A drug cocktail of rapamycin, acarbose, and phenylbutyrate enhances resilience to features of early-stage Alzheimer's disease in aging mice

The process of aging is defined by the breakdown of critical maintenance pathways leading to an accumulation of damage and its associated phenotypes. Aging affects many systems and is considered the greatest risk factor for a number of diseases. Therefore, interventions aimed at establishing resilience to aging should delay or prevent the onset of age-related diseases. Recent studies have shown a three-drug cocktail consisting of rapamycin, acarbose, and phenylbutyrate delayed the onset of physical, cognitive, and biological aging phenotypes in old mice. To test the ability of this drug cocktail to impact Alzheimer’s disease (AD), an adeno-associated-viral vector model of AD was created. Mice were fed the drug cocktail 2 months prior to injection and allowed 3 months for phenotypic development. Cognitive phenotypes were evaluated through a spatial navigation learning task. To quantify neuropathology, immunohistochemistry was performed for AD proteins and pathways of aging. Results suggested the drug cocktail was able to increase resilience to cognitive impairment, inflammation, and AD protein aggregation while enhancing autophagy and synaptic integrity, preferentially in female cohorts. In conclusion, female mice were more susceptible to the development of early stage AD neuropathology and learning impairment, and more responsive to treatment with the drug cocktail in comparison to male mice. Translationally, a model of AD where females are more susceptible would have greater value as women have a greater burden and incidence of disease compared to men. These findings validate past results and provide the rationale for further investigations into enhancing resilience to early-stage AD by enhancing resilience to aging.

Open Access Paper: A drug cocktail of rapamycin, acarbose, and phenylbutyrate enhances resilience to features of early-stage Alzheimer’s disease in aging mice - PMC

Unfortunately the ITP didn’t have much luck with phenylbuyrate:

Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex.
Source: New Richard Miller / ITP Paper: Astaxanthin and meclizine extend lifespan 12%, 8% respectively

It seems cocktails are all the rage these days:

Here: A cocktail of rapamycin, acarbose and phenylbutyrate prevents age-related cognitive decline in mice by altering aging pathways

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

Here: Pharmaceutical interventions to slow human aging. Are we ready for cocktails?


Sometimes I wonder if a supplement only works well in combination. For instance oil and gas for your car. If you’re lacking in one, you still aren’t going to go very far. But when you have enough of both…

Phenylbutyrate may need Rapamycin to be effective.

Doesn’t acarbose promote butyrate production?

Multiple ways to optimize gut does increase butyrate and has also be increased per the post and one around them below. Pendulum’s GC cocktail also is explicitly designed to increase butyrate.

But it seems like butyrate (SCFA) is a different molecule than phenylbutyrate (a medicine)? Do you know if higher butyrate levels in the gut lead to phenylbutyrate in humans/mammals?


There is also the door bell effect, i.e. you push a door bell but it doesn’t ring and then you push harder and it works. Sometimes a dose of medicine produces no effect and then a little more works.

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