Abstract
Aging is the time-dependent process that all living organisms go through characterized by declining physiological function due to alterations in metabolic and molecular pathways. Many decades of research have been devoted to uncovering the cellular changes and progression of aging and have revealed that not all organisms with the same chronological age exhibit the same age-related declines in physiological function. In assessing biological age, factors such as epigenetic changes, telomere length, oxidative damage, and mitochondrial dysfunction in rescue mechanisms such as autophagy all play major roles. Recent studies have focused on autophagy dysfunction in aging, particularly on mitophagy due to its major role in energy generation and reactive oxidative species generation of mitochondria. Mitophagy has been implicated in playing a role in the pathogenesis of many age-related diseases, including Alzheimer’s disease (AD), Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. The purpose of our article is to highlight the mechanisms of autophagy and mitophagy and how defects in these pathways contribute to the physiological markers of aging and AD. This article also discusses how mitochondrial dysfunction, abnormal mitochondrial dynamics, impaired biogenesis, and defective mitophagy are related to aging and AD progression. This article highlights recent studies of amyloid beta and phosphorylated tau in relation to autophagy and mitophagy in AD.
Highlights
Aging is generally thought of as the time-dependent accumulation of cellular damage and decline in physiological function
Many events can lead to cellular dysfunction, several factors have been identified as the defining characteristics of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, cellular senescence, stem cell exhaustion, altered intercellular communication, and mitochondrial dysfunction (Figure 1; Lopez-Otin et al, 2013)
Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mutant amyloid precursor protein (APP) (mAPP)-HT22 cells. These findings suggest that hippocampal accumulation of mAPP and Amyloid beta (Aβ) is responsible for the abnormal mitochondrial dynamics and defective biogenesis of MAP2, autophagy, mitophagy, and synaptic proteins as well as reduced dendritic spines and mitochondrial structural changes in mAPP hippocampal cells
Summary
Aging is generally thought of as the time-dependent accumulation of cellular damage and decline in physiological function. Many events can lead to cellular dysfunction, several factors have been identified as the defining characteristics of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, cellular senescence, stem cell exhaustion, altered intercellular communication, and mitochondrial dysfunction (Figure 1; Lopez-Otin et al, 2013). To help protect from these threats, most organisms have evolved multiple forms of protective DNA mechanisms that collectively help minimize damage and maintain genomic stability. One such mechanism is the existence of telomeres on the end of chromosomal DNA, which are DNA repeats that prevent erosion of coding segments of DNA during replication. Most mammalian cells do not express telomerase, which leads to the progressive loss of the protective factor of telomeres (Blackburn et al, 2006). This article will highlight how mitochondrial dysfunction, abnormal mitochondrial dynamics, and impaired biogenesis are related to aging and AD pathogenesis
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