Disruption of protein kinase A in mice enhances healthy aging.
Disruption of protein kinase A in mice enhances healthy aging.
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DOI：
10.1371/journal.pone.0005963
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发表时间：
2009-06-18
期刊：
影响因子：
3.7
通讯作者：
Ladiges WC
中科院分区：
文献类型：
--
作者：
Enns LC;Morton JF;Treuting PR;Emond MJ;Wolf NS;Dai DF;McKnight GS;Rabinovitch PS;Ladiges WC
导致蛋白激酶A（PKA）活性降低的突变已被证明可以延长酵母的寿命。哺乳动物RIIβ（PKA的一个调节亚基，在脑和脂肪组织中表达）功能的丧失导致小鼠消瘦和胰岛素敏感。因此，假设RIIB null（RIIβ−/−）小鼠将表达抗衰老表型。我们使用40只突变型和40只野生型（WT）同窝仔进行了寿命研究，发现与WT同窝仔相比，突变型雄性的中位寿命和最大寿命均显著增加。中位寿命从884天增加到1005天（p = 0.006，由对数秩检验确定），80%寿命（此处定义为80%死亡）从941天增加到1073天（p = 0.004，由Wang-Allison检验确定）。 女性基因型的中位寿命或80%寿命没有差异。两种性别的野生型小鼠随着年龄的增长变得越来越肥胖，而突变型小鼠在老年时保持其瘦的表型。肥胖症被发现与寿命只有男性。50%的雄性小鼠在30和35 g之间，相当于约5%的体脂，对于任一基因型，存活超过1000天。在此体重范围之外的雄性小鼠均未达到此寿命。在生命的最后一个月，WT小鼠开始减轻体重（雄性和雌性分别减轻8%和15%的体重），但RIIβ−/−雄性小鼠保持其瘦体重至生命结束。在雌性突变小鼠中未观察到这种下降的衰减。老年雄性突变小鼠一生都对胰岛素敏感。与WT相比，两种性别在老年突变体中均显示出适度较低的血糖水平。雄性突变体也对年龄诱导的脂肪肝有抵抗力。对来自生命末期雄性突变小鼠的组织的病理学评估显示肿瘤发生率降低、肾脏病变严重程度降低以及年龄相关心脏病理学降低的趋势。这些发现有助于建立PKA的高度保守性，并表明PKA的破坏会影响已知与健康衰老相关的生理机制。
Mutations that cause a reduction in protein kinase A (PKA) activity have been shown to extend lifespan in yeast. Loss of function of mammalian RIIβ, 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 (RIIβ−/−) 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 RIIβ−/− male mice maintained their lean body mass to end of life. This attenuation of decline was not seen in female mutant mice. Old male mutant mice were insulin sensitive throughout their life. Both genders showed modestly lower blood glucose levels in old mutants compared to WT. Male mutants were also resistant to age-induced fatty liver. Pathological assessment of tissues from end of life male mutant mice showed a decrease in tumor incidence, decreased severity of renal lesions, and a trend towards a decrease in age-related cardiac pathology. These findings help establish the highly conserved nature of PKA and suggest that disruption of PKA affects physiological mechanisms known to be associated with healthy aging.
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DOI：
10.1016/j.jsbmb.2007.09.001
发表时间：
2008-02-01
影响因子：
4.1
作者：
Blouin, Karine;Boivin, Ariane;Tchernof, Andre
通讯作者：
Tchernof, Andre
影响因子：
9.8
作者：
CEFALU, WT;WANG, ZQ;ANDERSON, R
通讯作者：
ANDERSON, R
影响因子：
16.2
作者：
Fujimoto, WY;Bergstrom, RW;Wahl, PW
通讯作者：
Wahl, PW
影响因子：
4.8
作者：
Amieux, PS;Cummings, DE;McKnight, GS
通讯作者：
McKnight, GS
影响因子：
5.3
作者：
Flurkey, K;Papaconstantinou, J;Harrison, DE
通讯作者：
Harrison, DE