Body‐Wide Inactivation of the Myc‐Like Mlx Transcription Factor Network Accelerates Aging and Increases the Lifetime Cancer Incidence

The “Mlx” and “Myc” transcription factor networks cross‐communicate and share many common gene targets. Myc's activity depends upon its heterodimerization with Max, whereas the Mlx Network requires that the Max‐like factor Mlx associate with the Myc‐like factors MondoA or ChREBP. The current work demonstrates that body‐wide Mlx inactivation, like that of Myc, accelerates numerous aging‐related phenotypes pertaining to body habitus and metabolism. The deregulation of numerous aging‐related Myc target gene sets is also accelerated. Among other functions, these gene sets often regulate ribosomal and mitochondrial structure and function, genomic stability, and aging. Whereas “MycKO” mice have an extended lifespan because of a lower cancer incidence, “MlxKO” mice have normal lifespans and a higher cancer incidence. Like Myc, the expression of Mlx, MondoA, and ChREBP and their control over their target genes deteriorate with age in both mice and humans. Collectively, these findings underscore the importance of lifelong and balanced cross‐talk between the two networks to maintain proper function and regulation of the many factors that can affect normal aging. The related Mlx and Myc transcription factors co‐maintain many processes that deteriorate with age. Mlx loss deregulates genes involved in these processes, accelerates aging, and increases cancer incidence. Myc loss also accelerates aging but extends life span due to a lower lifetime cancer risk. Tissue‐specific declines in Mlx and Myc and deregulation of their target genes likely contribute to normal aging and tumorigenesis.