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Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.
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Anorexia , Inhibidor de la Unión a Diazepam , Animales , Inhibidor de la Unión a Diazepam/metabolismo , Anorexia/tratamiento farmacológico , Anorexia/metabolismo , Humanos , Ratones Transgénicos , Ratones , Anorexia Nerviosa/metabolismo , Anorexia Nerviosa/tratamiento farmacológico , Lipocalina 2/metabolismo , Lipocalina 2/sangre , Hipotálamo/metabolismo , Masculino , Femenino , Ratones Endogámicos C57BL , Restricción Física , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacosRESUMEN
ADAM29 (a disintegrin and metalloprotease domain 29) is a member of the membrane-anchored ADAM family of proteins, which is highly expressed in testis and may mediate different physiological and pathological processes. Although the functions of many ADAM family members have been well characterized, the biological relevance of ADAM29 has remained largely unknown. Here, we report the generation of an Adam29-deficient mouse model to delve deeper into the in vivo functions of this ADAM family member. We show that ADAM29 depletion does not affect mice viability, development, or fertility, but somehow impinges on metabolism and energy expenditure. We also report herein that ADAM29 deficiency leads to an accelerated wound healing process, without affecting cell reprogramming in mouse-derived fibroblasts. Collectively, our findings provide new insights into ADAM29 biological functions, highlighting the importance of non-catalytic ADAM proteases.
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Cellular senescence is a hallmark of advanced age and a major instigator of numerous inflammatory pathologies. While endothelial cell (EC) senescence is aligned with defective vascular functionality, its impact on fundamental inflammatory responses in vivo at single-cell level remain unclear. To directly investigate the role of EC senescence on dynamics of neutrophil-venular wall interactions, we applied high resolution confocal intravital microscopy to inflamed tissues of an EC-specific progeroid mouse model, characterized by profound indicators of EC senescence. Progerin-expressing ECs supported prolonged neutrophil adhesion and crawling in a cell autonomous manner that additionally mediated neutrophil-dependent microvascular leakage. Transcriptomic and immunofluorescence analysis of inflamed tissues identified elevated levels of EC CXCL1 on progerin-expressing ECs and functional blockade of CXCL1 suppressed the dysregulated neutrophil responses elicited by senescent ECs. Similarly, cultured progerin-expressing human ECs exhibited a senescent phenotype, were pro-inflammatory and prompted increased neutrophil attachment and activation. Collectively, our findings support the concept that senescent ECs drive excessive inflammation and provide new insights into the mode, dynamics, and mechanisms of this response at single-cell level.
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Aging and cancer exhibit apparent links that we will examine in this review. The null hypothesis that aging and cancer coincide because both are driven by time, irrespective of the precise causes, can be confronted with the idea that aging and cancer share common mechanistic grounds that are referred to as 'hallmarks'. Indeed, several hallmarks of aging also contribute to carcinogenesis and tumor progression, but some of the molecular and cellular characteristics of aging may also reduce the probability of developing lethal cancer, perhaps explaining why very old age (> 90 years) is accompanied by a reduced incidence of neoplastic diseases. We will also discuss the possibility that the aging process itself causes cancer, meaning that the time-dependent degradation of cellular and supracellular functions that accompanies aging produces cancer as a byproduct or 'age-associated disease'. Conversely, cancer and its treatment may erode health and drive the aging process, as this has dramatically been documented for cancer survivors diagnosed during childhood, adolescence, and young adulthood. We conclude that aging and cancer are connected by common superior causes including endogenous and lifestyle factors, as well as by a bidirectional crosstalk, that together render old age not only a risk factor of cancer but also an important parameter that must be considered for therapeutic decisions.
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Envejecimiento , Neoplasias , Humanos , Neoplasias/patología , Neoplasias/metabolismo , Neoplasias/etiología , Animales , Susceptibilidad a Enfermedades , Factores de RiesgoRESUMEN
Acyl-CoA binding protein (ACBP) encoded by diazepam binding inhibitor (DBI) is an extracellular inhibitor of autophagy acting on the gamma-aminobutyric acid A receptor (GABAAR) γ2 subunit (GABAARγ2). Here, we show that lipoanabolic diets cause an upregulation of GABAARγ2 protein in liver hepatocytes but not in other major organs. ACBP/DBI inhibition by systemically injected antibodies has been demonstrated to mediate anorexigenic and organ-protective, autophagy-dependent effects. Here, we set out to develop a new strategy for developing ACBP/DBI antagonists. For this, we built a molecular model of the interaction of ACBP/DBI with peptides derived from GABAARγ2. We then validated the interaction between recombinant and native ACBP/DBI protein and a GABAARγ2-derived eicosapeptide (but not its F77I mutant) by pull down experiments or surface plasmon resonance. The GABAARγ2-derived eicosapeptide inhibited the metabolic activation of hepatocytes by recombinant ACBP/DBI protein in vitro. Moreover, the GABAARγ2-derived eicosapeptide (but not its F77I-mutated control) blocked appetite stimulation by recombinant ACBP/DBI in vivo, induced autophagy in the liver, and protected mice against the hepatotoxin concanavalin A. We conclude that peptidomimetics disrupting the interaction between ACBP/DBI and GABAARγ2 might be used as ACBP/DBI antagonists. This strategy might lead to the future development of clinically relevant small molecules of the ACBP/DBI system.
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Inhibidor de la Unión a Diazepam , Ácido gamma-Aminobutírico , Animales , Ratones , Inhibidor de la Unión a Diazepam/farmacologíaRESUMEN
The eight biological hallmarks of health that we initially postulated (Cell. 2021 Jan 7;184(1):33-63) include features of spatial compartmentalization (integrity of barriers, containment of local perturbations), maintenance of homeostasis over time (recycling & turnover, integration of circuitries, rhythmic oscillations) and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, repair & regeneration). These hallmarks affect all eight somatic strata of the human body (molecules, organelles, cells, supracellular units, organs, organ systems, systemic circuitries and meta-organism). Here we postulate that mental and socioeconomic factors must be added to this 8×8 matrix as an additional hallmark of health ("psychosocial adaptation") and as an additional stratum ("psychosocial interactions"), hence building a 9×9 matrix. Potentially, perturbation of each of the somatic hallmarks and strata affects psychosocial factors and vice versa. Finally, we discuss the (patho)physiological bases of these interactions and their implications for mental health improvement.
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The gut microbiota is a complex community of different microbial species that influence many aspects of health. Consequently, shifts in the composition of gut microbiome have been proposed to exert negative effects on the host physiology, leading to the pathogenesis of various age-related disorders, including cardiovascular and neurological diseases, type 2 diabetes, obesity, non-alcoholic liver disease, and other pathological conditions. Thus, understanding how the gut microbiota influences the aging-related decline is particularly topical. Advances in next-generation sequencing techniques, together with mechanistic experiments in animal models, have provided substantial improvements in microbiome analysis. However, standardization and best practices are needed to limit experimental variation between different studies. Here, we detail a simple method for microbiota composition analysis in mouse fecal samples using 16S rRNA next-generation sequencing.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Microbiota , Ratones , Animales , ARN Ribosómico 16S/genética , Microbiota/genética , Heces , Microbioma Gastrointestinal/genéticaRESUMEN
Aging is a multifactorial process characterized by an age-related decline in organismal fitness. This deterioration is the major risk factor for chronic diseases such as cardiovascular pathologies, neurodegeneration, or cancer, and it represents one of the main challenges of modern society. Therefore, understanding why and how we age would be a fundamental pillar to design strategies to promote a healthy aging. In the last decades, the study of the molecular bases of disease has been revolutionized by the discovery of different types of noncoding RNAs (ncRNAs) with regulatory potential. In this work, we will review the implication of ncRNAs in aging, with the aim to provide a first approach to the different aging-associated ncRNAs, their mechanism of action, and their potential relevance as therapeutic targets and disease biomarkers.
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Longevidad , MicroARNs , Longevidad/genética , ARN no Traducido/genética , MicroARNs/genéticaRESUMEN
The inexorability of the aging process has sparked the curiosity of human beings since ancient times. However, despite this interest and the extraordinary scientific advances in the field, the complexity of the process has hampered its comprehension. In this context, The Hallmarks of Aging were defined in 2013 with the aim of establishing an organized, systematic and integrative view of this topic, which would serve as a conceptual framework for aging research. Ten years later and promoted by the progress in the area, an updated version included three new hallmarks while maintaining the original scope. The aim of this review is to determine to what extent The Hallmarks of Aging achieved the purpose that gave rise to them. For this aim, we have reviewed the literature citing any of the two versions of The Hallmarks of Aging and conclude that they have served as a conceptual framework not only for aging research but also for related areas of knowledge. Finally, this review discusses the new candidates to become part of the Hallmarks list, analyzing the evidence that supports whether they should or should not be incorporated.
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Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition that arises from a single nucleotide alteration in the LMNA gene, leading to the production of a defective lamin A protein known as progerin. The accumulation of progerin accelerates the onset of a dramatic premature aging phenotype in children with HGPS, characterized by low body weight, lipodystrophy, metabolic dysfunction, skin, and musculoskeletal age-related dysfunctions. In most cases, these children die of age-related cardiovascular dysfunction by their early teenage years. The absence of effective treatments for HGPS underscores the critical need to explore novel safe therapeutic strategies. In this study, we show that treatment with the hormone ghrelin increases autophagy, decreases progerin levels, and alleviates other cellular hallmarks of premature aging in human HGPS fibroblasts. Additionally, using a HGPS mouse model (LmnaG609G/G609G mice), we demonstrate that ghrelin administration effectively rescues molecular and histopathological progeroid features, prevents progressive weight loss in later stages, reverses the lipodystrophic phenotype, and extends lifespan of these short-lived mice. Therefore, our findings uncover the potential of modulating ghrelin signaling offers new treatment targets and translational approaches that may improve outcomes and enhance the quality of life for patients with HGPS and other age-related pathologies.
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Envejecimiento Prematuro , Progeria , Adolescente , Niño , Humanos , Ratones , Animales , Progeria/tratamiento farmacológico , Progeria/genética , Progeria/metabolismo , Envejecimiento Prematuro/tratamiento farmacológico , Envejecimiento Prematuro/genética , Ghrelina/farmacología , Calidad de Vida , Piel/metabolismo , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , EnvejecimientoRESUMEN
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (LmnaG609G/G609G and Zmpste24-/- mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging.
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Envejecimiento Prematuro , Progeria , Humanos , Ratones , Animales , Progeria/metabolismo , Envejecimiento Prematuro/genética , Proteómica , Proteoma/metabolismo , Secretoma , Lamina Tipo A/genética , Lamina Tipo A/metabolismoRESUMEN
As long as breast cancer (BC) stays under immunosurveillance, it can be controlled by treatments eliciting anticancer immune responses. However, once BC escapes immunosurveillance, it becomes therapeutically uncontrollable. A paper in the Journal for ImmunoTherapy of Cancer describes a new hormone receptor-positive BC cell line generating incurable tumors in C57BL/6 mice.
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Carcinoma , Inmunoterapia , Ratones , Animales , Ratones Endogámicos C57BLRESUMEN
ABBREVIATIONS: ATG4 (autophagy related 4 cysteine peptidase); ATG4A (autophagy related 4A cysteine peptidase); ATG4B (autophagy related 4B cysteine peptidase); ATG4C (autophagy related 4C cysteine peptidase); ATG4D (autophagy related 4D cysteine peptidase); Atg8 (autophagy related 8); GABARAP (GABA type A receptor-associated protein); GABARAPL1(GABA type A receptor-associated protein like 1); GABARAPL2 (GABA type A receptor-associated protein like 2); MAP1LC3A/LC3A (microtubule associated protein 1 light chain 3 alpha); MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta); mATG8 (mammalian Atg8); PE (phosphatidylethanolamine); PS (phosphatydylserine); SQSTM1/p62 (sequestosome 1).
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Proteínas Relacionadas con la Autofagia , Autofagia , Animales , Proteínas Relacionadas con la Autofagia/metabolismo , Cisteína , Ácido gamma-Aminobutírico , Mamíferos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , RatonesRESUMEN
Acyl coenzyme A binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is a phylogenetically ancient protein present in some eubacteria and the entire eukaryotic radiation. In several eukaryotic phyla, ACBP/DBI transcends its intracellular function in fatty acid metabolism because it can be released into the extracellular space. This ACBP/DBI secretion usually occurs in response to nutrient scarcity through an autophagy-dependent pathway. ACBP/DBI and its peptide fragments then act on a range of distinct receptors that diverge among phyla, namely metabotropic G protein-coupled receptor in yeast (and likely in the mammalian central nervous system), a histidine receptor kinase in slime molds, and ionotropic gamma-aminobutyric acid (GABA)A receptors in mammals. Genetic or antibody-mediated inhibition of ACBP/DBI orthologs interferes with nutrient stress-induced adaptations such as sporulation or increased food intake in multiple species, as it enhances lifespan or healthspan in yeast, plant leaves, nematodes, and multiple mouse models. These lifespan and healthspan-extending effects of ACBP/DBI suppression are coupled to the induction of autophagy. Altogether, it appears that neutralization of extracellular ACBP/DBI results in "autophagy checkpoint inhibition" to unleash the anti-aging potential of autophagy. Of note, in humans, ACBP/DBI levels increase in various tissues, as well as in the plasma, in the context of aging, obesity, uncontrolled infection or cardiovascular, inflammatory, neurodegenerative, and malignant diseases.
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Proteínas Portadoras , Inhibidor de la Unión a Diazepam , Animales , Humanos , Ratones , Acilcoenzima A/metabolismo , Envejecimiento , Autofagia , Inhibidor de la Unión a Diazepam/metabolismo , Mamíferos/metabolismo , Saccharomyces cerevisiae/metabolismoRESUMEN
BACKGROUND: Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR+) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. METHODS: BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females. RESULTS: One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER+) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER+ TS/A cell-derived tumors in BALB/C mice, and of ER- E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice. CONCLUSIONS: B6BC is the first transplantable HR+ BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR+ BC naturally resistant to PD-1 immunotherapy.
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Carcinoma , Progesterona , Ratones , Femenino , Animales , Transición Epitelial-Mesenquimal , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Línea Celular Tumoral , Microambiente TumoralRESUMEN
In the past years, microRNAs (miRNAs) have emerged as important biomarkers and essential regulators of many pathophysiological processes. Several studies have focused on the importance of these noncoding RNAs (ncRNAs) in maintaining mitochondrial function, introducing the term mitochondrial microRNAs (mitomiRs) to refer to those miRNAs controlling mitochondrial activity, either by targeting cytoplasmatic messenger RNAs (mRNAs) or by acting inside the mitochondria. Mitochondrial homeostasis is paramount in the cardiovascular system, where an important energy supply is needed to maintain the homeostasis of tissues, such as the myocardium. In this review, we will address the relevance of mitomiRs in cardiovascular pathologies by dissecting and categorizing their effect in mitochondrial function in order to provide a robust framework for new mitomiR-based therapeutical approaches to this group of diseases.
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Enfermedades Cardiovasculares , MicroARNs , Humanos , MicroARNs/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/terapia , Mitocondrias/genética , ARN no Traducido , ARN MensajeroRESUMEN
BACKGROUND: Personalized precision medicine represents a paradigm shift and a new reality for the health care system in Spain, with training being fundamental for its full implementation and application in clinical practice. In this sense, health care professionals face educational challenges related to the acquisition of competencies to perform their professional practice optimally and efficiently in this new environment. The definition of competencies for health care professionals provides a clear guide on the level of knowledge, skills, and attitudes required to adequately carry out their professional practice. In this context, this acquisition of competencies by health care professionals can be defined as a dynamic and longitudinal process by which they use knowledge, skills, attitudes, and good judgment associated with their profession to develop it effectively in all situations corresponding to their field of practice. OBJECTIVE: This report aims to define a proposal of essential knowledge domains and common competencies for all health care professionals, which are necessary to optimally develop their professional practice within the field of personalized precision medicine as a fundamental part of the medicine of the future. METHODS: Based on a benchmark analysis and the input and expertise provided by a multidisciplinary group of experts through interviews and workshops, a new competency framework that would guarantee the optimal performance of health care professionals was defined. As a basis for the development of this report, the most relevant national and international competency frameworks and training programs were analyzed to identify aspects that are having an impact on the application of personalized precision medicine and will be considered when developing professional competencies in the future. RESULTS: This report defines a framework made up of 58 competencies structured into 5 essential domains: determinants of health, biomedical informatics, practical applications, participatory health, and bioethics, along with a cross-cutting domain that impacts the overall performance of the competencies linked to each of the above domains. Likewise, 6 professional profiles to which this proposal of a competency framework is addressed were identified according to the area where they carry out their professional activity: health care, laboratory, digital health, community health, research, and management and planning. In addition, a classification is proposed by progressive levels of training that would be advisable to acquire for each competency according to the professional profile. CONCLUSIONS: This competency framework characterizes the knowledge, skills, and attitudes required by health care professionals for the practice of personalized precision medicine. Additionally, a classification by progressive levels of training is proposed for the 6 professional profiles identified according to their professional roles.