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.

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.

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.

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.

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.

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.

[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.

Obesity Is Associated with Oxidative Stress Markers and Antioxidant Enzyme Activity in Mexican Children.

The relationship between metabolic disorders and oxidative stress is still controversial in the child population. The present cross-sectional study aimed to analyze the associations between obesity, cardiometabolic traits, serum level of carbonylated proteins (CPs), malondialdehyde (MDA), and the enzyme activity of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in children from Mexico City (normal weight: 120; obesity: 81). Obesity resulted in being positively associated with CAT (ß = 0.05 ± 0.01, p = 5.0 × 10-3) and GPx (ß = 0.13 ± 0.01, p = 3.7 × 10-19) enzyme activity. A significant interaction between obesity and sex was observed in MDA and SOD enzymatic activity (PMDA = 0.03; PSOD = 0.04). The associations between obesity, MDA level, and SOD enzyme activity were only significant in boys (boys: PMDA = 3.0 × 10-3; PSOD = 7.0 × 10-3; girls: p ≥ 0.79). In both children with normal weight and those with obesity, CP levels were positively associated with SOD enzyme activity (PNormal-weight = 2.2 × 10-3; PObesity = 0.03). In conclusion, in Mexican children, obesity is positively associated with CAT and GPx enzyme activity, and its associations with MDA levels and SOD enzyme activity are sex-specific. Therefore, CP level is positively related to SOD enzyme activity independently of body weight.

[Hormesis: What doesn't kill you makes you stronger]. / Hormesis: lo que no mata, fortalece.

Living organisms have always had to cope with harsh environmental conditions and in order to survive, they have developed complex mechanisms to deal with them. These responses have been assembled in a concept called hormesis, which has been identified as an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to higher stress level. The main hormetic agents identified so far are irradiation, heat, heavy metals, antibiotics, ethanol, pro-oxidants, exercise and food restriction. The hormetic response involves the expression of genes that encode cytoprotective proteins such as chaperones like heat-shock proteins, antioxidant enzymes and growth factors. In this review we will discuss the hormetic response mainly during an oxidative challenge, and its relationship with senescence and aging, and some related diseases such as diabetes and neurodegeneration.

Chronic consumption of a hypercaloric diet increases neuroinflammation and brain senescence, promoting cognitive decline in middle-aged female Wistar rats.

Being overweight and obesity are world health problems, with a higher prevalence in women, defined as abnormal or excessive fat accumulation that increases the risk of chronic diseases. Excess energy leads to adipose expansion, generating hypertrophic adipocytes that produce various pro-inflammatory molecules. These molecules cause chronic low-intensity inflammation, affecting the organism's functioning and the central nervous system (CNS), inducing neuroinflammation. The neuroinflammatory response during obesity occurs in different structures of the CNS involved in memory and learning, such as the cortex and the hippocampus. Here we analyzed how obesity-related peripheral inflammation can affect CNS physiology, generating neuroinflammation and promoting cellular senescence establishment. Since some studies have shown an increase in senescent cells during aging, obesity, and neurodegenerative diseases, we proposed that cellular senescence participation may contribute to the cognitive decline in an obesity model of middle-aged female Wistar rats. The inflammatory state of 6 and 13 months-old female Wistar rats fed with a hypercaloric diet was measured in serum and CNS (cortex and hippocampus). Memory was evaluated using the novel object recognition (NOR) test; the presence of senescent markers was also determined. Our data suggest that the systemic inflammation generated by obesity induces a neuroinflammatory state in regions involved in learning and memory, with an increase in senescent markers, thus proposing senescence as a potential participant in the negative consequences of obesity in cognition.

Telomerase activity in response to mild oxidative stress.

We have analysed telomerase activity to determine whether it can be modified when BCL-2 is endogenously overexpressed in response to a mild oxidative stress treatment as part of a survival mechanism, in contrast with an exogenous bcl-2 overexpression due to a retroviral infection. Endogenous bcl-2 overexpression was induced after a low oxidative insult of H2O2 in mice primary lung fibroblasts and L929 cell, whereas bcl-2 exogenous overexpression was performed using a retroviral infection in L929 cells. Telomerase activity was quantified in Bcl-2 overexpressing cells by the TRAP assay. When the cells were treated with different H2O2 concentrations, only those exposed to 50 µM showed increased telomerase activity. This correlates with BCL-2 expression as part of the endogenous response to mild oxidative stress. Oxidative stress generated during the toxic mechanism of chemotherapeutic drugs might induce BCL-2 increment, enhancing telomerase activity and reactivating the oncogenic process. Clinical trials should take into consideration the possibility of telomerase activation following increased BCL-2 expression when treating patients with ROS (reactive oxygen species) generation by anti-cancer drugs.

Moderate exercise combined with metformin-treatment improves mitochondrial bioenergetics of the quadriceps muscle of old female Wistar rats.

Sarcopenia is a syndrome that leads to physical disability and that deteriorates elderly people´s life quality. The etiology of sarcopenia is multifactorial, but mitochondrial dysfunction plays a paramount role in this pathology. Our research group has shown that the combined treatment of metformin (MTF) and exercise has beneficial effects for preventing muscle loss and fat accumulation, by modulating the redox state. To get an insight into the mechanism of the combined treatment, the mitochondrial bioenergetics was studied in the mitochondria isolated from old female Wistar rats quadriceps muscles. The animals were divided into six groups; three performed exercise on a treadmill for 5 days/week for 20 months, and the other three were sedentary. Also, two groups of each were treated with MTF for 6 or 12 months. The rats were euthanized at 24 months. The mitochondria were isolated and supercomplexes formation along with oxygen consumption, ATP synthesis, and ROS generation were evaluated. Our results showed that the combined treatment for 12 months increased the complex I and IV activities associated with the supercomplexes, simultaneously, ATP synthesis increased while ROS production decreased, indicating a tightly coupled mitochondria. The role of exercise plus the MTF treatment against sarcopenia in old muscles is discussed.

The Obese Brain: Mechanisms of Systemic and Local Inflammation, and Interventions to Reverse the Cognitive Deficit.

Overweight and obesity are now considered a worldwide pandemic and a growing public health problem with severe economic and social consequences. Adipose tissue is an organ with neuroimmune-endocrine functions, which participates in homeostasis. So, adipocyte hypertrophy and hyperplasia induce a state of chronic inflammation that causes changes in the brain and induce neuroinflammation. Studies with obese animal models and obese patients have shown a relationship between diet and cognitive decline, especially working memory and learning deficiencies. Here we analyze how obesity-related peripheral inflammation can affect central nervous system physiology, generating neuroinflammation. Given that the blood-brain barrier is an interface between the periphery and the central nervous system, its altered physiology in obesity may mediate the consequences on various cognitive processes. Finally, several interventions, and the use of natural compounds and exercise to prevent the adverse effects of obesity in the brain are also discussed.

DHEA inhibits proliferation, migration and alters mesenchymal-epithelial transition proteins through the PI3K/Akt pathway in MDA-MB-231 cells.

Cancer is one of the leading causes of death worldwide, and breast cancer is the most common among women. Dehydroepiandrosterone (DHEA), the most abundant steroid hormone in human serum, inhibits proliferation and migration of breast cancer cells, modulating the expression of proteins involved in mesenchymal-epithelial transition (MET). However, the underlying molecular mechanisms are not fully understood. DHEA effects on the triple-negative breast cancer cell line MDA-MB-231 (mesenchymal stem-like) could be exerted by binding to receptors tyrosine kinase (RTKs) and signaling through MEK/ERK and/or PI3K/Akt pathways. In this study, MDA-MB-231 cells were exposed to DHEA in the presence of pharmacological inhibitors of these pathways and a siRNA against PIK3CA gene, which blocks PI3K pathway. Cell proliferation was measured by crystal violet staining, migration by the wound healing and transwell assays, and MET protein expression by western blot. A xenograft tumor growth in nude mice (nu-/nu-) using a siRNA against PI3K was also performed. Results showed that neither of the inhibitors used reverted the antiproliferative activity of DHEA. However, wortmannin and LY294002, inhibitors of the PI3K/Akt pathway, abolished the up- and down-regulation of E- and N-cadherin expression respectively, and inhibition of migration induced by DHEA in MDA-MB-231 cells. The siRNA that blocks the PI3K pathway, abolished the effects of DHEA on proliferation, migration, MET proteins expression and the growth of tumors in nude mice. In conclusion, these results suggest that PI3K/Akt pathway participates in the effects of DHEA on breast cancer cells.

Metformin and tBHQ Treatment Combined with an Exercise Regime Prevents Osteosarcopenic Obesity in Middle-Aged Wistar Female Rats.

Osteosarcopenic obesity (OSO) is characterized by bone density, mass, and muscle strength loss, in conjunction with adipose tissue increase. OSO impairs physical activity and mobility, provoking autonomy loss; also, it is known that augmenting body fat in the elderly decreases life expectancy. The main factors influencing this health deterioration are the inflammatory environment induced by adipose tissue and its infiltration into muscle tissue, which leads to oxidative stress generation. Currently, there are several treatments to delay OSO, among which exercise training stands out because it improves muscle fiber quality and quantity and decreases adipose tissue. We have recently demonstrated that the combined treatment between moderate exercise and metformin slows sarcopenia's onset by a mechanism that includes adipose reduction and REDOX regulation. On the other hand, tert-butylhydroquinone (tBHQ) is a well-known antioxidant that counteracts oxidative stress. Therefore, to slow down obesity's harmful effects on muscle mass and bone mineral density, we performed different interventions, including combining a Fartlek-type exercise routine with metformin and tBHQ administration, in a model of middle-aged female Wistar rats with obesity induced with a hypercaloric diet. Our results showed that the combined exercise-metformin-tBHQ treatment increased muscle mass and strength, decreased body weight, body mass index, and fat percentage, and improved redox status, thus increasing animal survival.

Low-Intensity Exercise Routine for a Long Period of Time Prevents Osteosarcopenic Obesity in Sedentary Old Female Rats, by Decreasing Inflammation and Oxidative Stress and Increasing GDF-11.

The loss of skeletal muscle mass and strength is known as sarcopenia; it is characterized as a progressive and generalized muscle disorder associated with aging. This deterioration can seriously compromise the elderly's health and reduce their quality of life. In addition to age, there are other factors that induce muscle mass loss, among which are sedentary lifestyle, chronic diseases, inflammation, and obesity. In recent years, a new clinical condition has been observed in older adults that affects their physical capacities and quality of life, which is known as osteosarcopenic obesity (OSO). Osteoporosis, sarcopenia, and obesity coexist in this condition. Physical exercise and nutritional management are the most widely used interventions for the treatment and prevention of sarcopenia. However, in older adults, physical exercise and protein intake do not have the same outcomes observed in younger people. Here, we used a low-intensity exercise routine for a long period of time (LIERLT) in order to delay the OSO appearance related to sedentarism and aging in female Wistar rats. The LIERLT routine consisted of walking at 15 m/min for 30 min, five days a week for 20 months. To evaluate the effects of the LIERLT routine, body composition was determined using DXA-scan, additionally, biochemical parameters, inflammatory profile, oxidative protein damage, redox state, and serum concentration of GDF-11 at different ages were evaluated (4, 8, 12, 18, 22, and 24 months). Our results show that the LIERLT routine delays OSO phenotype in old 24-month-old rats, in a mechanism involving the decrease in the inflammatory state and oxidative stress. GDF-11 was evaluated as a protein related to muscle repair and regeneration; interestingly, rats that perform the LIERLT increased their GDF-11 levels.

Sulforaphane - role in aging and neurodegeneration.

In the last several years, numerous molecules derived from plants and vegetables have been tested for their antioxidant, anti-inflammatory, and anti-aging properties. One of them is sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables. SFN activates the antioxidant and anti-inflammatory responses by inducing Nrf2 pathway and inhibiting NF-κB. It also has an epigenetic effect by inhibiting HDAC and DNA methyltransferases and modifies mitochondrial dynamics. Moreover, SFN preserves proteome homeostasis (proteostasis) by activating the proteasome, which has been shown to lead to increased cellular lifespan and prevent neurodegeneration. In this review, we describe some of the molecular and physical characteristics of SFN, its mechanisms of action, and the effects that SFN treatment induces in order to discuss its relevance as a "miraculous" drug to prevent aging and neurodegeneration.

Long-Term Moderate Exercise Combined with Metformin Treatment Induces an Hormetic Response That Prevents Strength and Muscle Mass Loss in Old Female Wistar Rats.

Sarcopenia is a syndrome characterized by a progressive and generalized skeletal muscle mass and strength loss, as well as a poor physical performance, which as strongly been associated with aging. Sedentary lifestyle in the elderly contributes to this condition; however, physical activity improves health, reducing morbidity and mortality. Recent studies have shown that metformin (MTF) can also prevent muscle damage promoting muscular performance. To date, there is great controversy if MTF treatment combined with exercise training improves or nullifies the benefits provided by physical activity. This study is aimed at evaluating the effect of long-term moderate exercise combined with MTF treatment on body composition, strength, redox state, and survival rate during the life of female Wistar rats. In this study, rats performed moderate exercise during 20 of their 24 months of life and were treated with MTF for one year or for 6 months, i.e., from 12 to 24 months old and 18 to 24 months old. The body composition (percentage of fat, bone, and lean mass) was determined using a dual-energy X-ray absorption scanner (DXA), and grip strength was determined using a dynamometer. Likewise, medial and tibial nerve somatosensory evoked potentials were evaluated and the redox state was measured by HPLC, calculating the GSH/GSSG ratio in the gastrocnemius muscle. Our results suggest- that the MTF administration, both in the sedentary and the exercise groups, might activate a mechanism that is directly related to the induction of the hormetic response through the redox state modulation. MTF treatment does not eliminate the beneficial effects of exercise throughout life, and although MTF does not increase muscle mass, it increases longevity.