Mito-Omics and immune function: Applying novel mitochondrial omic techniques to the context of the aging immune system (original) (raw)
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The mitochondrial genome (mtDNA) represents a tiny fraction of the whole genome, comprising just 16.6 kilobases encoding 37 genes involved in oxidative phosphorylation and the mitochondrial translation machinery. Despite its small size, much interest has developed in recent years regarding the role of mtDNA as a determinant of both aging and age-associated diseases. A number of studies have presented compelling evidence for key roles of mtDNA in age-related pathology, although many are correlative rather than demonstrating cause. In this review we will evaluate the evidence supporting and opposing a role for mtDNA in age-associated functional declines and diseases. We provide an overview of mtDNA biology, damage and repair as well as the influence of mitochondrial haplogroups, epigenetics and maternal inheritance in aging and longevity.
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The mitochondrial theory of aging, a mainstream theory of aging which once included accumulation of mitochondrial DNA (mtDNA) damage by reactive oxygen species (ROS) as its cornerstone, has been increasingly losing ground and is undergoing extensive revision due to its inability to explain a growing body of emerging data. Concurrently, the notion of the central role for mtDNA in the aging process is being met with increased skepticism. Our progress in understanding the processes of mtDNA maintenance, repair, damage, and degradation in response to damage has largely refuted the view of mtDNA as being particularly susceptible to ROS-mediated mutagenesis due to its lack of "protective" histones and reduced complement of available DNA repair pathways. Recent research on mitochondrial ROS production has led to the appreciation that mitochondria, even in vitro, produce much less ROS than previously thought, automatically leading to a decreased expectation of physiologically achi...
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The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging.
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The population of elderly individuals has increased significantly over the past century and is predicted to rise even more rapidly in the future. Ageing is a major risk factor for many diseases such as neurodegenerative disease, diabetes and cancer. This highlights the importance of understanding the mechanisms involved in the ageing process. One plausible mechanism for ageing is accumulation of mutations in the mitochondrial genome. In this review, we discuss some of the most convincing data surrounding age-related mtDNA mutations and the evidence that these mutations contribute to the ageing process.
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Among the numerous theories that explain the process of aging, the mitochondrial theory of aging has received the most attention. This theory states that electrons leaking from the ETC (electron transfer chain) reduce molecular oxygen to form O2•− (superoxide anion radicals). O2•−, through both enzymic and non-enzymic reactions, can cause the generation of other ROS (reactive oxygen species). The ensuing state of oxidative stress results in damage to ETC components and mtDNA (mitochondrial DNA), thus increasing further the production of ROS. Ultimately, this ‘vicious cycle’ leads to a physiological decline in function, or aging. This review focuses on recent developments in aging research related to the role played by mtDNA. Both supportive and contradictory evidence is discussed.
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Mitochondria are eukaryotic organelles known best for their roles in energy production and metabolism. While often thought of as simply the 'powerhouse of the cell,' these organelles participate in a variety of critical cellular processes including reactive oxygen species (ROS) production, regulation of programmed cell death, modulation of inter-and intracellular nutrient signaling pathways, and maintenance of cellular proteostasis. Disrupted mitochondrial function is a hallmark of eukaryotic aging, and mitochondrial dysfunction has been reported to play a role in many aging-related diseases. While mitochondria are major players in human diseases, significant questions remain regarding their precise mechanistic role. In this review, we detail mechanisms by which mitochondrial dysfunction participate in disease and aging based on findings from model organisms and human genetics studies.
Journal of Scientific Research, 2010
According to the mitochondrial theory of aging, accrual of mutations in mitochondrial DNA (mtDNA) plays the paramount function in the cellular pathology of aging and in development of age-related degenerative ailments. Reactive oxygen species (ROS), which are byproducts of oxidative phosphorylation (OX-PHOS) in aerobic (mitochondrial) respiration, cause oxidative stress-induced damage to mtDNA. This damaged DNA, whose normal role is to encode proteins many of which are players in the electron transport chain (ETC), now codes for defective proteins. Such faulty proteins lead to a considerable impairment in the efficacy of ETC, thereby generating more ROS, which cause further damage to mtDNA in turn, leading to further defects in proteins, aggravated ETC dysfunction, and even more ROS. Hence, a ‘vicious cycle’ propagates that ultimately directs tissue cells towards structural and functional decline, or in other words, degeneration and aging. However, in spite of a wide acceptance of t...
Mitochondrial form, function and signalling in aging
The Biochemical journal, 2016
Aging is often accompanied by a decline in mitochondrial mass and function in different tissues. Additionally, cell resistance to stress is frequently found to be prevented by higher mitochondrial respiratory capacity. These correlations strongly suggest mitochondria are key players in aging and senescence, acting by regulating energy homeostasis, redox balance and signalling pathways central in these processes. However, mitochondria display a wide array of functions and signalling properties, and the roles of these different characteristics are still widely unexplored. Furthermore, differences in mitochondrial properties and responses between tissues and cell types, and how these affect whole body metabolism are also still poorly understood. This review uncovers aspects of mitochondrial biology that have an impact upon aging in model organisms and selected mammalian cells and tissues.
Aging impairs mitochondrial respiratory capacity in classical monocytes
Experimental Gerontology, 2018
Aging is a critical healthcare concern, with age-related inflammation disposing individuals to a variety of diseases. Monocytes are affected by the aging process, with increased inflammation and impaired cellular functions such as phagocytosis. Mechanisms by which aging alters monocyte function are unknown, but recent research suggests that the balance of metabolic processes determine immune cell phenotype and function. Given the known association between aging and mitochondrial dysfunction in other tissues, we hypothesized that aging would impair mitochondrial function in monocytes. To test this, we isolated classical monocytes from young and older adults and tested mitochondrial function by a Seahorse assay. Aging reduced mitochondrial respiratory capacity and spare capacity in monocytes. Mitochondrial dysfunction is a potential mechanism by which aging alters monocyte phenotype and may impair inflammatory functions, especially in low-glucose environments where oxidative metabolism is necessary to meet energy demands.