Biology subjects

Sousa-Soares, C.

Publications and source records attributed to Sousa-Soares, C..

3 recordsLinked to original sources

bioRxiv2025

FOXM1 enhances DNA repair in aged cells to maintain the peripheral heterochromatin barrier to senescence enhancers

DNA damage is a key driver of aging, contributing to epigenetic erosion, senescence, and chronic inflammation. However, genoprotective strategies to counteract aging remain intangible. Here we show that FOXM1 repression during aging accounts for a global transcriptional shutdown of DNA repair genes and the accrual of DNA damage. Restored FOXM1 activity in aged cells reduces DNA damage and epigenetic alterations driving senescence. Mechanistically, FOXM1 drives the transcription of DNA repair genes, which prevents the DNA damage-driven degradation of the G9a methyltransferase and subsequent loss of H3K9me2 at the nuclear periphery. Remarkably, we show that amendment of the H3K9me2 guidepost for peripheral heterochromatin by FOXM1 induction in aged cells inactivates enhancers of the AP-1-driven senescence and inflammation program. These findings establish FOXM1 as an age-reversal factor capable of restoring (epi)genetic integrity to inhibit the senescence enhancer landscape, offering a promising therapeutic avenue to address the fundamental causes of aging.

cell biology↗

bioRxiv2025

Lonafarnib Partially Reverses Cardiac Senescence in Human and Mouse Progeria Models via Autophagy Activation

Hutchinson-Gilford Progeria Syndrome (HGPS), characterised by accelerated ageing, causes cardiovascular defects resembling aspects of cardiovascular ageing. We used human left ventricle cardiomyocytes (CMs) derived from HGPS-induced pluripotent stem cells (iPSCs), and their isogenic-corrected controls, to investigate HGPS-CM dysfunction and identify potential therapies. Our results revealed that HGPS-iPSC-CMs exhibit greater maturity and associated elevated oxidative stress compared to controls, which they could not contend with, leading to cellular senescence. Increased senescence was also observed in cardiac tissue from mouse and human physiologically-aged and HGPS individuals. Functionally, HGPS-iPSC-CMs showed dysregulated mitochondrial respiration and calcium handling. Amongst the six drugs tested, rapamycin and lonafarnib were the most effective against HGPS-cardiac phenotypes. Although lonafarnib raised safety concerns, it partially reverted the cardiac senescent phenotype by inducing cellular autophagy and decreasing progerin expression in progeroid mice. Our study supports the use of HGPS-iPSC-CMs to identify novel biomarkers and therapies for HGPS, and potentially cardiac physiological-ageing.

cell biology↗

bioRxiv2025

Chemical enhancement of DNA repair in aging

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.

pathology↗