Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice

Abstract

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.

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

“…Targeting multiple factors that contribute to the progression of aging will likely provide a more robust attenuation of age-related cognitive dysfunction than any single drug [2]. Significant improvement of cognitive performance was observed in middle-aged mice treated for three months with a drug cocktail composed of Rap, Acb and Pba [13]. Selection of these specific drugs for a multiplex approach was based on their well-established roles in promoting health-span and prolonging lifespan in mice [6,9,10].…”

“…Middle-aged mice treated for three months with a drug cocktail consisting of Rap, Acb and Pba showed improvements in multiple aspects of health span [12] including significant delays in the appearance of cognitive impairment. Learning parameters were measured by a spatial navigation learning task [13]. Old mice that received cocktail and Rap showed enhanced learning abilities compared to all other cohorts.…”

Long-term treatment with Elamipretide enhances healthy aging phenotypes in mice

“…Gender differences observed in this study may be related to underlying differences in metabolic pathways targeted by Elam in female mice compared to male mice but additional studies are warranted to address this issue. Drugs in combination (cocktails) that target multiple processes of aging have now been shown to be more effective in slowing aging than any individual drug in the cocktail [34], so there is always the possibility of combining Elam with other anti-aging drugs to target a variety of aging pathways.…”

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

“…So, are we ready for clinical trials to see if drug cocktails can enhance resilience to aging in middle-aged people? The study by Jiang et al [5] provides promising evidence that cocktails work in middle-aged mice and paves the way for more comprehensive studies in mice and preliminary studies in humans.…”

“…This approach can be used for testing drug cocktails. Jiang et al [5] published a study in middle-aged mice treated for three months with a combination of rapamycin, acarbose, and phenylbutyrate and showed the cocktail to be superior to any of the individual drugs in slowing aging as defined by decreased age-related lesion severity as well as increased physiological performance. The drug cocktail targets multiple pathways of aging.…”