Identification of evolutionarily conserved genetic regulators of cellular aging

To identify new genetic regulators of cellular aging and senescence, we performed genome-wide comparative RNA profiling with selected human cellular model systems, reflecting replicative senescence, stress-induced premature senescence, and distinct other forms of cellular aging. Gene expression profiles were measured, analyzed, and entered into a newly generated database referred to as the GiSAO database. Bioinformatic analysis revealed a set of new candidate genes, conserved across the majority of the cellular aging models, which were so far not associated with cellular aging, and highlighted several new pathways that potentially play a role in cellular aging. Several candidate genes obtained through this analysis have been confirmed by functional experiments, thereby validating the experimental approach. The effect of genetic deletion on chronological lifespan in yeast was assessed for 93 genes where (i) functional homologues were found in the yeast genome and (ii) the deletion strain was viable. We identified several genes whose deletion led to significant changes of chronological lifespan in yeast, featuring both lifespan shortening and lifespan extension. In conclusion, an unbiased screen across species uncovered several so far unrecognized molecular pathways for cellular aging that are conserved in evolution.     

Commentary: Spermidine-triggered autophagy ameliorates memory during aging

The aging process drives the progressive deterioration of an organism and is thus subject to a complex interplay of regulatory and executing mechanisms. Our understanding of this process eventually aims at the delay and/or prevention of age-related pathologies, among them the age-dependent decrease in cognitive performance (e.g., learning and memory). Using the fruit fly Drosophila melanogaster, which combines a generally high mechanistic conservation with an efficient experimental access regarding aging and memory studies, we have recently unveiled a protective function of polyamines (including spermidine) against age-induced memory impairment (AMI). The flies’ age-dependent decline of aversive olfactory memory, an established model for AMI, can be rescued by both pharmacological treatment with spermidine and genetic modulation that increases endogenous polyamine levels. Notably, we find that this effect strictly depends on autophagy, which is remarkable in light of the fact that autophagy is considered a key regulator of aging in other contexts. Given that polyamines in general and spermidine in particular are endogenous metabolites, our findings place them as candidate target substances for AMI treatment.     

Yeast unravels epigenetic apoptosis control: deadly chat within a histone tail

An important paper by David Allis and colleagues (Ahn et al., 2006 [this issue of Molecular Cell]) describes a specific deacetylation/phosphorylation crosstalk at the histone H2B tail required for apoptosis induction in yeast, thus giving first insights into the poorly understood epigenetic regulation of cell death.     

Nouveautés sur la séquence du Pléistocène final et l’Holocène initial dans le versant méditerranéen de la péninsule Ibérique à travers l’industrie lithique

This paper explores the cultural sequence for the period 12,500–9000 BP in the Mediterranean coast of the Iberian Peninsula. According to the traditional division by Fortea, this period starts with the end of the Upper Magdalenian, followed by two facies: the Microlaminar Epipalaeolithic and the Geometric Epipalaeolithic (Filador type), (related to Sauveterrian facies). The data collected in recent years suggest a change or amendment to this previous proposal, which now would be divided into four phases: Final Upper Magdalenian, Early Epimagdalenian, Recent Epimagdalenian and Microlaminar Sauveterroid. This paper discusses each of these periods examining the evolution of the stone tools and concluding that in the Mediterranean coast of the Iberian Peninsula the Magdalenian tradition continues with little changes until the advent of the Mesolithic.     

Prognostic impact of vitamin B6 metabolism in lung cancer

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.     

The Warburg Effect Suppresses Oxidative Stress Induced Apoptosis in a Yeast Model for Cancer

Background

Otto Warburg observed that cancer cells are often characterized by intense glycolysis in the presence of oxygen and a concomitant decrease in mitochondrial respiration. Research has mainly focused on a possible connection between increased glycolysis and tumor development whereas decreased respiration has largely been left unattended. Therefore, a causal relation between decreased respiration and tumorigenesis has not been demonstrated.

Methodology/Principal Findings

For this purpose, colonies of Saccharomyces cerevisiae, which is suitable for manipulation of mitochondrial respiration and shows mitochondria-mediated cell death, were used as a model. Repression of respiration as well as ROS-scavenging via glutathione inhibited apoptosis and conferred a survival advantage during seeding and early development of this fast proliferating solid cell population. In contrast, enhancement of respiration triggered cell death.

Conclusion/Significance

Thus, the Warburg effect might directly contribute to the initiation of cancer formation - not only by enhanced glycolysis - but also via decreased respiration in the presence of oxygen, which suppresses apoptosis.     

Necrosis in yeast

Necrosis was long regarded as an accidental cell death process resulting from overwhelming cellular injury such as chemical or physical disruption of the plasma membrane. Such a definition, however, proved to be inapplicable to many necrotic scenarios. The discovery that genetic manipulation of several proteins either protected or enhanced necrotic cell death argued in favor of a regulated and hence programmed process, as it is the case for apoptosis. For more than a decade, yeast has served as a model for apoptosis research; recently, evidence accumulated that it also harbors a necrotic program. Here, we summarize the current knowledge about factors that control necrotic cell death in yeast. Mitochondria, aging and a low pH are positive regulators of this process while cellular polyamines (e.g. spermidine) and endonuclease G as well as homeostatic organelles like the vacuole or peroxisomes are potent inhibitors of necrosis. Physiological necrosis may stimulate intercellular signaling via the release of necrotic factors that promote viability of healthy cells and, thus, assure survival of the clone. Together, the data obtained in yeast argue for the existence of a necrotic program, which controls longevity and whose physiological function may thus be aging.     

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.     

Loss of peroxisome function triggers necrosis

Disturbance of peroxisome function can lead to various degenerative diseases during ageing. Here, we show that in yeast deletion of PEX6, encoding a protein involved in a key step of peroxisomal protein import, results in an increased accumulation of reactive oxygen species and an enhanced loss of viability upon acetic acid treatment and during early stationary phase. Cell death of ageing-like yeast cells lacking PEX6 does not depend on the apoptotic key players Yca1p and Aif1p, but instead shows markers of necrosis. Thus, we conclude that loss of peroxisomal function leads to a form of necrotic cell death.