Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

#1

Results: Our findings suggest that genetically proxied mTOR inhibition may increase the odds of attaining top 1% longest lifespan in the population (OR=1.24, OR* 95%CI*=1-1.53, pvalue=0.048). Moreover, mTOR inhibition significantly reduced body mass index (BMI), basal metabolic rate (BMR), height, and age at menopause, while increasing bone mineral density.

Interestingly, there was generally little evidence linking mTOR inhibition to cardiovascular disease incidence, with the exception of weak evidence for a protective effect against heart failure (OR=0.94, OR* 95%CI*=0.89-0.99, p-value=0.039). Chronic mTOR inhibition did not causally affect prostate cancer incidence but increased the risk of developing type 2 diabetes. A higher-than-expected (p-value = 0.05) number of genes in the mTOR pathway were causally associated with BMR.

Conclusions: This study highlights the potential lifespan-extending effects of mTOR inhibition and its significant influence on metabolic risk factors and disease. Members of the mTOR complex, especially mTORC1, play a disproportionate role in influencing BMR and BMI, which provides valuable insight for potential therapeutic target development.

2023.10.02.23296427v1.full.pdf (1.2 MB)

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Mendelian Randomization and mTOR
#2

That’s it. Rapamycin works.

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#3

So the slight increase in apoB particles is either counteracted by the reduction in inflammation or is too low to matter.

Chronic mTOR inhibition did not causally affect prostate cancer incidence but increased the risk of developing type 2 diabetes.

As with statins, the benefit outweighs the risk. Still, taking it together with acarbose would be best.

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#4

This is just one academic study focused on genetic analysis, so I don’t put too much weight on it. Just one data point among many.

#5

Only problem it hasn’t been peer reviewed yet.

#7

But aren’t they referring to chronic use? Does that include intermittent use?

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#8

In the Mannick study, some simulation suggest chronic and intermittent inhibits a down-stream target almost similarly:

Modeling and simulation
based on mTOR-mediated phosphorylation of its downstream target S6
kinase (S6K) predicted that the 20 mg weekly dosing regimen inhibited
mTOR-mediated S6K phosphorylation almost completely, the 5 mg weekly
dosing regimen inhibited S6K phosphorylation by more than 50%, and the
0.5 mg daily dosing regimen inhibited S6K phosphorylation by about 38%
over the dosing interval (12).

But of course they are not the same. Another thing is that the ‘chronic’ mTOR inhibition as assessed by this genetic study was also throughout childhood etc, which might give negative effects on healthspan.

T2D can be tracked and mitigated IMO, so it shouldn’t be that concerning.
Same with blood lipids.

#9

Anyone know if the pre-print is being published or has been presented at meetings?