Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis

Presbycusis is characterized by an age-related progressive decline of auditory function, and arises mainly from the degeneration of hair cells or spiral ganglion (SG) cells in the cochlea. Here we show that caloric restriction suppresses apoptotic cell death in the mouse cochlea and prevents late onset of presbycusis. Caloric restricted mice, which maintained body weight at the same level as that of young control (YC) mice, retained normal hearing and showed no cochlear degeneration. CR mice also showed significantly fewer TUNEL-positive staining cells and fewer cleaved caspase-3-positive staining cells relative to middle-age control (MC) mice. Microarray analysis revealed that CR down-regulated the expression of 28 proapoptotic genes, including Bak and Bim. Taken together, our findings suggest that loss of critical cells through apoptosis is an important mechanism of presbycusis in mammals, and that CR or staying lean can retard this process by suppressing apoptosis in the inner ear tissue. Keywords: Effect of aging, effect of caloric restriction, time course, disease state analysis To examine the effects of aging, a comparison of cochlea tissues from YC (3 samples) and MC (3 samples) mice was conducted. To examine the effects of calorie restriction (CR), a comparison of cochleae from MC (3 samples) and CR (3 samples) mice was conducted. We examined age-related changes in gene expression in the cochlea and calorie restriction-induced changes in gene expression in the cochlea. We pooled four cochleae from two mice for one sample and used three samples per group (n = 3). Quality control measures were not used. No replicates were done. Dye swap was not used.

老年性聋（presbycusis）以年龄相关性听觉功能进行性减退为特征，其发病主要源于耳蜗毛细胞或螺旋神经节（spiral ganglion, SG）细胞的变性。本研究证实，热量限制（caloric restriction, CR）可抑制小鼠耳蜗的细胞凋亡，并延缓老年性聋的迟发进程。维持体重与年轻对照组（young control, YC）小鼠一致的热量限制组小鼠，听力保持正常且未出现耳蜗变性。与中年对照组（middle-age control, MC）小鼠相比，热量限制组小鼠的TUNEL阳性染色细胞及活化半胱天冬酶-3（cleaved caspase-3）阳性染色细胞数量均显著减少。微阵列（microarray）分析显示，CR可下调包括Bak与Bim在内的28个促凋亡基因的表达。综上，本研究结果表明，通过凋亡途径丢失关键细胞是哺乳动物老年性聋的重要致病机制，而CR或维持体重偏瘦可通过抑制内耳组织的细胞凋亡延缓该病变进程。
关键词：衰老影响、热量限制效应、时间进程、疾病状态分析
为探究衰老的影响，本研究对年轻对照组（YC，3份样本）与中年对照组（MC，3份样本）小鼠的耳蜗组织开展了对比分析。为探究热量限制（CR）的影响，本研究对中年对照组（MC，3份样本）与热量限制组（CR，3份样本）小鼠的耳蜗组织开展了对比分析。本研究检测了耳蜗中年龄相关性基因表达变化及热量限制诱导的耳蜗基因表达变化。我们将2只小鼠的4个耳蜗混为1份样本，每组使用3份样本（n=3）。本研究未采用质量控制措施，未设置生物学重复，也未进行染料互换（dye swap）。