Brain aging and neurodegeneration: from a mitochondrial point of view

Abstract

Aging is defined as a progressive time-related accumulation of changes responsible for or at least involved in the increased susceptibility to disease and death. The brain seems to be particularly sensitive to the aging process since the appearance of neurodegenerative diseases, including Alzheimer's disease, is exponential with the increasing age. Mitochondria were placed at the center of the 'free-radical theory of aging', because these paramount organelles are not only the main producers of energy in the cells, but also to main source of reactive oxygen species. Thus, in this review, we aim to look at brain aging processes from a mitochondrial point of view by asking: (i) What happens to brain mitochondrial bioenergetics and dynamics during aging? (ii) Why is the brain so sensitive to the age-related mitochondrial impairments? (iii) Is there a sex difference in the age-induced mitochondrial dysfunction? Understanding mitochondrial physiology in the context of brain aging may help identify therapeutic targets against neurodegeneration.

Disease‐associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria

“…Our results suggest that tau can exacerbate its own mitochondrial toxicity by interfering with a neuron's ability to selectively remove the organelles it itself has damaged. Neurons are energetically demanding cells and the exacerbation of damage to the mitochondrial pool could have lasting implications not only for cellular energy requirements, but also for oxidative stress levels and redox balance (Grimm & Eckert, 2017). In the case of tau-associated diseases such as AD and FTD, impaired mitophagy and the associated accumulation of dysfunctional mitochondria are likely to comprise an important pathomechanism of neurodegeneration.…”

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…These unsatisfactory effects force people to pay attention on more targeted and etiology-oriented strategies [315]. Due to the notion that aging has been acknowledged as one of the major risk factors of AD pathogenesis [316], anti-aging drugs have become a promising therapeutic strategy against AD, which mainly occurs among the elderly population and features senescent phenotypes of affected neurons (Fig. 8).…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…They include analysis of mitochondria-specific proteins, functional interrogation of isolated mitochondria or mitochondria in synaptosome preparations, and manipulation of genes that encode mitochondrial proteins (Grimm and Eckert, 2017). Comparisons of mitochondria isolated from brain tissue of animals reveal numerous age-related alterations, including mitochondrial enlargement or fragmentation (Stahon et al, 2016; Morozov et al, 2017), increased oxidative damage to mitochondrial DNA (Kim and Chan, 2001; Santos et al, 2013), impaired function of the electron transport chain (ETC) (Yao et al, 2010; Pandya et al, 2015, 2016; Pollard et al, 2016), increased numbers of mitochondria with depolarized membranes (Lores-Arnaiz et al, 2016), impaired Ca 2+ handling (Leslie et al, 1985; Pandya et al, 2015), and a reduced threshold for triggering mPTP formation (Brown et al, 2004).…”