20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans.
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.
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; and sgonos@eie.gr nikichon@eie.gr.
Niki
N
Chondrogianni
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; and.
Konstantina
K
Georgila
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Crete, Greece.
Nikos
N
Kourtis
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Crete, Greece.
Nektarios
N
Tavernarakis
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece; and sgonos@eie.gr nikichon@eie.gr.
Efstathios S
ES
Gonos
D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence; D003001:Cloning, Molecular; D051858:Forkhead Transcription Factors; D008136:Longevity / Q000235:genetics*; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D025801:Ubiquitin; C108831:daf-16 protein, C elegans; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex
aging; daf-16; longevity; proteostasis