Reeves Joshua, Tournier Pierre, Becquart Pierre, Carton Robert, Tang Yin, Vigilante Alessandra, Fang Dong, Habib Shukry J
Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
Centre for Gene Therapy and Regenerative Medicine King's College London, London, United Kingdom.
Elife. 2024 Dec 18;13:RP104068. doi: 10.7554/eLife.104068.
Aging is marked by a decline in tissue regeneration, posing significant challenges to an increasingly older population. Here, we investigate age-related impairments in calvarial bone healing and introduce a novel two-part rejuvenation strategy to restore youthful repair. We demonstrate that aging negatively impacts the calvarial bone structure and its osteogenic tissues, diminishing osteoprogenitor number and function and severely impairing bone formation. Notably, increasing osteogenic cell numbers locally fails to rescue repair in aged mice, identifying the presence of intrinsic cellular deficits. Our strategy combines Wnt-mediated osteoprogenitor expansion with intermittent fasting, which leads to a striking restoration of youthful levels of bone healing. We find that intermittent fasting improves osteoprogenitor function, benefits that can be recapitulated by modulating NAD-dependent pathways or the gut microbiota, underscoring the multifaceted nature of this intervention. Mechanistically, we identify mitochondrial dysfunction as a key component in age-related decline in osteoprogenitor function and show that both cyclical nutrient deprivation and Nicotinamide mononucleotide rejuvenate mitochondrial health, enhancing osteogenesis. These findings offer a promising therapeutic avenue for restoring youthful bone repair in aged individuals, with potential implications for rejuvenating other tissues.
衰老的特征是组织再生能力下降，这给日益老龄化的人口带来了重大挑战。在此，我们研究了与年龄相关的颅骨愈合损伤，并引入了一种新颖的两部分恢复活力策略来恢复年轻状态下的修复能力。我们证明，衰老对颅骨结构及其成骨组织产生负面影响，减少了骨祖细胞的数量和功能，并严重损害骨形成。值得注意的是，在老年小鼠中局部增加成骨细胞数量并不能挽救修复过程，这表明存在内在的细胞缺陷。我们的策略将Wnt介导的骨祖细胞扩增与间歇性禁食相结合，这导致年轻水平的骨愈合得到显著恢复。我们发现间歇性禁食可改善骨祖细胞功能，通过调节NAD依赖途径或肠道微生物群也可重现这些益处，突出了这种干预措施的多方面性质。从机制上讲，我们确定线粒体功能障碍是与年龄相关的骨祖细胞功能下降的关键组成部分，并表明周期性营养剥夺和烟酰胺单核苷酸均可恢复线粒体健康，增强骨生成。这些发现为恢复老年个体年轻的骨修复提供了一条有前景的治疗途径，对恢复其他组织的年轻状态也具有潜在意义。
