Review
Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain

https://doi.org/10.1016/j.biocel.2004.05.003Get rights and content

Abstract

In order to successfully respond to stress all cells rely on the ability of the proteasomal and lysosomal proteolytic pathways to continually maintain protein turnover. Increasing evidence suggests that as part of normal aging there are age-related impairments in protein turnover by the proteasomal proteolytic pathway, and perturbations of the lysosomal proteolytic pathway. Furthermore, with numerous studies suggest an elevated level of a specialized form of lysosomal proteolysis (autophagy or macroautophagy) occurs during the aging of multiple cell types. Age-related alterations in proteolysis are believed to contribute to a wide variety of neuropathological manifestations including elevations in protein oxidation, protein aggregation, and cytotoxicity. Within the brain altered protein turnover is believed to contribute to elevations in multiple forms of protein aggregation ranging from tangle and Lewy body formation, to lipofuscin-ceroid accumulation. In this review we discuss and summarize evidence for proteolytic alterations occurring in the aging brain, the contribution of oxidative stress to disruption of protein turnover during normal aging, the evidence for cross-talk between the proteasome and lysosomal proteolytic pathways in the brain, and explore the contribution of altered proteolysis as a mediator of oxidative stress, neuropathology, and neurotoxicity 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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