease systemic inflammation

  • Rapalogs aren’t great at inducing autophagy, but RTB101 at high doses was very good at inducing autophagy although it’s hard to achieve those concentrations in the brain

  • But… if you combine a rapalog with RTB101, you can lower the concentration of RTB101 that’s needed to induce autophagy so you don’t have to get so much across the blood brain barrier

From the Eileen White Podcast with Peter Attia:

Figure 1. (Above)

Role of autophagy in starvation, tumor suppression, and tumor promotion:
A, induction of autophagy-mediated survival in starvation.
B, autophagy deficiency produces the accumulation of damaged proteins, particularly p62, and organelles. This causes cell death, tissue damage, DNA damage, oncogenic signaling, chronic inflammation, stem/progenitor expansion, and tumor initiation.
C, autophagy is activated in tumors and promotes survival and growth, whereas loss of autophagy causes substrate accumulation, tumor cell growth arrest, senescence, and death and restricts tumor progression to benign disease.**
Image credit: (White et al. 2015)

Stressors that induce autophagy

Three pathways at the mechanistic level :

1—The mTOR pathway, which is mostly sensing amino acids

2—AMPK pathway, which is mostly sensing energy and ATP in general

3—The Acetyl-CoA protein deacetylation pathway, which is also just basically sensing substrate of fatty acid and glucose

  • Those are three ways that low nutrients can still trigger the same pathway

4—Additionally, stresses that result in i) organelle damage–such as depolarization or dysfunction of mitochondria, ii) activation of protein misfolding, and iii) generation of protein aggregates

What are some stresses that come from outside of the cell that induce autophagy?

  • Temperature extremes would induce protein misfolding and induce autophagy as a remedy for that
  • Exercise induces autophagy very potently because exercise damages the muscle, and autophagy is one of the processes that helps mitigate the damage that occurs during damage
  • Hypoxia potently induces autophagy
    • Tumors are well known to have hypoxia in the center
    • When Eileen engineered tumor cells to be genetically deficient for autophagy, you’ll see that the tumor is hollow, meaning…
      • the further the cells get from a blood supply, the more susceptible they are to hypoxia, and they’re dead
      • The middle of a tumor is hypoxic… that’s where the autophagy is most active, and if you genetically knock out autophagy in the tumor, you end up with a hollow tumor because the tumor cells in the middle don’t survive.

Importance of autophagy to the brain

Using Alzheimer’s disease specifically as an example…

  • When you think about the toxicities that are driving neurodegeneration, there’s a lot of crap that’s basically getting accumulated in neurons
  • This would be an elegant way to suggest that autophagy is keeping that at bay
  • The brain, therefore, is extremely autophagy dependent

-What other tissues are more (or less) autophagy dependent than others?

  • When looking at an adult mouse that lacked autophagy…
  • The lungs looked relatively normal suggesting it’s not autophagy dependent
  • The liver , on the other hand, was very sensitive
    • If you did a liver-specific knockout of an essential autophagy gene, they developed fatty liver disease
    • Suggesting that autophagy probably plays a role in preventing
      • i) fat accumulation, and
      • ii) accumulation of mallory bodies, which are large protein aggregates composed of a protein called p62

The difference between the brain and liver is that…

  • The liver manages to tolerate it, the brain does not and it just accumulates all the crap

-Was there evidence that the brain, in some last ditch effort to survive, was undergoing more apoptosis of neurons?

  • Yes, a common feature is increased apoptosis in the brain
  • This has been part of a major effort to generate autophagy stimulators as a remedy or as a means to delay neurodegenerative diseases .

The mechanisms that can trigger autophagy to support longevity [40:00]

Fasting

Fasting is one of the most potent stimulators of autophagy. I spend a lot of time thinking about how does fasting fit into our toolkit of longevity…

…I think it’s very safe to say, based on all the animal data, and frankly all the centenarian data, that the key to living longer is delaying the onset of chronic disease…

…So even when you look at centenarians who are genetically gifted with tools to live longer, if you unpack what the gift is, it’s delaying the onset of the disease, not living longer once you have the disease…

…So the centenarians, once they get cancer and once they get heart disease, they die at about the same rate, over the same duration, as the rest of us schmucks. The difference is, they get those diseases 20-25 years later. And again, that suggests to me that if you want to live longer, you have to delay the onset of these things, not live longer once you have them…

…It’s hard to think that fasting doesn’t play an essential role in that when you realize the role that fasting plays in the mitigation of Alzheimer’s disease and metabolic disease.

Molecules that induce autophagy

We can also induce autophagy sort of pharmacologically or chemically. The first thing that would jump to your mind is anything that mimics fasting. The first thing that comes to mind would be metformin, rapamycin, and things like…

…We talked about these huge pathways that tell the body nutrients are scarce. So when mTOR activity is down, that’s a sign that we’re deficient in amino acids. We can also do that with rapamycin…

…When AMPK is up, that’s the cell being told we’re deficient in ATP. Another way that you can do that is to give Metformin.

Evidence for cancer treatment by blocking autophagy [42:30]

Eileen had two questions she wanted to answer :

-Question 1—If you inhibited autophagy in an adult mouse, what would happen?

-Question 2—When you knock out autophagy in a mouse with cancer, which dies first: the mouse of the tumor?

  • This mouse had lung cancer
  • First, shut the autophagy pathway off
  • Then, see which died first, the mouse or the tumor
  • The answer ? ⇒ Tumor died first
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This is the article that got me thinking about this - I don’t follow this Dr. very closely don’t have an opinion on his knowledge on this area yet:

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Worthwhile topic.

I see no reason to deviate from the central tenet of Blagosklonny that we don’t die from aging, we die from diseases that are related to aging. Rapamycin delays the onset of those diseases be they heart attack, stroke, cancer,or neurodegenerative.

The primary mechanism is inhibition of mTOR which , at least in part, prevents geroconversion of arrested cells to senescent cells. Prevention of senescence will inhibit the process of hyperfunction.

At a cellular level all kinds of things are going on like autophagy, mitophagy, stem cell rejuvenation and even changes in gene expression. Not to mention changes in the microbiome that are still poorly understood.

Even with all of that, we still don’t fully understand rapamycin and its effects, nor do we know for certain that it will translate to humans, but there are certainly reasons for optimism.

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Yes, all true.

But I’m re-evaluating my approach to longevity a bit. It seems like you can take many different approaches to longevity:

  1. Target the hallmarks of aging by looking at each hallmark, then identifying most proven therapeutic approaches to each hallmark, or
  2. Targeting the specific pathways and proteins (e.g. MTOR, AMPK, NFkB, etc.) that seem most connected to the aging process and then identifying the best therapeutics in each area that target these pathways, and I guess I would include the process of Autophagy in that group.

Under autophagy it seems we have two major categories - activities we can take to increase autophagy, and compounds we can ingest (or otherwise get into our body) to increase autophagy.

I’ve dabbled in fasting for 3 day periods but not consistently, but the more I read about autophagy, the more it seems to me that I might want to focus a little more on fasting (specifically 3+ days of fasting) every month. This seems like an easier (for me) approach and perhaps more effective (though lacking good data to support this) to increasing Autophagy than time restricted feeding at a high level (I’m ok with eating 12 noon to 7pm, but narrower than that can get hard).

And, also in the area of Autophagy, it seems it might be valuable to get a good list together and track all the supplements and drugs that are known autophagy inducers - and track them for ongoing progress in their clinical testing for efficacy and specificity to tissue type, cell type, etc.

Eg.

and

Natural small-molecule enhancers of autophagy induce autophagic cell death in apoptosis-defective cells

https://www.nature.com/articles/srep05510

Long term I suspect we’ll see many more lifespan improving agents coming out of this list.

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Certainly see what you’re saying and you may be right, but things at the cellular level are just too complex for me. There’s a million things going on with each affecting the other, it’s all finely tuned and regulated, all kinds of feedback loops, just too complicated.

Even just isolating autophagy, we’re not sure exactly how to regulate it, or even if its safe to do so. Too much can lead to cell death, especially heart cells, and may even be cancer promoting.

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Cancerous and senescent cells are two key cells types that contribute to mortality, and rapamycin reduces both of them. Most cancers primarily use glycolysis for energy, and are stressed by rapamycin forcing them into oxidative phosphorylation. Senescent cells become so through overactive mTor and cytokine signalling, and rapa somehow (autophagy or perhaps lower growth patterns that allow cellular machinery to resume normally?) allows some of them to return to quiescence and harmlessness.

There are many causes of aging that rapamycin probably does not address (crosslinks, immune system changes, telomere shortening, gross organ damage, among others). I don’t believe that rapamycin alone will greatly extend life because of all of the other ways we age, but there may be a lot of overlaps in the aging processes that will be amenable to the same therapies. For example, we know that rapamycin changes the microbiome, presumably toward health, but we don’t know much about how that might help the immune system.

Because of the many unknowns in aging, I take a multifactorial approach of pulsed stresses, including exercise, fasting, and xenohormesis. Fasting not only increases autophagy, but also apoptosis of damaged cells, and primes stem cells to proliferate and make new healthy tissue. Fasting seems to be the unique activity that does this, though therapeutics with Yamanaka factors may eventually be available.

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Melatonin as an autophagy enhancer via sirt-1.

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mTOR and the cascade of reduced cellular proliferation rate. It’s abundantly clear, rodents given rapamycin have reduced growth factors, which “slows” the aging process across various tissues/organs. They still die of cancer…just later. A recent study of post natal mice given rapamycin was glaringly indicative of this paradigm…growth was crushed. Middle aged mice given rapamycin undergo significant mass reduction. The rodent literature is filled with repeated confirmation of this central thesis. There are likely DOZENS of other pathways, not known, or fully elucidated/measured; infinitely complex with a myriad of genes up/down regulated, and intersecting.

I am agnostic on a singular “holy grail” pathway to longevity; I don’t believe it exists in humans, most especially translating from mice. Does slowing cellular proliferation from rapamycin teachings “influence” my approach to longevity, yes somewhat. Eating less, eating a less cellular growth stimulating diet, and fasting are direct human translation outputs for me.

I am highly skeptical on exogenous supplementation and pan cellular autophagy in humans, so I would hardly categorize exogenous as “major”…more like fanciful. I do, however, strongly believe that “some type” of extended fasting is pro-longevity. Fasting is a quasi mTOR mimetic, that is my rationale for why I think it has some very strong tangible benefits, even IF it has very little to do with autophagy per se, and acts on other pathways (lower inflammation, stronger immune system, suppression of cancer and tumor cells, lower IGF-1/glucose AUC, removal of pathogens and toxins, improved mitochondrial functioning, stem cell rejuvenation). This is low hanging fruit. Autophagy has never been measured in humans, so pure translation speculation. Last I read, we’re a decade+ away.

Agreed, why I’m agnostic to one pathway. My philosophy is very simply to hit as many pathways as practically possible in an attempt to “dampen” the aging signal, with human data most compelling.

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Good points MAC, but to me fasting, while on rapamycin, especially after age 60, just seems redundant.

Melatonin works on a whole series of anti aging pathways and could be very synergistic with rapamycin. Not just a CR mimetic. Would love to see someone test the combination.

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I don’t…there are way too many pathways to make a one sided best. I am not over hedging rapamycin as a panacea, take my foot off the pedal. Consider just ONE biomarker…chronic rapamycin will increase lipids and glucose, yet fasting QUASHES! You call that redundant…I call that “stack and hack”

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Calorie restriction and rapamycin is additive in mice. See nature article.

We’re suppose to take a leap from an in-vitro study?

Why hasn’t melatonin been studied in the ITP?

A critical paper in 1995, called “Melatonin Madness,”pointed out this mistake (ME: the use of mice strains that’ don’t produce melatonin, which mice normally do not), and pointed out that in another study on a strain of mouse that does produce melatonin (C3H/He), the treated mice actually had shorter lifespans because they developed more tumors. On the other hand, there’s been additional evidence that melatonin can extend life, even in melatonin-producing animals. In C3H mice (which produce melatonin), melatonin in drinking water prolongs the life of male mice by about 20% (p < 0.01) but not female mice.[4] In CBA mice, which also produce melatonin, those given melatonin in their night-time drinking water were significantly more likely than controls to get lung cancer and lymphoma, but their lifespan still was extended by 5% relative to controls.

Hmmm, dosen’t seem too compelling to me since we’re in the rodent translation protocol.

Here’s a very interesting paper, on CR vs ad libitum fed rats, longevity, and melatonin.

Food restriction retards aging of the pineal gland
https://sci-hub.se/https://doi.org/10.1016/0006-8993(91)91270-B

Fasted (and long lived) rats had reduced melatonin through impact on pineal gland.

“When compared with 3-month-old, ad libitum fed rats, pineal N-acetyltransferase (NAT) activity had declined to less than 30% and pineal and serum levels of melatonin to 40% after 28 months when feeding had been ad libitum. It is concluded that aging in the rat (Fisher 344) is accompanied by a reduction of pineal NAT activity, thereby reducing the production of melatonin and causing a buildup of 5-HT in the pineal gland. It is furthermore proposed that food restriction, which markedly increases the life span and reduces age-related physiological deterioration and diseases in many animals, may mediate some of its effects through a SUSTAINED pineal activity in old age.”

“Several studies have shown that the aging pineal undergoes ultrastructural changes, including loss of pinealocytes which may progressively reduce the gland’s ability and capacity to produce melatonin. When food restriction was continued for the whole life span, as in the present study, it was reported that old rats had preserved a 'youthful pineal’. This observation was based on histological evidence of a profound retardation of cell loss when compared with rats that had been fed ad libitum and is in good accordance with the present demonstration of maintained
pineal function.”

And this paper suggests that exogenous melatonin may suppress endogenous production which might have theoretical potential for pineal gland atrophy.

So reduced melatonin is associated with aging…an association effect. And we think exogenous administration is going to causally increase pineal activity and increased lifespan?

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@tongMD Indeed, thanks for reminder.

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

https://www.nature.com/articles/s41467-022-29714-6

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Less painful methods using supplements to control lipids.

I’m a big believer in all types of circadian rhythms. That includes eating rhythms as well as sleeping.

It’s also difficult to get in my EVOO, nuts, salmon, whole grains, vegetable and fruits daily while on a strict CR or fasting protocol.

Wonder why the male/ female response dichotomy keeps popping up in regards to longevity?

Lymphoma is an odd bird. It also affected females on high doses of rapamycin in MK’ s study.

If you show me the study showing this comparison, especially with dysregulation from rapa, I’m on board. Until then, I’ll hedge with some form of fasting.

This is yet again a HUMAN IMPOSED constraint…biology cares not. Don’t forget your rapamycin!

Mice also need very large rapamycin doses for adequate mTOR suppression, so the more the merrier. Not certain that that’s the case with us.

Would love your thoughts on this post:

This is tricky.
Many of the HSC’s have probably also lost their Y’s but if you have Some that have retained their chromosomes then it may be possible with blood donations. Of course, it would only replace RBC’s and not the WBC’s.

I feel like I’m a stuck record on this point but everyone consistently overlooks it. You must start CR early in life to have a significant impact on longevity.

And even assuming you do I am almost certain that 2+2 < 4