You might recall that researchers recently reported that the combination of rapamycin, acarbose, and phenylbutyrate appear to meaningfully improve physical function in old mice. Here, the same team reports on the efforts of this intervention on cognitive function in mice. Individually, these treatments, applied over the long term, are all shown to slow aging to some degree in mice. It remains to be seen whether combination treatments of this sort, upregulation of cellular stress responses, mimicking aspects of the cellular response to exercise and calorie restriction, will be as useful in humans. It is the case that life span is not greatly affected by this type of strategy in long-lived mammals, only in short-lived mammals do adjustments to metabolism mimicking calorie restriction produce sizable life extension.
Aging is a primary risk factor for cognitive dysfunction and exacerbates multiple biological processes in the brain, including but not limited to nutrient sensing dysregulation, insulin sensing dysfunction and histone deacetylation. Therefore, pharmaceutical intervention of aging targeting several distinct but overlapping pathways provides a basis for testing combinations of drugs as a cocktail. A recent study showed that middle-aged mice treated with a drug cocktail of rapamycin, acarbose, and phenylbutyrate for three months had increased resilience to age related cognitive decline. This finding provided the rationale to investigate the comprehensive transcriptomic and molecular changes within the brain of mice that received this cocktail treatment or control substance.
Transcriptome profiles were generated through RNA sequencing and pathway analysis was performed by gene set enrichment analysis to evaluate the overall RNA message effect of the drug cocktail. Molecular endpoints representing aging pathways were measured through immunohistochemistry to further validate the attenuation of brain aging in the hippocampus of mice that received the cocktail treatment, each individual drug or controls. Results indicated that biological processes that enhance aging were suppressed, while autophagy was increased in the brains of mice given the drug cocktail. The molecular endpoint assessments indicated that treatment with the drug cocktail was overall more effective than any of the individual drugs for relieving cognitive impairment by targeting multiple aging pathways.