Birkisdóttir María B, van Galen Ivar, Brandt Renata M C, Barnhoorn Sander, van Vliet Nicole, van Dijk Claire, Nagarajah Bhawani, Imholz Sandra, van Oostrom Conny T, Reiling Erwin, Gyenis Ákos, Mastroberardino Pier G, Jaarsma Dick, van Steeg Harry, Hoeijmakers Jan H J, Dollé Martijn E T, Vermeij Wilbert P
Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
Oncode Institute, Utrecht, Netherlands.
Front Aging. 2022 Oct 12;3:1005322. doi: 10.3389/fragi.2022.1005322. eCollection 2022.
Despite efficient repair, DNA damage inevitably accumulates with time affecting proper cell function and viability, thereby driving systemic aging. Interventions that either prevent DNA damage or enhance DNA repair are thus likely to extend health- and lifespan across species. However, effective genome-protecting compounds are largely lacking. Here, we use and DNA repair-deficient mutants as two accelerated aging mouse models to test propitious anti-aging pharmaceutical interventions. and mice show shortened lifespan with accelerated aging across numerous organs and tissues. Previously, we demonstrated that a well-established anti-aging intervention, dietary restriction, reduced DNA damage, and dramatically improved healthspan, strongly extended lifespan, and delayed all aging pathology investigated. Here, we further utilize the short lifespan and early onset of signs of neurological degeneration in and mice to test compounds that influence nutrient sensing (metformin, acarbose, resveratrol), inflammation (aspirin, ibuprofen), mitochondrial processes (idebenone, sodium nitrate, dichloroacetate), glucose homeostasis (trehalose, GlcNAc) and nicotinamide adenine dinucleotide (NAD) metabolism. While some of the compounds have shown anti-aging features in WT animals, most of them failed to significantly alter lifespan or features of neurodegeneration of our mice. The two NAD precursors; nicotinamide riboside (NR) and nicotinic acid (NA), did however induce benefits, consistent with the role of NAD in facilitating DNA damage repair. Together, our results illustrate the applicability of short-lived repair mutants for systematic screening of anti-aging interventions capable of reducing DNA damage accumulation.
尽管DNA损伤能够得到有效修复，但随着时间的推移，它仍不可避免地会累积，影响细胞的正常功能和活力，从而推动全身衰老。因此，能够预防DNA损伤或增强DNA修复的干预措施可能会延长所有物种的健康期和寿命。然而，目前在很大程度上缺乏有效的基因组保护化合物。在这里，我们使用两种DNA修复缺陷型突变体作为加速衰老的小鼠模型，来测试有利的抗衰老药物干预措施。这两种小鼠表现出寿命缩短，多个器官和组织加速衰老。此前，我们证明了一种成熟的抗衰老干预措施——饮食限制，可以减少DNA损伤，显著改善健康期，大幅延长寿命，并延缓所有所研究的衰老病理过程。在这里，我们进一步利用这两种小鼠的短寿命和神经退行性变迹象的早期出现，来测试影响营养感知（二甲双胍、阿卡波糖、白藜芦醇）、炎症（阿司匹林、布洛芬）、线粒体过程（艾地苯醌、硝酸钠、二氯乙酸）、葡萄糖稳态（海藻糖、N-乙酰葡糖胺）和烟酰胺腺嘌呤二核苷酸（NAD）代谢的化合物。虽然其中一些化合物在野生型动物中已显示出抗衰老特性，但它们中的大多数未能显著改变我们实验小鼠的寿命或神经退行性变特征。然而，两种NAD前体，烟酰胺核糖（NR）和烟酸（NA），确实产生了有益效果，这与NAD在促进DNA损伤修复中的作用一致。总之，我们的结果说明了短命修复突变体在系统筛选能够减少DNA损伤积累的抗衰老干预措施方面的适用性。
