Diverse geroprotectors differently affect a mechanism linking cellular aging to cellular quiescence in budding yeast.

We propose a hypothesis of a mechanism linking cellular aging to cellular quiescence in chronologically aging budding yeast. Our hypothesis posits that this mechanism integrates four different processes, all of which are initiated after yeast cells cultured in a medium initially containing glucose consume it. Quiescent cells that develop in these cultures can be separated into the high- and low-density sub-populations of different buoyant densities.

Caloric restriction causes a distinct reorganization of the lipidome in quiescent and non-quiescent cells of budding yeast.

After budding yeast cells cultured in a nutrient-rich liquid medium with 0.2% glucose (under caloric restriction conditions) or 2% glucose (under non-caloric restriction conditions), ferment glucose to ethanol and then consume ethanol, they enter the stationary phase. The process of their chronological aging begins.

Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors.

Caloric restriction and the mutation are robust geroprotectors in yeast and other eukaryotes. Lithocholic acid is a potent geroprotector in . Here, we used liquid chromatography coupled with tandem mass spectrometry method of non-targeted metabolomics to compare the effects of these three geroprotectors on the intracellular metabolome of chronologically aging budding yeast.

Quantitative Metabolomics of Saccharomyces Cerevisiae Using Liquid Chromatography Coupled with Tandem Mass Spectrometry.

Metabolomics is a methodology used for the identification and quantification of many low-molecular-weight intermediates and products of metabolism within a cell, tissue, organ, biological fluid, or organism. Metabolomics traditionally focuses on water-soluble metabolites. The water-soluble metabolome is the final product of a complex cellular network that integrates various genomic, epigenomic, transcriptomic, proteomic, and environmental factors.

Mechanisms that Link Chronological Aging to Cellular Quiescence in Budding Yeast.

After cells cultured in a medium with glucose consume glucose, the sub-populations of quiescent and non-quiescent cells develop in the budding yeast culture. An age-related chronology of quiescent and non-quiescent yeast cells within this culture is discussed here. We also describe various hallmarks of quiescent and non-quiescent yeast cells.

Discovery of fifteen new geroprotective plant extracts and identification of cellular processes they affect to prolong the chronological lifespan of budding yeast.

In a quest for previously unknown geroprotective natural chemicals, we used a robust cell viability assay to search for commercially available plant extracts that can substantially prolong the chronological lifespan of budding yeast. Many of these plant extracts have been used in traditional Chinese and other herbal medicines or the Mediterranean and other customary diets. Our search led to a discovery of fifteen plant extracts that significantly extend the longevity of chronologically aging yeast not limited in calorie supply.

Quantitative Analysis of the Cellular Lipidome of Saccharomyces Cerevisiae Using Liquid Chromatography Coupled with Tandem Mass Spectrometry.

Lipids are structurally diverse amphipathic molecules that are insoluble in water. Lipids are essential contributors to the organization and function of biological membranes, energy storage and production, cellular signaling, vesicular transport of proteins, organelle biogenesis, and regulated cell death. Because the budding yeast Saccharomyces cerevisiae is a unicellular eukaryote amenable to thorough molecular analyses, its use as a model organism helped uncover mechanisms linking lipid metabolism and intracellular transport to complex biological processes within eukaryotic cells.

Mechanisms by which PE21, an extract from the white willow , delays chronological aging in budding yeast.

We have recently found that PE21, an extract from the white willow , slows chronological aging and prolongs longevity of the yeast more efficiently than any of the previously known pharmacological interventions. Here, we investigated mechanisms through which PE21 delays yeast chronological aging and extends yeast longevity. We show that PE21 causes a remodeling of lipid metabolism in chronologically aging yeast, thereby instigating changes in the concentrations of several lipid classes.

Aging and Age-related Disorders: From Molecular Mechanisms to Therapies.

Our understanding of the molecular mechanisms underlying cellular and organismal aging andaging-associated pathology has advanced greatly in recent years [...

Mechanisms Through Which Some Mitochondria-Generated Metabolites Act as Second Messengers That Are Essential Contributors to the Aging Process in Eukaryotes Across Phyla.

Recent studies have revealed that some low-molecular weight molecules produced in mitochondria are essential contributing factors to aging and aging-associated pathologies in evolutionarily distant eukaryotes. These molecules are intermediates or products of certain metabolic reactions that are activated in mitochondria in response to specific changes in the nutrient, stress, proliferation, or age status of the cell. After being released from mitochondria, these metabolites directly or indirectly change activities of a distinct set of protein sensors that reside in various cellular locations outside of mitochondria.

Quiescence Entry, Maintenance, and Exit in Adult Stem Cells.

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.

Pairwise combinations of chemical compounds that delay yeast chronological aging through different signaling pathways display synergistic effects on the extent of aging delay.

We have recently discovered six plant extracts that delay yeast chronological aging. Most of them affect different nodes, edges and modules of an evolutionarily conserved network of longevity regulation that integrates certain signaling pathways and protein kinases; this network is also under control of such aging-delaying chemical compounds as spermidine and resveratrol. We have previously shown that, if a strain carrying an aging-delaying single-gene mutation affecting a certain node, edge or module of the network is exposed to some of the six plant extracts, the mutation and the plant extract enhance aging-delaying efficiencies of each other so that their combination has a synergistic effect on the extent of aging delay.

Mechanisms through which lithocholic acid delays yeast chronological aging under caloric restriction conditions.

All presently known geroprotective chemical compounds of plant and microbial origin are caloric restriction mimetics because they can mimic the beneficial lifespan- and healthspan-extending effects of caloric restriction diets without the need to limit calorie supply. We have discovered a geroprotective chemical compound of mammalian origin, a bile acid called lithocholic acid, which can delay chronological aging of the budding yeast under caloric restriction conditions. Here, we investigated mechanisms through which lithocholic acid can delay chronological aging of yeast limited in calorie supply.

Caloric restriction delays yeast chronological aging by remodeling carbohydrate and lipid metabolism, altering peroxisomal and mitochondrial functionalities, and postponing the onsets of apoptotic and liponecrotic modes of regulated cell death.

A dietary regimen of caloric restriction delays aging in evolutionarily distant eukaryotes, including the budding yeast . Here, we assessed how caloric restriction influences morphological, biochemical and cell biological properties of chronologically aging yeast advancing through different stages of the aging process. Our findings revealed that this low-calorie diet slows yeast chronological aging by mechanisms that coordinate the spatiotemporal dynamics of various cellular processes before entry into a non-proliferative state and after such entry.

Yeast Cells Exposed to Exogenous Palmitoleic Acid Either Adapt to Stress and Survive or Commit to Regulated Liponecrosis and Die.

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 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 .

Some Metabolites Act as Second Messengers in Yeast Chronological Aging.

The concentrations of some key metabolic intermediates play essential roles in regulating the longevity of the chronologically aging yeast . These key metabolites are detected by certain ligand-specific protein sensors that respond to concentration changes of the key metabolites by altering the efficiencies of longevity-defining cellular processes. The concentrations of the key metabolites that affect yeast chronological aging are controlled spatially and temporally.

Caloric restriction extends yeast chronological lifespan via a mechanism linking cellular aging to cell cycle regulation, maintenance of a quiescent state, entry into a non-quiescent state and survival in the non-quiescent state.

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.

Lipid metabolism and transport define longevity of the yeast Saccharomyces cerevisiae.

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.

Diindolylmethane and its halogenated derivatives induce protective autophagy in human prostate cancer cells via induction of the oncogenic protein AEG-1 and activation of AMP-activated protein kinase (AMPK).

3,3'-Diindolylmethane (DIM) and its synthetic halogenated derivatives 4,4'-Br- and 7,7'-ClDIM (ring-DIMs) have recently been shown to induce protective autophagy in human prostate cancer cells. The mechanisms by which DIM and ring-DIMs induce autophagy have not been elucidated. As DIM is a mitochondrial ATP-synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of intracellular AMP/ATP ratios and activation of AMP-activated protein kinase (AMPK) signaling in prostate cancer cells.

Mechanisms Underlying the Essential Role of Mitochondrial Membrane Lipids in Yeast Chronological Aging.

The functional state of mitochondria is vital to cellular and organismal aging in eukaryotes across phyla. Studies in the yeast 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.

Specific changes in mitochondrial lipidome alter mitochondrial proteome and increase the geroprotective efficiency of lithocholic acid in chronologically aging yeast.

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.