Scientists have shown that a combination of rapamycin, acarbose, and phenylbutyrate has a synergetic rejuvenation effect when administered to 20-month-old mice for three months .
Fighting on multiple fronts
In this paper, the authors argue that to tackle such a multifaced process as aging, it might be beneficial to target different molecular pathways using several compounds. Therefore, they selected three drugs that had previously demonstrated anti-aging effects on their own: rapamycin, an antibiotic that inhibits mTOR signaling; acarbose, an anti-diabetic medication; and phenylbutyrate, a naturally occurring metabolite and a popular treatment for urea cycle disorders.
The researchers expected these compounds to have a synergistic effect that is greater than simply adding up their individual effects, and impressively, that’s exactly what this study has revealed.
In order to make the study results more translatable to humans, instead of treating young mice through their lifespans, the researchers applied the treatment to 20-month-old mice and limited the treatment to three months. First, the researchers compared the effect of a full-dose cocktail, containing each drug at a dose used in previous studies, and a half-dose cocktail.
Mice in both groups demonstrated decreased cognitive impairment compared to controls. However, the full-dose cocktail was more effective at improving other physical functions and organ rejuvenation, so it was used for further analysis. Along with a control group, the researchers included groups of mice treated with individual drugs.
The first major change the researchers in the full-dose cocktail group was weight loss along with decreased body fat mass. This effect seems to be due to acarbose mimicking caloric restriction.
Next, the researchers performed a series of behavioral tests regarding the physiological performance of old mice. Cocktail-treated mice outperformed control mice in all three tests: walking ability, hand grip, and cognitive function. Interestingly, mice in the rapamycin-only group also demonstrated improved cognition compared to controls, suggesting a neuroprotective effect of the drug.
To determine the organ-specific effects of the treatments, the researchers used a geropathology system that involved organ dissection, staining, and pathology-based grading. They calculated the lesion scores of the heart, lungs, liver and kidneys. The drug cocktail was effective at decreasing lesions in all of the organs and, in general, more so than any individual drug.
However, rapamycin also effectively decreased lesions in the kidney. This organ was shown to have extensive inflammation in the old control group’s tissue samples, prompting further investigation. The researchers then measured the expression of inflammatory cytokines in the kidney and showed that the drug cocktail decreased their expression in old mice, bringing them down to the level of young animals and demonstrating the anti-inflammatory nature of the drug combination.
Sex- and strain-specific differences
This study design included separate analyses of male and female mice, and some differences were observed. Drug cocktail-induced weight loss was not seen in females after three months of treatment, and female mice in the rapamycin-only and acarbose-only groups gained weight, unlike males.
Female mice showed improved grip strength when treated with only acarbose, which was not the case for males. Rapamycin was as effective as the drug combination at decreasing age-associated lesions in the hearts and livers of females but not males. However, acarbose and phenylbutyrate were effective in the kidneys of males but not females.
To test strain-specific drug responses, the researchers validated their results on a second strain of mice used exclusively in lifespan studies. In this part of the research, only the drug cocktail and the control groups were included. In this strain, both female and male mice treated with the drug cocktail lost a significant amount of weight over the three-month period.
Surprisingly, the drug combination did not combat cognitive impairment in these old mice, while the walking speed improved only in males. The drug cocktail was also ineffective in reducing liver and lung lesions in female and male mice, respectively.
Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs targeting different but overlapping processes. In order to determine if combining drugs shown to extend lifespan and healthy aging in mice would have greater impact than any individual drug, a cocktail diet containing 14 ppm rapamycin, 1000 ppm acarbose, and 1000 ppm phenylbutyrate was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice treated with the cocktail showed a sex and strain-dependent phenotype consistent with healthy aging including decreased body fat, improved cognition, increased strength and endurance, and decreased age-related pathology compared to mice treated with individual drugs or control. The severity of age-related lesions in heart, lungs, liver, and kidney was consistently decreased in mice treated with the cocktail compared to mice treated with individual drugs or control, suggesting an interactive advantage of the three drugs. This study shows that a combination of three drugs, each previously shown to enhance lifespan and health span in mice, is able to delay aging phenotypes in middle-aged mice more effectively than any individual drug in the cocktail over a 3-month treatment period.
This promising study is yet another demonstration of an effective approach that targets multiple pathways. Drug synergy has previously been shown to extend healthy lifespan in C. elegans . Although this study did not study lifespan extension, it clearly showed that this cocktail reverses several aspects of age-related pathologies in mice.
In addition to demonstrating that the drug cocktail is more beneficial than each of its individual components, the study highlights its different effects between mice of different sexes and strains. Therefore, metabolic responses that are dependent on sex and genetic background will have to be taken into account when determining if such a cocktail is effective in people.
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 Jiang, Z. et al. Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice. Sci. Rep. 12, 7300 (2022).
 Admasu, T. D. et al. Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling. Dev. Cell 47, 67–79.e5 (2018).
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