molecules Review The Lipidome Fingerprint of Longevity Mariona Jové, Natàlia Mota-Martorell, Irene Pradas, José Daniel Galo-Licona, Meritxell Martín-Gari , Èlia Obis, Joaquim Sol and Reinald Pamplona * Department of Experimental Medicine, Lleida University (UdL), Lleida Biomedical Research Institute (IRBLleida), 25198 Lleida, Spain; [email protected] (M.J.); [email protected] (N.M.-M.); [email protected] (I.P.); [email protected] (J.D.G.-L.); [email protected] (M.M.-G.); [email protected] (È.O.); [email protected] (J.S.) * Correspondence: [email protected]; Tel.: +34-973-702440 Academic Editor: Pierluigi Plastina Received: 29 August 2020; Accepted: 18 September 2020; Published: 22 September 2020 Abstract: Lipids were determinants in the appearance and evolution of life. Recent studies disclose the existence of a link between lipids and animal longevity. Findings from both comparative studies and genetics and nutritional interventions in invertebrates, vertebrates, and exceptionally long-lived animal species—humans included—demonstrate that both the cell membrane fatty acid profile and lipidome are a species-specific optimized evolutionary adaptation and traits associated with longevity. All these emerging observations point to lipids as a key target to study the molecular mechanisms underlying differences in longevity and suggest the existence of a lipidome profile of long life. Keywords: fatty acids; lipidomics; longevity; membrane unsaturation; peroxidation index 1. Introduction In contrast to life expectancy (also named mean lifespan, and frequently and wrongly termed “longevity”) that may be modified depending on living conditions, maximum longevity (henceforth referred to as “longevity” for practical purposes) is a species-specific feature. For instance, for the world as a whole, human life expectancy has increased more than two-fold in the last century, from 30 years in 1900 to 65 years in 2000 and is estimated to increase to 81 by the end of the 21st century. However, our longevity has remained at approximately 120 years [1]. At the same time, longevity varies widely among animal species with differences of up to 5000 times occurring, for example, between some invertebrates and the mollusk Arctica islandica, which at 507 years has the record for animal longevity [2,3], demonstrating the evolutionary plasticity of longevity. Therefore, animal (and human) longevity is flexible, regulated, and evolves rapidly during animal species evolution. Despite the importance of understanding the mechanisms involved in longevity, the existence and nature of the molecular mechanisms determining and controlling this biological trait remains unclear. Some mechanisms discovered from studies within and among animal species, but not exclusively, include oxidative stress-related pathways [4,5], insulin signaling pathways [6–9] and mechanistic targets of rapamycin pathway [10–13]. Notably, genetic, dietary and pharmacological manipulations targeting some of these pathways resulted in more than 10-fold longevity extension in the worm Caenorhabditis elegans [14], but only about 1.4-fold longevity extension in rodents [15,16]. Evidence accumulated during the last 25 years demonstrate that lipids are determinant players of animal (and human) longevity. Thus, genomic studies demonstrate that genetic changes in genes controlling lipid metabolism play a role in human longevity [17–20], as well as in longevity differences among animal species [21,22] and lipid studies on changes in membrane lipid unsaturation and lipidomic profiles (see next sections) among animal species clearly point to lipids as a good potential target for research on molecular mechanisms underlying differences in longevity among animal species. Molecules 2020, 25, 4343; doi:10.3390/molecules25184343 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 21 as a good potential target for research on molecular mechanisms underlying differences in longevity among animal species. Molecules 2020, 25, 4343 2 of 21 2. Lipids Are Essential for Life 2. LipidsLipids Are possess Essential an inherent for Life ability to spontaneously self-organize to generate membranes [23]. This propertyLipids possess of lipids an was inherent determinant ability for to spontaneouslythe origin and early self-organize evolution to ofgenerate life [24,25]. membranes The relevance [23]. ofThis lipids property in life of is lipidsfound was in the determinant fact that, without for the origin exception, and early all organisms evolution ofin lifethe [three24,25 ].domains The relevance of life (eukaryotes,of lipids in lifebacteria, is found and in archaea) the fact that,have withoutlipid membranes exception, [26]. all organismsIndeed, this in thehydrophobic three domains film of of aroundlife (eukaryotes, 30 Å of thickness bacteria, marks and archaea) the limit have between lipid life membranes and death [26 for]. Indeed,cells [27]. this The hydrophobic unique trait filmof the of firstaround lipids 30 Åto ofform thickness membranes marks was the limitexpanded between during life andevolution death forto cell cells signaling [27]. The as unique new functional trait of the property,first lipids and to form finally membranes to the energy was expanded storage during[28]. This evolution diversification to cell signaling of functional as new properties functional demandedproperty, and and finally was supported to the energy by storagean enlargement [28]. This in diversification the structural of and functional functional properties diversity demanded of lipid speciesand was that supported conformed by anearly enlargement organisms in and the that structural evolved and toward functional more diversity complex of cell lipid systems. species This that complexityconformed earlyis reflected organisms in the and genetic that evolved code, whic towardh assigns more complexmore than cell 5% systems. of their This genes complexity for the biosynthesisis reflected in of the thousands genetic code,of different which lipids assigns [29], more which than participate 5% of their in genes multitude for the of biosynthesispathways and of mechanismsthousands of that different are essential lipids [29 for], whichcell physiology. participate in multitude of pathways and mechanisms that are essentialIn agreement for cell physiology. with the current classification system, lipids are categorized into eight groups: sterolIn (ST) agreement and prenol with thelipids current (PR), classification saccharolipid system,s (SL) lipids and arepolyketides categorized (PK), into glycerolipids eight groups: (GL), sterol sphingolipids(ST) and prenol (SP), lipids glycerophospho (PR), saccharolipidslipids (SL) (GP), and and polyketides fatty acyls (PK), (FA). glycerolipids There are, (GL), at sphingolipids present, no consistent(SP), glycerophospholipids assessments on the (GP), number and fatty of discrete acyls (FA). lipid There compounds are, at present, in nature, no consistentbut the estimations assessments of theon thecellular number lipid of profile discrete comprise lipid compounds thousands in of nature, different but molecular the estimations species of [30]. the cellular This complexity lipid profile is magnifiedcomprise thousandswhen the ofmembrane different molecularcompositional species diversity [30]. Thisis considered. complexity For is magnifiedinstance, whenthe lipid the compositionalmembrane compositional profile varies diversity between is considered.animal spec Fories, instance,between thetissues–orga lipid compositionaln, between profile subcellular varies organelles,between animal between species, membrane between domains, tissues–organ, and between between the subcellular two leaflets organelles, of the lipid between bilayer membrane[27,31–46] (Figuredomains, 1). and However, between the the twocomplexity leaflets ofincreases the lipid when bilayer this [27 ,31diversity–46] (Figure in spatial1). However, distribution the complexity must be addedincreases as whena temporal this diversity distribution in spatial variable. distribution Thus, mustthe lipid be added profile as avaries temporal in time distribution according variable. with circadianThus, the lipidrhythmicity profile varies[47], inthe time physiological according withstate, circadian the vital rhythmicity cycle of [an47 ],organism, the physiological and during state, evolutionthe vital cycle [45,48–50]. of an organism, and during evolution [45,48–50]. Figure 1. Specific lipidomic profiles at subcellular, tissue, and animal species level. (A) Specific Figure 1. Specific lipidomic profiles at subcellular, tissue, and animal species level. (A) Specific lipidomic profile defines different subcellular components such as endoplasmic reticulum (ER) lipidomic profile defines different subcellular components such as endoplasmic reticulum (ER), mitochondrial-associated membranes (MAM), and mitochondrion (MIT). (B) Specific lipidomic profile mitochondrial-associated membranes (MAM), and mitochondrion (MIT). (B) Specific lipidomic for rat tissues. Principal component analysis (PCA) representation of the lipidome of all the tissues in profile for rat tissues. Principal component analysis (PCA) representation of the lipidome of all the positive ionization. Modified with permission from [46]. (C) Specific plasma lipidomic profiles for mammalian species. PCA representation (positive ionization molecules) showing that plasma lipidomic Molecules 2020, 25, 4343 3 of 21 profiles are species-specific. Modified with permission from [35]. (D) Human extreme