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.

使用 2020 年出生的遗传异质 UM-HET3 小鼠来测试 α-酮戊二酸 (AKG)、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)，并评估卡格列净 (Cana) 在 16 个月大时开始使用的效果。 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%)。从 16 个月大时开始使用 Cana 也导致雄性的显着增加（14%，p = 0.004）和 雌性的 显着下降（6%，p = 0.03）。正如我们之前的研究一样，在 6 个月大时给予小鼠 Cana 导致雄性寿命延长，而雌性寿命没有任何变化，这表明这种药物可能会导致雌性特有的晚年伤害。我们发现，老年女性的 Cana 血液水平比年轻男性高约 20 倍，这表明其作用存在性别差异的可能机制。 NEBI 还被发现会导致女性寿命下降（4%，p  = 0.03）。其他测试的药物都没有对任何性别的寿命带来益处。这些数据使经过 ITP 测试的药物清单增加到 7 种，这些药物可使一种或两种性别的寿命延长至少 10%，添加第四种药物，已证明对中年寿命有好处，并提供了一个可检验的假设，可以解释性行为SGLT2 抑制剂 Cana 寿命效应的二态性。