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


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 and kidney was decreased in mice fed the cocktail diet compared to mice fed individual drug or control diets suggesting an interactive advantage of the three drugs.

Senescence and inflammatory cytokine levels in kidneys from mice fed the cocktail diet were lower than in kidneys from mice fed control diet, and consistent with low expression levels in kidneys from young untreated mice, suggesting the cocktail diet delayed aging partly by senolytic and anti-inflammatory effects.

More information on phenylbutyrate, also known as sodium phenylbutyrate:

Generic name: sodium phenylbutyrate (SOE dee um FEN il BUE ti rate)
Brand names: Buphenyl, SPB11

Sodium phenylbutyrate is an FDA approved orphan drug, marketed by Ucyclyd Pharma under the trade name Buphenyl, by Swedish Orphan International (Sweden) as Ammonaps, aby Fyrlklövern Scandinavia as triButyrate and by Scandinavian Formulas, Inc. (Sellersville, PA)

It is used together with a proper diet to help treat urea cycle disorders (including a specific liver enzyme deficiency) that help remove ammonia (nitrogen) from the body.

The drug has been also used in the long-term treatment of patients with ornithine transcarbamylase deficiency at the median dose of 352 mg/kg per day for an average of 26 months. Long-term use in this population is well tolerated.

Sodium phenylbutyrate is metabolized safely and naturally, helping the kidneys eliminate wastes and controlling the expression of certain genes that may cause cancer and other diseases.

The maximally tolerated dose of sodium phenylbutyrate was determined to be 410 mg/kg/day (28.7 g/day for a 70 kg individual) as there were no dose-limiting toxicities at this dose and no patients required dose-reductions or escalations. Although there have been normal pregnancies on sodium phenylbutyrate, there remains a concern about possible teratogenic effects.

Sodium phenylbutyrate has been used since 1987 as an investigational new drug, and was approved for marketing in the US in 1996 and the EU in 1999. However, sodium phenylbutyrate has an aversive odor and taste, which may compromise patients’ compliance, and many patients have reported difficulty in taking this drug.

More information: How Sodium Phenylbutyrate Works

Typical Cost: This is an expensive drug because it’s use is quite rare, and it is classified as an orphan drug. The price seems to be approximately $5,000 for 250 grams - per phenylbutyrate

A much less expensive option would seem to be to purchase the drug from a lab / reagent supply companies (for people who work in the biology/chemistry business or teach these subjects or who know someone who does). Here, for example, one company is selling 500 grams for approx. $2,000. The issue, however, is likely that the reagent version of this drug does not have the encapsulation / granulization that protects the consumer from what is, apparently, a very foul tasting and smelling drug.
MedKoo Biosciences Sodium Phenylbutyrate

Full Research Paper Below
(viewable in-line on your desktop/laptop computer browser, downloadable on mobile)

2021.10.21.465380v1.full.pdf (599.8 KB)

Prescription Details on sodium phenylbutyrate (Buphenyl):

PhenylbutyrateBuphenyl.pdf (91.6 KB)

Related Research Papers:

Life extension in Drosophila by feeding a drug

We report that feeding Drosophila throughout adulthood with 4-phenylbutyrate (PBA) can significantly increase lifespan, without diminution of locomotor vigor, resistance to stress, or reproductive ability. Treatment for a limited period, either early or late in adult life, is also effective. At the higher concentrations, 20 mM and 40 mM, PBA was apparently toxic, reducing survival; there is a narrow range of PBA concentration that is effective for lifespan extension. Ten millimolar PBA extends median survival by 33% (mean survival by 36%, maximum survival by 52%).

A randomized trial to examine the impact of food on pharmacokinetics of 4-phenylbutyrate and change in amino acid availability after a single oral administration in healthy volunteers

Phenylbutyrate Ameliorates High-Fat Diet-Induced Obesity via Brown Adipose Tissue Activation

The Taste Issue: Developing a new formulation of sodium phenylbutyrate

Phenylbutyric Acid: simple structure - multiple effects

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives


That’s a great study–thank you! I wonder how much of the PBA benefits could be gained with simple sodium butyrate, which is cheap and easy to get. Or even hydroxybutyric acid, which is the main ingredient in exogenous ketones.

This summary of the research is also interesting (a little old - 2018) but still a good overview and summary up to that date:

Sodium-phenylbutyrate-Cognitive-Vitality-For-Researchers.pdf (316.6 KB)

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Phenylbutyrate seems difficult to buy, but sodium butyrate is simple. Any idea whether it’s an acceptable substitute?