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1.
Aging (Albany NY) ; 11(16): 6175-6198, 2019 08 30.
Article in English | MEDLINE | ID: mdl-31469660

ABSTRACT

Senescent cells accumulate in various tissues and organs with aging altering surrounding tissue due to an active secretome, and at least in mice their elimination extends healthy lifespan and ameliorates several chronic diseases. Whether all cell types senesce, including post-mitotic cells, has been poorly described mainly because cellular senescence was defined as a permanent cell cycle arrest. Nevertheless, neurons with features of senescence have been described in old rodent and human brains. In this study we characterized an in vitro model useful to study the molecular basis of senescence of primary rat cortical cells that recapitulates senescent features described in brain aging. We found that in long-term cultures, rat primary cortical neurons displayed features of cellular senescence before glial cells did, and developed a functional senescence-associated secretory phenotype able to induce paracrine premature senescence of mouse embryonic fibroblasts but proliferation of rat glial cells. Functional autophagy seems to prevent neuronal senescence, as we observed an autophagic flux reduction in senescent neurons both in vitro and in vivo, and autophagy impairment induced cortical cell senescence while autophagy stimulation inhibited it. Our findings suggest that aging-associated dysfunctional autophagy contributes to senescence transition also in neuronal cells.


Subject(s)
Autophagy/physiology , Cellular Senescence/physiology , Cerebral Cortex/cytology , Neurons/physiology , Aging , Animals , Cell Proliferation , Cell Survival , Male , Rats , Rats, Wistar
2.
Biogerontology ; 19(5): 415-433, 2018 10.
Article in English | MEDLINE | ID: mdl-30097900

ABSTRACT

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.


Subject(s)
Astrocytes , Cellular Senescence , Central Nervous System , Dehydroepiandrosterone/pharmacology , Isothiocyanates/pharmacology , Neurons , Animals , Animals, Newborn , Anti-Inflammatory Agents/pharmacology , Astrocytes/drug effects , Astrocytes/immunology , Cellular Senescence/drug effects , Cellular Senescence/immunology , Central Nervous System/drug effects , Central Nervous System/immunology , Central Nervous System/metabolism , Inflammation , Interleukin-1alpha/immunology , Membrane Potential, Mitochondrial/drug effects , Models, Animal , Neurons/drug effects , Neurons/metabolism , Oxidative Stress/physiology , Rats , Rats, Wistar , Sulfoxides
3.
Antioxid Redox Signal ; 28(18): 1704-1723, 2018 06 20.
Article in English | MEDLINE | ID: mdl-28467755

ABSTRACT

SIGNIFICANCE: Cellular senescence, characterized by permanent cell cycle arrest, has been extensively studied in mitotic cells such as fibroblasts. However, senescent cells have also been observed in the brain. Even though it is recognized that cellular energetic metabolism and redox homeostasis are perturbed in the aged brain and neurodegenerative diseases (NDDs), it is still unknown which alterations in the overall physiology can stimulate cellular senescence induction and their relationship with the former events. Recent Advances: Recent findings have shown that during prolonged inflammatory and pathologic events, the blood-brain barrier could be compromised and immune cells might enter the brain; this fact along with the brain's high oxygen dependence might result in oxidative damage to macromolecules and therefore senescence induction. Thus, cellular senescence in different brain cell types is revised here. CRITICAL ISSUES: Most information related to cellular senescence in the brain has been obtained from research in glial cells since it has been assumed that the senescent phenotype is a feature exclusive to mitotic cells. Nevertheless, neurons with senescence hallmarks have been observed in old mouse brains. Therefore, although this is a controversial topic in the field, here we summarize and integrate the observations from several studies and propose that neurons indeed senesce. FUTURE DIRECTIONS: It is still unknown which alterations in the overall metabolism can stimulate senescence induction in the aged brain, what are the mechanisms and signaling pathways, and what is their relationship to NDD development. The understanding of these processes will expose new targets to intervene age-associated pathologies.-Antioxid. Redox Signal. 28, 1704-1723.


Subject(s)
Brain/cytology , Brain/metabolism , Cellular Senescence , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Neurons/metabolism , Animals , Humans , Oxidation-Reduction
4.
Rev Med Inst Mex Seguro Soc ; 55(4): 490-497, 2017.
Article in Spanish | MEDLINE | ID: mdl-28591504

ABSTRACT

Cellular senescence has been traditionally characterized by cell cycle arrest of pot-mitotic cells as a response to a cellular damage. Now is known that senescent cells secret a diverse array of cytokines, chemokines, growth factors and other that altogether are called senescence associates secretory phenotype (SASP), which might have beneficial or deleterious effects on neighbor cells. This review describes those effects as well as the relationship between the SASP and several age related diseases. We also analyze the direction that recent investigations are turning in order to modulate or avoid the effect of the SASP in those pathologies.


La senescencia celular es un fenómeno que tradicionalmente se ha caracterizado por la detención de la proliferación de células post-mitóticas como respuesta a algún tipo de daño. Ahora se sabe que las células senescentes secretan un conjunto de moléculas, entre las que se encuentran quimiocinas, citocinas, factores de crecimiento y otras que, en conjunto, han sido denominadas fenotipo secretor asociado a la senescencia (SASP). Estas moléculas pueden tener efectos benéficos o dañinos sobre las células vecinas a ellas. Esta revisión describe dichos efectos, así como la relación del SASP con diversas enfermedades asociadas a la edad. También se analiza el rumbo que han tomado las investigaciones recientes para tratar de modular o eliminar el efecto del SASP en dichas patologías.


Subject(s)
Atherosclerosis/physiopathology , Cellular Senescence/physiology , Diabetes Mellitus, Type 2/physiopathology , Neurodegenerative Diseases/physiopathology , Sarcopenia/physiopathology , Aging/physiology , Humans , Phenotype
5.
Gac Med Mex ; 151(4): 491-500, 2015.
Article in Spanish | MEDLINE | ID: mdl-26290026

ABSTRACT

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.


Subject(s)
Aging/genetics , Cellular Senescence/genetics , Neoplasms/genetics , Humans , Phenotype
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