No abstract

In chronologically aging yeast, longevity can be extended by administering a caloric restriction (CR) diet or some small molecules. These life-extending interventions target the adaptable target of rapamycin (TOR) and cAMP/protein kinase A (cAMP/PKA) signaling pathways that are under the stringent control of calorie availability. We designed a chemical genetic screen for small molecules that increase the chronological life span of yeast under CR by targeting lipid metabolism and modulating housekeeping longevity pathways that regulate longevity irrespective of the number of available calories. Our screen identifies lithocholic acid (LCA) as one of such molecules. We reveal two mechanisms underlying the life-extending effect of LCA in chronologically aging yeast. One mechanism operates in a calorie availability-independent fashion and involves the LCA-governed modulation of housekeeping longevity assurance pathways that do not overlap with the adaptable TOR and cAMP/PKA pathways. The other mechanism extends yeast longevity under non-CR conditions and consists in LCA-driven unmasking of the previously unknown anti-aging potential of PKA. We provide evidence that LCA modulates housekeeping longevity assurance pathways by suppressing lipid-induced necrosis, attenuating mitochondrial fragmentation, altering oxidation-reduction processes in mitochondria, enhancing resistance to oxidative and thermal stresses, suppressing mitochondria-controlled apoptosis, and enhancing stability of nuclear and mitochondrial DNA.

The non-reducing disaccharide trehalose has been long considered only as a reserve carbohydrate. However, recent studies in yeast suggested that this osmolyte can protect cells and cellular proteins from oxidative damage elicited by exogenously added reactive oxygen species (ROS). Trehalose has been also shown to affect stability, folding, and aggregation of bacterial and firefly proteins heterologously expressed in heat-shocked yeast cells. Our recent investigation of how a lifespan-extending caloric restriction (CR) diet alters the metabolic history of chronologically aging yeast suggested that their longevity is programmed by the level of metabolic capacity – including trehalose biosynthesis and degradation – that yeast cells developed prior to entry into quiescence. To investigate whether trehalose homeostasis in chronologically aging yeast may play a role in longevity extension by CR, in this study we examined how single-gene-deletion mutations affecting trehalose biosynthesis and degradation impact (1) the age-related dynamics of changes in trehalose concentration; (2) yeast chronological lifespan under CR conditions; (3) the chronology of oxidative protein damage, intracellular ROS level and protein aggregation; and (4) the timeline of thermal inactivation of a protein in heat-shocked yeast cells and its subsequent reactivation in yeast returned to low temperature. Our data imply that CR extends yeast chronological lifespan in part by altering a pattern of age-related changes in trehalose concentration. We outline a model for molecular mechanisms underlying the essential role of trehalose in defining yeast longevity by modulating protein folding, misfolding, unfolding, refolding, oxidative damage, solubility, and aggregation throughout lifespan.

Growing evidence supports the view that LDs (lipid droplets) are dynamic organelles that can serve both as an intracellular signalling compartment and as an organizing platform orchestrating many vital processes in eukaryotic cells. It has become clear that the LDs-confined deposition and lipolytic degradation of neutral lipids define longevity in multicellular eukaryotic organisms and yeast. We summarize the evidence in support of the essential role that LDs play in longevity regulation and propose several molecular mechanisms by which these dynamic organellar compartments control the aging process in multicellular eukaryotes and yeast.

y These authors contributed equally to this work.