Foxo proteins get crafty when it comes to improving longevity

The FOXO transcription factor can help in promoting stem cell multipotency during quiescence under adverse conditions, improving longevity, new research shows.

Aging has been long known to be associated with cardiovascular diseases, cancer, and neurodegenerative diseases. Healthy aging and human longevity are influenced by both genetic and environmental factors. Research has been carried out on certain protective genes that are found in long-lived individuals [1]. Several studies have reported that Forkhead box O (FOXO) transcription factors play important roles in determining aging and longevity.

Longevity.Technology: The FOXO protein class acts as downstream regulators for insulin and insulin-like signalling growth factors. These proteins comprise of a conserved DNA-binding domain that participates in important cellular processes such as apoptosis, cell cycle arrest, and metabolism along with longevity. FOXO proteins are conserved from budding yeast to our old friend the nematode worm Caenorhabditis elegans (C elegans) to mammals.

Mammals are known to possess four FOXO genes, FOXO1 (FKHR), FOXO3 (FKHRL1), FOXO4 (AFX), and FOXO6 while C elegans has to settle for only one FOXO gene, daf-16. Daf-16 is known to encode eight different transcripts, from daf-16a to daf-16h [2]. Daf-16/FOXO integrates signals from different pathways such as the insulin and IGF-1 signalling (IIS) pathway, TOR Pathway, JNK (Jun N-terminal kinase) signalling pathway, AMP-activated protein kinase (AMPK) pathway and germline signalling to modulate aging and longevity. Studies have shown that C elegans with mutations in the insulin/IGF-1 receptor live longer than the wild-type C elegans.

Stem cells are undifferentiated cells that are capable of generating specialised types of cells in our bodies. Division of tissue-specific stem cells is required to replenish those cells that have been lost due to injury or normal wear and tear. Many types of stem cells are known to retain their capacity to produce multiple cell types during periods of non-division or quiescence with the help of FOXO transcription factors. The single FOXO ortholog of C elegans, daf-16 promotes entry into a stress-resistant and quiescent stage known as dauer – a sort of stasis – in response to adverse environmental conditions.

The dauer stage is impacted by three major signalling pathways. During favourable environmental conditions, one of the pathways which is the insulin/IGF signalling blocks the activity of the downstream DAF-16/FOXO transcription factor. However, during adverse conditions, DAF-16 is activated and regulates the expression of genes that promote dauer entry. DAF-16/FOXO is also required for stem cell maintenance as well as promoting the differentiation of stem/progenitor cells into correct cell types. Therefore, the dauer stage plays an important role in modulating longevity in C elegans.

A new study led by Central Michigan University aimed to determine the role of daf-16/FOXO in maintaining multipotency in C elegans stem cells during dauer. Multipotent cells are those that can develop into more than one cell type, but are more limited than pluripotent cells. Several heterochronic genes help to specify stage-specific seam cell fate at adult and larval stages. Heterochronic genes function as a cascade that helps in the progression of successive cell fates. However, the timing of developmental progression is altered during dauer formation. Maybe this is the reason why extensive modulation of the heterochronic pathway has been observed in pre-and post-dauer stages [3].

A heterochronic gene, lin-41 that promotes larval cell fate was observed to block adult cell fate during dauer by acting downstream of daf-16. The study showed that both daf-16 and lin-41 were required to prevent the expression of adult cell fate marker, col-19p::gfp. daf-16 was also found to block adult collagen expression through several factors except for lin-29, which is a major regulator of adult cell fate. The study also suggests that daf-16/FOXO plays a major role in promoting multipotent cell fate during dauer due to its ability to regulate several developmental pathways [3].

DAF-16 thus plays an important role in the regulation of stem cell quiescence as well as stem cell plasticity. The connection between daf-16/FOXO and lin-41 that has been observed in C elegans may be relevant for mammalian stem cells due to the conserved nature of the FOXO transcription factors. Maintenance of multipotency of stem cells, therefore, can help to improve longevity in mammals as observed in C elegans.

Apart from maintenance of adult stem cell homeostasis, several studies with humans have indicated that organs that are responsible for glucose homeostasis express higher levels of FOXO proteins, these proteins promote apoptosis signalling pathways, regulate the immune system, maintain protein homeostasis, protect the heart and blood vessels, and prevent cancer by inhibiting tumour growth [4]. Therefore, FOXO proteins play important roles in improving longevity as well as promoting healthy aging in humans, although translating this knowledge to actual therapy will require more detailed research.