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

[José]

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

Published September 30, 2019

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%.

https://www.pnas.org/doi/10.1073/pnas.1913212116

also

Transient and late-life rapamycin for healthspan extension | Aging

[RapAdmin]

“Transient and Late Life Rapamycin” - This is a great paper. A good read especially for anyone relatively new to Rapamycin.

[RapAdmin]

Longevity Cocktails are the future:

Cocktail of Rapamycin, Acarbose and Phenylbutyrate Slows Aging in Mice (2)

[Cocktailsm3] In this recent study they sought to determine if combining drugs previously shown to improve lifespan would have greater impact than any individual drug, a diet containing rapamycin at 14 ppm, acarbose at 1000 ppm, and phenylbutyrate at 1000 ppm was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice fed the cocktail diet showed a strain and gender-dependent phenotype consistent with healthy aging including decreased body fat and blood glucose, improved cognition, and increased grip strength and walking ability compared to mice fed individual drug or control diets. A cocktail diet containing one-half dosing of each compound was overall less effective than the full dose. The composite age-related lesion score of heart, lungs, liver an…

[Emaginate]

This link is blank when I tried to read it. (I’ll Google it.) Thank-u
Jan Stein

Aging| doi:10.18632/aging.102947. Ellen K. Quarles, Peter S. Rabinovitch

[RapAdmin]

aging-v12i5-102947.pdf (500.1 KB)

[nikney]

This study found that lithium improves rapamycin-induced dyslipidemia, which is a good point. Second, even the dual combination of rapamycin, lithium, and trametinib in different ways is more successful than using them alone. Each one targets a different growth pathway.

[Joseph_Lavelle]

From paper

“ At 2mg/kg per day, every five days, beginning at 20 months of age in mice, rapamycin could increase medial and maximal lifespan without detrimental effects on glucose homeostasis. This was also in the absence of metabolic effects seen in models using higher/longer-term doses of rapamycin. Intermittent treatment may, therefore, help to balance the minimization of off-target effects with the desired continual boost to health-span.”

Sounds like @John_Hemming dosing…(roughly speaking)…ie, big and infrequent.

[John_Hemming]

A lot depends on the half-life