Pathways to Brain Aging and Their Modifiers: Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS) Model - A Mini-Review

Abstract

In this mini-review, we survey the extant literature on brain aging, with the emphasis on longitudinal studies of neuroanatomy, including regional brain volumes and white matter microstructure. We assess the impact of vascular, metabolic, and inflammatory risk factors on the trajectories of change in regional brain volumes and white matter properties, as well as the relationships between neuroanatomical and physiological changes and their influence on cognitive performance. We examine these findings in the context of current biological theories of aging and propose the means of integrating noninvasive measures - spectroscopic indices of brain energy metabolism and regional iron deposits - as valuable proxies for elucidating the basic neurobiology of human brain aging. In a brief summary of the recent findings pertaining to age-related changes in the brain structure and their impact on cognition, we discuss the role of vascular, metabolic, and inflammatory risk factors in shaping the trajectories of change. Drawing on the extant biological theories of aging and mindful of the brain's role as a disproportionately voracious energy consumer in mammals, we emphasize the importance of the fundamental bioenergetic mechanisms as drivers of age-related changes in brain structure and function. We sketch out a model that builds on the conceptualization of aging as an expression of cumulative cellular damage inflicted by reactive oxygen species and ensuing declines in energy metabolism. We outline the ways and means of adapting this model, Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS), to human aging and testing it within the constraints of noninvasive neuroimaging.

Keywords: Brain energy metabolism; Longitudinal studies; Magnetic resonance imaging; Magnetic resonance spectroscopy; Mitochondria; Myelin; Neuropil; Reactive oxygen species; White matter.

Figure 1

FRIENDS Model of Cognitive Aging. Gradually reduced production of energy sources (ATP and NADH) in the brain leads to an impairment in sequestration and transport of iron, which in turn causes reduction in mitochondrial energy metabolism. Mitochondrial dysfunction leads to shift in ROS homeostasis and excess of ROS further damages the mitochondria. As a result of this cascade, energy available for maintenance of cell membranes and myelin is further reduced and brain plasticity is abridged. Myelin and neuropil are gradually reduced and with that loss, information processing capabilities of the brain networks are degraded, with the system becoming progressively noisier. Noise in the information processing system affects all cognitive operations, with the more complex of them fairing the worst of all.