Biology subjects

de la Torre, C.

Publications and source records attributed to de la Torre, C..

5 recordsLinked to original sources

bioRxiv2025

The Multiomics Blueprint of Extreme Human Lifespan

The indexed individual, from now on termed M116, was the worlds oldest verified living person from January 17th 2023 until her passing on August 19th 2024, reaching the age of 117 years and 168 days (https://www.supercentenarian.com/records.html). She was a Caucasian woman born on March 4th 1907 in San Francisco, USA, from Spanish parents and settled in Spain since she was 8. A timeline of her life events and her genealogical tree are shown in Supplementary Fig. 1a-b. Although centenarians are becoming more common in the demographics of human populations, the so-called supercentenarians (over 110 years old) are still a rarity. In Catalonia, the historic nation where M116 lived, the life-expectancy for women is 86 years, so she exceeded the average by more than 30 years (https://www.idescat.cat). In a similar manner to premature aging syndromes, such as Hutchinson-Gilford Progeria and Werner syndrome, which can provide relevant clues about the mechanisms of aging, the study of supercentenarians might also shed light on the pathways involved in lifespan. To unfold the biological properties exhibited by such a remarkable human being, we developed a comprehensive multiomics analysis of her genomic, transcriptomic, metabolomic, proteomic, microbiomic and epigenomic landscapes in different tissues, as depicted in Fig. 1a, comparing the results with those observed in non-supercentenarian populations. The picture that emerges from our study shows that extremely advanced age and poor health are not intrinsically linked and that both processes can be distinguished and dissected at the molecular level. O_FIG O_LINKSMALLFIG WIDTH=156 HEIGHT=200 SRC="FIGDIR/small/639740v1_fig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1705be6org.highwire.dtl.DTLVardef@1a16e4borg.highwire.dtl.DTLVardef@15005f1org.highwire.dtl.DTLVardef@b6297b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1C_FLOATNO Chromosomes and genes.a, Schematic representation of all -omics studied in the supercentenarian. b, Telomeres marked with Cy3 (yellow) in nuclei stained with DAPI (blue) observed in HT-qFISH from M116 and younger womens PBMCs. Scale bars: 20 {micro}m. c, Telomere length (Kb) calculation (left) and percentage of extremely short telomeres (below the 20th percentile) (right) in M116 (orange) using standard curve from samples previously analyzed (black) and control women (blue) (Online Methods). d, Circos plot with chromosomal alterations detected through optical genome mapping in supercentenarian. e, Variants of interest (VOI)-harboring genes found in supercentenarians genomic DNA contributing to immune function, cardiovascular health, neuroprotection, metabolism, and DNA dynamics. f, Significantly enriched functions of VOI-harboring genes in the supercentenarian. g, VOI-harbouring genes significantly contributing to enriched functions. h, VOI-harboring genes found in supercentenarians genomic and mitochondrial DNA contributing to mitochondrial function. i, Mean fluorescence intensity of TMRE (a marker of mitochondrial membrane potential) and SOX (a marker of mitochondrial superoxide ion) in PBMCs from the supercentenarian (orange) and healthy controls across various ages (gray). Unpaired t-test was used to statistically compare M116 to the mean of all control women. *p < 0.05. C_FIG

genomics↗

bioRxiv2022

SIRT1 regulates DNA damage signaling through the PP4phosphatase complex

The Sirtuin family of NAD+-dependent enzymes plays an important role in maintaining genome stability upon stress. Several mammalian Sirtuins have been linked directly or indirectly to the regulation of DNA damage during replication through Homologous recombination (HR). The role of one of them, SIRT1, is intriguing as it seems to have a general regulatory role in the DNA damage response (DDR) that has not yet been addressed. SIRT1-deficient cells show impaired DDR reflected in a decrease in repair capacity, increased genome instability and decreased levels of {gamma}H2AX. Here we unveil a close functional antagonism between SIRT1 and the PP4 phosphatase multiprotein complex in the regulation of the DDR. Upon DNA damage, SIRT1 interacts specifically with the catalytical subunit PP4c and promotes its inhibition by deacetylating the WH1 domain of the regulatory subunits PP4R3/{beta}. This in turn regulates {gamma}H2AX and RPA2 phosphorylation, two key events in the signaling of DNA damage and repair by HR. We propose a mechanism whereby during stress, SIRT1 signaling ensures a global control of DNA damage signaling through PP4.

molecular biology↗

bioRxiv2021

RhoA/ROCK2 signalling is enhanced by PDGF-AA in fibro-adipogenic progenitor cells in DMD

The lack of dystrophin expression in Duchenne muscular dystrophy (DMD) leads to muscle necrosis and replacement of muscle tissue by fibro-adipose tissue. Although the role of some growth factors in the process of fibrogenesis has been previously studied, the pathways that are activated by PDGF-AA in muscular dystrophies have not been described so far. Herein we report the effects of PDGF-AA on the fibrotic process in muscular dystrophies by performing a quantitative proteomic study in DMD isolated fibro-adipogenic precursor cells (FAPs) treated with PDGF-AA. In vitro studies showed that RhoA/ROCK2 pathway is activated by PDGF-AA and induces the activation of FAPs. The inhibition of RhoA/ROCK signalling pathway by C3-exoenzyme or fasudil attenuated the effects of PDGF-AA. The blocking effects of RhoA/ROCK pathway were analysed in the dba/2J-mdx murine model with fasudil. Grip strength test showed an improvement in the muscle function and histological studies demonstrated reduction of the fibrotic area. Our results suggest that blockade of RhoA/ROCK could attenuate the activation of FAPs and could be considered a potential therapeutic approach for muscular dystrophies.

molecular biology↗

bioRxiv2020

YAP orchestrates heterotypic endothelial cell communication via HGF/c-MET signaling in liver tumorigenesis

Next to cell autonomous mechanisms, the oncogene yes-associated protein (YAP) controls liver tumor initiation and progression via cell extrinsic functions creating a tumor-supporting environment. However, how YAP affects the microenvironment and in particular the vascular niche, which contributes to liver disease and hepatocarcinogenesis, is poorly understood. In this study, histo-morphological and molecular characterization of murine liver endothelial cells (ECs) populations and human single cell data revealed the presence of liver sinusoidal endothelial cells (LSECs) and capillary endothelial cells (CECs) in healthy liver tissue. In YAPS127A-induced tumorigenesis, a gradual replacement of LSECs by CECs was associated with dynamic changes in the expression of genes involved in EC subtype-specific paracrine communication. The formation of new potential communication hubs connecting CECs and LSECs included the hepatocyte growth factor (Hgf)/c-Met signaling pathway. In hepatocytes and tumor cells, YAP/TEA domain transcription factor 4 (TEAD4)-dependent transcriptional induction of osteopontin (Opn) stimulated c-Met expression in ECs with CEC phenotype, which sensitized these cells to the pro-migratory effects of LSEC-derived Hgf. In human HCCs, the presence of a migration-associated tip-cell signature correlated with poor clinical outcome and the loss of LSEC marker gene expression. In addition, the replacement of LSECs by CECs with exclusive c-MET expression in a CEC subpopulation was confirmed at the single cell level. In summary, YAP-dependent changes of the liver vascular niche comprise the formation of heterologous communication hubs (e.g. the HGF/c-Met axis), in which tumor cell-derived factors modify the crosstalk between LSECs and CECs.

cancer biology↗

bioRxiv2019

SirT7 auto-ADP-ribosylation regulates glucose starvation response through macroH2A1.1

Sirtuins are key players in the response to oxidative, metabolic and genotoxic stress, and are involved in genome stability, metabolic homeostasis and aging. Originally described as NAD+-dependent deacetylases, some sirtuins are also characterized by a poorly understood mono-ADP-ribosyltransferase (mADPRT) activity. Here we report that the deacetylase SirT7 is a dual sirtuin as it also features auto-mADPRT activity. Molecular and structural evidence suggests that this novel activity occurs at a second previously undefined active site that is physically separated in another domain. Specific abrogation of this activity alters SirT7 chromatin distribution, suggesting a role for this modification in SirT7 chromatin binding specificity. We uncover an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader macroH2A1.1, a histone variant involved in chromatin organization, metabolism and differentiation. Glucose starvation (GS) boosts this interaction and promotes SirT7 relocalization to intergenic regions in a macroH2A1-dependent manner. Both SirT7 activities are in turn required to promote GS-dependent enrichment of macroH2A1 in a subset of nearby genes, which results in their specific up- or downregulation. Consistently, the expression changes of these genes associated to calorie restriction (CR) or aging are abrogated in SirT7-/- mice, reinforcing the link between Sirtuins, CR and aging. Our work provides a novel perspective about sirtuin duality and suggests a key role for SirT7/macroH2A1.1 axis in mammalian glucose homeostasis, calorie restriction signaling and aging.

molecular biology↗