FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence

Nat Commun. 2018 Jul 19;9(1):2834. doi: 10.1038/s41467-018-05258-6.

Abstract

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Here we show, through direct live-cell imaging of young, middle-aged, and old-aged primary human dermal fibroblasts, that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome mis-segregation in elderly mitotic cells correlates with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives G2/M gene expression. FoxM1 induction in elderly and Hutchison-Gilford progeria syndrome fibroblasts prevents aneuploidy and, importantly, ameliorates cellular aging phenotypes. Moreover, we show that senescent fibroblasts isolated from elderly donors' cultures are often aneuploid, and that aneuploidy is a key trigger into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • Aging / metabolism
  • Aneuploidy*
  • Cellular Senescence / genetics
  • Child
  • Child, Preschool
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Forkhead Box Protein M1 / genetics*
  • Forkhead Box Protein M1 / metabolism
  • G2 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression Regulation, Developmental
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mitosis*
  • Primary Cell Culture
  • Progeria / ethnology
  • Progeria / genetics*
  • Progeria / metabolism
  • Progeria / pathology
  • White People

Substances

  • FOXM1 protein, human
  • Forkhead Box Protein M1