FOXO Transcriptional Factors and Long-Term Living

Abstract

Several pathologies such as neurodegeneration and cancer are associated with aging, which is affected by many genetic and environmental factors. Healthy aging conceives human longevity, possibly due to carrying the defensive genes. For instance, FOXO (forkhead box O) genes determine human longevity. FOXO transcription factors are involved in the regulation of longevity phenomenon via insulin and insulin-like growth factor signaling. Only one FOXO gene (FOXO DAF-16) exists in invertebrates, while four FOXO genes, that is, FOXO1, FOXO3, FOXO4, and FOXO6 are found in mammals. These four transcription factors are involved in the multiple cellular pathways, which regulate growth, stress resistance, metabolism, cellular differentiation, and apoptosis in mammals. However, the accurate mode of longevity by FOXO factors is unclear until now. This article describes briefly the existing knowledge that is related to the role of FOXO factors in human longevity.

Figure 1

Various modes of aging.

Figure 2

The crucial intracellular pathways targeted by FOXOs are presented here as modes of longevity effects of FOXOs. FOXOs are known to regulate translation of environment-induced stimuli into gene expression. FOXO-mediated longevity (especially through FOXO3) could be due to upregulated target genes pertained to apoptosis, cell cycle arrest, and resistance to stress leading to prevention of aging and age-associated diseases such as cancer and neurodegenerative diseases. The green part of the above figure illustrates cellular redox potential in mitochondria restoring NAD⁺. It results in the calorie restriction leading to various processes such as ameliorated autophagy, inhibited mTOR activity, and sirtuin-mediated activation of FOXOs giving rise to long-term living. While the red part of the above figure shows elevated levels of NADH due to excessive calorie intake resulting in lipogenesis, activated mTOR, excessive release of ROS, and suppressed autophagy leading to frailty. TCAC = tricarboxylic acid cycle; CAD = coronary artery disease; PPARγC1α = peroxisome proliferator-activated receptor-γ coactivator 1α; GCN1l1 = general control of amino acid synthesis 1-like 1; HNF4a = hepatocyte nuclear factor 4α; O-GlcNAc = O-linked N-acetylglucosamine.