Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling.
Protein misfolding, accumulation, and aggregation characterize many aging-related diseases. Protein aggregates do not accumulate in unstressed cells primarily because of the existence of competent cellular "quality control" machinery. The endoplasmic reticulum (ER) is a major part of this quality control system. Accumulation of misfolded proteins in the ER causes ER stress and activates a signaling pathway called the unfolded protein response (UPR). The UPR limits protein load by upregulating ER chaperones such as Ig binding protein (BiP)/glucose-regulated protein 78 (GRP78) and by attenuating protein translation through eukaryotic initiation factor 2 alpha (eIF2alpha) phosphorylation. Acute sleep deprivation (6 h) in young mice leads to induction of the UPR with upregulation of BiP/GRP78 and attenuation of protein translation. We demonstrate here that aging impairs this adaptive response to sleep deprivation. Aged mice do not display an increase in BiP expression with acute sleep deprivation. In addition, there is decreased basal expression of BiP/GRP78 in aged mice. There is a decline in eIF2alpha phosphorylation in aged mouse cerebral cortex that is associated with higher levels of GADD34 (growth arrest and DNA damage 34) and proapoptotic proteins such as CCAAT/enhancer-binding protein-homologous protein and activated caspase-12, suggesting that young animals possess an efficient ER adaptive response that declines with aging.
Naidoo
Nirinjini
N
Division of Sleep Medicine and Center for Sleep and Respiratory Neurobiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. naidoo@mail.med.upenn.edu
Ferber
Megan
M
Master
Monali
M
Zhu
Yan
Y
Pack
Allan I
AI
D000222:Adaptation, Physiological / Q000502:physiology; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D017510:Protein Folding; D054645:Protein Phosphatase 1; D015398:Signal Transduction / Q000502:physiology*; D012892:Sleep Deprivation / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology
D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1