Exploring the fuzzy border between senolytics and senomorphics with chemoinformatics and systems pharmacology.

Senescent cells accumulate within tissues during aging and secrete an array of pro-inflammatory molecules known as senescent-associated secretory phenotype (SASP), which contribute to the appearance and progression of various chronic degenerative diseases. Novel pharmacological approaches aimed at modulating or eliminating senescent cells´ harmful effects have recently emerged: Senolytics are molecules that selectively eliminate senescent cells, while senomorphics modulate or decrease the inflammatory response to specific SASP. So far, the physicochemical, structural, and pharmacological properties that define these two kinds of pharmacological approaches remain unclear. Therefore, the identification and correct choice of molecules, based on their physicochemical, structural, and pharmacological properties, likely to exhibit the desired senotherapeutic activity is crucial for developing effective, selective, and safe senotherapies. Here we compared the physicochemical, structural, and pharmacological properties of 84 senolytics and 79 senomorphics using a chemoinformatic and systems pharmacology approach. We found great physicochemical, structural, and pharmacological similarities between them, also reflected in their cellular responses measured through transcriptome perturbations. The identified similarities between senolytics and senomorphics might explain the dual activity of some of those molecules. These findings will help design and discover new, more effective, and highly selective senotherapeutic agents.

Contribution of senescent and reactive astrocytes on central nervous system inflammaging.

Astrocytes, the most predominant cells in the central nervous system (CNS), have well-recognized neuroprotective functions. However, during the CNS aging, astrocytes can become neurotoxic and contribute to chronic inflammation in age-associated brain deterioration and disease. Astrocytes are known to become senescent or reactive due to the exposure to stressful stimuli, in both cases they contribute to an impaired cognitive function through the production of pro-inflammatory mediators. Although both scenarios (senescence and reactive gliosis) have been studied independently, there are no direct studies comparing their secretomes simultaneously in the aging-brain. In this review we discuss the most recent studies in that respect, in order to analyze their simultaneous participation in brain aging.

Long-term sulforaphane-treatment restores redox homeostasis and prevents cognitive decline in middleaged female and male rats, but cannot revert previous damage in old animals.

Aging is a complex and detrimental process, which disrupts most organs and systems within the organisms. The nervous system is morphologically and functionally affected during normal aging, and oxidative stress has been involved in age-related damage, leading to cognitive decline and neurodegenerative processes. Sulforaphane (SFN) is a hormetin that activates the antioxidant and anti-inflammatory responses. So, we aimed to evaluate if SFN long-term treatment was able to prevent age-associated cognitive decline in adult and old female and male rats. Memory was evaluated in adult (15-month-old), and old (21-month-old) female and male Wistar rats after three months of SFN treatment. Young rats (4-month-old) were used as age controls. The antioxidant response induction, the redox state (GSH/GSSG), and oxidative damage were determined in the brain cortex (Cx) and hippocampus (Hc). Our results showed that SFN restored redox homeostasis in the Cx and Hc of adult rats, thus preventing cognitive decline in both sexes; however, the redox responses were not the same in males and females. Old rats were not able to recover their redox state as adults did, but they had a mild improvement. These results suggest that SFN mainly prevents rather than reverts neural damage; though, there might also be a range of opportunities to use hormetins like SFN, to improve redox modulation in old animals.

Increased CD47 and MHC Class I Inhibitory Signals Expression in Senescent CD1 Primary Mouse Lung Fibroblasts.

Cellular senescence is more than a proliferative arrest in response to various stimuli. Senescent cells (SC) participate in several physiological processes, and their adequate removal is essential to maintain tissue and organism homeostasis. However, SC accumulation in aging and age-related diseases alters the tissue microenvironment leading to deterioration. The immune system clears the SC, but the specific scenarios and mechanisms related to recognizing and eliminating them are unknown. Hence, we aimed to evaluate the existence of three regulatory signals of phagocytic function, CD47, major histocompatibility complex class I (MHC-I), and calreticulin, present in the membrane of SC. Therefore, primary fibroblasts were isolated from CD1 female mice lungs, and stress-induced premature senescence (SIPS) was induced with hydrogen peroxide. Replicative senescence (RS) was used as a second senescent model. Our results revealed a considerable increment of CD47 and MHC-I in RS and SIPS fibroblasts. At the same time, no significant changes were found in calreticulin, suggesting that those signals might be associated with evading immune system recognition and thus averting senescent cells clearance.

Sleep loss disrupts pericyte-brain endothelial cell interactions impairing blood-brain barrier function.

Sleep loss in the rat increases blood-brain barrier permeability to circulating molecules by disrupting interendothelial tight junctions. Despite the description of the ultrastructure of cerebral microvessels and the evidence of an apparent pericyte detachment from capillary wall in sleep restricted rats the effect of sleep loss on pericytes is unknown. Here we characterized the interactions between pericytes and brain endothelial cells after sleep loss using male Wistar rats. Animals were sleep-restricted 20 h daily with 4 h sleep recovery for 10 days. At the end of the sleep restriction, brain microvessels (MVs) were isolated from cerebral cortex and hippocampus and processed for Western blot and immunocytochemistry to evaluate markers of pericyte-endothelial cell interaction (connexin 43, PDGFR-ß), tight junction proteins, and proinflammatory mediator proteins (MMP9, A2A adenosine receptor, CD73, NFκB). Sleep restriction reduced PDGFR-ß and connexin 43 expression in MVs; in addition, scanning electron microscopy micrographs showed that pericytes were detached from capillary walls, but did not undergo apoptosis (as depicted by a reduced active caspase-3 expression). Sleep restriction also decreased tight junction protein expression in MVs and increased BBB permeability to low- and high-molecular weight tracers in in vivo permeability assays. Those alterations seemed to depend on a low-grade inflammatory status as reflected by the increased expression of phosphorylated NFκB and A2A adenosine receptor in brain endothelial cells from the sleep-restricted rats. Our data show that pericyte-brain endothelial cell interaction is altered by sleep restriction; this evidence is essential to understand the role of sleep in regulating blood-brain barrier function.

Synergetic effects of immune challenge and stress depress cortisol, inflammatory response and antioxidant activity in fish-eating Myotis.

One of the most common tools in conservation physiology is the assessment of environmental stress via glucocorticoid measurement. However, little is known of its relationship with other stress-related biomarkers, and how the incidence of an immune challenge during long-term stress could affect an individual's overall stress response. We investigated here the relationship between basal and post-acute stress fecal cortisol metabolite (FC) with different antioxidant enzymes, oxidative damage and immune parameters in the fish-eating bat, Myotis vivesi We found that in both basal and post-stress conditions, FC was highly related with a number of antioxidant enzymes and immune parameters, but not to oxidative damage. We also assessed changes of FC through the seasons. Basal FC samples and stress reactivity after short-duration stress displayed similar levels during summer, autumn and early winter, but lower concentrations in late winter. Stress reactivity after long-duration stress was greater in summer and early winter. Finally, we tested the effect of a simultaneous exposure to a long, strong stress stimulus with an immune response stimulation by administrating adrenocorticotropic hormone (ACTH) and phytohemagglutinin (PHA) after 42 h. Results showed that when both stimuli were administrated, FC concentrations, inflammation and some antioxidant activity were lowered in comparison with the control and individual administration of the challenges. Our findings support the idea that animals maintain constant basal glucocorticoid levels when living in challenging environments, but response to acute stress differs seasonally and immune defense mechanisms and stress responses might be compromised when confronted with multiple challenges.

Effect of long-term moderate-exercise combined with metformin-treatment on antioxidant enzymes activity and expression in the gastrocnemius of old female Wistar rats.

Oxidative stress is known to be involved in the etiology of sarcopenia, a progressive loss of muscle mass and force related to elderly incapacity. A successful intervention to prevent this condition has been exercise-based therapy. Metformin (MTF), an anti-diabetic drug with pleiotropic effects, is known to retain redox homeostasis. However, the combined use of MTF with exercise has shown controversial experimental results. Our research group has shown that MTF-treatment does not limit the benefits provided by exercise, probably by inducing a hormetic response. Hence, our aim was to evaluate the effect of exercise in combination with MTF-treatment on the redox state of old female Wistar rats. Animals were divided into six groups; three groups preformed exercise on a treadmill for 5 days/week for 20 months and the other three were sedentary. Also, two groups of each, exercised and sedentary animals were treated with MTF for 6 or 12 months correspondingly, beside the untreated groups. Rats were euthanized at 24 months. Muscular functionality was analyzed as the relation between the lean mass free of bone with respect to the grip strength. Superoxide dismutase, catalase, and glutathione peroxidase content, enzymatic activity and redox state were determined in the gastrocnemius muscle. Our results showed that the exercised group treated with MTF for 12 months presented higher GSH/GSSG rate and high antioxidant scavenging power in contrast to the MTF-treatment for 6 months, where the beneficial effect was less noticeable.

Health-related quality of life among Jewish older persons in Mexico and its determinants.

PURPOSE: Aging research in Mexico has significantly increased in the past decades, however, little is known on health related quality of life (HRQoL) of older adults. The aim of this study was to expand this field by examining HRQL in a representative sample of Jewish older adults in Mexico, and to investigate its association with different factors. METHODS: This was a cross-sectional survey of a random sample of community dwelling Jewish men and women aged 60 years and older. HRQoL was measured using the Short Form Health Survey (SF-36). Bivariate analysis was performed to estimate the association of scores of HRQoL and different characteristics of the study sample and multiple linear regression models were estimated using ordinary least squares (OLS), to explore determinant factors associated to HRQoL in this sample, for the eight domains of the SF-36 sub-scales separately. RESULTS: Two hundred ninety-five older persons were interviewed. Mean age was 72.7 years (SD 7.9), men made up 57% of the sample, 67% were married and 52% reported living with another person, mostly the spouse. Higher HRQoL was associated with higher educational attainment, being married, and having higher social support, while lower HRQoL was associated with being widowed, in worse financial situation, having chronic diseases and being in the oldest age groups. CONCLUSIONS: Findings show that gender, socioeconomic level, educational attainment, marital status as well as social support & community participation are relevant factors influencing HRQoL in our study sample. With respect to the SF-36 subscales, HRQoL of Jewish older adults in Mexico present higher scores than that of adults and older adults previously found in other studies in Mexico. Further studies comparing other characteristics among them could help bring further understanding of these differentiated ageing processes.

The Effect of MPP+ on the Viability of Primary Cortical Astrocytes Isolated from Female and Male Wistar Rats of Different Ages.

Although age is known to be the main risk for developing chronic and neurodegenerative diseases, those illnesses have a different prevalence depending on the sex. It has been questioned whether genetic and hormonal differences are preserved in primary cultures from individuals of different genders. Therefore, here we studied the susceptibility of astrocytes, obtained from female and male Wistar rats of different ages (newborn, 9 and 24 months-old), to the well-known toxin MPP+ after 2 weeks in vitro, at different concentrations and exposure times. Our results showed that there are no variances due to gender, but that there are important differences associated to age in terms of the viability against this toxin.

Correction to: The Effect of MPP+ on the Viability of Primary Cortical Astrocytes Isolated from Female and Male Wistar Rats of Different Ages.

The original version of this article unfortunately contained a mistake in author names. The given name and family name was swapped erroneously for the three authors and published incorrectly as Alarcon-Aguilar Adriana, Luna-Lopez Armando and Königsberg Mina.The author names should read as Adriana Alarcón-Aguilar, Armando Luna-López and Mina Königsberg.The original article has been corrected.

Some naturally occurring compounds that increase longevity and stress resistance in model organisms of aging.

Humans and other organisms show age-related signs of deterioration, which makes aging an interesting process to study. In the present work, we review the anti-aging evidence of several of the most promising natural compounds. Quercetin, rapamycin, resveratrol, spermidine, curcumin or sulforaphane administration increase longevity and stress resistance in model organisms such as yeasts, nematodes, flies and mice. Even more, rapamycin, resveratrol, and curcumin are currently in preclinical tests on the Interventions Testing Program of the National Institute on Aging due to their encouraging results in model organisms. The potential mechanisms underlying the beneficial effects of these compounds are briefly described.

Dinámica mitocondrial en las enfermedades neurodegenerativas.

Neurodegenerative diseases are a group of heterogeneous diseases characterized by a gradual, progressive and selective decrease in nervous system functions. The etiology of these pathologies remains unknown; however, mitochondrial function has been proposed as a common factor that could be involved in the establishment of these diseases, owing to the high energy requirement neurons have in order to carry out their physiological functions. Mitochondria are extremely dynamic organelles that can change their morphology and function in response to different physiological stimuli and, for this reason, mitochondrial dynamics have started being studied as one of cell survival main regulators. This event comprises different processes, such as the generation of new mitochondria and their elimination when they are no longer functional, as well as mitochondrial fusion and fission processes and the traffic of these organelles within the cellular environment. All these processes are highly regulated, and their main purpose is optimal functionality of mitochondria and cellular homeostasis.

Las enfermedades neurodegenerativas son un grupo heterogéneo caracterizado por la disminución gradual, progresiva y selectiva de las funciones del sistema nervioso. La etiología de estas patologías aún se desconoce, sin embargo, se ha propuesto que la función mitocondrial pudiese estar participando en el establecimiento de estas enfermedades, debido al alto requerimiento energético que tienen las neuronas para realizar sus funciones fisiológicas. La mitocondria es un organelo dinámico que puede cambiar su morfología y función en respuesta a diferentes estímulos fisiológicos, por ello se ha empezado a estudiar a la dinámica mitocondrial como uno de los principales reguladores de la supervivencia celular. Este evento comprende diferentes procesos como la generación de nuevas mitocondrias y su eliminación cuando ya no son funcionales, así como los procesos de fusión y fisión mitocondrial y el tráfico de estos organelos en el entorno celular. Todos estos procesos son altamente regulados y tienen como finalidad la óptima funcionalidad de la mitocondria y la homeostasis celular.

The secretory phenotype of senescent astrocytes isolated from Wistar newborn rats changes with anti-inflammatory drugs, but does not have a short-term effect on neuronal mitochondrial potential.

In the central nervous system (CNS), senescent astrocytes have been associated with neurodegeneration. Senescent cells secrete a complex mixture of pro-inflammatory factors, which are collectively called Senescence Associated Secretory Phenotype (SASP). The SASP components can vary depending on the cell type, senescence inducer and time. The SASP has been mainly studied in fibroblasts and epithelial cells, but little is known in the context of the CNS. Here, the SASP profile in senescent astrocytes isolated from Wistar newborn rats induced to senescence by oxidative stress or by proteasome inhibition was analyzed. Senescent astrocytes secreted predominantly chemokines and IL-1α, but no IL-6. The effect of the anti-inflammatory drugs, sulforaphane (SFN) and dehydroepiandrosterone (DHEA), on the SASP profile was evaluated. Our results showed that SFN and DHEA decreased IL-1α secretion while increasing IL-10, thus modifying the SASP to a less anti-inflammatory profile. Primary neurons were subjected to the conditioned media obtained from drug-treated senescent astrocytes, and their mitochondrial membrane potential was evaluated.

Immunization with neural derived peptides plus scar removal induces a permissive microenvironment, and improves locomotor recovery after chronic spinal cord injury.

BACKGROUND: Immunization with neural derived peptides (INDP) as well as scar removal-separately-have shown to induce morphological and functional improvement after spinal cord injury (SCI). In the present study, we compared the effect of INDP alone versus INDP with scar removal on motor recovery, regeneration-associated and cytokine gene expression, and axonal regeneration after chronic SCI. Scar removal was conducted through a single incision with a double-bladed scalpel along the stump, and scar renewal was halted by adding α,α'-dipyridyl. RESULTS: During the chronic injury stage, two experiments were undertaken. The first experiment was aimed at testing the therapeutic effect of INDP combined with scar removal. Sixty days after therapeutic intervention, the expression of genes encoding for TNFα, IFNγ, IL4, TGFß, BDNF, IGF1, and GAP43 was evaluated at the site of injury. Tyrosine hydroxylase and 5-hydroxytryptamine positive fibers were also studied. Locomotor evaluations showed a significant recovery in the group treated with scar removal + INDP. Moreover; this group presented a significant increase in IL4, TGFß, BDNF, IGF1, and GAP43 expression, but a decrease of TNFα and IFNγ. Also, the spinal cord of animals receiving both treatments presented a significant increase of serotonergic and catecholaminergic fibers as compared to other the groups. The second experiment compared the results of the combined approach versus INDP alone. Rats receiving INDP likewise showed improved motor recovery, although on a lesser scale than those who received the combined treatment. An increase in inflammation and regeneration-associated gene expression, as well as in the percentage of serotonergic and catecholaminergic fibers was observed in INDP-treated rats to a lesser degree than those in the combined therapy group. CONCLUSIONS: These findings suggest that INDP, both alone and in combination with scar removal, could modify the non-permissive microenvironment prevailing at the chronic phase of SCI, providing the opportunity of improving motor recovery.

Relationship of inflammatory profile of elderly patients serum and senescence-associated secretory phenotype with human breast cancer cells proliferation: Role of IL6/IL8 ratio.

Aging is considered a systemic, chronic and low-grade inflammatory state, called "inflammaging", which has been contemplated as a risk factor for cancer development and progression in the elderly population. Cellular senescence is a multifactorial phenomenon of growth arrest and distorted function, which has been recognized as a contributor to aging. Senescent cells have an altered secretion pattern called Senescent Associated Secretory Phenotype (SASP), that comprise a complex mix of factors including cytokines, growth factors, chemokines and matrix metalloproteinases among others. The SASP secreted by accumulated senescent cells during old age has been related to local inflammation that leads to cellular transformation and therefore may be supporting the inflammaging process. Here, we evaluated if the pro-inflammatory profile within the serum obtained from elderly patients (EPS) was able to induce cellular proliferation in the breast cancer transformed cell line (MCF-7), in a similar way to the proliferation stimulated by the SASP obtained from WI-38 primary cells prematurely induced to senescence by oxidative stress (SIPS). At the same time, the participation of IL-6/IL-8 ratio was determined. Our results showed that not all the EPS increased MCF-7 proliferation. However, there was an interesting relationship between IL-6 and IL-8 concentrations, when the IL-6 was higher than IL-8. Similar results were found with SASP from SIPS-WI-38 on the MCF-7 proliferation. Although it is known that those cytokines are fundamental factors to induce proliferation; the occurrence of other components in the cellular microenvironment is necessary to carry out this effect.

Bik subcellular localization in response to oxidative stress induced by chemotherapy, in Two different breast cancer cell lines and a Non-tumorigenic epithelial cell line.

Cancer chemotherapy remains one of the preferred therapeutic modalities against malignancies despite its damaging side effects. An expected outcome while utilizing chemotherapy is apoptosis induction. This is mainly regulated by a group of proteins known as the Bcl-2 family, usually found within the endoplasmic reticulum or the mitochondria. Recently, these proteins have been located in other sites and non-canonic functions have been unraveled. Bik is a pro-apoptotic protein, which becomes deregulated in cancer, and as apoptosis is associated with oxidative stress generation, our objective was to determine the subcellular localization of Bik either after a direct oxidative insult due to H2 O2 , or indirectly by cisplatin, an antineoplastic agent. Experiments were performed in two human transformed mammary gland cell lines MDA-MB-231 and MCF-7, and one non-tumorigenic epithelial cell line MCF-10A. Our results showed that in MCF-7, Bik is localized within the cytosol and that after oxidative stress treatment it translocates into the nucleus. However, in MDA-MB-231, Bik localizes in the nucleus and translocates to the cytosol. In MCF10A Bik did not change its cellular site after either treatment. Interestingly, MCF10A were more resistant to cisplatin than transformed cell lines. This is the first report showing that Bik is located in different cellular compartments depending on the cancer stage, and it has the ability to change its subcellular localization in response to oxidative stress. This is associated with increased sensitivity when exposed to toxic agents, thus rendering novel opportunities to study new therapeutic targets allowing the development of more active and less harmful agents.

The N-Methyl-d-Aspartate Receptor Antagonist MK-801 Prevents Thallium-Induced Behavioral and Biochemical Alterations in the Rat Brain.

Thallium (Tl(+)) is a toxic heavy metal capable of increasing oxidative damage and disrupting antioxidant defense systems. Thallium invades the brain cells through potassium channels, increasing neuronal excitability, although until now the possible role of glutamatergic transmission in this event has not been investigated. Here, we explored the possible involvement of a glutamatergic component in the Tl(+)-induced toxicity through the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) in rats. The effects of MK-801 (1 mg/kg, intraperitoneally [ip]) on early (24 hours) motor alterations, lipid peroxidation, reduced glutathione (GSH) levels, and GSH peroxidase activity induced by Tl(+) acetate (32 mg/kg, ip) were evaluated in adult rats. MK-801 attenuated the Tl(+)-induced hyperactivity and lipid peroxidation in the rat striatum, hippocampus and midbrain, and produced mild effects on other end points. Our findings suggest that glutamatergic transmission via NMDA receptors might be involved in the Tl(+)-induced altered regional brain redox activity and motor performance in rats.

[Involvement of phenotype secretor of senescent cells in the development of cancer, aging and the diseases associated with age]. / Participación del fenotipo secretor de las células senescentes en el desarrollo del cáncer, el envejecimiento y las enfermedades asociadas a la edad.

Cellular senescence is defined as the physiological program of terminal growth arrest; in mammals it is an important tumor-suppressor mechanism since it stops premalignant cell proliferation. However, senescence also contributes to the decline associated to aging and the development of several diseases. This is explained by the fact that senescent cells secrete diverse molecules, which compromise the cellular microenvironment, and altogether are referred as senescent-associated secretory phenotype (SASP). The SASP is composed by cytokines, chemokines, growth factors, proteases, etc., whose function is to maintain the antiproliferative state and promote senescent cell clearance by the immune system. Nevertheless, over time, and particularly during old age, SASP might stimulate proliferation and premalignant cell transformation. The multifunctional roles of SASP would depend on the cell type and their physiological nature. Therefore, relying on the biological context, SASP could be beneficial and participate in the repair and regeneration processes, or detrimental and induce degenerative pathologies and cancer.

Cell proliferation arrest and redox state status as part of different stages during senescence establishment in mouse fibroblasts.

Senescence phenotype can be achieved by multiple pathways. Most of them involve the activation of negative cell cycle regulators as well as a shift to an oxidative status. However, the exact participation of these events in senescence establishment and maintenance is not completely understood. In this study we investigated the content of three final cell cycle regulators, as well as the redox state in some critical points during the pre-senescent and the full-senescent states. Our results highlight the existence of a critical pre-phase in senescent phenotype establishment, in which cell proliferation stops with the participation of the cell cycle inhibitors, and a second maintenance stage where the exacerbated pro-oxidant state inside the cell induces the physiological decline characteristic in senescent cells.