Reenan Robert A, Rogina Blanka
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
Aging Cell. 2008 Mar;7(2):179-86. doi: 10.1111/j.1474-9726.2008.00368.x. Epub 2008 Jan 15.
General locomotor activity decreases with normal aging in animals and could be partially explained by decreases in neuronal function. Voltage-gated Na(+) channels are essential in initiating and propagating rapid electrical impulses underlying normal locomotor activity and behavior in animals. Isolation of mutations conferring temperature-sensitive (ts) paralysis has been an extremely powerful paradigm for identifying genes involved in neuronal functions, such as membrane excitability and synaptic transmission. For instance, decreased expression of wild-type Na(+) channels in flies harboring the no-action-potential (nap) mutant allele (mle(napts)) confers rapid and reversible ts paralysis, because of failure of action potential propagation. Here, we report that aging wild-type Drosophila gradually develops an acquired susceptibility to ts paralysis that is indistinguishable from that seen in young ts paralytic mle(napts) mutants. Moreover, we show that this general age-dependent susceptibility is also present in mle(napts) flies, although the effects are shifted to lower temperature regimes. The mle(napts) flies also exhibit decreased lifespan and increased frailty. Paralysis and decreased lifespan of mle(napts) flies were partially rescued by increasing the dosage of para, the structural gene for the major action potential Na(+) channel in central nervous system of Drosophila. Lastly, we show a dramatic scaling of ts paralysis susceptibility with chronological age in short-lived and long-lived mutant flies, further demonstrating that this age-dependent risk is independent of genetic background. Thus, decreased neural transmission, a hallmark of which is ts paralysis, is a biomarker of aging.
在动物中，一般的运动活动会随着正常衰老而减少，这可能部分是由神经元功能的下降所解释的。电压门控钠通道对于启动和传播动物正常运动活动和行为背后的快速电冲动至关重要。分离赋予温度敏感（ts）麻痹的突变一直是识别参与神经元功能（如膜兴奋性和突触传递）的基因的极其强大的范例。例如，携带无动作电位（nap）突变等位基因（mle(napts)）的果蝇中野生型钠通道的表达降低会导致快速且可逆的ts麻痹，这是由于动作电位传播失败。在这里，我们报告衰老的野生型果蝇逐渐对ts麻痹产生获得性易感性，这与年轻的ts麻痹mle(napts)突变体中所见的情况无法区分。此外，我们表明这种一般的年龄依赖性易感性在mle(napts)果蝇中也存在，尽管其影响转移到了较低的温度范围。mle(napts)果蝇还表现出寿命缩短和脆弱性增加。通过增加果蝇中枢神经系统中主要动作电位钠通道的结构基因para的剂量，部分挽救了mle(napts)果蝇的麻痹和寿命缩短。最后，我们表明在短命和长寿突变果蝇中，ts麻痹易感性与 chronological 年龄呈显著的比例关系，进一步证明这种年龄依赖性风险与遗传背景无关。因此，神经传递减少，其标志是ts麻痹，是衰老的生物标志物。
