One of the holy grails of medicine is a cure for aging, and it has been the inspiration of many myths and legends, such as the Elixir of Life, the Philosopher’s Stone, and the Fountain of Youth. Although lifespan can vary, aging is an inevitable outcome of virtually all animals. As we start to develop a better understanding of the underlying biological processes that contribute to aging, the quest for an anti-aging remedy becomes less of a myth and more of a reality.
One of the most prominent theories of aging revolves around mitochondria, the main energy producers of cells. Each cell in our body possesses hundreds of these intracellular structures, which facilitate the reaction between carbohydrates and oxygen to produce ATP, the main energy molecule of the cell. They are also essential for helping the cell digest other nutrients, such as amino acids and lipids, and can act as a switch to initiate cell death. The mitochondrial theory of aging, therefore, proposes that a decline in mitochondrial function is one of the causal factors of aging.
While most of a cell’s genetic information is stored within the nucleus as DNA, the mitochondria also harbour some DNA of their own, termed mitochondrial DNA (mtDNA). This mtDNA encodes a small number of the cellular machinery required for the mitochondria to perform some of their metabolic functions. With age, mtDNA becomes increasingly prone to mutations, and the resulting machinery produced using this DNA is less efficient at coupling oxygen metabolism with ATP synthesis, leading to the production of toxic oxygen by-products, called “reactive oxygen species” or ROS. These ROS, in turn, can further promote DNA mutations both within the mitochondria and in other parts of the cell, as well as react with other cell components like proteins and lipids in a chemical process known as oxidation. The buildup of ROS can directly damage mitochondrial and other cellular proteins, as oxidized metabolic proteins lose efficiency. Lipid oxidation can also impair the structural integrity of the cell. The release of ROS and cell debris following cell death into the extracellular space within a given tissue could also trigger inflammation. All in all, these processes result in a loss of efficiency in cell metabolism and cell death due to oxidative stress. The mitochondrial theory of aging, therefore, proposes that the accumulation of damaged biomolecules and subsequent mitochondria dysfunction leading to cell death, drives aging.
While it may be easy to believe how this elaborate tale of mitochondrial dysfunction, ROS release, and cell death could lead to aging, does this theory have any weight? How do we connect the dots between mitochondrial dysfunction and the overall declining health seen in aging individuals? Indeed, mitochondria are theorized to play a role in many age-associated diseases and other aspects of human health that develop with age. For example, age is a risk factor for both atherosclerosis, which involves the buildup of fats and cholesterol along the artery walls leading to inflammation, and osteoarthritis, which is characterized by the wear and tear of cartilage cells in joint tissues. In both diseases, mtDNA mutations were associated with disease severity, suggesting that mitochondrial dysfunction and excess ROS production may be contributing to cell loss and inflammation.
In addition to disease outcomes, mitochondrial dysfunction has also been linked to visible signs of aging, such as grey hair and wrinkle formation. Healthy mitochondria play an important role in providing energy to cells for tissue regeneration, which becomes less efficient with age, making elderly individuals more prone to injury and muscle weakening. In the semitendinosus muscle of elderly individuals, there is an increase in mitochondrial factors that induce cell death, which could explain the decline in functionality and muscle volume with age.
As regular mitochondrial function becomes compromised, cells attempt to recycle these faulty mitochondria into healthy ones, a process that becomes less efficient with age. While healthy mitochondria may not be the only component required to extend lifespan, many of our long-lived animal counterparts, such as the bivalve mollusc, Arctica Icelandica, that can live >500 years, have extremely efficient mitochondria that produce limited toxic by-products. Can restoring mitochondrial function in humans be a possible remedy for aging?
Popular health trends, such as caloric restriction and daily physical activity, are emerging as efficient strategies to slow down mitochondrial aging and delay age-related dysfunction through efficiently processing oxygen to avoid ROS production. In addition, the health benefits of red wine can be attributed to the natural compound resveratrol, which can improve mitochondrial numbers and function, and has been heralded as possessing “anti-aging” properties.
All in all, our knowledge of the biological mechanism of aging is improving, as reflected in these lifestyle trends. The progress we have made in our understanding thus far offers hope that a remedy for aging might indeed be something that exists outside of the realm of science fiction, and unlocking the secrets of mitochondria biology may lie at the heart of this fabled cure.
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