In Search of Lipid Signatures of Longevity in Mammalian Species

The research here makes a good companion piece to older work in which scientists correlate the lipid composition of cell membranes to species longevity, in the course of evaluating what is known as the membrane pacemaker hypothesis. Among other things, this points to the significance of mitochondrial function and mitochondrial damage in aging, given that, all other things being equal, species characterized by more resilient mitochondrial structures appear to live longer. This is probably far from the only reason why there might be specific lipid signatures associated with longer-lived or shorter-lived species, however.

In contrast to average life expectancy that may change depending on living conditions, maximal lifespan (MLS) is a stable characteristic of a species. At the same time, MLS varies greatly among species. In mammals it ranges from 3-4 years in small rodents to as long as 150-200 years in bowhead whales. More remarkably, MLS evolves rapidly, resulting in markedly different lifespans and, consequently, different time of aging onset, even among closely related species. For instance, humans and macaques diverged only around 30 million years ago (MYA), yet over this time their MLS has diverged as much as three-fold.

Despite remarkable evolutionary plasticity of MLS, the existence and nature of the molecular mechanisms controlling this variation remains unclear. Most studies so far have focused on mechanisms of lifespan plasticity within species, resulting in identification of longevity-related pathways, such as insulin signaling pathways and targets of rapamycin pathway, shared across a wide range of animal species: from worms to mice. Genetic, dietary and pharmacological manipulation targeting these pathways resulted in more than 10-fold lifespan extension in short-living nematode worms, but only approximately 40% (1.4-fold) lifespan extension in short-living mammals such as laboratory mice. At the same time, natural variation in MLS among mammalian species exceeds 50-fold.

In this study we searched for a link between MLS and another marker of species' physiology - concentrations of hydrophobic metabolic compounds (henceforth referred to as "lipids" for simplicity). Recent scans of gene expression variation among 33 mammalian species with MLS differences of over 30-fold has shown that expression variation of 11-18% of analyzed 19,643 genes could be associated with MLS variation. There is however a stronger evidence of genetic changes in genes controlling lipid metabolism to play a role in human longevity, as well as in MLS differences among species, and changes in lipid saturation levels, pointing to lipids as a good potential target for investigation of molecular mechanisms underlying differences in MLS among mammalian species.

Our results show that long lifespan is associated with distinct lipidome features shared across three mammalian clades. Lipid predictors of long MLS differ across tissues, but overlap within brain and non-neural tissue types. The long MLS predictors identified in brain are especially conserved among clades, allowing long-living species identification within a clade solely based on lipid predictors from the other two clades. While little can be said about functional significance of these changes one potentially important feature stands out: the genomes of long-living primate and rodent species show increased evolutionary selection acting upon the amino acid sequences of enzymes linked to lipid predictors of long MLS. These enzymes cluster in specific functional categories associated with signaling and protein modification processes, as well as the corresponding cellular compartments: Golgi apparatus and plasma membrane.



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