Biology subjects

Logarinho, E.

Publications and source records attributed to Logarinho, E..

7 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

Brain biomechanics governs mitotic fidelity of embryonic neural progenitors

Accurate chromosome segregation is essential to maintain genetic stability and prevent the onset of diseases such as developmental disorders, infertility, and cancer. While many intrinsic factors and processes involved in mitosis have been extensively characterized, less is known about how extrinsic factors and tissue properties contribute to mitotic fidelity. In this study, using both in vivo and ex vivo systems, in combination with pharmacological perturbations and high-resolution microscopy, we investigated mitosis in apical radial glial (aRG) cells--the primary neural progenitors in the developing mammalian brain. We found that the high cell density typical of early neurogenic stages enhances microtubule polymerization rates from the spindle poles, thereby influencing chromosome segregation. Mechanistically, our results indicate that cortical actin and elevated cortical tension function as sensors of biomechanical stress during mitosis. These findings identify biomechanics as a threat to mitotic fidelity in the embryonic brain.

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↗

bioRxiv2025

Feedback regulation between FOXM1 and APC/CCdh1 determines the changes in cell cycle dynamics during aging

Aging is characterised by a loss of regenerative capacity, though it remains elusive how aged proliferating cells slowdown cycling eventually becoming senescent. We previously found that repression of the FOXM1 transcription factor accounts for mitotic decline during aging due to a global transcriptional shutdown of mitotic genes in proliferating cells. Intriguingly, a 1.5-fold increase in both cell cycle and mitosis durations was observed in elderly cells in deviancy to a previous study showing mitosis to be temporally insulated from variability in earlier cell cycle phases due to the robustness of the positive feedback loop controlling CDK1-Cyclin B1 activity. Thus, we asked if molecular thresholds controlling cell cycle phase transitions become unfitted with aging. Here, we used live-cell imaging of primary human dermal fibroblasts of advancing age donors in combination with high-throughput image analysis, to investigate age-related changes in cell cycle dynamics. Interestingly, we found mitosis insularity to be gradually lost along aging due to defective switch-like activation of CDK1 at mitotic entry driven by FOXM1 repression. Moreover, we found the levels of FZR1/Cdh1 co-activator of APC/C, the E3-ubiquitin ligase directing the proteolytic degradation of FOXM1 at mitotic exit, to increase with advancing age. Importantly, FZR1/Cdh1 repression was shown to restore cell cycle fitness and FOXM1 levels in aged proliferating cells, preventing the accumulation of cell cycle inhibitors and senescence markers in their progeny. Thus, changes in FOXM1 and APC/CCdh1 interlinked activities account for the loss of proliferative capacity and senescence accrual during aging, thereby delivering useful markers and/or targets to explore in anti-aging approaches.

cell biology↗

bioRxiv2023

FOXM1 expression reverts aging chromatin profiles through repression of the senescence-associated pioneer factor AP-1

Aging is characterized by changes in gene expression that drive deleterious cellular phenotypes leading to senescence. The transcriptional activation of senescence genes has been mainly attributed to epigenetic shifts, but the changes in chromatin accessibility and its underling mechanisms remain largely elusive in natural aging. Here, we profiled chromatin accessibility in human dermal fibroblasts (HDFs) from neonatal and octogenarian individuals. We found that AP-1 binding motifs are prevalent in elderly specific accessible regions of the chromatin while neonatal-specific regions are highly enriched for TEAD binding motifs. We further show that TEAD4 and FOXM1 share a conserved transcriptional regulatory landscape controlled by an age-dependent enhancer that closes with aging and drives senescence when deleted. Finally, we demonstrate that FOXM1 ectopic expression in elderly cells partially resets chromatin accessibility to a youthful state due to FOXM1 repressive function in the promoters of several members of the AP-1 complex. These results place FOXM1 at a top hierarchical level in chromatin remodeling required to prevent senescence.

genetics↗

bioRxiv2018

Molecular basis of mitotic decline during human aging

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Supported by direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, we found that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome segregation defects in elderly mitotic cells correlated with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives expression of most G2/M genes. By restoring FoxM1 levels in elderly and Hutchison-Gilford Progeria Syndrome fibroblasts we prevented aneuploidy and, importantly, ameliorated cellular phenotypes associated with aging. Moreover, senescent fibroblasts isolated from elderly donors cultures were mostly aneuploid, suggesting that aneuploidy is a key player in the progression into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes.

cell biology↗