FOXO4-DRI

Retro-inverso design reverses a peptide's sequence and substitutes D-amino acids for L. Because both changes invert the geometry, the side-chain arrangement approximates the original while the backbone is unrecognisable to proteases. It is a way of keeping a binding surface and discarding a molecule's fragility.

FOXO4-DRI applies that method to a fragment of the FOXO4 transcription factor, targeting its interaction with p53.

Senescent cells stop dividing but do not die, and accumulate with age while secreting inflammatory mediators. Their resistance to apoptosis depends in part on FOXO4 binding p53 and holding it in the nucleus, away from the mitochondrial apoptotic pathway. FOXO4-DRI competes for that interaction, freeing p53 — and the published result is that senescent cells undergo apoptosis while normal cells, which are not relying on the interaction, are unaffected.

• Senescent cell clearance in culture and in aged mice

• Senescence-associated secretory phenotype, and its inflammatory output

• Chemotherapy-induced senescence models

• Renal and hepatic function in aged animals, the endpoints of the original mouse work

• Retro-inverso design itself, as a delivery strategy of general interest

Epithalon approaches ageing through replicative capacity rather than senescent cell clearance — the two represent genuinely different hypotheses about what ageing is. SS-31 and MOTS-c take the mitochondrial route.