Lipid Metabolism in Aging and Age-Related Disease

Lipids are everywhere in our biochemistry. Where they are present in cell structures and molecular mechanisms that are important to any specific age-related disease, or are among the underlying root causes of aging, it will tend to be the case that differences between species (and possibly individuals) can lead to changes in the pace of aging and disease. For example, lipid composition determines resistance to oxidative damage to cell membranes. A range of evidence supports the membrane pacemaker hypothesis of aging, in that longer-lived species tend to have more resilient cell membranes, based on their lipid composition.

Today's open access paper uses lipids as an anchoring point for a wide-ranging discussion on aging, biomarkers of aging, and the differences in aging between species. The authors are, I feel, justifiably pessimistic about the prospects for the eventual production of therapies based on most of the means to slow aging demonstrated in short-lived laboratory species. There are indeed radical differences between the biochemistry of short-lived species and long-lived species such as our own. Yet even when mechanisms are in fact proven to be much the same in all of worms, flies, mice, and humans, as is the case for calorie restriction and its upregulation of cellular maintenance processes, we cannot expect that therapies will automatically be effective enough to justify development. The practice of calorie restriction extends life in mice by up to 40%, but while it improves health in humans, it certainly doesn't significantly extend human life span in the same way.

The role of lipid metabolism in aging, lifespan regulation, and age-related disease

Due to the sheer amount of time and cost required to validate a study in humans, the bulk of our aging and lifespan data come from shorter-lived yeast, worms, flies, and rodents. With the exception of research showing that caloric restriction improves health and survival in rhesus monkeys, little aging work has been done in longer-lived organisms. The bulk of our understanding regarding aging comes from genetic experiments in model organisms, and we do not yet know how similar or dissimilar human aging is. Rather than screen every lifespan-extending intervention in humans to better understand how human aging works, another approach would be to utilize aging biomarkers.

Biomarkers that strongly correlate with aging, lifespan, and healthspan can teach us about which processes are involved in human aging. Ideally, a robust and practical biomarker would be one that incurs a low monetary cost and can be measured safely, repeatedly, and easily. Blood draws are especially appealing because they are inexpensive, simple, low risk, and can be taken as needed throughout a patient's lifetime. While several biomarker studies have focused on protein-based markers, the advancement of metabolomic techniques has made it feasible to look closely into a large array of metabolites. Metabolomic lipids and lipid-related proteins represent a large, rich source of potential biomarkers that are easily measured in the blood. Compounds in lipid metabolism can take many forms, such as phospholipids, triglycerides, waxes, steroids, and fatty acids. They also play diverse physiological roles, such as forming cell membranes and exerting powerful cell signaling effects. Lipids are perhaps the most well-known for the paramount roles they play in both the storage and mobilization of energy.

Although lipids have been traditionally treated as detrimental and as simply associated with age-related diseases, numerous studies have shown that lipid metabolism potently regulates aging and lifespan. For example, researchers assessed the plasma lipidomic profiles of 11 different mammalian species with longevities varying from 3.5 to 120 years. They found that a lipidomic profile could accurately predict an animal's lifespan and that, in particular, plasma long-chain free fatty acids, peroxidizability index, and lipid peroxidation-derived product content are inversely correlated with longevity. Evidence from animals with extreme longevity also links lipid metabolism to aging. The ocean quahog clam Arctica islandica, an exceptionally long-lived animal that can survive for more than 500 years, exhibits a unique resistance to lipid peroxidation in mitochondrial membranes. Naked mole rats, which enjoy remarkably long lifespans and healthspans for rodents, have a unique membrane phospholipid composition that has been theorized to contribute to their exceptional longevity.

A plethora of dietary, pharmacological, genetic, and surgical lipid-related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17-α-estradiol, or a ketogenic diet.

In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid-related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers.

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