Longevity ⇒ Breakthrough on Rapamycin May Allow For All the Longevity Benefits Without Any of the Severe Side Effects

[jocko6889]

In a study published by the University of Wisconsin in July, 2019, scientists discovered that a rapamycin analog called DL001 inhibits mTOR without all the severe side effects, such as suppression of the immune system, glucose, or liver toxicity. Suppression of mTOR has been associated with better health and longer life. mTOR is activated by eating foods like red meat, so finding a way to suppress mTOR without all the harmful side effects would be a major breakthrough.

Scientists have known that mTOR is composed of two complexes, called mTORC1 and mTORC2. As it turns out, you only need to suppress one of them, mTORC1 to get all the positive longevity benefits associated with rapamycin. Suppressing mTORC2 is what has caused many of the negative side effects of rapamycin, so discovering that the rapamycin analog DL001 suppresses mTORC1 without suppressing mTORC2 is the breakthrough that may finally allow us to get the benefits of rapamycin without the severe side effects.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/

[AlbertY]

Very interesting! Earlier this year, there is a study shows that inhibition of mTORC2 will block the beneficial effect of autophagy (recycling old/useless proteins in cells, a pro-longevity process that downstream to AMPK and sirtuin), and even shorten the lifespan of the animal with a high level of autophagy.

So it's definitely good news!

[jocko6889]

Very interesting! Earlier this year, there is a study shows that inhibition of mTORC2 will block the beneficial effect of autophagy (recycling old/useless proteins in cells, a pro-longevity process that downstream to AMPK and sirtuin), and even shorten the lifespan of the animal with a high level of autophagy.

So it's definitely good news!

So not only does blocking mTORC2 cause severe side effects but it also counters some of the longevity effects of blocking mTORC1. This really shows why rapamycin shouldn't be taken even in small doses. I will wait for for DL001 to become available.

[drkris69]

Interesting......and I was thinking about supplementing Rapamycin.....I think I will wait.

[Fred]

I agree with Jocko that taking rapamycin at this stage is premature. It is a potent drug.

In fruitflies, combining rapamycin with lithium counteracted some of the adverse effects of rapamycin and had a synergistic effect on lifespan. They also used a third drug and achieved a 48% increase in lifespan:

https://www.pnas.org/content/early/2019 ... BGWNEA6ynE

A triple drug combination targeting components of the nutrient-sensing network maximizes longevity

Abstract
Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages.

Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms.

However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging.

We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in Drosophila.

Remarkably, the triple drug combination increased lifespan by 48%. Furthermore, the combination of lithium with rapamycin cancelled the latter’s effects on lipid metabolism.

In conclusion, a polypharmacology approach of combining established, prolongevity drug inhibitors of specific nodes may be the most effective way to target the nutrient-sensing network to improve late-life health.

[AlbertY]

Very interesting! Earlier this year, there is a study shows that inhibition of mTORC2 will block the beneficial effect of autophagy (recycling old/useless proteins in cells, a pro-longevity process that downstream to AMPK and sirtuin), and even shorten the lifespan of the animal with a high level of autophagy.

So it's definitely good news!

So not only does blocking mTORC2 cause severe side effects but it also counters some of the longevity effects of blocking mTORC1. This really shows why rapamycin shouldn't be taken even in small doses. I will wait for for DL001 to become available.

Yes, but rapamycin just partially inhibit mTORC2, so together it still does more good than harm and extends lifespan dramatically (at least in mice and dogs). DL001 will certainly be far better if it does what rapamycin does without blocking mTOR2.