mTOR (Mammalian Target of Rapamycin): Hitting the Bull’s Eye for Enhancing Neurogenesis After Cerebral Ischemia?
Ischemic stroke remains a leading cause of morbidity and disability around the world. The sequelae of serious neurological damage are irreversible due to body’s own limited repair capacity. However, endogenous neurogenesis induced by cerebral ischemia plays a critical role in the repair and regeneration of impaired neural cells after ischemic brain injury. mTOR (mammalian target of rapamycin) kinase has been suggested to regulate neural stem cells ability to self-renew and differentiate into proliferative daughter cells, thus leading to improved cell growth, proliferation, and survival. In this review, we summarized the current evidence to support that mTOR signaling pathways may enhance neurogenesis, angiogenesis, and synaptic plasticity following cerebral ischemia, which could highlight the potential of mTOR to be a viable therapeutic target for the treatment of ischemic brain injury.
It’s a fair view that “hallmarks of lifespan” is fundamentally different than a unitary process of “aging”. It just depends on the definition of “aging” you are using. I’m not trying to get into semantic debates, but what is aging is a good question to continually reassess.
I’ve been very clear early on that mTOR inhibition isn’t really the only option nor is it guaranteed (even calorie restriction doesn’t necessarily extend lifespan in all the animals studied - it’s a very common misconception), but many still believe that mTOR = a central “clock” in the unitary physiologic and molecular basis rate of aging (which is still incompletely defined), and thus consequently believe that healthspan tradeoffs like bone mineral density or lean mass are negligible - when there is evidence that it’s most likely a bad gamble as they are endocrine organs too. Adipose tissue is an important endocrine organ too, but the CR groups often think of all these organs as inherently of little use.
What mTOR and GH/IGF-1/thyrotropin/prolactin really represent is pretty good evidence that there is a synchronized “aging process” that delays age-associated damage in multiple tissues in parallel (through unknown associations). For simplicity’s sake, I use “anti-aging” sometimes because most people here are not well-conversed in biogerontology terminology but it’s more accurate to use maximal lifespan and some people do use that term here. Rapamycin may have beneficial effects on lifespan in humans and likely does in several mammals, especially when I saw pharmacologic mTOR inhibition in older adult human trials improved responses to influenza vaccination with the biomarkers one would expect.
Meanwhile, we already know mice are mostly dying of cancer. I’ve repeated it so many times - the mice studies don’t guarantee any strong evidence of postponing say coronary atherosclerosis and Alzheimer’s disease. They literally don’t get heart attacks or Alzheimer’s! Even our closest cousins the chimps basically don’t get heart attacks, so the CR studies on monkeys aren’t particularly useful as oft claimed. Even if we are right about mTOR inhibitors on maximal lifespan, the slowing of the known parts of the core age-associated damage through these potential pathways doesn’t matter if say one is frail and dies of a fall or gets a heart attack. No.1 on your list should be heart attack (particularly atherosclerosis) if you care about lifespan and healthspan. We have no real evidence to prove rapamycin goes towards lowering heart attacks - it might even increase heart attacks. As for acarbose and canagliflozin particularly in male mice, it should definitely be noted that diabetes is quite rare in the mice studied. So it’s clear to me the acarbose and rapamycin combination is probably not a horrible bet.
I’d also point out that if we can identify 70-year-olds with excellent eyesight and hearing without cancer, chest pain, diabetes, arthritis, great vaccination responses, cognitive retention, and functional strength - that “phenotype” is a far stronger genetic candidate for “true” “anti-aging” than the “longevity genes” that predicts survival to the age of 100 that we currently follow. Luckily though, at least I have a few of the top ones that do predict longevity to 100 i.e. FOXO3A - so I like my genetic lottery odds so far, despite some crappy ones I’ve been dealt with, especially if I can keep cognition intact - but central IGF-1 and mTOR is probably not worth suppressing to the max at the moment - we know neuropsychiatric problems do occur in kidney transplant patients on rapamycin. We also don’t really know when exactly the brain “matures” or if there really is a specific time that it “matures enough”, yet it is critical to compare aging vs development. Many “anti-aging” influencers seem to neglect this a lot.
