Rapamycin to newborns

Wait. How can this be? Isn’t the mTOR theory built on antagonistic pleiotropy? Something that’s necessary early in life is detrimental later on?
In this study they give rapamycin to newborn mice and it improves both healthspan and lifespan. They discover genetic mechanisms operating very early in life that, when turned on, influenced longevity.

As it turns out, rapamycin unregulated a sulfotransferase gene that seems to be responsible for lifespan regulation. Actually never heard of sulfotransferase. They repeated these results in Drosophila showing an evolutionary conservation.

What? Is it all about some predetermined gene expression that can be regulated by rapamycin? Where does inhibition of geroconversion and hyperfunction fit ? Can rapamycin play a dual role of epigenetics when very young and then the more well known mechanisms in older age?

This is a head scratcher for me, that’s for sure.

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Study here:

https://www.embopress.org/doi/full/10.15252/embr.202255299

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Well, maybe throw out that mTOR theory to the dust bin?

Yet another enzymatic rabbit hole. Honestly, I do NOT think we know the myriad of pathways impacted by rapamycin beyond simple mTOR. Clearly we don’t.

Predetermined gene expression…some programmed theory of gene expression evolution? Perhaps, but there are a myriad of interventions that can alter gene expression…epigenetics? Studying monozygotic twins, we see large impacts of environmental epigenetics on longevity. So why not pharmacological at different lifetime time points?

I don’t know if Dr B’s theory is the holy grail of hyperfunction and longevity, but we DO know emphatically that dosing rapamycin to mice mid life only results in massive lifespan extension. FAR greater than this post natal study resulting in less than 10%. Forget the why, it’s a fact…that’s more important to me for translation than the why.

MK’s seminal study. “A single three-month treatment regimen can extend lifespan and healthspan in C57BL/6JNia mice starting at 20–21 months of age. We show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice

100%…because we do NOT know it’s full impact. This study also showed classic mTOR reduction, in addition to some new pathways (sulfotransferase). Rapamycin is going to suppress mTOR to some degree, no matter when given yes?

Other comments.

The P4-P30 intervention, massive reduction in body size…“honey I shrunk the kids”. I’ve never seen a rapmycin intervention with such a dramatic impact on body weight. At P30, these baby mice were approx 33% of their normal size??!!

I find it interesting that many of the seminal rapamycin/mice studies that showed SIGNIFICANT lifespan increases…all had a SIGNIFICANT body weight reduction effect. CR in mice does the same thing, without rapamycin, hmmm? Fontana has shown in many long lived cohorts…they had a significant CR component in their lives (Okinawans). We also know from epidemiological studies, the U shaped curve shows BMI around 20 is “associated” with longevity. That’s a skinny phenotype. Is there some “master” epigenetic signal(s) associated with less growth/size??

Trying to find HUMAN biomarkers for rapamycin is a big conundrum/bottleneck. Many studies on chronic treatment of rapamycin in humans (cancer/renal transplants) monitor liver/kidney function. In renal transplants, rapamycin IMPROVES liver function tests. An mTOR proxy?

In this study, they also hone in on the liver:

“To identify genes modulated by rapamycin, several groups have analyzed the hepatic gene signature in old mice subjected to continuous rapamycin treatment (Tyshkovskiy et al, 2019). Indeed, the liver controls several processes (i.e., hepatic glucose, insulin signaling and lipid homeostasis) potentially implicated in lifespan regulation in mammals. Sampled on the last day of treatment” (of course).

What if we could correlate liver mTOR with conventional liver (kidney) lab tests as whole body proxy?

ALT, AST, ALP, GGT, EGFR, Cystatin C, Albumin

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So many questions, so few answers.

I’m certainly getting convinced that the actions of rapamycin are more complex than we thought. Maybe when Matt transiently dosed the mice with high doses he turned on certain gene expressions while, at the same time, inhibiting mTOR and all that that entails. He then got both a short term and a long term double whammy.

Can’t imagine parents giving their newborns a blast of rapamycin- maybe adding it to their bottles- but that may actually be the first step for max life extension. You then hit it again at mid life followed by chronic, intermittent therapy at 55-60 or so.

I previously had blood work 15 years ago and when I did it the other day my LFT’s were unchanged.

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Another dart. In every rapamycin study ever done, rapamycin has indeed modified dozens/hundreds of genes and pathways…good luck deciphering through that?!

Let’s just agree/accept that the effect is WAY beyond mTOR.

Identification and application of gene expression signatures associated with lifespan extension

We identified 127 up- and 100 down regulated genes for rapamycin. The difference in the gene expression response between CR and rapamycin was previously noted, but was not well understood. Our data provide a case for largely distinct mechanisms by which these interventions act in the liver. Rapamycin also showed significant overlap with the other interventions (58.8% and 47.1% of transcriptional factors were shared with CR and GH deficiency, respectively. Therefore, it appears that even though rapamycin exhibits a distinct pattern at the level of individual genes, its effect partly converges with other interventions at the level of molecular pathways and transcriptional regulation

Note the liver as a hub/node for these lifespan extending interventions. We need to somehow better translate/harness the liver as a rapamycin biomarker.

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Pretty amazing all of the genes impacted by rapamycin. About 40% doesn’t overlap with CR. They’re not identical

Bilirubin might be a useful marker. That’s the only LFT that changed for me after 5 years of rapa. Went from 0.4. to 0.6. I have to look into bilirubin some.

So mild CR plus rapa…maybe additive??

I wrote to the author of this paper about using liver and kidney markers.

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Good idea. Let’s see what they say.