Phosphatidylcholine Synthesis Declines with Age to Contribute to Mitochondrial Dysfunction
Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that evolved to become components of the cell. Along the way most of the original mitochondrial genome migrated into the cell nucleus, leaving only a small remnant genome inside mitochondria. The primary task undertaken by mitochondria is the production of the chemical energy store molecule adenosine triphosphate (ATP), used to power cell activities. This is produced via energetic processes that also produce reactive oxygen species capable of damaging structures in the cell. Mitochondria, like all cell structures, are subject to replacement when damaged or dysfunctional. Mitochondria are recycled via the complex process of mitophagy, whereby a mitochondrion is conveyed to a lysosome to be disassembled into raw materials for protein synthesis. Mitochondria, like the ancestral bacteria they evolved from, make up lost numbers by replicating.
Unfortunately all of this glorious complexity runs awry with age. In old tissues, cells contain mitochondria characterized by altered morphology, impaired ATP production, increased reactive oxygen species production, and other dysfunctions, such as leakage of mitochondrial DNA fragments into the body of the cell where they trigger inflammatory reactions that evolved to combat infectious pathogens. Researchers are interested in trying to understand the causes of mitochondrial dysfunction with age, in a search for ways to address the issues. Much of it results from changes in gene expression in the cell nucleus, but it is a slow process to identify, one by one, important mechanisms that are impaired with age and then uncover possible ways to address each issue. Today's open access paper is an example of this sort of discovery, and since the findings point to choline supplementation as a way to address the problem, it seems likely to be only a minor contribution to overall mitochondrial dysfunction in our species. After all, choline supplementation is widely used and doesn't produce world-changing outcomes to health.
Mitochondrial dysfunction is clearly one of the best recognized hallmarks of aging, and in addition to causing cellular deterioration in late life, it blunts the efficacy of anti-aging interventions that rely on metabolic plasticity such as dietary restriction (DR) and DR mimetics. Despite extensive studies linking genetic impairments of mitochondrial homeostasis (e.g., altered fidelity of mitochondrial DNA synthesis, mitochondrial unfolded protein response (UPR), oxidative phosphorylation (OXPHOS) and others) to diseases and accelerated aging, it is less clear what endogenous processes instigate mitochondrial decline during normal aging. The identification of such "natural" drivers of mitochondrial aging is however crucial because they likely comprise suitable intervention targets towards restoration of mitochondrial integrity and organismal health in late life.
In this work, we combined omics, genetics, and functional analyses in C. elegans, with transcriptomics and metabolomics analysis in humans, and metabolic resilience tests in cell culture models to discover previously unrecognized interventions that improve mitochondrial health and metabolic plasticity during advanced aging. Our studies revealed a decline in phosphatidylcholine (PC) synthesis as a previously unappreciated, conserved driver of natural mitochondrial aging, which can be overcome by dietary supplements.
We initially used longitudinal proteomics analysis in wild type C. elegans and long-lived mitochondrial mutants, which was coupled to RNAi-mediated gene inactivation and longevity testing, to demonstrate that S-adenosylmethionine synthetase SAMS-1 is required for longevity maintenance in the context of mitochondrial impairments. Concurrently, we found SAMS-1 to be among the strongest downregulated proteins in old wild type nematodes in line with previous observations, and same strong and progressive downregulation with age was discovered for phosphoethanolamine N-methyltransferases PMT-1 and PMT-2, which utilize S-adenosylmethionine (SAM, the product of SAMS-1) in the nematode pathway of methylation-dependent PC synthesis.
We next explored the mechanistic basis of the longevity link between sams-1 gene inactivation and mitochondrial impairments, and discovered that knockdowns (KDs) of sams-1, pmt-1 and pmt-2 genes cause an early life increase of mitochondrial fragmentation and a decline of mitochondrial respiration that are comparable to structural and functional alterations of mitochondria observed during normal aging.
Importantly we could alleviate these defects by dietary provision of PC or choline (is converted to PC by the CDP-choline pathway) both in the KDs and also during WT aging. The impact of aging and the above gene knockdowns on the abundance of PC and its derivative lysophosphatidylcholine (LPC) were validated by lipidomics, and the restorative effect of choline supplementation was also detected in this case. While choline can enter several metabolic pathways once inside the cell, the collective evidence presented in this study suggests that the effects of choline provision on mitochondrial function are largely mediated through its conversion to PC.
Interestingly, we discovered by using the GTEx dataset (v8) and previously pre-processed gene expression data that levels of the human PMT-1/2 analog PEMT decline with age in several tissues and especially in organs showing overall highest PEMT expression. We followed up by analyzing the metabolomics data of the UK biobank cohort to discover that PC levels decline with age also in humans and especially in post-menopausal females known to be affected by mitochondrial insufficiency. This data indicates that aging-associated decrease of methylation-dependent PC synthesis is evolutionary conserved and may contribute to "natural" aging of mitochondria across species while other factors - such as the age-related upregulation of phospholipase activity, may also play a role in reducing PC levels with age.