细胞衰老的系统性重编程：代谢、表观遗传与蛋白稳态的协同调控^*

Systemic Reprogramming of Cellular Senescence: Coordinated Regulation of Metabolism, Epigenetics, and Proteostasis

摘要

细胞衰老长期被视为不可逆过程，但基于“部分重编程”的突破，研究表明细胞实际上处于一种可被重置的亚稳态。本综述指出，抗衰老干预需整合三大核心维度：首先，通过提升烟酰胺腺嘌呤二核苷酸（NAD⁺）水平进行代谢重编程，为系统重启提供不可或缺的能量与辅酶基础；其次，利用时空受控的OSKM因子或化学小分子进行适度的表观遗传重置，以恢复年轻态转录程序且不丧失细胞身份；最后，依赖自噬及泛素-蛋白酶体等系统的蛋白稳态恢复，作为清除受损废料与确保新生蛋白正确折叠的最后执行保障。然而，目前细胞年轻化研究仍面临重编程安全窗口界定不清、组织特异性递送效率有限以及长期干预安全性证据不足等挑战。未来需要结合单细胞组学、DNA甲基化时钟及人工智能辅助分析等技术，建立精准的年轻化评估体系；同时发展脂质纳米颗粒（LNP）、工程化外泌体等新型递送平台，实现多层级协同干预的精准调控。未来的抗衰老医学正从单一通路干预，全面迈向“代谢-表观-蛋白稳态”多轴协同的系统性重编程框架。

Abstract

Cellular senescence has long been considered an irreversible process. However, recent breakthroughs in partial cellular reprogramming have demonstrated that senescent cells maintain a metastable state amenable to resetting. This review outlines a systemic framework for anti-aging interventions that integrate three core dimensions. First, metabolic reprogramming through the elevation of nicotinamide adenine dinucleotide (NAD⁺) levels provides the energetic and coenzymatic foundation necessary for a systemic reset. Second, spatiotemporally controlled epigenetic resetting, mediated by Oct4-Sox2-Klf4-c-Myc (OSKM) factors or small molecules, restores youthful transcriptional programs without compromising cellular identity. Third, the restoration of proteostasis via the autophagy-lysosome and ubiquitin-proteasome systems serves as the critical execution mechanism that eliminates damaged biomaterials and ensures the proper folding of newly synthesized proteins. Despite these advances, the research field still faces major challenges, including the lack of a clearly defined therapeutic window for safe reprogramming, limited efficiency of tissue-specific delivery, and insufficient evidence regarding the long-term safety of therapeutic interventions. Future studies should focus on integrating single-cell omics, DNA methylation clocks, and artificial intelligence-assisted analyses to establish precision-based evaluation metrics for evaluating cellular rejuvenation. In addition, the development of next-generation delivery platforms, including lipid nanoparticles (LNPs) and engineered exosomes, will facilitate precision-based regulation of multi-level synergistic interventions. Ultimately, anti-aging medicine is evolving from single-pathway interventions toward a comprehensive paradigm of systemic reprogramming driven by the multi-axial synergy of metabolism, epigenetics, and proteostasis.

关键词

衰老 / 细胞重编程 / 烟酰胺腺嘌呤二核苷酸 / 表观遗传学 / 蛋白质稳态

Key words

Aging / Cellular reprogramming / Nicotinamide adenine dinucleotide / Epigenetics / Proteostasis

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基金资助

*四川省科技计划(2026NSFSC1596)