Defective Autophagy and Mitophagy in Aging and Alzheimer’s Disease

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.

Autophagic Organelles in DNA Damage Response

“…Aging is known to be a major factor in causing cardiovascular disease (Liang and Gustafsson, 2020) and is also known as a major reason for age-related diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), and amyotrophic lateral sclerosis. Such aging proceeds according to biological conditions such as oxidative damage, telomere length, and mitochondrial dysfunction, and it is known that mitophagy is involved in regulating these abnormal environments (Tran and Reddy, 2020). When mitochondria are damaged, it is widely known to affect aging and neurodegeneration.…”

Neuroinflammation in Alzheimer’s Disease

“…Aging is characterized by dysregulated immune [ 1 ] and metabolic homeostasis [ 2 , 3 ] where there is chronic sterile low-grade inflammation or inflammaging [ 4 ] that involves cellular senescence [ 5 , 6 ], immunosenescence [ 7 , 8 , 9 , 10 ], mitochondrial dysfunction [ 11 , 12 ], defective autophagy [ 13 , 14 ] and mitophagy [ 15 , 16 ], dysregulation of the ubiquitin–proteasome system [ 17 , 18 ], activation of the DNA damage response [ 19 , 20 ], meta-inflammation or metaflammation from chronic overnutrition or obesity [ 21 , 22 ], and gut microbiota dysbiosis [ 5 , 23 , 24 , 25 ]. These are reflected by changes in circulating immune markers including C-reactive protein (CRP) [ 26 ], interleukin-6 (IL-6) [ 27 ], tumor necrosis factor alpha (TNF-α) [ 28 ] and its soluble receptors (tumor necrosis factor receptor I (TNFR-I) and tumor necrosis factor receptor II (TNFR-II)) [ 28 ], vascular cell adhesion molecule I (VCAM-I) [ 29 ], d-dimer [ 30 ], and sirtuin signaling [ 31 , 32 ].…”

DNA Damage-Induced Neurodegeneration in Accelerated Ageing and Alzheimer’s Disease

“…DNA damage not only accumulates in chromosomal DNA, but also in mtDNA, leading to mitochondrial dysfunction [58]. Dysfunctional mitochondria are targeted for lysosomal destruction through mitophagy and are recycled for cell utilization, as well as being degraded by the ubiquitin-proteasome system (UPS) [59].…”