The International Journal of Biochemistry & Cell Biology
ReviewAutophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain
Section snippets
Oxidative stress, protein oxidation, and lipofuscin during aging
Since at least 1956, when Harman put forth the free radical theory of aging (Beckman & Ames, 1998; Davies, 1995; Golden, Hinerfeld, & Melov, 2002; Harman, 1956, Harman, 2001; Sohal, Mockett, & Orr, 2002; Sohal & Weindruch, 1996), oxidative stress has been seriously considered as one of the principle mediators for the progressive decline in cellular function that is observed during normal aging. In the last several decades, an increasing number of studies have demonstrated direct evidence that
Oxidative stress in the aging brain
The brain appears to be more vulnerable to age-related increases in oxidative stress, as compared to organs and tissues, although the basis for this increased vulnerability has not been elucidated. Most studies have focused on the possibility that increased levels of ROS are present within the brain compared to other organs. Such reports highlight the fact that the brain has multiple factors that contribute to elevated ROS levels including a high metabolic rate, high levels of reactive trace
Protein aggregation and the aging brain
It has long been known that the aggregation of specific proteins occurs as part of normal brain aging, and in many age-related neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Delacourte et al., 2002; Forloni et al., 2002; Gerschwind, 2003; Hashimoto, Rockstein, Crews, & Masliah, 2003). Increasing evidence suggest that protein oxidation may be a particularly important mediator of the aggregation observed for specific proteins in each of these disorders.
Alterations in proteasome-mediated proteolysis in the aging brain
Age-related declines in proteasome activity have been reported in multiple organ systems, including the brain (Ding & Keller, 2001; Grune, 2000, Grune et al., 2004; Keller et al., 2000a, Keller et al., 2000d; Keller, Huang, & Markesbery, 2000b; Keller, Huang, Dimayuga, & Maragos, 2000c). Interestingly, there is tremendous overlap between brain regions that have age-related increases in protein oxidation, and brain regions which have age-related declines in individual proteasome proteolytic
Lysosomal alterations and macroautophagy in the aging brain
While the role of proteasome inhibition as a cause of age-related increases in protein oxidation, and specifically increased lipofuscin is becoming increasingly established, the role of lysosomal dysfunction in each of these age-related events is less clear (Bahr & Nendiske, 2002; Brunk, Jones, & Sohal, 1992; Cuervo & Dice, 2000; Dunlop, Rodgers, & Dean, 2002; Lynch & Bi, 2003; Ward, 2002). Gross impairments in multiple aspects of lysosomal proteolysis are general features of aging in most
Acknowledgements
The authors wish to thank Dr. William R. Markesbery for his continual support, and Dr. Ana Cuervo for helpful discussions. The authors also thank Sonya Anderson and Ann Tudor for assistance with human tissue analysis. The present work was supported by the Hereditary Disease Foundation (J.N.K), and grants from the National Institutes of Health [AG018437 (J.N.K), AG005119 (J.N.K)].
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Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence
2023, International ImmunopharmacologyCitation Excerpt :and is directly related to the mechanism of cell senescence [6]. It is well predicted that the number of senescent cells in tissues and organs increases by exacerbating the stress [7,8]. Telomeres are DNA-protein complexesthat cover the ends of the linear chromosomal DNA to minimize genomic damage.