尽管MYC是研究最为深入的致癌基因之一，但其在正常发育中的作用尚未确定，因为My c-/-小鼠无法维持到中期妊娠以后。Myc ±小鼠的寿命比其野生型对照小鼠更长，并且较为缓慢地积累多种与年龄相关的表型。然而，Myc 半数缺陷可能掩盖了其他重要的表型，因为许多高亲和力的Myc靶基因仍然可以正常调控。最近，通过延迟Myc的失活直到出生后，可以研究全身丧失基因的后果，从而推断其正常功能。与预期不同的是，这些“MycKO”小鼠的寿命明显比对照野生型小鼠更长，但表现出明显的早老表型。这种看似矛盾的行为可能通过癌症的终生发生率显著降低来解释，而癌症通常是小鼠和常常是由Myc驱动的死因。Myc的丧失加速了多个“衰老标志”的积累，包括线粒体和核糖体的结构和功能完整性丧失、活性氧物质的产生、遗传毒性损伤的获取、新陈代谢的负面重构和衰老的开始。在小鼠和人类中，许多组织的正常衰老伴随着Myc的下调和Myc靶基因调控的丧失。与大多数基于单基因DNA损伤识别和修复的早衰小鼠模型不同，MycKO小鼠模型直接影响大多数衰老标志，因此可能更真实地复制小鼠和人类的正常衰老过程。它进一步证明了衰老与癌症之间的强烈关联可以在遗传上分离，并由一个单一基因维持。版权所有 © 2023 Prochownik and Wang.

Despite MYC being among the most intensively studied oncogenes, its role in normal development has not been determined as Myc-/- mice do not survival beyond mid-gestation. Myc ± mice live longer than their wild-type counterparts and are slower to accumulate many age-related phenotypes. However, Myc haplo-insufficiency likely conceals other important phenotypes as many high-affinity Myc targets genes continue to be regulated normally. By delaying Myc inactivation until after birth it has recently been possible to study the consequences of its near-complete total body loss and thus to infer its normal function. Against expectation, these "MycKO" mice lived significantly longer than control wild-type mice but manifested a marked premature aging phenotype. This seemingly paradoxical behavior was potentially explained by a >3-fold lower lifetime incidence of cancer, normally the most common cause of death in mice and often Myc-driven. Myc loss accelerated the accumulation of numerous "Aging Hallmarks", including the loss of mitochondrial and ribosomal structural and functional integrity, the generation of reactive oxygen species, the acquisition of genotoxic damage, the detrimental rewiring of metabolism and the onset of senescence. In both mice and humans, normal aging in many tissues was accompaniued by the downregulation of Myc and the loss of Myc target gene regulation. Unlike most mouse models of premature aging, which are based on monogenic disorders of DNA damage recognition and repair, the MycKO mouse model directly impacts most Aging Hallmarks and may therefore more faithfully replicate the normal aging process of both mice and humans. It further establishes that the strong association between aging and cancer can be genetically separated and is maintained by a single gene.Copyright © 2023 Prochownik and Wang.