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Loss of Mitochondrial Function with Age in Monocytes may Contribute to the Development of Atherosclerosis

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Posted 25 March 2020 - 10:22 AM

Macrophage cells are derived from circulating monocytes, and, among many other tasks, are responsible for clearing out lipid deposits from blood vessel walls. The conventional view on the age-related nature of atherosclerosis, the build up of fatty deposits that narrow and weaken blood vessels, is that macrophages are vulnerable to oxidized lipids, particularly oxidized cholesterols such as 7-ketocholesterol. These oxidized lipids are far more prevalent in older people, a consequence of the cellular damage of aging. Macrophages in old tissues are overwhelmed by oxidized lipids and become inflammatory, dysfunctional foam cells, and then die, adding their debris to a growing atherosclerotic plaque.

Researchers here argue that the well known decline in mitochondrial function found in all tissues also affects the behavior of monocytes and macrophages in significant ways. Thus loss of mitochondrial function may make a meaningful contribution to the development of atherosclerosis, and methods of restoring mitochondrial function may help to slow the onset of the condition by making macrophages more resilient to the aged environment. As ever, determining the relative size of different contributing mechanisms is a challenging process. The only practical way forward is to put a halt to each different mechanism in isolation, and then observe the results.

Age-related changes at the cellular level include the dysregulation of metabolic and signaling pathways. Analyses of blood leukocytes have revealed a set of alterations that collectively lower their ability to fight infections and resolve inflammation later in life. We studied the transcriptomic, epigenetic, and metabolomic profiles of monocytes extracted from younger adults and individuals over the age of 65 years to map major age-dependent changes in their cellular physiology.

We found that the monocytes from older persons displayed a decrease in the expression of ribosomal and mitochondrial protein genes and exhibited hypomethylation at the HLA class I locus. Additionally, we found elevated gene expression associated with cell motility, including the CX3CR1 and ARID5B genes, which have been associated with the development of atherosclerosis.

Furthermore, the downregulation of two genes, PLA2G4B and ALOX15B, which belong to the arachidonic acid metabolism pathway involved in phosphatidylcholine conversion to anti-inflammatory lipoxins, correlated with increased phosphatidylcholine content in monocytes from older individuals. We found age-related changes in monocyte metabolic fitness, including reduced mitochondrial function and increased glycose consumption without the capacity to upregulate it during increased metabolic needs, and signs of increased oxidative stress and DNA damage.

Link: https://doi.org/10.1111/acel.13127

View the full article at FightAging
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