Abstract
Partial inhibition of PI3K is one of the best-validated and evolutionary conserved manipulations to extend longevity. The best known health beneficial effects of reduced PI3K are related to metabolism and include increased energy expenditure, reduced nutrient storage, and protection from obesity. We have previously shown that a dual chemical inhibitor of the alpha and delta PI3K isoforms (CNIO-PI3Ki) reduces obesity in mice and monkeys, without evident toxic effects after long-term treatment. Here, we dissect the role of the alpha and delta PI3K isoforms by making use of selective inhibitors against PI3Kɑ (BYL-719 also known as alpelisib) or PI3Kδ (GS-9820 also known as acalisib). Treatment of mice with the above mentioned inhibitors indicated that BYL-719 increases energy expenditure in normal mice and efficiently reduces body weight in obese (ob/ob) mice, whereas these effects were not observed with GS-9820. Of note, the dose of BYL-719 required to reduce obesity was 10-times higher than the equivalent dose of CNIO-PI3Ki, which could suggest that simultaneous inhibition of PI3K alpha and delta is more beneficial than single inhibition of the alpha isoform. In summary, we conclude that inhibition of PI3Kɑ is sufficient to increase energy expenditure and reduce obesity, and suggest that concomitant PI3Kδ inhibition could play an auxiliary role.
Highlights
The first gene mutation found to extend longevity in an animal was in the age-1 gene of Caenorhabditis elegans [1], which was later shown to encode the catalytic p110alpha subunit of class I phosphatidylinositol-4,5bisphosphate 3-kinase (PI3Kα) [2]
The higher efficiency of CNIO-PI3Ki may be due to a number of reasons, such as for example a better pharmacokinetics, but it could reflect a contribution of PI3Kδ inhibition in the reduction of obesity in the context of simultaneous PI3Kα inhibition
Previous work by us has shown that a dual PI3Kα and PI3Kδ inhibitor, namely CNIO-PI3Ki, reduces obesity and elevates energy expenditure in mice
Summary
The first gene mutation found to extend longevity in an animal was in the age-1 gene of Caenorhabditis elegans [1], which was later shown to encode the catalytic p110alpha subunit of class I phosphatidylinositol-4,5bisphosphate 3-kinase (PI3Kα) [2]. Partial genetic reduction of the insulin and IGF1 signaling (IIS) pathways at different levels extends longevity in worms, flies and mice [3]. Similar to worms, heterozygous inactivation of the gene encoding PI3Kα extends longevity in mice [4]. Despite the strong link between PI3K down-modulation and longevity, it remains unclear which of its multiple physiological consequences are responsible for the beneficial effects on health and aging. The beneficial metabolic effects of reduced PI3K signaling could explain, at least in part, the improved healthspan and delayed aging. Inhibition of the PI3K downstream effector mTOR by rapamycin increases longevity [6] and reduces body weight [7]
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