20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans

Abstract

Protein homeostasis (proteostasis) is one of the nodal points that need to be preserved to retain physiologic cellular/organismal balance. The ubiquitin‐proteasome system (UPS) is responsible for the removal of both normal and damaged proteins, with the proteasome being the downstream effector. The proteasome is the major cellular protease with progressive impairment of function during aging and senescence. Despite the documented age‐retarding properties of proteasome activation in various cellular models, simultaneous enhancement of the 20S core proteasome content, assembly, and function have never been reported in any multicellular organism. Consequently, the possible effects of the core proteasome modulation on organismal life span are elusive. In this study, we have achieved activation of the 20S proteasome at organismal level. We demonstrate enhancement of proteasome levels, assembly, and activity in the nematode Caenorhabditis elegans, resulting in life span extension and increased resistance to stress. We also provide evidence that the observed life span extension is dependent on the transcriptional activity of Dauer formation abnormal/Forkhead box class O (DAF‐16/FOXO), skinhead‐1 (SKN‐1), and heat shock factor‐1 (HSF‐1) factors through regulation of downstream longevity genes. We further show that the reported beneficial effects are not ubiquitous but they are dependent on the genetic context Finally, we provide evidence that proteasome core activation might be a potential strategy to minimize protein homeostasis deficiencies underlying aggregation‐related diseases, such as Alzheimer's disease (AD) or Huntington's disease (HD). In summary, this is the first report demonstrating that 20S core proteasome up‐regulation in terms of both content and activity is feasible in a multicellular eukaryotic organism and that in turn this modulation promotes extension of organismal health span and life span.—Chondrogianni, N., Georgila, K., Kourtis, N., Tavernarakis, N., Gonos, E. S. 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J. 29, 611‐622 (2015). http://www.fasebj.org

Sympatric speciation revealed by genome-wide divergence in the blind mole ratSpalax

“…High proteasome activity enhances the removal of damaged proteins and thereby improves the quality of the proteome and the maintenance of proteostasis. This may increase longevity (25,26), and helps the cell to resist oxidative stress (25,27). High levels of proteasome activity have also been seen in other underground-burrowing animals, such as the naked mole rat.…”

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

“…Likewise, most of the mammalian proteasome genes are regulated by Nrf2 in response to antioxidants such as 3H-1,2-dithiole-3-thione (D3T) (34). We have previously shown that SKN-1 is involved in proteasome activation in C. elegans following pbs-5 overexpression (8). Moreover, treatment of human fibroblasts with 18a-glycyrrhetinic acid (18a-GA) triterpenoid promotes Nrf2 activation, leading to proteasome activation, and enhanced cellular stress resistance and life span (27).…”

“…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). Given the restraints of genetic manipulation in humans, identification of proteasome-activating compounds is needed to promote proteasome enhancement ideally through human normal diet.…”

Ultraviolet-A triggers photoaging in model nematode Caenorhabditis elegans in a DAF-16 dependent pathway

“…The model nematode Caenorhabditis elegans which are widely used as a model in aging studies (Fawcett et al 2015;Chondrogianni et al 2015) were used to study the physiological and molecular changes in a biological system during UV-A exposure. Many natural compounds with antioxidants that have anti-aging activity have been successfully tested in this model (Zheng et al 2014;Sonani et al 2014).…”