A body of evidence supports the view that the signaling pathways governing cellular aging - as well as mechanisms of their modulation by longevity-extending genetic, dietary and pharmacological interventions - are conserved across species. The scope of this review is to critically analyze recent advances in our understanding of cell-autonomous mechanisms of chronological aging in the budding yeast Saccharomyces cerevisiae. Based on our analysis, we propose a concept of a biomolecular network underlying the chronology of cellular aging in yeast. The concept posits that such network progresses through a series of lifespan checkpoints. At each of these checkpoints, the intracellular concentrations of some key intermediates and products of certain metabolic pathways - as well as the rates of coordinated flow of such metabolites within an intricate network of intercompartmental communications - are monitored by some checkpoint-specific ʺmaster regulatorʺ proteins. The concept envisions that a synergistic action of these master regulator proteins at certain early-life and late-life checkpoints modulates the rates and efficiencies of progression of such processes as cell metabolism, growth, proliferation, stress resistance, macromolecular homeostasis, survival and death. The concept predicts that, by modulating these vital cellular processes throughout lifespan (i.e., prior to an arrest of cell growth and division, and following such arrest), the checkpoint-specific master regulator proteins orchestrate the development and maintenance of a pro- or anti-aging cellular pattern and, thus, define longevity of chronologically aging yeast.

A yeast culture grown in a nutrient-rich medium initially containing 2% glucose is not limited in calorie supply. When yeast cells cultured in this medium consume glucose, they undergo cell cycle arrest at a checkpoint in late G1 and differentiate into quiescent and non-quiescent cell populations. Studies of such differentiation have provided insights into mechanisms of yeast chronological aging under conditions of excessive calorie intake. Caloric restriction is an aging-delaying dietary intervention. Here, we assessed how caloric restriction influences the differentiation of chronologically aging yeast cultures into quiescent and non-quiescent cells, and how it affects their properties. We found that caloric restriction extends yeast chronological lifespan via a mechanism linking cellular aging to cell cycle regulation, maintenance of quiescence, entry into a non-quiescent state and survival in this state. Our findings suggest that caloric restriction delays yeast chronological aging by causing specific changes in the following: 1) a checkpoint in G1 for cell cycle arrest and entry into a quiescent state; 2) a growth phase in which high-density quiescent cells are committed to become low-density quiescent cells; 3) the differentiation of low-density quiescent cells into low-density non-quiescent cells; and 4) the conversion of high-density quiescent cells into high-density non-quiescent cells.

Our studies revealed that lithocholic acid (LCA), a bile acid, is a potent anti-aging natural compound that in yeast cultured under longevity-extending caloric restriction (CR) conditions acts in synergy with CR to enable a significant further increase in chronological lifespan. Here, we investigate a mechanism underlying this robust longevity-extending effect of LCA under CR. We found that exogenously added LCA enters yeast cells, is sorted to mitochondria, resides mainly in the inner mitochondrial membrane, and also associates with the outer mitochondrial membrane. LCA elicits an age-related remodeling of glycerophospholipid synthesis and movement within both mitochondrial membranes, thereby causing substantial changes in mitochondrial membrane lipidome and triggering major changes in mitochondrial size, number and morphology. In synergy, these changes in the membrane lipidome and morphology of mitochondria alter the age-related chronology of mitochondrial respiration, membrane potential, ATP synthesis and reactive oxygen species homeostasis. The LCA-driven alterations in the age-related dynamics of these vital mitochondrial processes extend yeast longevity. In sum, our findings suggest a mechanism underlying the ability of LCA to delay chronological aging in yeast by accumulating in both mitochondrial membranes and altering their glycerophospholipid compositions. We concluded that mitochondrial membrane lipidome plays an essential role in defining yeast longevity.

Organelles within a eukaryotic cell respond to age-related intracellular stresses and environmental factors by altering their functional states to generate, direct and process the flow of interorganellar information that is essential for establishing a pro-or antiaging cellular pattern. The scope of this review is to critically analyze recent progress in understanding how various intercompartmental (i.e., organelle-organelle and organelle-cytosol) communications regulate cellular aging in evolutionarily distant eukaryotes. Our analysis suggests a model for an intricate network of intercompartmental communications that underly cellular aging in eukaryotic organisms across phyla. This proposed model posits that the numerous directed, coordinated and regulated organelle-organelle and organelle-cytosol communications integrated into this network define the long-term viability of a eukaryotic cell and, thus, are critical for regulating cellular aging. V C 2013 IUBMB Life, 65(8):665-674, 2013

The peroxisome is an organelle that has long been known for its essential roles in oxidation of fatty acids, maintenance of reactive oxygen species (ROS) homeostasis and anaplerotic replenishment of tricarboxylic acid (TCA) cycle intermediates destined for mitochondria. Growing evidence supports the view that these peroxisome-confined metabolic processes play an essential role in defining the replicative and chronological age of a eukaryotic cell. Much progress has recently been made in defining molecular mechanisms that link cellular aging to fatty acid oxidation, ROS turnover, and anaplerotic metabolism in peroxisomes. Emergent studies have revealed that these organelles not only house longevity-defining metabolic reactions but can also regulate cellular aging via their dynamic communication with other cellular compartments. Peroxisomes communicate with other organelles by establishing extensive physical contact with lipid bodies, maintaining an endoplasmic reticulum (ER) to peroxisome connectivity system, exchanging certain metabolites, and being involved in the bidirectional flow of some of their protein and lipid constituents. The scope of this review is to summarize the evidence that peroxisomes are dynamically integrated into an endomembrane system that governs cellular aging. We discuss recent progress in understanding how communications between peroxisomes and other cellular compartments within this system influence the development of a pro- or anti-aging cellular pattern. We also propose a model for the integration of peroxisomes into the endomembrane system governing cellular aging and critically evaluate several molecular mechanisms underlying such integration.