Abstract
The aging process is associated with significant alterations in mitochondrial function. These changes in mitochondrial function are thought to involve increased production of reactive oxygen species (ROS), which over time contribute to cell death, senescence, tissue degeneration, and impaired tissue repair. The mitochondrial permeability transition pore (mPTP) is likely to play a critical role in these processes, as increased ROS activates mPTP opening, which further increases ROS production. Injury and inflammation are also thought to increase mPTP opening, and chronic, low-grade inflammation is a hallmark of aging. Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening; however, NAD+ levels are known to decline with age, further stimulating mPTP opening and increasing ROS release. Research on neurodegenerative diseases, particularly on Parkinson's disease (PD) and Alzheimer's disease (AD), has uncovered significant findings regarding mPTP openings and aging. Parkinson's disease is associated with a reduction in mitochondrial complex I activity and increased oxidative damage of DNA, both of which are linked to mPTP opening and subsequent ROS release. Similarly, AD is associated with increased mPTP openings, as evidenced by amyloid-beta (Aβ) interaction with the pore regulator cyclophilin D (CypD). Targeted therapies that can reduce the frequency and duration of mPTP opening may therefore have the potential to prevent age-related declines in cell and tissue function in various systems including the central nervous system.
Highlights
The number of older adults is growing worldwide
It is important to note that neuroinflammation is observed in Parkinson’s disease (PD) [64], and inflammation leads to extracellular acidification [33] which in turn leads to increased reactive oxygen species (ROS) production in the cell driving further mitochondrial reactive oxygen species (mROS) release from the matrix of the mitochondria via the mitochondrial permeability transition pore (mPTP) [5, 34, 35]
Mitochondrial dysfunction is thought to play a significant role in the tissue degeneration and loss of function that occurs in multiple organ systems with advanced age
Summary
The number of older adults is growing worldwide. As a result, the incidence of age-associated diseases including AD, osteoporosis, sarcopenia, and osteoarthritis is increasing. As will be discussed later, ROS released from the mitochondria can damage nuclear DNA and lead to proapoptotic signals which increase mPTP openings [54,55,56]. ROS production within the cell leads to mPTP opening and subsequent mROS release.
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