Lifespan extension by diet restriction in DNA repair deficient progeroid Ercc1delta/- mice [mRNA]

DNA repair-deficient Ercc1delta/- mice show premature cell death, senescence and numerous accelerated aging features limiting lifespan to 4-6 month. Simultaneously they exhibit a 'survival response', which suppresses growth and enhances maintenance, resembling the anti-aging response induced by dietary restriction (DR). Here we report that subjecting these progeroid, dwarf mutants to actual dietary restriction (DR) resulted in the largest lifespan increase recorded in mammals. Thirty percent DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated aging, e.g. DR animals retained 50% more neurons and maintained full motoric function. The DR response in Ercc1delta/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1delta/- liver expression profiles showed preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Our findings strengthen the link between DNA damage and aging, establish Ercc1delta/- mice as powerful model for identifying interventions to promote healthy aging, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and DR-like interventions for preventing neurodegenerative diseases. 20 samples (4 groups with 5 replicates each) analyzed on Affymetrix genechipsDNA修复缺陷型Ercc1delta/-小鼠（Ercc1delta/- mice）会出现过早细胞死亡、细胞衰老及多种加速衰老表型，寿命仅为4至6个月。与此同时，该类小鼠还会激活一种“存活应答”，抑制生长并强化机体维持能力，其表现与饮食限制（dietary restriction, DR）诱导的抗衰老应答相似。 本研究发现，对这类早衰老侏儒突变小鼠实施真实饮食限制（DR）后，其寿命延长幅度为哺乳动物中已报道之最。30%饮食限制使小鼠的中位剩余寿命与最大剩余寿命均延长至原来的3倍，并显著延缓了多种加速衰老进程：例如，实施DR的小鼠保留了多50%的神经元，且运动功能完好无损。 Ercc1delta/-小鼠的DR应答与野生型小鼠一致，均表现为胰岛素信号通路活性降低。值得注意的是，自由进食的Ercc1delta/-小鼠肝脏转录组谱显示，长链基因的表达优先被抑制，这与全基因组范围内随机产生的转录阻断损伤的累积相符——这类损伤对长链基因的影响远大于短链基因。DR可在很大程度上阻止这种转录输出量的下降，表明DR能够维持基因组功能。 本研究结果强化了DNA损伤与衰老之间的关联，确立了Ercc1delta/-小鼠作为筛选促进健康衰老干预手段的高效模型，揭示了降低内源性损伤的未开发潜力，为解析DR的分子机制提供了新方向，并提出了一种反直觉的类DR疗法，可用于治疗人类早衰老性基因组不稳定综合征，同时也为预防神经退行性疾病提供了类DR干预思路。本研究采用Affymetrix基因芯片（Affymetrix genechips）对20份样本进行了分析，分为4组，每组5个生物学重复。