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The power plants of the cell are, of course, the mitochondria. Every cell has a herd of hundreds of mitochondria roaming its cytoplasm, working to generate ever more copies of the chemical energy store molecule adenosine triphosphate that is used power cellular processes. Mitochondria are the distant descendants of ancient symbiotic bacteria. Like bacteria they replicate by division, but also tend to fuse together and promiscuously pass around component parts. Since the original symbiosis, mitochondria have evolved into component parts of the cell. They have their own remnant DNA, but much of the original genome has migrated into the cell nucleus over evolutionary time. Further, mitochondria are monitored and recycled when worn or damaged by the cell’s autophagic mechanisms, a constant process of quality control.
Mitochondrial function declines with age. In a minority of cells, mitochondrial DNA becomes damaged in ways that allow mutant mitochondria to outcompete their functional counterparts in the herd. The cell becomes pathological, exporting harmful oxidative molecules into the surrounding tissue. This contributes to conditions such as atherosclerosis via the creation of oxidized lipids that cause macrophages to become harmful, inflammatory foam cells. In the majority of cells, mitochondria undergo a form of general malaise, becoming structurally altered and less effective in their primary role of providing energy for the cell. This may be due to a failure of quality control mechanisms, which in turn may be due to declining mitochondrial fission, but the deeper roots of these issues are unclear.
It is generally acknowledged in the research community that at least slowing and preferably turning back the course of mitochondrial dysfunction in aging is a good idea. Mitochondrial dysfunction is quite clearly implicated in many age-related diseases, particularly neurodegenerative conditions. It may underlie more subtle and pervasive manifestations of aging such as declining stem cell function that leads to reduced tissue maintenance throughout the body, as well as the many downstream issues resulting from that. I have to say that, despite this consensus, all too little of the research community is working on means of addressing mitochondrial aging that have the potential for true rejuvenation of function.
Outside of the SENS rejuvenation research programs, the mainstream of the scientific community looks toward calorie restriction mimetics and other means of tinkering with mitochondrial function without addressing the root causes of decline. Increasing the amount of NAD+ in circulation in cells, for example, is presently popular. This will produce benefits in older individuals, and the initial trials seem promising in that respect, but it doesn’t solve the underlying problems. Thus this approach cannot achieve more than modest improvements in health and longevity, as those underlying problems remain, to gnaw away at the function of cells and tissues in myriad ways. The open access paper here is an example of this sort of focus, in that it does not look beyond ways to alter mitochondrial metabolism, perhaps making mitochondria a little more active or a little more resilient in the face of underlying damage. We can and must do better than this.
In a bid to unravel how and why aging occurs, a plethora of different theories of aging have surfaced over the decades. The free radical theory, which was first proposed in 1957 is one of the most well-known and longstanding theories of aging. The free radical theory suggests that mitochondria play a crucial role in aging, as they are the main source of reactive oxygen species (ROS), leading to increased mitochondrial DNA (mtDNA) mutations. Such aging-associated mtDNA mutations thus perturb mitochondrial function resulting in pathological conditions. Mitochondria, the molecular batteries of the cell, play a crucial role in regulating the energy of the cells by producing adenosine triphosphate (ATP) through oxidative phosphorylation. Their prominent role in cell homeostasis in almost all tissues thus explains its postulated widespread effects on aging.
In light of the wide-ranging effects of aging and the associated neurodegenerative diseases on mitochondrial dysfunction, negative conditioning thus surfaces as a solution to tackle the problem. Despite the fact that the mechanism of action of neurodegenerative conditions on mitochondrial dysfunction remains to be elucidated, the possible mechanisms and the potential key molecules involved have been narrowed, and could lead to new avenues for therapeutic intervention to improve mitochondrial quality and function.
Molecular evidence of mitochondrial dysfunctions opens up possibilities for targeting specific molecules or complexes for biochemical or pharmacological therapeutic interventions. Given the neuroprotective function conferred by Parkin and PINK1, their deficiencies could be targeted to restore mitochondrial function in Parkinson’s disease patients. For instance, nilotinib, a c-Abl tyrosine kinase inhibitor that is able to cross the blood brain barrier, can be used to increase Parkin levels. Parkin recruitment could also be increased by upregulating mutant PINK1 activity via kinetin triphosphate, an ATP analogue. Rapamycin is well-known to specifically inhibit the mammalian target of rapamycin (mTOR), which is a master regulator of growth and metabolism. Experimental evidence has shown that rapamycin reduced mitochondrial dysfunction after cerebral ischemia and this reduction was linked to significantly upregulated mitophagy.
Recently, researchers have looked at phytochemicals, natural compounds of vegetal origin, as a potential means of therapy. This approach is perceived to be closer to ‘natural’ treatment since the compounds are consumed in the diet, occur at physiological concentrations, or are known as traditional medicine. Notably, resveratrol, curcumin, quercetin, and sulforaphane are phytochemicals with the ability to contribute to negative conditioning of mitochondrial dysfunction. They do so by altering mitochondrial function and processes.
Dietary energy restriction (DR) by daily calorie restriction (CR) or intermittent fasting (IF) has been shown to extend lifespan and health span in various animal models. In addition, both CR and IF protect against age-related cardiovascular diseases and neurodegenerative diseases. Under CR, reactive oxygen species (ROS) generation has been observed to decrease especially at the liver and heart mitochondrial complex I in several studies. Such finding sheds light on how decreasing ROS can reduce disease occurrence. In an attempt to elucidate the molecular mechanism involved, numerous hypotheses have been put forth to explain how CR reduces ROS. One such hypothesis is that lowering the inner mitochondrial membrane potential along with the associated proton leak, may lead to a reduction in ROS generation. Due to reduced plasma concentration of hormones like thyroxin (T4) and insulin by CR, loss of double bonds in the membrane phospholipids is induced, resulting in a decline in the unsaturation/saturation index in several animal models tested. Such reduction increases membrane resistance to peroxidation injury thus lowering oxidative damage.
While numerous unresolved questions persist about the mechanistic link between neurodegenerative diseases and mitochondrial dysfunction, the fact that mitochondrial dysfunction plays a crucial role in the pathogenesis is clear. Mitochondrial dysfunction is a wide-ranging phenomenon that is triggered by a cohort of molecules, often incurring damage via multiple pathways. Despite decades of research on neurodegenerative diseases, treatment options remain purely symptomatic due to the unknown etiology. Given the common role played by mitochondrial dysfunction in neurodegenerative conditions, it provides a potential avenue for effective therapeutic intervention, and hopefully a platform for early intervention.
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