Proteasome activation: An innovative promising approach for delaying aging and retarding age-related diseases

Chondrogianni, Niki; Voutetakis, Konstantinos; Καπετάνου, Μαριάννα; Delitsikou, Vasiliki; Papaevgeniou, Nikoletta; Sakellari, Marianthi; Lefaki, Maria; Filippopoulou, Konstantina; Gonos, Efstathios S.

doi:10.1016/j.arr.2014.12.003

Cited by 94 publications

(66 citation statements)

References 259 publications

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“…On the other hand, proteasome activation has been suggested as a potential antiaging (9) and retardation strategy against the progression of age-related diseases (16). Lately, proteasome activation was achieved in multicellular organisms through genetic manipulation of either 20S or 19S subunits with positive outcomes on aging, stress resistance, and aggregation-related neuropathies (8,55,58).…”

Section: Introductionmentioning

confidence: 99%

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18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression inCaenorhabditiselegansand Neuronal Cultures

Papaevgeniou

Sakellari

Jha

et al. 2016

Antioxidants & Redox Signaling

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Aims: Proteasomes are constituents of the cellular proteolytic networks that maintain protein homeostasis through regulated proteolysis of normal and abnormal (in any way) proteins. Genetically mediated proteasome activation in multicellular organisms has been shown to promote longevity and to exert protein antiaggregation activity. In this study, we investigate whether compound-mediated proteasome activation is feasible in a multicellular organism and we dissect the effects of such approach in aging and Alzheimer's disease (AD) progression. Results: Feeding of wild-type Caenorhabditis elegans with 18a-glycyrrhetinic acid (18a-GA; a previously shown proteasome activator in cell culture) results in enhanced levels of proteasome activities that lead to a skinhead-1-and proteasome activation-dependent life span extension. The elevated proteasome function confers lower paralysis rates in various AD nematode models accompanied by decreased Ab deposits, thus ultimately decelerating the progression of AD phenotype. More importantly, similar positive results are also delivered when human and murine cells of nervous origin are subjected to 18a-GA treatment. Innovation: This is the first report of the use of 18a-GA, a diet-derived compound as prolongevity and antiaggregation factor in the context of a multicellular organism. Conclusion: Our results suggest that proteasome activation with downstream positive outcomes on aging and AD, an aggregation-related disease, is feasible in a nongenetic manipulation manner in a multicellular organism. Moreover, they unveil the need for identification of antiaging and antiamyloidogenic compounds among the nutrients found in our normal diet. Antioxid. Redox Signal. 25, 855-869.

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Section: Introductionmentioning

confidence: 99%

“…Moreover, it is considered as a major risk factor for several pathologies, including aggregation-related disorders such as Alzheimer's disease (AD) (37). The various cellular proteolytic systems are among the major guardians of proteostasis, with the proteasome playing a catalytic role (16).…”

Section: Introductionmentioning

confidence: 99%

18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression inCaenorhabditiselegansand Neuronal Cultures

Papaevgeniou

Sakellari

Jha

et al. 2016

Antioxidants & Redox Signaling

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“…Although the consequences of proteasome activation are yet not completely predictable, the currently known consequences are the extension of the life span in many species and cellular models 4 and the prevention of protein aggregation, as reported in a few publications 6,8,24 . Both effects are greatly stimulating research in the field, considering the potentially high impact of the prevention of aggregation on degenerative processes.…”

Section: Consequences Of Proteasome Activationmentioning

confidence: 99%

“…Progress toward the discovery of exogenous proteasome agonists has been slow. Proteasome activation was first achieved by inducing the overexpression of its catalytic units or the chaperone involved in its assembly 4 . Afterwards, some drugs acting by stimulating Keap1-Nrf2 signaling also indirectly induced the overexpression of proteasome subunits 15,16 .…”

Section: Mechanisms Of Proteasome Activationmentioning

confidence: 99%

“…No attempt to explore proteasome activation was made until the overexpression of the β5-catalytic subunit of the proteasome in fibroblast cells, which promoted the extension of the fibroblast life span and increased the degradation of oxidized proteins 3 . Afterward, many achievements on proteasome activation were reported 4 . The most frequently explored effect of proteasome activation has been the extension of life span.…”

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Activation of the ubiquitin-proteasome system: implications for neurodegeneration, aging, and tumorigenesis

Demasi¹

2017

J Neurol Neuromedicine

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Since the discovery of the proteasome (1986), many years passed before researchers explored the benefits of its activation. However, its inhibition, which was first observed in the beginning of the 1990s, gained wide acceptance because of its anti-tumor effect, as proteasome inhibition induces apoptosis. Currently, a proteasome inhibitor is utilized as a clinical tool. However, proteasome activation has been shown to either extend the life span of many cellular and animal models or prevent the accumulation of protein aggregates. Later effect might have an important contribution to neurodegenerative diseases with the hallmark of protein aggregation and the impairment of the proteasome. This short review presents prominent data on proteasome activation, focusing on the 20S catalytic proteasome particle. In addition, the benefits and consequences of proteasome activation in tumor development and progression are discussed.

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Impaired Proteasomal Function in Human Osteoarthritic Chondrocytes Can Contribute to Decreased Levels of SOX9 and Aggrecan

Serrano

Chen

Lotz

et al. 2018

Arthritis & Rheumatology

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Objective Osteoarthritis (OA) chondrocytes have impaired autophagy, one arm of the proteostasis network that coordinates proteome and organelle quality control and degradation. Deficient proteostasis impacts differentiation and viability, and inflammatory processes in aging and disease. Studying OA chondrocytes, we assessed ubiquitin proteasome system proteasomal function. Methods We evaluated human knee cartilages by immunohistochemistry, and assessed proteasomal function, levels of proteasomal core subunits and chaperones, and autophagy in cultured chondrocytes. Assays included Western blotting, quantitative RT-PCR, proteasomal protease activity and cell immunofluorescence. Results Human knee OA cartilages demonstrated polyubiquitin accumulation, with increased ubiquitin K48-linked polyubiquitinated proteins in situ, suggesting proteasomal impairment. Cultured OA chondrocytes demonstrated accumulation of K48 polyubiquitinated proteins, significantly decreased 20S proteasome core protease activity, and decreased levels of phosphorylated FOXO4 and PSMD11, a FOXO4-inducible promoter of proteasomal activation. Levels of proteasomal core subunits PSMB3, 5, 6, and assembly chaperone PSMG1 were not decreased in OA chondrocytes. In normal chondrocytes, PSMD11 siRNA knockdown stimulated certain autophagy machinery elements, elevated nitric oxide (NO) release, and decreased levels of chondrocytic master transcription factor SOX9 protein (and mRNA) and aggrecan (AGC1) mRNA. PSMD11 gain of function by transfection increased proteasomal function, raised levels of SOX9-induced AGC1 mRNA, stimulated elements of the autophagic machinery, and inhibited IL-1-induced NO and MMP13 release in OA chondrocytes. Conclusion Deficient PSMD11, associated with less phosphorylated FOXO4, promotes impaired proteasomal function in OA chondrocytes, dysregulated chondrocytic homeostasis, and decreased levels of SOX9 mRNA, SOX9 protein, and AGC1 mRNA. Chondrocyte proteasomal impairment may be a therapy target for OA.

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Proteasome activation: An innovative promising approach for delaying aging and retarding age-related diseases

Cited by 94 publications

References 259 publications

18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression inCaenorhabditiselegansand Neuronal Cultures

18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression inCaenorhabditiselegansand Neuronal Cultures

Activation of the ubiquitin-proteasome system: implications for neurodegeneration, aging, and tumorigenesis

Impaired Proteasomal Function in Human Osteoarthritic Chondrocytes Can Contribute to Decreased Levels of SOX9 and Aggrecan

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