Yeast programmed cell death : an intricate puzzle

Yeasts as eukaryotic microorganisms with simple, well known and tractable genetics, have long been powerful model systems for studying complex biological phenomena such as the cell cycle or vesicle fusion. Until recently, yeast has been assumed as a cellular ‘clean room’ to study the interactions and the mechanisms of action of mammalian apoptotic regulators. However, the finding of an endogenous programmed cell death (PCD) process in yeast with an apoptotic phenotype has turned yeast into an ‘unclean’ but even more powerful model for apoptosis research. Yeast cells appear to possess an endogenous apoptotic machinery including its own regulators and pathway(s). Such machinery may not exactly recapitulate that of mammalian systems but it represents a simple and valuable model which will assist in the future understanding of the complex connections between apoptotic and non-apoptotic mammalian PCD pathways. Following this line of thought and in order to validate and make the most of this promising cell death model, researchers must undoubtedly address the following issues: what are the crucial yeast PCD regulators? How do they play together? What are the cell death pathways shared by yeast and mammalian PCD? Solving these questions is currently the most pressing challenge for yeast cell death researchers

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial

Background: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer’s disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. Methods: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. Discussion: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer’s disease

Yeast programed cell death and aging

[Excerpt] Similarly to metazoans, yeast cells can exhibit several characteristics of apoptosis, including chromatin condensation, DNA breakage, flipping of phosphatidylserine to the outer leaflet of the plasma membrane, accumulation of reactive oxygen species (ROS), and release of pro-death factors such as cytochrome c or Endonuclease G from mitochondria. Yeast programed cell death has been shown to occur in response to a variety of stimuli, such as oxidative stress, exposure to acetic acid, and expression of mammalian pro-apoptotic proteins. This program is also inherent to the yeast life cycle, as aged mother cells and cells exposed to pheromone also display an apoptotic and necrotic phenotype. Yeast therefore comprises a conserved core programed cell death process that shares several regulators with mammalian cells, which play major roles in the pathogenesis of human diseases. At the same time, it lacks many of the cell death regulators that have evolved in higher eukaryotes, probably due to the invention of multicellularity. The simplicity of the yeast model allows elucidating the basic molecular pathways of programed cell death without interference from multifaceted regulation, due to various protein isoforms or cellular specificity often observed in studies using mammalian systems. In addition, yeast heterologous expression systems offer the opportunity to exploit the individual functional and mechanistic properties of mammalian apoptotic regulators. [...

Polyamines in aging and disease

Polyamines are polycations that interact with negatively charged molecules such as DNA, RNA and proteins. They play multiple roles in cell growth, survival and proliferation. Changes in polyamine levels have been associated with aging and diseases. Their levels decline continuously with age and polyamine (spermidine or high-polyamine diet) supplementation increases life span in model organisms. Polyamines have also been involved in stress resistance. On the other hand, polyamines are increased in cancer cells and are a target for potential chemotherapeutic agents. In this review, we bring together these various results and draw a picture of the state of our knowledge on the roles of polyamines in aging, stress and diseases

Viral killer toxins induce caspase-mediated apoptosis in yeast

In yeast, apoptotic cell death can be triggered by various factors such as H2O2, cell aging, or acetic acid. Yeast caspase (Yca1p) and cellular reactive oxygen species (ROS) are key regulators of this process. Here, we show that moderate doses of three virally encoded killer toxins (K1, K28, and zygocin) induce an apoptotic yeast cell response, although all three toxins differ significantly in their primary killing mechanisms. In contrast, high toxin concentrations prevent the occurrence of an apoptotic cell response and rather cause necrotic, toxin-specific cell killing. Studies with Δyca1 and Δgsh1 deletion mutants indicate that ROS accumulation as well as the presence of yeast caspase 1 is needed for apoptosis in toxin-treated yeast cells. We conclude that in the natural environment of toxin-secreting killer yeasts, where toxin concentration is usually low, induction of apoptosis might play an important role in efficient toxin-mediated cell killing

Dietary spermidine for lowering high blood pressure

Loss of cardiac macroautophagy/autophagy impairs heart function, and evidence accumulates that an increased autophagic flux may protect against cardiovascular disease. We therefore tested the protective capacity of the natural autophagy inducer spermidine in animal models of aging and hypertension, which both represent major risk factors for the development of cardiovascular disease. Dietary spermidine elicits cardioprotective effects in aged mice through enhancing cardiac autophagy and mitophagy. In salt-sensitive rats, spermidine supplementation also delays the development of hypertensive heart disease, coinciding with reduced arterial blood pressure. The high blood pressure-lowering effect likely results from improved global arginine bioavailability and protection from hypertension-associated renal damage. The polyamine spermidine is naturally present in human diets, though to a varying amount depending on food type and preparation. In humans, high dietary spermidine intake correlates with reduced blood pressure and decreased risk of cardiovascular disease and related death. Altogether, spermidine represents a cardio- and vascular- protective autophagy inducer that can be readily integrated in common diets

Why yeast cells can undergo apoptosis: death in times of peace, love, and war

The purpose of apoptosis in multicellular organisms is obvious: single cells die for the benefit of the whole organism (for example, during tissue development or embryogenesis). Although apoptosis has also been shown in various microorganisms, the reason for this cell death program has remained unexplained. Recently published studies have now described yeast apoptosis during aging, mating, or exposure to killer toxins (Fabrizio, P., L. Battistella, R. Vardavas, C. Gattazzo, L.L. Liou, A. Diaspro, J.W. Dossen, E.B. Gralla, and V.D. Longo. 2004. J. Cell Biol. 166:1055–1067; Herker, E., H. Jungwirth, K.A. Lehmann, C. Maldener, K.U. Frohlich, S. Wissing, S. Buttner, M. Fehr, S. Sigrist, and F. Madeo. 2004. J. Cell Biol. 164:501–507, underscoring the evolutionary benefit of a cell suicide program in yeast and, thus, giving a unicellular organism causes to die for