Nadege Minois

Induction of autophagy by spermidine promotes longevity

Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.

Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan

Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response.

Molecular Basis of the ‘Anti-Aging' Effect of Spermidine and Other Natural Polyamines - A Mini-Review

Background: Spermidine, a naturally occurring polyamine, has recently emerged as exhibiting anti-aging properties. Its supplementation increases lifespan and resistance to stress, and decreases the occurrence of age-related pathology and loss of locomotor ability. Its mechanisms of action are just beginning to be understood. Objectives: An up-to-date overview of the so far identified mechanisms of action of spermidine and other polyamines on aging is presented. Methods: Studies of aging and of the molecular effects of polyamines in general and spermidine in particular are used to synthesize our knowledge on what molecular mechanisms spermidine and other polyamines trigger to positively affect aging. Results: Autophagy is the main mechanism of action of spermidine at the molecular level. However, recent research shows that spermidine can act via other mechanisms, namely inflammation reduction, lipid metabolism and regulation of cell growth, proliferation and death. It is suggested that the main pathway used by spermidine to trigger its effects is the MAPK pathway. Conclusions: Given that polyamines can interact with many molecules, it is not surprising that they affect aging via several mechanisms. Many of these mechanisms discovered so far have already been linked with aging and by acting on all of these mechanisms, polyamines may be strong regulators of aging.

Spermidine promotes stress resistance in Drosophila melanogaster through autophagy-dependent and -independent pathways.

The naturally occurring polyamine spermidine (Spd) has recently been shown to promote longevity across species in an autophagy-dependent manner. Here, we demonstrate that Spd improves both survival and locomotor activity of the fruit fly Drosophila melanogaster upon exposure to the superoxide generator and neurotoxic agent paraquat. Although survival to a high paraquat concentration (20 mM) was specifically increased in female flies only, locomotor activity and survival could be rescued in both male and female animals when exposed to lower paraquat levels (5 mM). These effects are dependent on the autophagic machinery, as Spd failed to confer resistance to paraquat-induced toxicity and locomotor impairment in flies deleted for the essential autophagic regulator ATG7 (autophagy-related gene 7). Spd treatment did also protect against mild doses of another oxidative stressor, hydrogen peroxide, but in this case in an autophagy-independent manner. Altogether, this study establishes that the protective effects of Spd can be exerted through different pathways that depending on the oxidative stress scenario do or do not involve autophagy.

Phosphatidylethanolamine positively regulates autophagy and longevity

Autophagy is a cellular recycling program that retards ageing by efficiently eliminating damaged and potentially harmful organelles and intracellular protein aggregates. Here, we show that the abundance of phosphatidylethanolamine (PE) positively regulates autophagy. Reduction of intracellular PE levels by knocking out either of the two yeast phosphatidylserine decarboxylases (PSD) accelerated chronological ageing-associated production of reactive oxygen species and death. Conversely, the artificial increase of intracellular PE levels, by provision of its precursor ethanolamine or by overexpression of the PE-generating enzyme Psd1, significantly increased autophagic flux, both in yeast and in mammalian cell culture. Importantly administration of ethanolamine was sufficient to extend the lifespan of yeast (Saccharomyces cerevisiae), mammalian cells (U2OS, H4) and flies (Drosophila melanogaster). We thus postulate that the availability of PE may constitute a bottleneck for functional autophagy and that organismal life or healthspan could be positively influenced by the consumption of ethanolamine-rich food.

Spermidine feeding decreases age-related locomotor activity loss and induces changes in lipid composition.

Spermidine is a natural polyamine involved in many important cellular functions, whose supplementation in food or water increases life span and stress resistance in several model organisms. In this work, we expand spermidine’s range of age-related beneficial effects by demonstrating that it is also able to improve locomotor performance in aged flies. Spermidine’s mechanism of action on aging has been primarily related to general protein hypoacetylation that subsequently induces autophagy. Here, we suggest that the molecular targets of spermidine also include lipid metabolism: Spermidine-fed flies contain more triglycerides and show altered fatty acid and phospholipid profiles. We further determine that most of these metabolic changes are regulated through autophagy. Collectively, our data suggests an additional and novel lipid-mediated mechanism of action for spermidine-induced autophagy.

RNA Interference in Ageing Research – A Mini-Review

Background: The search for genetic mechanisms affecting life-span and ageing represents an important part of ageing research, especially since the discovery of single-gene mutations with dramatic effects on these traits. Due to its relative ease of use and its power to specifically target arbitrary genes, RNA interference (RNAi) has rapidly been adopted as a technique for silencing gene expression. The feasibility of genome-wide RNAi screens potentially much simplifies the identification of novel ageing-related genes. Objective: In a review of applications of RNAi in ageing research with a focus on the model organisms Caenorhabditis elegans and Drosophila melanogaster and discussing recent technical developments, we aim to highlight the current and future impact of this technology in the field. Method: We show how RNAi has successfully been used to complement classic mutant studies. Moreover, we discuss the novel opportunities and challenges of an application of RNAi in genome-wide screens in D. melanogaster, which has become possible with the recent availability of a comprehensive transgenic RNAi library for the fly. We highlight, in particular, how the flexible control of RNAi induction can support the study of dynamic processes like ageing through specific experiments and the development of matching computational methods. In an overview of complementary approaches we discuss the challenge of extracting insight from the high-dimensional measurement datasets that are required for the study of dynamic effects and interaction dependencies. Conclusion: RNAi has emerged as a powerful tool for the study of ageing, allowing the further characterization of the roles of specific genes in the ageing process as well as the efficient identification of new genes implicated. RNAi has contributed to our understanding of age-related diseases especially by making genes amenable to manipulation for which mutants were not easily available. Recent developments enable genome-wide screens with unprecedented temporal and spatial control of RNAi induction. Specific RNAi time-course experiments provide an opportunity for the analysis of high-resolution gene expression profiles capturing the dynamics of ageing-relevant processes and gene interactions. Research exploiting new avenues opened by the growing RNAi toolbox will considerably contribute to the next steps in researching the genetics of ageing and age-related diseases.

The use of genetically engineered model systems for research on human aging.

A major goal in the field of aging research is to identify molecular mechanisms of aging at the cellular level, which are anticipated to form the basis for the development of age-associated dysfunctions and diseases in human beings. Recent progress in research into model organisms of aging has allowed determining precise molecular mechanisms and genetic determinants of the aging process, which appear to be conserved in evolution and some of which apply to human aging as well. The consortium of the authors focuses on aging mechanisms at the cellular level, and exploits the potential of genetic analyses in lower eukaryotic model organisms for a better understanding of regulatory pathways implicated in aging processes. We have established a new database (GiSAO), which provides a unique resource for the analysis of genome-wide expression patterns as being regulated by senescence, apoptosis and oxidative stress in our model systems. This has led to the identification of candidate genes, which are being tested for their impact on lifespan regulation in yeast, the fruit fly Drosophila melanogaster and the nematode C. elegans.

Corrigendum: Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan

Corrigendum: Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan