FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs

Abstract

Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs. FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes. Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292 , which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292 -encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.

Multivariate genomic scan implicates novel loci and haem metabolism in human ageing

“…However, colocalisation of gene expression could be due to pleiotropy rather than causality, and there is a need to validate the effects of genetic variants in experimental models to confirm their role in disease aetiology. For example, we have found life-extending variants colocalise with decreased expression of FOXO3 in blood, which itself becomes increasingly expressed with increasing age, but experiments suggest the gene has many protective functions including detoxification of reactive oxygen species and DNA damage repair 15 . The observed inverse relationship between healthy life and FOXO3 expression may reflect healthy individuals have less oxidative damage and require less FOXO3 to mitigate this damage.…”

“…Ten regions are of particular interest as they associate with all three ageing traits and are as such likely candidates to capture intrinsic ageing processes, rather than extrinsic sources of ageing. Five of the loci of interest are not associated at a genome-wide significant level in any individual dataset, including the region near FOXO3, which has thus far only been highlighted in candidate gene association studies (reviewed in Sanese et al 15 ) and never at genome-wide significance. The effects of loci of interest on male and female lifespan are largely the same, although their effect on survival may be slightly stronger in middle age (40-60 years) compared to old age (>80 years).…”

The DNA methylation of FOXO3 and TP53 as a blood biomarker of late-onset asthma

“…The results further demonstrated that the mRNA expression of FOXO3 was elevated in patients with mild to moderate LOA, whereas decreased in patients with severe LOA. FOXO3 had a pivotal role in inhibiting apoptosis, resisting oxidation, extending cell lifespan and preventing against aging-related diseases [ 54 ]. The increased FOXO3 expression may be due to the trigger of protective self-defense mechanisms in mild and moderate LOA patients.…”

Identification of novel genes associated with longevity in Drosophila melanogaster - a computational approach

“…The overexpression of the Pten gene was found to delay the process of proteostatis and therefore resulted in a decrease in the loss of muscle strength during muscle aging, increasing maximum lifespan in Drosophila by up to 7.7% in comparison with matched controls [50]. Interestingly, the human PTEN (phosphatase and tensin homolog) gene was found to encode upstream regulators for the FOXO3 gene [51], one of the few loci robustly associated with longevity in humans [10], stressing that longevity-associated SNPs may reside in regulatory regions as well as in protein-coding genes [52]. The Drosophila ortholog of the FOXO3 gene, foxo , a transcription factor involved in the regulation of the insulin signaling pathway, is a commonly known longevity gene [53–56].…”