2020年出生的遗传异质性UM-HET3小鼠用于测试α-酮戊二酸(AKG)可能的寿命影响,2,4-二硝基苯酚(DNP),肼屈嗪(HYD),奈必洛尔(NEBI),16α-羟基雌三醇(OH_Est),和硫代硫酸钠(THIO),并评估16个月大时开始使用canagliflozin(Cana)的效果。OH_Est使男性的中位寿命增加了15%(p=0.0001),但导致女性寿命显着下降(7%)。Cana,从16个月开始,也导致了显著的增长(14%,p=0.004)在男性中,并且显著下降(6%,p=0.03)在女性中。卡纳在6个月时给老鼠服用,和我们之前的研究一样,在女性寿命没有任何变化的情况下增加男性寿命,这表明这种药物可能会导致女性特有的晚年伤害。我们发现,老年女性的Cana血液水平比年轻男性高大约20倍,提出了性别差异影响的可能机制。NEBI还被发现产生女性特异性下降(4%,p=0.03)的寿命。其他测试药物都没有提供任何性别的寿命益处。这些数据显示了经过ITP测试的药物清单,这些药物在一种或两种性别中都能诱导至少10%的寿命增加,添加第四种药物,对寿命具有中年益处,并提供了一个可测试的假设,可以解释SGLT2抑制剂Cana对寿命的影响。
Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.