Aging & Longevity: Mitochondrial Genetic Pathways

Over the last decade, we have seen a growth in the Elderly population. A broad set of socioeconomic and biochemical challenges are included in the aging process. While the human species has increased their longevity, aging and the molecular mechanisms that come with it need to be addressed and modulated to decrease the risk of degenerative diseases. 

By understanding the molecular function of aging, we can tell that mitochondrial function is a cornerstone of this process. Therefore, we need a multidisciplinary anti-aging approach to improve mitochondrial function to treat, modulate, and reverse degenerative diseases.

Aging:

Aging associates with a progressive decline of organ function, increasing the risk of degenerative disease and death. From a molecular point of view, aging is a consequence of the lifelog damage accumulation in tissues, such as lipidic membranes, proteins, and DNA sequences. Furthermore, genetic research has identified multiple mitochondrial signaling pathways that influence the aging rate of organisms. In addition, these pathways have evolved to modulate critical processes, which depend directly on the availability of substrates like nutrients and energy. 

Most evolutionary theories in aging report that this mechanism is less likely to be a programmed process, where the mechanism is to sacrifice the older individual in favor of the young. Otherwise known as natural selection. On the other hand, research supports the principle in which the optimization of resources, such as energy and nutrients, contributes to growth and reproduction or maintenance and repair functions in organisms. In fact, this theory might explain the differences in aging between species. For example, some species prioritized growth and reproduction, increasing the aging and degeneration rate. On the other hand, longer-lived species focused their resources on repair and maintenance by enabling genetic adaptation to the environment leading to better survival. 

If this theory is correct (and I do believe it is), the next step is to determine which cellular components harvest the most damage in their structure, leading to functional decline. Consequently, this will provide a practical approach that will deliver the substrates to modulate the pathways that ensure maintenance and repair of the organism.

Mitochondria and its functions.

Commonly known as the powerhouse of the cell, mitochondria are membrane-bound organelles. Mitochondria anatomy is comprised of 4 significant compartments, each one of them with its structural function.

• Mitochondrial outer membrane: This is a highly porous structure, perforated with large channels that enable the entry of molecules. It also contains enzymes involved in mitochondrial lipid synthesis.
• Mitochondrial intermembrane space: The space between the inner and the outer membrane, this compartment gathers the H protons, enabling ATP formation by ATP-synthase.
• Mitochondrial inner membrane: It is considered an impermeable layer comprised of folder cardiolipin-rich cristae. It holds all the protein complexes of the electron transport chain (ETC) and ATP synthase. 
• Mitochondrial Matrix: This is the internal space of the mitochondrion. It holds the Krebs cycle enzymes, mtDNA, ribosomes, GSH, mtRNA, and nitric oxide.

Mitochondrial functions rely on the integrity of its anatomical structure that enables the harvest of H+ protons and maintains ion gradients, calcium buffering, production of ROS, cell signaling, growth regulation, and energy production in the form of ATP. Furthermore, all of these capacities position mitochondrial function in the spotlight of bioenergetic research.

Mitochondrial function, repair, and apoptosis depend on an intricate bi-directional pathway between the mitochondrial and the nucleus. Furthermore, the mtDNA structure is organized into nucleoids, which are closely associated with the mitochondrial inner membrane. Indeed, the inner membrane produces ROS, and this mechanism is why mtDNA is expected to go under constant oxidative damage. Nevertheless, DNA repair pathways, such as base excision repair (BER), seem to play a crucial role in repairing DNA structure mainly through nucleotides recycled from the mitochondrial metabolic processes or imported by the cytoplasm.

Therefore any genetic defect on the mechanisms that supply nucleotides would reflect in mtDNA depletion syndromes (MDS), resulting in mitochondrial dysfunction.

Aging has become a diagnosis, not just something that happens over time. All the theories point out that dysregulation of mitochondrial function is a cornerstone of significant organ dysfunction and degenerative diseases. Understanding how the mitochondria regulate, modulate, and produce energy and ROS will provide the proper treatment to counteract the oxidative process and increase mitochondrial biogenesis. – Ana Paola Rodríguez Arciniega, MS

References:

Akbari, Mansour et al. “Mitochondria in the signaling pathways that control longevity and healthspan.” Aging research reviews vol. 54 (2019): 100940. doi:10.1016/j.arr.2019.100940

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