Interplay between bioenergetics and oxidative stress at normal brain aging. Aging as a result of increasing disbalance in the system oxidative stress–energy provision


At normal aging, the brain exhibits signs of compromised bioenergetic and increased levels of products of interaction between reactive oxygen/nitrogen species (ROS/RNS) and brain constituents. Under normal conditions, steady-state levels of ATP and ROS/RNS fluctuate in certain ranges providing basis for stable homeostasis. However, from time to time these parameters leave a “comfort zone,” and at adulthood, organisms are able to cope with these challenges efficiently, whereas at aging, efficiency of the systems maintaining homeostasis declines. That is very true for the brain due to high ATP demands which are mainly covered by mitochondrial oxidative phosphorylation. Such active oxidative metabolism gives rise to intensive ROS generation as side products. The situation is worsened by high brain level of polyunsaturated fatty acids which are substrates for ROS/RNS attack and production of lipid peroxides. In this review, organization of energetic metabolism in the brain with a focus on its interplay with ROS at aging is discussed. The working hypothesis on aging as a disbalance between oxidative stress and energy provision as a reason for brain aging is proposed. From this point of view, normal age-related physiological decline in the brain functions results from increased disbalance between decrease in capability of the brain to control constantly increased incapability to maintain ROS levels and produce ATP due to amplification of vicious cycles intensification of oxidative stress <----> impairment of energy provision.

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Acetyl coenzyme A


Electron transport chain


Ketone bodies


Lipid peroxidation


Nuclear magnetic resonance


Oxidative phosphorylation


Pentose phosphate pathway


Reactive nitrogen species


Reactive oxygen species

TCA cycle:

Tricarboxylic acid cycle


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The author would like to thank Drs. H. Semchyshyn and M. Bayliak for critical reading of the manuscript and two anonymous reviewers for their careful reading of the manuscript and their many constructive comments with suggestions that resulted in better presentation of the material.


This work was partially supported by a grant #90233 from the Volkswagen Foundation (VolkswagenStiftung, Germany) and a grant #0118U003477 from the Ministry of Education and Science of Ukraine.

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Lushchak, V.I. Interplay between bioenergetics and oxidative stress at normal brain aging. Aging as a result of increasing disbalance in the system oxidative stress–energy provision. Pflugers Arch - Eur J Physiol (2021).

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  • Glucose
  • Glycolysis
  • Ketone bodies
  • Oxidative phosphorylation
  • Reactive oxygen species