Biology subjects

Cox, L. S.

Publications and source records attributed to Cox, L. S..

4 recordsLinked to original sources

bioRxiv2025

Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage

mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, i.e. they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability. In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex-vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition. To test this in vivo, we conducted a placebo-controlled experimental medicine trial in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycins exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure, and even the hazards of cosmic radiation in space travel.

immunology↗

bioRxiv2023

Blimp-1 and c-Maf regulate common and unique gene networks to protect against distinct pathways of pathobiont-induced colitis

Intestinal immune responses to commensals and pathogens are controlled by IL-10 to avoid intestinal immune pathology. We show that the transcription factors Blimp-1 (Prdm-1) and c-Maf are co-dominant regulators of Il10 in Foxp3+ regulatory T cells, but also negatively regulate proinflammatory cytokines in effector T cells. Mice with T cell-specific deletion of Prdm-1, Maf or the combination of both transcription factors did not develop inflammatory intestinal pathologies at the steady state. Double deficient Prdm1fl/flMaffl/flCd4Cre mice infected with Helicobacter hepaticus developed severe colitis with a major increase in TH1/NK/ILC1 effector genes in lamina propria leucocytes (LPLs), while Prdm1fl/flCd4Cre and Maffl/flCd4Cre mice showed mild/moderate pathology and a less-marked Type I effector response. LPLs from infected Maffl/flCd4Cre mice showed increased Il17a expression and an accompanying increase in granulocytes and myeloid cells, which was less marked in Prdm1fl/flMaffl/flCd4Cre mice, with increased T cell-myeloid-neutrophil interactions inferred from scRNA-seq analysis and confirmed by immunofluorescent analysis of colon sections. Genes over-expressed in human IBD showed differential expression in the LPL from infected mice in the absence of Prdm1 or Maf, revealing potential pathobiologic mechanisms of human disease.

immunology↗

bioRxiv2020

Intercellular transfer of mitochondria between senescent cells through cytoskeleton-supported intercellular bridges requires mTOR and Cdc42 signalling

Cellular senescence is a state of irreversible cell proliferation arrest induced by various stressors including telomere attrition, DNA damage and oncogene induction. While beneficial as an acute response to stress, accumulation of senescent cells with increasing age is through to contribute adversely to development of cancer and a number of other age-related diseases, including neurodegenerative diseases for which there are currently no effective disease-modifying therapies. Non-cell autonomous effects of senescent cells have been suggested to arise through the SASP, a wide variety of pro-inflammatory cytokines, chemokines and exosomes secreted by senescent cells. Here, we report an additional means of cell communication utilised by senescent cells via large numbers of membrane-bound intercellular bridges - or tunnelling nanotubes (TNTs) - containing the cytoskeletal components actin and tubulin, and which form direct physical connections between cells. We observe the presence of mitochondria in these TNTs, and show organelle transfer through the TNTs to adjacent cells. While transport of individual mitochondria along single TNTs appears unidirectional, we show by differentially labelled co-culture experiments that organelle transfer through TNTs can occur both between different cells within senescent cell populations, and also between senescent and proliferating cells. Using small molecule inhibitors, we demonstrate that senescent cell TNTs are dependent on signalling through the mTOR pathway, which we further show is mediated at least in part through downstream actin-cytoskeleton regulatory factor Cdc42. These findings have significant implications for development of senomodifying therapies, as they highlight the need to account for local direct cell-cell contacts as well as the SASP in order to treat cancer and diseases of ageing in which senescence is a key factor.

cell biology↗

bioRxiv2018

EXD2 and WRN exonucleases are required for interstrand crosslink repair in Drosophila

Interstrand crosslinks (ICLs) present a major threat to genome integrity, preventing both the correct transcription of active chromatin and complete replication of the genome. This is exploited in genotoxic chemotherapy where ICL induction is used to kill highly proliferative cancer cells. Repair of ICLs involves a complex interplay of numerous proteins, including those in the Fanconi anemia (FA) pathway, though alternative and parallel pathways have been postulated. Here, we investigate the role of the 3-5 exonuclease, EXD2, and the highly related WRN exonuclease (implicated in premature ageing human Werner syndrome), in repair of interstrand crosslinks in the fruit fly, Drosophila melanogaster. We find that flies mutant for EXD2 (DmEXD2) have elevated rates of genomic instability resulting from chromosome breakage and loss of the resulting acentric fragments, in contrast to WRN exonuclease (DmWRNexo) mutants where excess homologous recombination is the principal mechanism of genomic instability. Most notably, we demonstrate that proliferating larval neuroblasts mutant for either DmWRNexo or DmEXD2 are deficient in repair of DNA interstrand crosslinks caused by diepoxybutane or mitomycin C, strongly suggesting that each nuclease individually plays a role in repair of ICLs in flies. These findings have significant implications not only for understanding the complex process of ICL repair in humans, but also for enhancing cancer therapies that rely on ICL induction, with caveats for cancer therapy in Werner syndrome and Fanconi anemia patients.

cell biology↗