In eucaryotic organisms (plants, animals, fungi, protists), the mTOR pathway is a central regulator of cellular metabolism, growth, and survival. It has long been postulated that mTOR activity is one of the central control knobs of the speed of aging, which can be regarded as a continuation of the pre-adulthood growth program.
When there are sufficient nutrients & amino acids (glucose, leucine, arginine, methionine) and sufficient extracellular growth signals (e.g., insulin, IGF-1, tissue-specific growth factors), the mTOR complex is activated and drives a host of anabolic processes, including growth and development.
However, because animals usually die long before aging kills them, evolution never bothered with reducing the activity of the mTOR pathway after sexual maturity had been reached. Thus, to the detriment of the old animal, mTOR is set at too high a level after growth and development have been completed.
mTOR inhibitors are a promising pharmacological fix for the problem evolution never bothered to confront.
Tactics to keep mTOR activity (fairly) low
- My thoughts on fasting & caloric restriction
- Metformin
- Rapamycin
- IGF-1 – A double-edged sword
Fasting & caloric restriction
Fasting and caloric restriction are powerful anti-aging interventions in almost every animal. It is thought that both exert many of their beneficial effects partly through mTOR downregulation. However, for me, both fasting and caloric restriction were a dead end.
Fasting and CR are not just unpleasant, but they might drive peripheral thyroid resistance, alter brain energy homeostasis, and cause a sustained reduction in IGF-1 and leptin signaling. Furthermore, both reduce vitality. I want to enjoy my life, and feeling cold, lethargic, and hungry all the time is not an option.
I discuss my experience with multi-day fasting in more detail here.
I discuss my experience with caloric restriction in more detail here.
Metformin
There is evidence that metformin indirectly inhibits the mTOR1 complex. In the past, I had been on metformin for about two years but I stopped because of a number of reasons.
I discuss my experience with metformin in more detail here.
Rapamycin
I take 4 mg of the mTOR inhibitor rapamycin once per week, nine months on and three months off.
mTOR is a protein kinase that has a finger in every major process in the cell and is partly responsible for regulating “growth mode” vs. “conserve resources mode”. The promise of rapamycin is that it can give me most of the benefits of fasting without the downsides.
Rapamycin is an mTOR inhibitor, mimicking starvation pharmacologically including an artificial induction of autophagy. The cells in my body are tiny machines based on the laws of chemistry and physics and programmed by their genetic code. In principle, they could not care less whether effects come from endogenous molecules, exogenous molecules, or lifestyle changes.
Furthermore, and counterintuitively, I suspect that taking rapamycin is somewhat safer than doing regular fasts (discussed in more detail here).
Some people claim that it is better to take rapamycin less frequently (e.g., every other week but double the dose) to have proportionately more of it make it across the blood-brain barrier. For now, I just copy what most people at the frontlines do, namely taking rapamycin once weekly at a dosage of 4-8mg/week.
I discuss my experience with rapamycin in more detail here.
IGF-1 – a double-edged sword
My IGF-1 levels are slightly above the upper end of the clinical reference range naturally. IGF-1 is a protein quite similar to insulin and the two are phylogenetically related. Hence also the name: insulin-like growth factor. Furthermore, their receptors are very similar and IGF-1 even has a glucose-lowering effect mechanistically identical to insulin.
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Both together are perhaps the two major systemic growth factors in the human body exerting their effect via powerful receptor-tyrosine-kinase-signaling, which downstream also activates the mTOR pathway. I discuss insulin signaling in more detail here.
IGF-1 is a double-edged sword. On the one hand, higher levels are associated with cancer (as it drives the mTOR pathway), and on the other hand, higher levels are associated with better mental health, cognition, vitality, muscle mass, bone structure, and a lower risk for dementia and atherosclerotic disease.
However, in part because my IGF-1 levels are naturally high, I try to keep AUC levels of insulin rather low by optimizing metabolic health (described here). Of note, insulin stimulates IGF-1 synthesis by the liver.
My Longevity Protocol (Long & Technical Version)
This article is part of a much larger post describing my complete longevity blueprint. For my full protocol, read here.
Sources & further information:
- Scientific article: Effect of rapamycin on aging and age-related diseases—past and future
- Scientific article: Cell senescence, rapamycin and hyperfunction theory of aging
- Scientific article: Rapamycin for longevity: opinion article
Disclaimer
The content on this website represents the opinion and personal experience of the author and does not constitute medical advice. The author does not endorse the use of supplements, pharmaceutical drugs, or hormones without a doctor’s supervision. The content presented is exclusively for informational and entertainment purposes. Never disregard professional medical advice or delay in seeking it because of something you have read on the internet.
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