Fight Aging!

The body contains hundreds of different types of lipid molecules, participating in cellular metabolism in ways that are just as complex and relevant to health as the activities of other biomolecules. In the context of aging, this broad range of lipids are perhaps understudied in comparison to levels and roles of proteins and patterns of gene expression. The situation is much the same, however: researchers can readily and cost-effectively amass a vast amount of data, but the analysis of this data lags far behind the accumulation of ever more and ever larger omics databases. It is ever unclear as to whether any particular association is useful or relevant. Is it only a consequence of meaningful processes, a side-effect, something that causes no further significant issues, or does it actually cause pathology, directly or indirection, to a level that makes it worth trying to intervene?

When one has to ask that question of hundreds or thousands of different biomolecules, it begins to look more sensible to focus on known root causes of aging and intervene there. First intervene and evaluate the outcome, rather than first working to increase understanding of the fine details of aging. Doing both is of course the right choice given unlimited time and funding, but that is a luxury that none of us has, least of all scientific organizations. Further, when researchers intervene by, say, clearing senescent cells or improving mitochondrial function, and thereby improve health and extend life, then the resulting changes in specific lipid levels will tell us just as much about the relevance of that data as would a much longer exercise in studying people of varied ages undergoing aging without intervention.

The lipidomic correlates of epigenetic aging across the adult lifespan: A population-based study

Despite the intriguing connection between lipid metabolism and aging, it is still unknown whether and how inter-individual differences in lipid profiles contribute to different rates of biological aging in the general population. The heterogeneous chemical structure of lipids poses challenges for their accurate quantification, and until now only a few lipid species have been investigated in the context of human aging and age-related health outcomes. We investigated 14 complex lipid classes, covering 964 molecular species and 267 fatty acid composites, with biological aging. We found complex lipid species to be differently associated with different rates of biological aging. Higher levels of molecular species belonging to the neutral lipids (MAG, DAG, TAG), phospholipids (PE, PE(O), PE(P)), and sphingolipids (CER, DCER) classes were associated with accelerated biological aging, whereas higher levels of distinct other molecular species (i.e., LPC, HCER, and LCER) were associated with slower biological aging. CE, PC, and LPE molecular species with odd-numbered (i.e., 15 and 17) fatty acid tail lengths were associated with slower biological aging, yet even-numbered fatty acid tail lengths were associated with faster biological aging. Importantly, in silico pathway analysis revealed that lipids that were associated with biological aging estimators were mainly involved in known longevity and aging-related pathways, revealing their role as potential determinants of biological aging across the lifespan in the general population.

Very little work has explicitly assessed the value of LPC species as potential human blood-derived biomarkers of human aging. Circulating LPCs are generated by phospholipases A2 from the PC. The most abundant LPC in human plasma is 16:0, followed by 18:2, 18:0, 18:1, 20:4, and other minor species. Here we found that higher levels of 13 out of 19 LPC species exhibit a robust association with slower biological aging, suggesting that LPC species may contribute to healthy aging. Our findings expand on those from recent epidemiological studies, which assessed a limited number of LPC species, and reported low concentrations of certain circulating LPCs (i.e., 18:2 and/or 17:0) to be associated with several aging-related phenotypes and disorders, including memory impairment, gait speed decline, and incident myocardial infarction. Moreover, elevated LPC (18:1) levels have been reported in centenarians. Potential biological mechanisms through which LPCs could contribute to slower biological aging and less age-associated functional decline are anti-oxidative stress and anti-inflammatory responses.

The major phospholipids in eukaryotic biomembranes are phosphatidylcholine (PC), and phosphatidylethanolamine (PE), which were also quantified in our study. PC can be synthesized by a three-step methylation of PE. We found that higher levels of various PE species were related to accelerated biological aging across the lifespan, whereas higher levels of polyunsaturated PCs were associated with slower biological aging. Higher levels of species with fewer double bonds tended to be associated with accelerated biological aging. These findings are in line with previous studies that found associations between higher levels of saturated and monounsaturated PCs and increased risk of cardiovascular diseases and type 2 diabetes. Conversely, polyunsaturated PC species have been linked to longevity, which might be due to their antioxidative and cardioprotective properties. PE species, the second most abundant membrane phospholipids, have been identified as modulators of inflammation and apoptosis, yet little is known about the properties of specific PE species.

Higher TAG levels are linked to an increased risk of cardiovascular diseases and Alzheimer's disease. Small-scale lipidomic profiling in longevity studies also found lower levels of TAG species (including TAG 46:5, 47:5, 52:1, 54:7, 54:6, 56:6, 56:7, 57:2) to be associated with healthy aging. Our findings extend these previous reports by showing that 361 out of 519 TAG species across different chain lengths and double bonds were associated with accelerated biological aging. Few studies have investigated the association between other neutral lipids (including CE, MAG, and DAG) and longevity or healthy aging. We found that higher levels of DAG species or lower levels of CE species were related to an accelerated rate of biological aging, indicating that almost all neutral lipids could potentially influence longevity.