FOXO4-DRI

What it is

FOXO4-DRI is a synthetic peptide of 46 amino acids engineered using a technique called D-retro-inversion, which flips the chain's amino acid building blocks into their mirror-image form and strings them together in reverse. This trick makes the peptide harder for the body normal protein-breaking enzymes to dismantle, while still letting it bind its intended target inside cells.

Its designers built it to interfere with a specific pairing inside cells between two proteins, FOXO4 and p53, that helps keep senescent cells, cells that have stopped dividing but resist dying, alive. When that pairing is disrupted, researchers report that the p53 protein is freed to move to a different part of the cell and trigger the cell own self-destruct process, in theory clearing out senescent cells selectively while sparing healthy ones. Researchers at Erasmus University Medical Center in the Netherlands, led by Peter de Keizer, first described this compound in 2017.

How it is studied

Every published study of FOXO4-DRI to date has used either mice or cells grown in a dish; no human clinical trial has been conducted. The original mouse study looked at animals given a chemotherapy drug and at naturally aged and fast-aging mice, measuring outcomes such as how thick their fur grew back, how well their kidneys worked, and their overall physical fitness. Separate laboratory experiments by other research groups have tested the peptide on senescent Leydig cells, which make testosterone, and on human cartilage-forming cells grown in a dish.

What studies report

• In the original 2017 study, a course of FOXO4-DRI protected mice against tissue damage from a chemotherapy drug and, in both naturally aged mice and a fast-aging mouse strain, restored fur density and kidney function and increased general fitness, while appearing well tolerated at the amounts tested. [baar-2017]
• In aged mice, FOXO4-DRI selectively triggered self-destruction in senescent testosterone-producing cells in the testes, improved the surrounding tissue environment, and eased the age-related drop in testosterone output, in a study by a different research group. [zhang-2020]
• In human cartilage-forming cells grown in a dish and expanded to the point where many had become senescent, FOXO4-DRI removed more than half of the cells and lowered markers of senescence, without significantly affecting cells that had not yet become senescent; treated cells did not go on to form better cartilage tissue in a follow-up test. [huang-2021]

What is not known

Because no human trial exists, it is not known whether the selective cell-clearing effect seen in mice and in cells grown in a dish happens the same way in people, at what amount, or with what balance of benefit and risk. A specific concern raised in the wider literature is that the peptide works through p53, a protein that also suppresses tumors, so the long-term consequences of repeatedly disrupting its normal regulation have not been studied. It is also not established whether removing senescent cells with this peptide translates into better tissue function in every context studied; in cartilage cells, for example, clearing senescent cells did not improve the tissue that formed afterward.

Regulatory status

Neither the United States Food and Drug Administration nor any other national medicines regulator has approved FOXO4-DRI for use in people, and no registered clinical trial has put it in front of a single human volunteer. The World Anti-Doping Agency does not name it among the banned substances on its list.