The role of oxidized lipids in aging is often studied in the context of comparative biology, comparing different species with divergent life spans in order to try to identify the properties of cellular metabolism that are most influential on life span. It appears that the degree to which lipids are resistant to oxidative reactions is an important factor, and this has given rise to the membrane pacemaker hypothesis. There is something in mitochondrial function and resilience of lipids in mitochondrial membranes to forms of damage that is important in life span, at least at the scale of differences between species. Do lipid variations have a noteworthy effect on aging and longevity within a species, however? The evidence here suggests that there is an effect, but says little about the size of the effect.

Maximum lifespan (MLSP) is a species-specific feature that may differ more than 5000-fold among animal species being about 120 years in humans. Centenarians are considered an exceptional human model of healthy aging and extreme longevity. Available evidences reveal the existence of a link between MLSP and lipids. Thus, the findings from several studies demonstrate that the membrane fatty acid profile differs between animal species (including vertebrates, invertebrates, and exceptionally long-lived animal species) and that cell membrane susceptibility to lipid peroxidation is inversely related to MLSP. Furthermore, a recent phylogenomic approach showed that genes involved in lipid metabolism have undergone an increased selective pressure in long-lived species, reinforcing the idea that cell membrane lipid profile has been an optimized evolutionary adaption.

The physiological role of ether lipids, and specially plasmalogens, is essentially linked to their function as membrane components. Thus, plasmalogens seem to play a key role in specific properties of cell membrane. Interestingly, an antioxidant effect has also been ascribed to plasmalogens. Effectively, the vinyl-ether linkage of the plasmalogens is particularly susceptible to oxidation by reactive species such as reactive oxygen species and hypochlorous acid, and thus, like a scavenger, could protect unsaturated membrane lipids (as well as lipoproteins) against oxidation.

Consequently, plasmalogens could have a modulatory effect on oxidative stress, lipid-derived inflammation and cell signalling mechanisms. Lipidomic studies reveal that ether lipids are inversely associated with genetic peroxisomal disorders, and also suggest that they are negatively associated with prevalent disease states such as obesity, prediabetes, type 2 diabetes mellitus, cardiovascular disease, cancer and Alzheimer's disease, among others. Notably, these pathological states share as common trait an increased oxidative stress, and a potential mechanistic role for plasmalogens.

Although the fact that systems biology-based approaches allow a comprehensive molecular characterization of complex biological systems, up to date no targeted lipidomic studies investigating differences in plasma of exceptionally long-lived humans have been reported. To this end, we have designed a study that represents the most detailed lipidomic analysis of plasma ether lipids associated with human longevity. We discovered a particular ether lipid signature related to the condition of extreme longevity, allowing the identification of potential mechanisms and biomarkers of healthy aging.