Atypical pathways of NF-kappaB activation and aging.
The eukaryotic transcription factor Nuclear Factor-kappaB (NF-kappaB) is a master regulator for inflammatory responses, mediating cellular defense against infectious agents and environmental and cellular stress. However, recent evidence-based studies have demonstrated that constitutive activation of NF-kappaB is a ubiquitous phenomenon among various cell types in the aging phenotype, contributing deleterious effects that oppose the acutely beneficial effects of NF-kappaB seen in the inflammatory response. Expression of NF-kappaB with age is consistent with elevated levels of inflammatory markers and a pro-inflammatory phenotype, manifested in many age-associated diseases. While inducible activating mechanisms for NF-kappaB in the innate immune response are well characterized, constitutive activation in aging cells warrants further investigation of mechanisms collectively called atypical pathways. In this review, we provide a comprehensive examination of such NF-kappaB activating mechanisms, including mitochondrial dysfunction, endoplasmic stress response, organelle cross-talk, secondary messengers and DNA damage. Investigation of mechanisms of NF-kappaB in aging as an important marker of cellular stress provides guidance for the development of a systems view of cellular aging.
Kriete
Andres
A
School of Biomedical Engineering, Science and Health Systems, Drexel University, Bossone Research Center, Philadelphia, PA 19104, USA. ak3652@drexel.edu
Mayo
Kelli L
KL
D000375:Aging / Q000235:genetics* / Q000502:physiology; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics* / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
D015220:Calcium Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C513338:ROMO1 protein, human