Chemical enhancement of DNA repair in aging

Logarinho, E., Macedo, J., Silva, M. M., Magalhaes, J. M., Sousa-Soares, C., Ala, M. I., Galhardo, M.

i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Portoi3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto · biorxiv

Paper

Abstract

DNA damage is a central driver of the aging process. We previously found that KIF2C, known to play a role in DNA repair, is repressed in aged cells. Here, we investigated if increased KIF2C activity counteracts DNA damage and its effects on aging phenotypes. We show that a small-molecule agonist of KIF2C enhances DNA repair in two distinct genetic disorders exhibiting DNA damage and accelerated aging, the Hutchinson-Gilford progeria (HGPS) and Down (DS) syndromes. Mechanistically, the KIF2C agonist improves the repair of DNA double-strand breaks by inducing nuclear envelope invaginations poked by cytoplasmic microtubules, which translated into amended epigenetic and transcriptional signatures of HGPS and DS. Moreover, subcutaneous administration of the KIF2C agonist in progeria mice mitigated aging phenotypes, extending their healthspan. Our study discloses a unique geroprotective pharmacological approach targeting DNA damage.

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Research summary

The paper claims that a small-molecule agonist of KIF2C enhances DNA repair and mitigates aging phenotypes in progeria mice. This research addresses the root cause of aging by focusing on DNA damage repair mechanisms, which are central to the aging process.

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