A fair amount of aging research starts in yeast (or worms, or flies) for reasons of cost, only later moving to mammals such as laboratory mice. A surprisingly large fraction of the cellular mechanisms relevant to aging are much the same in all of these species. Most of the ways in which metabolism determines natural variations in longevity, both between individuals and between species, were established very early in the evolution of cellular life. With this in mind, you might recall researchers demonstrating earlier this year that life span in yeast can be extended via provision of lithocholic acid. The open access paper here follows that with a consideration of the mechanisms involved: it appears to work via alteration of the composition of mitochondria, making them more resistant to damage.
The membrane pacemaker theory of aging puts mitochondrial composition front and center, based on comparisons of mitochondria between species with very different life spans. Longer-lived species tend to have mitochondria built out of more resilient lipids - though in this paper the researchers suggest that such differences in lipid composition are far more influential in the cell than simply a matter of damage resistance. Mitochondrial function and mitochondrial damage are any case considered to be very important in aging. Loss of mitochondrial activity is seen in many age-related diseases, and some forms of damage to mitochondria appear capable of creating dysfunctional cells that export harmful reactive molecules into the surrounding tissues. Restoring mitochondria to youthful function in the aged is an important component of rejuvenation research.
Mitochondria are indispensable for organismal physiology and health in all eukaryotes. The efficiencies with which these organelles generate the bulk of cellular ATP and make biosynthetic intermediates for amino acids, nucleotides, and lipids are known to deteriorate with age. Such age-related deterioration of mitochondrial functionality is the universal feature of aging in evolutionarily distant eukaryotic organisms.
A number of mechanisms underlie the essential roles of some traits of mitochondrial functionality in both modes of yeast aging. These traits in replicatively and chronologically aging yeast include mitochondrial electron transport chain and oxidative phosphorylation, membrane potential, reactive oxygen species (ROS) homeostasis, protein synthesis and proteostasis, iron-sulfur cluster formation, and synthesis of amino acids and NADPH. Until recently, it was unknown if such trait of mitochondrial functionality as the composition of mitochondrial membrane lipids can influence aging in yeast. Our recent studies have revealed that lithocholic bile acid (LCA) can delay the onset and decrease the rate of yeast chronological aging. We demonstrated that the robust geroprotective effect of exogenously added LCA is due to its ability to cause certain changes in lipid compositions of both mitochondrial membranes. These changes in mitochondrial membrane lipids enable mitochondria to establish and maintain an aging-delaying pattern of the entire cell.
This LCA-driven remodeling of mitochondrial lipidome triggers major changes in mitochondrial abundance and morphology and also alters mitochondrial proteome. These changes in the abundance, morphology, and protein composition of mitochondria lead to specific alterations in mitochondrial functionality. Our recent unpublished data indicate that the LCA-dependent alterations in mitochondrial lipidome, proteome, and morphology can also elicit changes in lipidomes of other organelles and in concentrations of a specific set of water-soluble metabolites. By sensing different aspects of mitochondrial functional state, a discrete set of ten transcription factors orchestrates a distinct transcriptional program for many nuclear genes. The denouement of this cascade of consecutive events is the establishment of a cellular pattern that delays the onset and slows the progression of yeast chronological aging.
Of note, the proposed mechanism here for how the LCA-dependent remodeling of mitochondrial lipidome in the yeast S. cerevisiae allows to establish an aging-delaying cellular pattern is reminiscent of the mechanism in which the mitochondrial unfolded protein response causes remodeling of the mitochondrial lipidome in the nematode C. elegans, and then triggers a cascade of events that institute an aging-delaying cellular pattern. Moreover, the essential role of mitochondrial lipid metabolism in defining the pace of yeast chronological aging further supports the notion that the vital role of lipid homeostasis in healthy aging has been conserved in eukaryotes.