REVIEW: On the Role of Normal Aging Processes in the Onset and Pathogenesis of Diseases Associated with the Abnormal Accumulation of Protein Aggregates

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Nikolay S. Ilyinsky^1,a*, Semen V. Nesterov^1,2, Elizaveta I. Shestoperova¹, Alexander V. Fonin^1,3, Vladimir N. Uversky^1,4, and Valentin I. Gordeliy^1,5,6

¹Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Moscow Region, Russia

²Institute of Cytochemistry and Molecular Pharmacology, 115404 Moscow, Russia

³Institute of Cytology, Russian Academy of Sciences, 194064 Saint Petersburg, Russia

⁴Morsani College of Medicine, University of South Florida, 33612 Tampa, USA

⁵Forschungszentrum Juelich, 52428 Juelich, Germany

⁶Institut de Biologie Structurale, 38000 Grenoble, France

^* To whom correspondence should be addressed.

Received August 8, 2020; Revised August 21, 2020; Accepted August 24, 2020

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Aging is a prime systemic cause of various age-related diseases, in particular, proteinopathies. In fact, most diseases associated with protein misfolding are sporadic, and their incidence increases with aging. This review examines the process of protein aggregate formation, the toxicity of such aggregates, the organization of cellular systems involved in proteostasis, and the impact of protein aggregates on important cellular processes leading to proteinopathies. We also analyze how manifestations of aging (mitochondrial dysfunction, dysfunction of signaling systems, changes in the genome and epigenome) facilitate pathogenesis of various proteinopathies either directly, by increasing the propensity of key proteins for aggregation, or indirectly, through dysregulation of stress responses. Such analysis might help in outlining approaches for treating proteinopathies and extending healthy longevity.

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KEY WORDS: proteostasis, protein aggregation, proteinopathy, aging, mitochondrial dysfunction, mutations, epigenetic changes

DOI: 10.1134/S0006297921030056

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