Cells of unicellular and multicellular eukaryotes can respond to certain environmental cues by arresting the cell cycle and entering a reversible state of quiescence. Quiescent cells do not divide, but can re-enter the cell cycle and resume proliferation if exposed to some signals from the environment. Quiescent cells in mammals and humans include adult stem cells. These cells exhibit improved stress resistance and enhanced survival ability. In response to certain extrinsic signals, adult stem cells can self-renew by dividing asymmetrically. Such asymmetric divisions not only allow the maintenance of a population of quiescent cells, but also yield daughter progenitor cells. A multistep process of the controlled proliferation of these progenitor cells leads to the formation of one or more types of fully differentiated cells. An age-related decline in the ability of adult stem cells to balance quiescence maintenance and regulated proliferation has been implicated in many aging-associated diseases. In this review, we describe many traits shared by different types of quiescent adult stem cells. We discuss how these traits contribute to the quiescence, self-renewal, and proliferation of adult stem cells. We examine the cell-intrinsic mechanisms that allow establishing and sustaining the characteristic traits of adult stem cells, thereby regulating quiescence entry, maintenance, and exit.

We discovered six plant extracts that increase yeast chronological lifespan to a significantly greater extent than any of the presently known longevity-extending chemical compounds. One of these extracts is the most potent longevity-extending pharmacological intervention yet described. We show that each of the six plant extracts is a geroprotector which delays the onset and decreases the rate of yeast chronological aging by eliciting a hormetic stress response. We also show that each of these extracts has different effects on cellular processes that define longevity in organisms across phyla. These effects include the following: 1) increased mitochondrial respiration and membrane potential; 2) augmented or reduced concentrations of reactive oxygen species; 3) decreased oxidative damage to cellular proteins, membrane lipids, and mitochondrial and nuclear genomes; 4) enhanced cell resistance to oxidative and thermal stresses; and 5) accelerated degradation of neutral lipids deposited in lipid droplets. Our findings provide new insights into mechanisms through which chemicals extracted from certain plants can slow biological aging.

Studies employing the budding yeast Saccharomyces cerevisiae as a model organism have provided deep insights into molecular mechanisms of cellular and organismal aging in multicellular eukaryotes and have demonstrated that the main features of biological aging are evolutionarily conserved. Aging in S. cerevisiae is studied by measuring replicative or chronological lifespan. Yeast replicative aging is likely to model aging of mitotically competent human cell types, while yeast chronological aging is believed to mimic aging of post-mitotic human cell types. Emergent evidence implies that various organelle-organelle and organelle-cytosol communications play essential roles in chronological aging of S. cerevisiae. The molecular mechanisms underlying the vital roles of intercompartmental communications in yeast chronological aging have begun to emerge. The scope of this review is to critically analyze recent progress in understanding such mechanisms. Our analysis suggests a model for how temporally and spatially coordinated movements of certain metabolites between various cellular compartments impact yeast chronological aging. In our model, diverse changes in these key metabolites are restricted to critical longevity-defining periods of chronological lifespan. In each of these periods, a limited set of proteins responds to such changes of the metabolites by altering the rate and efficiency of a certain cellular process essential for longevity regulation. Spatiotemporal dynamics of alterations in these longevity-defining cellular processes orchestrates the development and maintenance of a pro- or anti-aging cellular pattern.

Our recent study has revealed six plant extracts that slow yeast chronological aging more efficiently than any chemical compound yet described. The rate of aging in yeast is controlled by an evolutionarily conserved network of integrated signaling pathways and protein kinases. Here, we assessed how single-gene-deletion mutations eliminating each of these pathways and kinases affect the aging-delaying efficiencies of the six plant extracts. Our findings imply that these extracts slow aging in the following ways: 1) plant extract 4 decreases the efficiency with which the pro-aging TORC1 pathway inhibits the anti-aging SNF1 pathway; 2) plant extract 5 mitigates two different branches of the pro-aging PKA pathway; 3) plant extract 6 coordinates processes that are not assimilated into the network of presently known signaling pathways/protein kinases; 4) plant extract 8 diminishes the inhibitory action of PKA on SNF1; 5) plant extract 12 intensifies the anti-aging protein kinase Rim15; and 6) plant extract 21 inhibits a form of the pro-aging protein kinase Sch9 that is activated by the pro-aging PKH1/2 pathway.

Emergent evidence indicates that certain aspects of lipid synthesis, degradation and interorganellar transport play essential roles in modulating the pace of cellular aging in the budding yeast Saccharomyces cerevisiae. The molecular mechanisms underlying the vital roles of lipid metabolism and transport in defining yeast longevity have begun to emerge. The scope of this review is to critically analyze recent progress in understanding such mechanisms.

A disturbed homeostasis of cellular lipids and the resulting lipotoxicity are considered to be key contributors to many human pathologies, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer. The yeast Saccharomyces cerevisiae has been successfully used for uncovering molecular mechanisms through which impaired lipid metabolism causes lipotoxicity and elicits different forms of regulated cell death. Here, we discuss mechanisms of the “liponecrotic” mode of regulated cell death in S. cerevisiae. This mode of regulated cell death can be initiated in response to a brief treatment of yeast with exogenous palmitoleic acid. Such treatment prompts the incorporation of exogenously added palmitoleic acid into phospholipids and neutral lipids. This orchestrates a global remodeling of lipid metabolism and transfer in the endoplasmic reticulum, mitochondria, lipid droplets, and the plasma membrane. Certain features of such remodeling play essential roles either in committing yeast to liponecrosis or in executing this mode of regulated cell death. We also outline four processes through which yeast cells actively resist liponecrosis by adapting to the cellular stress imposed by palmitoleic acid and maintaining viability. These prosurvival cellular processes are confined in the endoplasmic reticulum, lipid droplets, peroxisomes, autophagosomes, vacuoles, and the cytosol.

We have previously found that exogenously added lithocholic acid delays yeast chronological aging. We demonstrated that lithocholic acid enters the yeast cell, is sorted to mitochondria, resides in both mitochondrial membranes, changes the relative concentrations of different membrane phospholipids, triggers changes in the concentrations of many mitochondrial proteins, and alters some key aspects of mitochondrial functionality. We hypothesized that the lithocholic acid-driven changes in mitochondrial lipidome may have a causal role in the remodeling of mitochondrial proteome, which may in turn alter the functional state of mitochondria to create a mitochondrial pattern that delays yeast chronological aging. Here, we test this hypothesis by investigating how the ups1?, ups2? and psd1? mutations that eliminate enzymes involved in mitochondrial phospholipid metabolism influence the mitochondrial lipidome. We also assessed how these mutations affect the mitochondrial proteome, influence mitochondrial functionality and impinge on the efficiency of aging delay by lithocholic acid. Our findings provide evidence that 1) lithocholic acid initially creates a distinct pro-longevity pattern of mitochondrial lipidome by proportionally decreasing phosphatidylethanolamine and cardiolipin concentrations to maintain equimolar concentrations of these phospholipids, and by increasing phosphatidic acid concentration; 2) this pattern of mitochondrial lipidome allows to establish a specific, aging-delaying pattern of mitochondrial proteome; and 3) this pattern of mitochondrial proteome plays an essential role in creating a distinctive, geroprotective pattern of mitochondrial functionality.

The functional state of mitochondria is vital to cellular and organismal aging in eukaryotes across phyla. Studies in the yeast Saccharomyces cerevisiae have provided evidence that age-related changes in some aspects of mitochondrial functionality can create certain molecular signals. These signals can then define the rate of cellular aging by altering unidirectional and bidirectional communications between mitochondria and other organelles. Several aspects of mitochondrial functionality are known to impact the replicative and/or chronological modes of yeast aging. They include mitochondrial electron transport, membrane potential, reactive oxygen species, and protein synthesis and proteostasis, as well as mitochondrial synthesis of iron-sulfur clusters, amino acids, and NADPH. Our recent findings have revealed that the composition of mitochondrial membrane lipids is one of the key aspects of mitochondrial functionality affecting yeast chronological aging. We demonstrated that exogenously added lithocholic bile acid can delay chronological aging in yeast because it elicits specific changes in mitochondrial membrane lipids. These changes allow mitochondria to operate as signaling platforms that delay yeast chronological aging by orchestrating an institution and maintenance of a distinct cellular pattern. In this review, we discuss molecular and cellular mechanisms underlying the essential role of mitochondrial membrane lipids in yeast chronological aging.