Dept. Bioquímica y Biología Molecular y Fisiología-IBGM, Universidad de Valladolid-CSIC, 47003 Valladolid, Spain.
Exp Gerontol. 2011 Jul;46(7):579-89. doi: 10.1016/j.exger.2011.02.014. Epub 2011 Mar 3.
Apolipoprotein D (ApoD), a member of the Lipocalin family, is the gene most up-regulated with age in the mammalian brain. Its expression strongly correlates with aging-associated neurodegenerative and metabolic diseases. Two homologues of ApoD expressed in the Drosophila brain, Glial Lazarillo (GLaz) and Neural Lazarillo (NLaz), are known to alter longevity in male flies. However, sex differences in the aging process have not been explored so far for these genes. Here we demonstrate that NLaz alters lifespan in both sexes, but unexpectedly the lack of GLaz influences longevity in a sex-specific way, reducing longevity in males but not in females. While NLaz has metabolic functions similar to ApoD, the regulation of GLaz expression upon aging is the closest to ApoD in the aging brain. A multivariate analysis of physiological parameters relevant to lifespan modulation uncovers both common and specialized functions for the two Lipocalins, and reveals that changes in protein homeostasis account for the observed sex-specific patterns of longevity. The response to oxidative stress and accumulation of lipid peroxides are among their common functions, while the transcriptional and behavioral response to starvation, the pattern of daily locomotor activity, storage of fat along aging, fertility, and courtship behavior differentiate NLaz from GLaz mutants. We also demonstrate that food composition is an important environmental parameter influencing stress resistance and reproductive phenotypes of both Lipocalin mutants. Since ApoD shares many properties with the common ancestor of invertebrate Lipocalins, we must benefit from this global comparison with both GLaz and NLaz to understand the complex functions of ApoD in mammalian aging and neurodegeneration.
载脂蛋白 D（ApoD）是脂联素家族的成员，是哺乳动物大脑中随年龄增长而上调最明显的基因。它的表达与衰老相关的神经退行性和代谢性疾病密切相关。在果蝇大脑中表达的 ApoD 的两个同源物，神经拉扎里洛（Neural Lazarillo，NLaz）和胶质拉扎里洛（Glial Lazarillo，GLaz），已知会改变雄性果蝇的寿命。然而，迄今为止，这些基因在衰老过程中的性别差异尚未得到探索。在这里，我们证明 NLaz 会改变两性的寿命，但出乎意料的是，GLaz 的缺乏以性别特异性的方式影响寿命，降低雄性寿命而不影响雌性寿命。虽然 NLaz 具有与 ApoD 相似的代谢功能，但 GLaz 表达的衰老调节与衰老大脑中的 ApoD 最为接近。对与寿命调节相关的生理参数的多元分析揭示了两种脂联素的共同和专门功能，并表明蛋白质平衡的变化解释了观察到的寿命的性别特异性模式。对氧化应激的反应和脂质过氧化物的积累是它们的共同功能，而对饥饿的转录和行为反应、日常运动活动模式、衰老过程中脂肪的储存、生育能力和求爱行为则使 NLaz 与 GLaz 突变体不同。我们还证明，食物组成是影响两种脂联素突变体应激抗性和生殖表型的重要环境参数。由于 ApoD 与无脊椎动物脂联素的共同祖先有许多共同特性，因此我们必须受益于与 GLaz 和 NLaz 的这种全球比较，以了解 ApoD 在哺乳动物衰老和神经退行性变中的复杂功能。
