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Aging (Albany NY) ; 10(5): 868-901, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29779015


Non-enzymatic protein modifications occur inevitably in all living systems. Products of such modifications accumulate during aging of cells and organisms and may contribute to their age-related functional deterioration. This review presents the formation of irreversible protein modifications such as carbonylation, nitration and chlorination, modifications by 4-hydroxynonenal, removal of modified proteins and accumulation of these protein modifications during aging of humans and model organisms, and their enhanced accumulation in age-related brain diseases.

Envelhecimento/metabolismo , Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Estresse Oxidativo/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Animais , Halogenação/fisiologia , Humanos , Carbonilação Proteica/fisiologia
Eur J Endocrinol ; 176(6): R283-R308, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28264815


Aging and its underlying pathophysiological background has always attracted the attention of the scientific society. Defined as the gradual, time-dependent, heterogeneous decline of physiological functions, aging is orchestrated by a plethora of molecular mechanisms, which vividly interact to alter body homeostasis. The ability of an organism to adjust to these alterations, in conjunction with the dynamic effect of various environmental stimuli across lifespan, promotes longevity, frailty or disease. Endocrine function undergoes major changes during aging, as well. Specifically, alterations in hormonal networks and concomitant hormonal deficits/excess, augmented by poor sensitivity of tissues to their action, take place. As hypothalamic-pituitary unit is the central regulator of crucial body functions, these alterations can be translated in significant clinical sequelae that can impair the quality of life and promote frailty and disease. Delineating the hormonal signaling alterations that occur across lifespan and exploring possible remedial interventions could possibly help us improve the quality of life of the elderly and promote longevity.

Envelhecimento/metabolismo , Sistema Endócrino/metabolismo , Estresse Oxidativo , Adjuvantes Imunológicos/uso terapêutico , Androgênios/uso terapêutico , Antioxidantes/uso terapêutico , Ritmo Circadiano , Desidroepiandrosterona/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Dietoterapia , Terapia de Reposição de Estrogênios , Retroalimentação Fisiológica , Feminino , Preservação da Fertilidade , Gonadotropinas/metabolismo , Terapia de Reposição Hormonal , Humanos , Hiperandrogenismo/metabolismo , Hipertireoidismo/metabolismo , Hipertireoidismo/terapia , Hipoglicemiantes/uso terapêutico , Hipogonadismo/tratamento farmacológico , Hipogonadismo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Menopausa/metabolismo , Reserva Ovariana , Medicina de Precisão , Qualidade de Vida , Transplante de Células-Tronco , Células-Tronco , Testosterona/uso terapêutico , Glândula Tireoide , Equilíbrio Hidroeletrolítico
Free Radic Biol Med ; 103: 226-235, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28034832


The age-associated decline of adult stem cell function contributes to the physiological failure of homeostasis during aging. The proteasome plays a key role in the maintenance of proteostasis and its failure is associated with various biological phenomena including senescence and aging. Although stem cell biology has attracted intense attention, the role of proteasome in stemness and its age-dependent deterioration remains largely unclear. By employing both Wharton's-Jelly- and Adipose-derived human adult mesenchymal stem cells (hMSCs), we reveal a significant age-related decline in proteasome content and peptidase activities, accompanied by alterations of proteasomal complexes. Additionally, we show that senescence and the concomitant failure of proteostasis negatively affects stemness. Remarkably, the loss of proliferative capacity and stemness of hMSCs can be counteracted through proteasome activation. At the mechanistic level, we demonstrate for the first time that Oct4 binds at the promoter region of ß2 and ß5 proteasome subunits and thus possibly regulates their expression. A firm understanding of the mechanisms regulating proteostasis in stem cells will pave the way to innovative stem cell-based interventions to improve healthspan and lifespan.

Células-Tronco Mesenquimais/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proliferação de Células , Células Cultivadas , Senescência Celular , Ativação Enzimática , Expressão Gênica , Humanos , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo
Ageing Res Rev ; 23(Pt A): 37-55, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25540941


Aging is a natural process accompanied by a progressive accumulation of damage in all constituent macromolecules (nucleic acids, lipids and proteins). Accumulation of damage in proteins leads to failure of proteostasis (or vice versa) due to increased levels of unfolded, misfolded or aggregated proteins and, in turn, to aging and/or age-related diseases. The major cellular proteolytic machineries, namely the proteasome and the lysosome, have been shown to dysfunction during aging and age-related diseases. Regarding the proteasome, it is well established that it can be activated either through genetic manipulation or through treatment with natural or chemical compounds that eventually result to extension of lifespan or deceleration of the progression of age-related diseases. This review article focuses on proteasome activation studies in several species and cellular models and their effects on aging and longevity. Moreover, it summarizes findings regarding proteasome activation in the major age-related diseases as well as in progeroid syndromes.

Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Geriatria , Humanos , Longevidade/genética , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/genética , Ativação Transcricional
Eur J Med Chem ; 83: 508-15, 2014 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-24996137


One-pot uncatalysed microwave-assisted 1,3-dipolar cycloaddition reactions between in situ generated nitrile oxides and alkynes bearing protected antioxidant substituents, were regioselectively afforded 3,5-disubstituted isoxazoles. The yields were moderate, based on the starting aldehydes, while the reaction times were in general shorter than those reported in the literature. The cytoprotective and anti-ageing effect of the final deprotected compounds was evaluated in vitro, on cellular survival following oxidative challenge and in vivo, on organismal longevity using the nematode Caenorhabditis elegans. The activity of the isoxazole analogues depends on the nature and the number of the antioxidant substituents. Analogue 17 bearing a phenolic group and a 6-OH-chroman group is a promising anti-ageing agent, since it increased survival of human primary fibroblasts following treatment with H2O2 and extended C. elegans lifespan.

Envelhecimento/efeitos dos fármacos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Micro-Ondas , Alquinos/química , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Linhagem Celular , Técnicas de Química Sintética , Humanos , Isoxazóis/química , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Óxidos/química , Estereoisomerismo , Especificidade por Substrato
PLoS One ; 9(7): e103365, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25061667


Processing bodies (PBs) and stress granules (SGs) are related, cytoplasmic RNA-protein complexes that contribute to post-transcriptional gene regulation in all eukaryotic cells. Both structures contain translationally repressed mRNAs and several proteins involved in silencing, stabilization or degradation of mRNAs, especially under environmental stress. Here, we monitored the dynamic formation of PBs and SGs, in somatic cells of adult worms, using fluorescently tagged protein markers of each complex. Both complexes were accumulated in response to various stress conditions, but distinct modes of SG formation were induced, depending on the insult. We also observed an age-dependent accumulation of PBs but not of SGs. We further showed that direct alterations in PB-related genes can influence aging and normal stress responses, beyond their developmental role. In addition, disruption of SG-related genes had diverse effects on development, fertility, lifespan and stress resistance of worms. Our work therefore underlines the important roles of mRNA metabolism factors in several vital cellular processes and provides insight into their diverse functions in a multicellular organism.

Envelhecimento/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Fatores de Iniciação em Eucariotos/metabolismo , Resposta ao Choque Térmico , RNA Mensageiro/metabolismo , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Fatores de Iniciação em Eucariotos/genética , Ligação Proteica , RNA Mensageiro/genética