disruption of protein kinase a in mice enhances healthy aging破坏蛋白质激酶的小鼠增强健康老龄化.pdfVIP

Disruption of Protein Kinase A in Mice Enhances Healthy Aging Linda C. Enns, John F. Morton, Piper R. Treuting, Mary J. Emond, Norman S. Wolf, G. S. McKnight, Peter S. Rabinovitch, Warren C. Ladiges* Departments of Comparative Medicine, Biostatistics, Pharmacology, and Pathology, School of Medicine, University of Washington, Seattle, Washington, United States of America Abstract Mutations that cause a reduction in protein kinase A (PKA) activity have been shown to extend lifespan in yeast. Loss of function of mammalian RIIb, a regulatory subunit of PKA expressed in brain and adipose tissue, results in mice that are lean and insulin sensitive. It was therefore hypothesized that RIIB null (RIIb2/ 2) mice would express anti-aging phenotypes. We conducted lifespan studies using 40 mutant and 40 wild type (WT) littermates of equal gender numbers and found that both the median and maximum lifespans were significantly increased in mutant males compared to WT littermates. The median lifespan was increased from 884 days to 1005 days (p = 0.006 as determined by the log rank test) and the 80% lifespan (defined here as 80% deaths) was increased from 941 days to 1073 days (p = 0.004 as determined by the Wang- Allison test). There was no difference in either median or 80% lifespan in female genotypes. WT mice of both genders became increasingly obese with age, while mutant mice maintained their lean phenotype into old age. Adiposity was found to correlate with lifespan for males only. 50% of male mice between 30 and 35 g, corresponding to about 5% body fat, for either genotype lived over 1000 days. No male mouse outside of this weight range achieved this lifespan. During their last month of life, WT mice began losing weight (a total of 8% and 15% of body weight was lost for males and females, respectively), but RIIb2/ 2 male mice maint