Longevity-Promoting Pathways and Transcription Factors Respond to and Control Extracellular Matrix Dynamics During Aging and Disease

Abstract

Aging is one of the largest risk factors for cancer, type 2 diabetes, osteoarthritis, cardiovascular diseases, and other age-related pathologies. Here, we give a detailed description of the interplay of chronic age-related pathologies with the remodeling of the extracellular matrix during disease development and progression. Longevity-promoting signaling pathways slow or prevent age-related diseases. In particular, we focus on the mTOR signaling pathway, sirtuins, and canonical longevity-promoting transcription factors, such as FOXO, NF-κB, and Nrf2. We extend our analysis using chromatin immunoprecipitation (ChIP) sequencing and transcriptomic data and report that many established and emerging longevity-promoting transcription factors, such as CREB1, FOXO1,3, GATA1,2,3,4, HIF1A, JUN, KLF4, MYC, NFE2L2/Nrf2, RELA/NF-κB, REST, STAT3,5A, and TP53/p53, directly regulate many extracellular matrix genes and remodelers. We propose that modulation of these pathways increases lifespan and protects from age-related diseases in part due to their effects on extracellular matrix remodeling. Therefore, to successfully treat age-related diseases, it is necessary to better understand the connection between extracellular matrix components and longevity pathways.

Keywords: FOXO transcription factors; NF-κB transcription factor; Nrf2 transcription factor; collagen; extracellular matrix; healthy aging; mTOR signaling pathway; matrisome.

FIGURE 1

Outside-in and inside-out interplay of longevity pathways and extracellular matrix components. Extracellular matrix components influence longevity pathways and transcription factors. Constitutive activation of the mTOR signaling pathway and transcription factor NF-κB can lead to the development of age-related diseases. By contrast, FOXO, NRF2, and sirtuins activation relate to an increased lifespan.

FIGURE 2

Direct regulation of matrisome genes by longevity transcription factors. We used previously published ChIP-seq studies to find target genes of transcription factors that are associated with longevity. We divided the target genes of each transcription factor into matrisome and non-matrisome genes. From selected longevity transcription factors, MYC regulates the highest number of overall genes, while the largest number of matrisome genes is regulated by STAT3.