Descriptive and predictive analysis identify centenarians' characteristics from the Basque population

BackgroundCentenarians exhibit extreme longevity and have been postulated, by some researchers, as a model for healthy aging. The identification of the characteristics of centenarians might be useful to understand the process of human aging.MethodsIn this retrospective study, we took advantage of demographic, clinical, biological, and functional data of deceased individuals between 2014 and 2020 in Guipúzcoa (Basque Country, Spain) taken from the Basque Health Service electronic health records data lake. Fifty characteristics derived from demographic, clinical, pharmaceutical, biological, and functional data were studied in the descriptive analysis and compared through differences in means tests. Twenty-seven of them were used to build machine learning models in the predictive analysis and their relevance for classifying centenarians was assessed.ResultsMost centenarians were women and lived in nursing homes. Importantly, they developed fewer diseases, took fewer drugs, and required fewer medical attendances. They also showed better biological profiles, exhibiting lower levels of glucose, hemoglobin, glycosylated hemoglobin, and triglycerides in blood analysis compared with non-centenarians. In addition, machine learning analyses revealed the main characteristics of the profiles associated with centenarians' status as being women, having fewer consultations, having fewer diagnoses of neoplasms, and having lower levels of hemoglobin.ConclusionsOur results revealed the main characteristics linked to centenarians in the Basque Country using Computational Biology programs. These results expand the knowledge on the characterization of the centenarian population and hence of human longevity

A strategy to study tyrosinase transgenes in mouse melanocytes

BACKGROUND: A number of transgenic mice carrying different deletions in the Locus Control Region (LCR) of the mouse tyrosinase (Tyr) gene have been developed and analysed in our laboratory. We require melanocytes from these mice, to further study, at the cellular level, the effect of these deletions on the expression of the Tyr transgene, without potential interference with or from the endogenous Tyr alleles. It has been previously reported that it is possible to obtain and immortalise melanocyte cell cultures from postnatal mouse skin. RESULTS: Here, we describe the efforts towards obtaining melanocyte cultures from our Tyr transgenic mice. We have bred our Tyr transgenic mice into Tyr (c-32DSD )mutant background, lacking the endogenous Tyr locus. In these conditions, we failed to obtain immortalised melanocytes. We decided to include the inactivation of the Ink4a-Arf locus to promote melanocyte immortalisation. For this purpose, we report the segregation of the Ink4a-Arf null allele from the brown (Tyrp1(b)) mutation in mice. Finally, we found that Ink4a-Arf (+/- )and Ink4a-Arf (-/- )melanocytes had undistinguishable tyrosine hydroxylase activities, although the latter showed reduced cellular pigmentation content. CONCLUSION: The simultaneous presence of precise genomic deletions that include the tyrosinase locus, such as the Tyr (c-32DSD )allele, the Tyr transgene itself and the inactivated Ink4a-Arf locus in Tyrp1(B )genetic background appear as the crucial combination to perform forthcoming experiments. We cannot exclude that Ink4a-Arf mutations could affect the melanin biosynthetic pathway. Therefore, subsequent experiments with melanocytes will have to be performed in a normalized genetic background regarding the Ink4a-Arf locus

Targeting Myotonic Dystrophy Type 1 with Metformin

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 patients. Metformin is a biguanide antidiabetic drug, with potential to delay aging at cellular and organismal levels. In DM1, different studies revealed that metformin rescues multiple phenotypes of the disease. This review provides an overview of recent findings describing metformin as a novel therapy to combat DM1 and their link with aging.M.G.-P. and A.S.-A. are recipient of predoctoral fellowships from the University of the Basque Country (PIF 15/245) and Carlos III Institute (FI17/00250), respectively. This work is supported by grants from the Carlos III Institute and FEDER funds (PI17/01841, DTS18/00181, PI19/01355, PI21/00557), Health Department from Basque Country (2017222021, 2018222021, 2020333008) and CIBERNED funds

Targeting mTOR as a Therapeutic Approach in Medulloblastoma

Mechanistic target of rapamycin (mTOR) is a master signaling pathway that regulates organismal growth and homeostasis, because of its implication in protein and lipid synthesis, and in the control of the cell cycle and the cellular metabolism. Moreover, it is necessary in cerebellar development and stem cell pluripotency maintenance. Its deregulation has been implicated in the medulloblastoma and in medulloblastoma stem cells (MBSCs). Medulloblastoma is the most common malignant solid tumor in childhood. The current therapies have improved the overall survival but they carry serious side effects, such as permanent neurological sequelae and disability. Recent studies have given rise to a new molecular classification of the subgroups of medulloblastoma, specifying 12 different subtypes containing novel potential therapeutic targets. In this review we propose the targeting of mTOR, in combination with current therapies, as a promising novel therapeutic approach.J.A. is recipient of a predoctoral fellowship from the Department of Education of the Basque Government. This work was supported by grants from the Department of Industry of the Basque Government (SAIO13-PC13BN011), and the European Regional Developmental Fund, Institute of Health Carlos III (ISCIII) (PI16/01730) to I.G

Myotonic Dystrophy type 1 cells display impaired metabolism and mitochondrial dysfunction that are reversed by metformin

Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of a multisystem accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. In this study, we characterized the impact of metabolism and mitochondria on fibroblasts and peripheral blood mononuclear cells (PBMCs) derived from patients with DM1 and healthy individuals. Our results revealed a decrease in oxidative phosphorylation system (OXPHOS) activity, oxygen consumption rate (OCR), ATP production, energy metabolism, and mitochondria! dynamics in DM1 fibroblasts, as well as increased accumulation of reactive oxygen species (ROS). PBMCs of DM1 patients also displayed reduced mitochondria! dynamics and energy metabolism. Moreover, treatment with metformin reversed the metabolic and mitochondria! defects as well as additional accelerated aging phenotypes, such as impaired proliferation, in DM1-derived fibroblasts. Our results identify impaired cell metabolism and mitochondria! dysfunction as important drivers of DM1 pathophysiology and, therefore, reveal the efficacy of metformin treatment in a pre-clinical setting.This work was supported by grants from the Instituto Salud Carlos III and FEDER funds (CP16/00039, PI16/01580, PI17/01841) and Health department from Basque Country (2017 and 2018-2017222021)

Zer dela-eta zahartzen gara?

Aging is a natural human process that produces functional impairment. Numerous hypotheses try to explain human aging, such as seeing aging as an effect of the exhaustion of stem cells. Stem cells have renewal and differentiation capacity and the number of these cells decreases with aging. Brain is one of the most affected organs during aging. The decrease of Neural Stem Cells (NSC) reduces neuronal regeneration, provoking cognitive decline. Neurogenesis occurs in specific niches of the brain: the subventricular zone and the dentate gyrus of the hippocampus. Recent studies have demonstrated that this neurogenesis occurs not only in the childhood but also as the individual ages. It is therefore extremely important to investigate how to maintain neural stem cell function during aging in order to reduce cognitive decline.; Zahartzea bizidun guztietan gertatzen den prozesu natural bat da, denbora igarotzea-ren ondoriozko gainbehera funtzional gisa defini daitekeena. Gaur egun, hainbat hipotesi proposatu dira zahartzearen zergatia azaltzeko, eta horien artean aurkitzen da zelula amak agortzearen ikerketa-lerroa. Zelula amak, berritze-gaitasuna izateaz gain, ondoren zelula diferentziatuak sortzeko gai dira, baina kopuru aldetik murriztuz doaz zahartzaroarekin. Zehazki, garuna da zahartzaroak fisiologikoki gehien kaltetzen duen organoa. Adinak eragindako garuneko zelula amen agortze honek neuronen berritzea zailtzen du eta, ondorioz, indibiduo helduetan ikus dezakegun gainbehera kognitiboa eragiten du. Neurogenesia garuneko eremu espezifikoetan gertatzen da, bentrikulu azpiko eremuan eta hipokanpoko granulu azpiko eremuan, eta azken ikerketen arabera, haurtzaroan zein zahartzaroan gertatzen den prozesu bat da. Beraz, oso garrantzitsua da zahartzaroan zehar zelula ama hauen funtzioa nola mantendu daitekeen ikertzea, alderdi kognitiboan gertatzen diren galerak ekiditeko

Impact of Stem Cell Genes in Gastric Cancer

Gastric cancer remains one of the leading causes of global cancer mortality. It has been shown that gastric cancer may originate from adult gastric stem cells and that it contains a subpopulation of cancer cells with stem cell characteristics, which are linked to Helicobacter pylori infection, therapy resistance and metastasis. Thus, the identification of transcription factors and related signal transduction pathways that regulate stem cell maintenance and lineage allocation is attractive from a clinical standpoint in that it may provide targets for novel cell- or drug-based therapies. This chapter summarizes the role of several important stem cell factors in gastric cancer biology

Role of SOX family of transcription factors in central nervous system tumors

SOX genes are developmental regulators with functions in the instruction of cell fate and maintenance of progenitor’s identity during embryogenesis. They play additional roles during tissue homeostasis and regeneration in adults particularly in the Central Nervous System (CNS). In the last years a growing number of evidences has shown that mutations and dysfunction of SOX factors are implicated in several human diseases, including a variety of cancers. In this review, we will summarize the current knowledge about SOX family in CNS tumors and their role in the origin and maintenance of the subpopulation of cancer stem cells in these tumors

In Vitro P38MAPK Inhibition in Aged Astrocytes Decreases Reactive Astrocytes, Inflammation and Increases Nutritive Capacity After Oxygen-Glucose Deprivation

Proper astroglial functioning is essential for the development and survival of neurons and oligodendroglia under physiologic and pathological circumstances. Indeed, malfunctioning of astrocytes represents an important factor contributing to brain injury. However, the molecular pathways of this astroglial dysfunction are poorly defined. In this work we show that aging itself can drastically perturb astrocyte viability with an increase of inflammation, cell death and astrogliosis. Moreover, we demonstrate that oxygen glucose deprivation (OGD) has a higher impact on nutritive loss in aged astrocytes compared to young ones, whereas aged astrocytes have a higher activity of the anti-oxidant systems. P38MAPK signaling has been identified to be upregulated in neurons, astrocytes and microglia after ischemic stroke. By using a pharmacological p38 alpha specific inhibitor (PH-797804), we show that p38MAPK pathway has an important role in aged astrocytes for inflammatory and oxidative stress responses with the subsequent cell death that occurs after OGD.Deutsche Forschungsgemeinschaft (SCHE 2078/2-1). Forderverein fur fruhgeborene Kinder an der Charite e.V. Basque Government Postdoc (2017_1_0095

Therapeutic Targeting of Replicative Immortality

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed “senescence,” can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells’ heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy