Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

No evidence of white adipocyte browning after endurance exercise training in obese men.

BACKGROUND/OBJECTIVES: The phenomenon of adipocyte 'beiging' involves the conversion of non-classic brown adipocytes to brown-like adipose tissue with thermogenic, fat-burning properties, and this phenomenon has been shown in rodents to slow the progression of obesity-associated metabolic diseases. Rodent studies consistently report adipocyte beiging after endurance exercise training, indicating that increased thermogenic capacity in these adipocytes may underpin the improved health benefits of exercise training. The aim of this study was to determine whether prolonged endurance exercise training induces beige adipogenesis in subcutaneous adipose tissues of obese men. SUBJECTS/METHODS: Molecular markers of beiging were examined in adipocytes obtained from abdominal subcutaneous (AbSC) and gluteofemoral (GF) subcutaneous adipose tissues before and after 6 weeks of endurance exercise training in obese men (n=6, 37.3±2.3 years, 30.1±2.3 kg m-2). RESULTS: The mRNAs encoding the brown or beige adipocyte-selective proteins were very lowly expressed in AbSC and GF adipose tissues and exercise training did not alter the mRNA expression of UCP1, CD137, CITED, TBX1, LHX8 and TCF21. Using immunohistochemistry, neither multilocular adipocytes, nor UCP1 or CD137-positive adipocytes were detected in any sample. MicroRNAs known to regulate brown and/or beige adipose development were highly expressed in white adipocytes but endurance exercise training did not impact their expression. CONCLUSIONS: The present study reaffirms emerging data in humans demonstrating no evidence of white adipose tissue beiging in response to exercise training, and supports a growing body of work demonstrating divergence of brown/beige adipose location, molecular characterization and physiological function between rodents and humans.