Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

Abstract

Aging constitutes the key risk factor for age-related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which "protective genes" are carried by long-lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin-like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

Keywords: FOXO transcription factors; aging; animal models; insulin and IGF-1 signaling pathway; longevity.

Figure 1

The key components of the PI3K signal transduction pathway are well conserved throughout evolution. The corresponding orthologues for these components in Hydra, Caenorhabditis elegans, Drosophila melanogaster and mammals are illustrated. It is important to note, that there is a single gene for many components, in Hydra, C. elegans and D. melanogaster whereas mammals have several isoforms of these components with the exception of PTEN. AGE‐1, ageing alteration 1; AKT, v‐akt murine thymoma viral oncogene homologue 1; DAF‐2, abnormal dauer formation‐2; FOXO, forkhead family of transcription factor; INR, insulin receptor; IRS, substrate; IST‐1, insulin receptor substrate (IRS)‐like adaptor; PDK, phosphatidylinositide‐dependent protein kinase 1; PTEN; phosphatase and tensin homologue.