FOXO4-DRI vs Humanin

FOXO4-DRI was described in a 2017 Cell paper that identified FOXO4 as central to the survival of senescent cells ¹. The peptide uses D-amino acids in a reversed sequence and is fused to the HIV-TAT sequence to enter cells ¹. In senescent human cell cultures (cell data) it caused p53 nuclear exclusion and apoptosis, and the effect was reduced when p53 was knocked down or caspases were blocked ¹. In fast-ageing and naturally aged mice (animal data), the authors reported restored fitness, fur density and kidney function ¹. A 2025 NMR study mapped its binding to the p53 transactivation domain ².

Other animal work points in several directions. In aged mice, it was reported to act on senescent Leydig cells and age-related testosterone decline ⁴. In mice, it reduced collagen deposition in a bleomycin lung-fibrosis model ¹⁶. In a 2023 Circulation study, however, removing senescent pulmonary endothelial cells with this peptide or another senolytic worsened pulmonary haemodynamics in mice ³. No human studies were identified ¹¹.

Humanin was identified in 2001 as a secreted polypeptide that, in cell culture, prevented neuronal death caused by several familial Alzheimer's disease genes and amyloid-beta ⁵. In cell studies it binds and inhibits the pro-apoptotic proteins Bax and Bid ⁶ and acts through a receptor complex involving CNTFR-alpha, WSX-1 and gp130 ⁷. In rodents (animal data), brain infusion of humanin and intravenous infusion of analogues changed insulin sensitivity ⁸.

Human evidence concerns the body's own humanin rather than giving the peptide. Circulating levels were lower with age in humans and mice ⁸, lower in 20 patients with coronary endothelial dysfunction than in 20 without ⁹, and rose after acute endurance exercise but not resistance exercise in a 30-person study ¹⁰. No interventional human trials were found ¹².