Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4458, USA.
Neuroscience. 2011 Nov 24;196:189-202. doi: 10.1016/j.neuroscience.2011.09.007. Epub 2011 Sep 12.
Longevity genes attenuate the aging process, but their expression in the brain during aging remains unknown. Loss of the majority of heteromeric brain nicotinic acetylcholine receptors (nAChRs) results in premature brain aging, and altered regulation of longevity genes could be involved. Using in situ hybridization, the expression of SIRT1, Ku70, Nampt, p53, forkhead Box O3 (FoxO3), and mitochondria uncoupling protein 5 (UCP5) was determined in neocortex and hippocampus of young adult 3-month and middle-aged 18-month-old wild-type (WT), and age-matched mice lacking β2* heteromeric nAChRs (β2-/-). Age-related structural changes were detected in WT mice. In particular, cortical thickness was decreased but neuronal density increased, and hippocampal volume increased with age. In contrast, young β2-/- mice exhibited increased cortical neuronal density, and with age, cortical thickness decreased more dramatically, and hippocampal volume did not increase. Thus, young β2-/- mice exhibited cortical signs of aging, and aging was accelerated at 18 months. The longevity genes probed exhibited similar expression patterns in frontal brain structures, with strong expression in hippocampus, medial habenula (MHb), and cortex. In WT mice, age significantly decreased expression of all genes except SIRT1 in cortical structures, and a similar pattern was detected in the MHb. Genotype had no effect on expression in young adults in either cortex or MHb, but increased mRNA expression of SIRT1, Nampt, and Ku70 was detected in cortex, hippocampus, and MHb of aged β2-/- mice compared with WT mice. This is the first study to determine age-related expression of survival genes in forebrain areas. Although, structural changes indicative of accelerated aging are evident in young β2-/- mice, the data suggest that nAChRs do not directly regulate expression of survival genes. However, loss of β2* nAChRs could result in augmented cellular stress, which indirectly increases expression of SIRT1, Nampt, and Ku70 as an adaptive response to provide protection against neurodegeneration.
长寿基因可减缓衰老过程，但它们在衰老过程中大脑中的表达情况尚不清楚。异源脑烟碱型乙酰胆碱受体（nAChRs）的大部分丧失会导致大脑早衰，而长寿基因的调节改变可能与此有关。本研究通过原位杂交技术，检测了年轻成年 3 个月和中年 18 个月的野生型（WT）和年龄匹配的β2异源型 nAChRs 缺失（β2-/-）小鼠新皮质和海马中的 SIRT1、Ku70、Nampt、p53、叉头框蛋白 O3（FoxO3）和线粒体解偶联蛋白 5（UCP5）的表达。在 WT 小鼠中发现了与年龄相关的结构变化。特别是皮质厚度降低而神经元密度增加，海马体积随年龄增长而增加。相比之下，年轻的β2-/-小鼠表现出皮质神经元密度增加，随着年龄的增长，皮质厚度下降更为显著，而海马体积没有增加。因此，年轻的β2-/-小鼠表现出皮质衰老的迹象，18 个月时衰老加速。研究中探测到的长寿基因在额叶脑结构中表现出相似的表达模式，在海马体、中脑内侧缰核（MHb）和皮质中有强烈表达。在 WT 小鼠中，除了皮质结构中的 SIRT1 外，所有基因的表达都随着年龄的增长而显著降低，在 MHb 中也检测到了类似的模式。在年轻成年 WT 小鼠的皮质和 MHb 中，基因型对基因表达没有影响，但与 WT 小鼠相比，老化的β2-/-小鼠的皮质、海马体和 MHb 中 SIRT1、Nampt 和 Ku70 的 mRNA 表达增加。这是第一项确定前脑区域与年龄相关的生存基因表达的研究。尽管年轻的β2-/-小鼠存在加速衰老的结构变化，但数据表明 nAChRs 不会直接调节生存基因的表达。然而，β2nAChRs 的缺失可能导致细胞应激增加，这会间接增加 SIRT1、Nampt 和 Ku70 的表达，作为对神经退行性变的保护的一种适应性反应。
