FOXO3 and Related Transcription Factors in Development, Aging, and Exceptional Longevity

摘要

In June 2013, a workshop was convened in San Francisco to explore, in depth, the role of the Forkhead transcription factor FOXO3 (and related FOXOs) in development, aging, and, in particular, exceptional longevity. The presentations covered results derived from model systems, computational analysis and bioinformatics, and genomics and genome-wide association studies of a number of cohorts. Although the data collectively strongly reinforce FOXO3 and the FOXO/FOXO3 pathway as very important determinants in aging and life span, much of the detail of how the latter is achieved still remains unknown, in part, because of the very large number of genes (similar to 2,200 in Caenorhabditis elegans) the transcription factor is involved in helping regulate. Particularly challenging at the present time is understanding the association of apparently nonfunctional specific variants (single nucleotide polymorphisms) of FOXO3 and exceptional longevity in humans, a finding replicated in a number of studies. Nonetheless, as summarized in this report, valuable information and insights were presented at the workshop on the transcription factor including but not limited to its role in determining longevity in C elegans and Drosophila (in flies, eg, an important interaction in aging occurs between dFOXO and the transforming growth factor-beta/activin pathway), stem cell function and aging (notably in hematopoiesis), downstream regulatory activity (eg, by binding near sites of RNAse occupancy and altering chromatin structure), and as a potential target for the development a healthy aging drug (in this example, using compounds developed and screened to effect FOXO function in cancer cells).