Longevity Factor FOXO3: A Key Regulator in Aging-Related Vascular Diseases

Abstract

Forkhead box O3 (FOXO3) has been proposed as a homeostasis regulator, capable of integrating multiple upstream signaling pathways that are sensitive to environmental changes and counteracting their adverse effects due to external changes, such as oxidative stress, metabolic stress and growth factor deprivation. FOXO3 polymorphisms are associated with extreme human longevity. Intriguingly, longevity-associated single nucleotide polymorphisms (SNPs) in human FOXO3 correlate with lower-than-average morbidity from cardiovascular diseases in long-lived people. Emerging evidence indicates that FOXO3 plays a critical role in vascular aging. FOXO3 inactivation is implicated in several aging-related vascular diseases. In experimental studies, FOXO3-engineered human ESC-derived vascular cells improve vascular homeostasis and delay vascular aging. The purpose of this review is to explore how FOXO3 regulates vascular aging and its crucial role in aging-related vascular diseases.

Keywords: FOXO3; aging; cardiovascular disease; vascular aging; vascular homeostasis.

Figure 1

FOXO3 is an integrator of multiple signaling pathways to maintain vascular homeostasis. Under normal conditions, FOXO3 is inactive due to the negative regulation by IIS-PI3K-Akt pathway. Akt phosphorylates FOXO3 at three highly conserved residues T32, S253, and S315, thereby establishing docking sites for the chaperone protein 14-3-3 and preventing it from re-entering the nucleus. PTEN antagonizes the effect of PI3K and induces FOXO3 activation. When cells are exposed to stress, including growth factor deprivation, metabolic stress, and oxidative stress, FOXO3 translocates into the nucleus and exhibits increased transcriptional activity. FOXO3 regulates a number of cellular processes, including apoptosis, autophagy, oxidative resistance, and metabolism, all of which are involved in the pathological process of vascular aging.

Figure 2

Effects of FOXO3 on vascular aging-related diseases. FOXO3 participates in various cellular processes implicated in the progression of vascular aging, including oxidative resistance, apoptosis, autophagy, energy metabolism, and ECM remodeling processes by targeting the expression of effector genes. FOXO3 is a key protective factor in maintaining vascular homeostasis. Dysregulation of FOXO3 has been shown to contribute to a variety of vascular aging-related diseases, including atherosclerosis, vascular calcification, hypertension, and vascular aging-related heart diseases, kidney diseases, and cerebrovascular diseases.