Rui Ribeiro

The FOXM1 transcription factor exhibits pleiotropic C-terminal transcriptional and N-terminal non-transcriptional functions in various biological processes critical for cellular homeostasis. We previously found that FOXM1 repression during cellular aging underlies the senescence phenotypes, which were vastly restored by overexpressing transcriptionally active FOXM1. Yet, it remains unknown whether increased expression of FOXM1 can delay organismal aging. Here, we show that in vivo cyclic induction of an N-terminal truncated FOXM1 transgene on progeroid and naturally aged mice offsets aging-associated repression of full-length endogenous Foxm1, reinstating both transcriptional and non-transcriptional functions. This translated into mitigation of several cellular aging hallmarks, as well as molecular and histopathological progeroid features of the short-lived Hutchison–Gilford progeria mouse model, significantly extending its lifespan. FOXM1 transgene induction also reinstated endogenous Foxm1 levels in naturally aged mice, delaying aging phenotypes while extending their lifespan. Thus, we disclose that FOXM1 genetic rewiring can delay senescence-associated progeroid and natural aging pathologies.

Mainstream approaches that are currently used as anti-aging therapies primarily explore the senescence and epigenetic drift aging hallmarks and they are at two ends of the spectrum. While senolytic therapies include either the selective elimination of senescent cells or the disruption of their secretome with the use of drugs or natural compounds, cellular reprogramming uses genetic manipulation to revert cells all the way back to pluripotency. Here, we describe the progress that has been made on these therapies, while highlighting the major challenges involved. Moreover, based on recent findings elucidating the impact of mitotic shutdown and aneuploidy in cellular senescence, we discuss the modulation of mitotic competence as an alternative strategy to delay the hallmarks of aging. We propose that a regulated rise in mitotic competence of cells could circumvent certain limitations that are present in the senolytic and reprogramming approaches, by acting to decelerate senescence and possibly restore the epigenetic landscape.

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.

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Supported by direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, we found that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome segregation defects in elderly mitotic cells correlated with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives expression of most G2/M genes. By restoring FoxM1 levels in elderly and Hutchison-Gilford Progeria Syndrome fibroblasts we prevented aneuploidy and, importantly, ameliorated cellular phenotypes associated with aging. Moreover, senescent fibroblasts isolated from elderly donors’ cultures were mostly aneuploid, suggesting that aneuploidy is a key player in the progression 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.