Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor

Abstract

The O-type forkhead domain transcription factor (FOXO) is involved in many biological processes such as aging, the oxidative stress response, and growth regulation. FOXO activity is tightly controlled within cells. In particular, growth factor signaling pathways and the oxidative stress response can both stimulate nuclear translocation of this transcription factor. Here, we show that tetrahydrocurcumin (THC), a curcumin metabolite, regulates the oxidative stress response and aging via FOXO. In NIH3T3 cells, THC induced nuclear accumulation of FOXO4, a member of the FOXO family of transcription factors, by inhibiting phosphorylation of protein kinase B (PKB)/Akt. In Drosophila melanogaster, THC attenuated the oxidative stress response, an effect that was blocked in a foxo mutant background. THC also extended the life span of Drosophila under normal conditions, and loss of either foxo or Sir2 activity eliminated this effect. Based on these results, THC may regulate the aging process via an evolutionarily conserved signaling pathway that includes both foxo and Sir2.

Healthy aging diets other than the Mediterranean: A focus on the Okinawan diet

“…Recently the possibility that curcumin and its metabolites can modulate pathways directly involved in the determination of lifespan and extension of longevity, has been also highlighted (Shen et al 2013). Tetrahydrocurcumin (THC), an active metabolite of curcumin, produced after its ingestion, has been shown to extend lifespan of drosophila under normal conditions, by attenuating oxidative stress via FOXO and Sir2 modulation (Xiang et al 2011). Curcuminoids may also affect mammalian longevity, as shown in mice fed diets containing THC starting at the age of 13 months, which showed significantly increased mean lifespan (Shen et al 2013).…”

Tetrahydrocurcumin Provides Neuroprotection in Experimental Traumatic Brain Injury and the Nrf2 Signaling Pathway as a Potential Mechanism

“…Moreover, the ability of THC to stimulate the activities of other antioxidant enzymes further strengthens its antioxidative characteristics [19, 20]. However, the inner mechanism through which THC protects the brain from oxidative insult is not clear.…”

Life Extension

“…Flies mutant for eas accumulate SREBP in the nucleus of cardiomyocytes, leading to the activation of lipogenic genes (Lim et al 2011). Either eas mutants or flies overexpressing SREBP in the heart show elevated triglycerides in the heart, resulting in arrhythmias, relaxation defects, increased sensitivity to pacing stress and increased heart rate (Lim et al 2011).…”

“…Flies mutant for eas accumulate SREBP in the nucleus of cardiomyocytes, leading to the activation of lipogenic genes (Lim et al 2011). Either eas mutants or flies overexpressing SREBP in the heart show elevated triglycerides in the heart, resulting in arrhythmias, relaxation defects, increased sensitivity to pacing stress and increased heart rate (Lim et al 2011). The cardiac phenotype of mutants can be completely rescued by interfering downstream with lipid biosynthesis, either by knocking down SREBP itself or its targets acetyl-coA carboxylase (acc) or fatty acid synthase (fas) (Lim et al 2011), demonstrating that the defects are completely dependent on the cardiac steatosis.…”