Combination treatment for the prevention or delay of brain aging is a compelling area of research. Age-related cognitive decline may be influenced by multiple factors and impact various biological processes in the brain. Learning to manipulate key factors will allow for control over major pathways of aging and prevention of severe degenerative conditions such as Alzheimer’s disease.
A recent study completed at the University of Washington investigated the impact of a 3-chemical cocktail on aging brain biology. This specific cocktail has already demonstrated cognitive protection in a previous study. This new study aimed to understand the transcriptomic and molecular changes caused by these chemicals.
Experimental:
In this study, an aged mouse model was treated with either an individual chemical or the combination of all 3: rapamycin, acarbose, and phenylbutyrate. The treatments were begun when the mice reached ‘old age’ at 20 months old. The mice were provided with medicated diets for the following 3 months. After this, the mice were euthanized and the brain tissues collected.
Data Analysis:
The brain tissues were then analyzed using RNA-seq, q-PCR, IHC, and QuPath. These analyses showed that rapamycin intake led to decreased mTOR1 signaling, which decreases nutrient signaling and extends longevity. They also showed that acarbose intake led to improved insulin sensitivity and decreased insulin signaling, which may prevent or reverse some of the effects of aging. In addition, phenylbutyrate intake was shown to downregulate histone deacetylation, which impacts the downstream cellular function.
Most interestingly, receiving the 3-chemical cocktail was shown to produce a synergistic interaction with the collective action producing even more positive results. The cocktail treatment produced lower levels of DNA damage than otherwise found, in addition to lower levels of biomarkers for senescence. The biomarkers for autophagy were increased, while the biomarkers for inflammation were decreased. Altogether, these brain tissues showed much improvement with greatly reduced characteristics of aging.
This study is an encouraging step toward the design of a combination treatment to decrease the risk of severe cognitive degeneration.
Jiang Z, He Q, Wezeman J, et al. A cocktail of rapamycin, acarbose, and phenylbutyrate prevents age-related cognitive decline in mice by targeting multiple aging pathways. Geroscience. 2024 Oct;46(5):4855-4868. PMID: 38755466