Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT

Gezonder ouder dankzij medicijn tegen diabetes

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Metformin-promoted lifespan involves mitohormesis in C. elegans

Ageing is seen as a progressive loss-of-function over time, generally thought to be due to the intrinsic accumulation of molecular damage. This leads to an increased susceptibility to intrinsic and environmental stressors and ultimately death. Ageing was long thought to be a passive and random process until pioneering studies near the end of the 20th century showed that a single mutation could increase the lifespan of the bacterivorous nematode Caenorhabditis elegans by more than half. This proved that the rate of ageing can be controlled by factors that are encoded in the genome and that ageing is, in other words, a biological process. As biological processes and pathways can be manipulated, this also started the search for compounds that could extend healthy lifespan. Metformin, an anti-glycaemic biguanide drug and the most common treatment of type II diabetes mellitus, has lifespan-extending capabilities both in rodents and nematodes. Several other human diseases, such as cancer and cardiovascular disease are potentially alleviated by metformin treatment as well. This suggests that metformin acts on common pathways involved in a spectrum of ageing-related disorders. Despite its widespread use, its mode of action is largely unknown.Via a quantitative proteomics approach using the model organism C. elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signalling cascade in which metformin-induced production of reactive oxygen species (ROS) increases overall life expectancy. These results further add to the increasing body of evidence that mild ROS production, while detrimental at higher concentrations, can cause a beneficial adaptive response leading to increased longevity. We further address an important issue in ageing research, wherein so far, the key molecular link that translates the ROS signal into a pro-longevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signalling might underlie a general principle of pro-longevity signalling.It was recently shown that neuronal ROS signalling is sufficient to extend lifespan in C. elegans, implying that the longevity-promoting effects of mitohormesis may be propagated by the endocrine system. While the endocrine factors involved are either largely or completely unknown, they are most likely specific neuropeptides. The development of a high-throughput quantitative peptidomics technique for the profiling of these peptides may lead to the identification of these promising mediators of longevity. In this thesis, we described a promising label-based approach for differential peptidomics that may, in time, be used to study the endocrine regulationof ageing. While this work mainly accentuates thepower of differential proteomics, using a more integrated approach combining proteomics, peptidomics, redox proteomics and others may lead to a more comprehensive map of the regulation of C. elegans longevity.nrpages: 166status: publishe

The essence of insect metamorphosis and aging: Electrical rewiring of cells driven by the principles of juvenile hormone-dependent Ca2+ homeostasis

In holometabolous insects the fall to zero of the titer of Juvenile Hormone ends its still poorly understood "status quo" mode of action in larvae. Concurrently it initiates metamorphosis of which the programmed cell death of all internal tissues that actively secrete proteins, such as the fat body, midgut, salivary glands, prothoracic glands, etc. is the most drastic aspect. These tissues have a very well developed rough endoplasmic reticulum, a known storage site of intracellular Ca(2+). A persistent high [Ca(2+)]i is toxic, lethal and causal to apoptosis. Metamorphosis becomes a logical phenomenon if analyzed from: (1) the causal link between calcium toxicity and apoptosis; (2) the largely overlooked fact that at least some isoforms of Ca(2+)-ATPases have a binding site for farnesol-like endogenous sesquiterpenoids (FRS). The Ca(2+)-ATPase blocker thapsigargin, like JH a sesquiterpenoid derivative, illustrates how absence of JH might work. The Ca(2+)-homeostasis system is concurrently extremely well conserved in evolution and highly variable, enabling tissue-, developmental-, and species specificity. As long as JH succeeds in keeping [Ca(2+)]i low by keeping the Ca(2+)-ATPases pumping, it acts as "the status quo" hormone. When it disappears, its various inhibitory effects are lifted. The electrical wiring system of cells, in particular in the regenerating tissues, is subject to change during metamorphosis. The possibility is discussed that in vertebrates an endogenous farnesol-like sesquiterpenoid, probably farnesol itself, acts as a functional, but hitherto completely overlooked Juvenile anti-aging "Inbrome", a novel concept in signaling.publisher: Elsevier articletitle: The essence of insect metamorphosis and aging: Electrical rewiring of cells driven by the principles of juvenile hormone-dependent Ca2+-homeostasis journaltitle: General and Comparative Endocrinology articlelink: http://dx.doi.org/10.1016/j.ygcen.2014.01.009 content_type: article copyright: Copyright © 2014 Elsevier Inc. All rights reserved.status: publishe

Life-prolonging measures for a dead theory?

In a recent review article, Selman and colleagues (Trends Ecol Evol 27:570-577, 2012) discuss the status quo of the oxidative stress theory of aging (OSTA) and how it links to life history evolution. They suggest that the OSTA should be tested in wild populations which might show effects masked in laboratory settings. We disagree with their propositions for several reasons. We argue that there is increasing evidence that reactive oxygen species (ROS) are not causally linked with aging and that ROS do not play a straightforward role in shaping life history evolution. We propose that laboratory animals and semi-wild populations rather than wild animals are suited best to test any hypothesized effect of reactive oxygen species. This is because data from controlled manipulative experiments rather than observational correlations are preferred to solve this issue. In addition, nonconventional model organisms will be useful in answering the question how relevant the OSTA could be for life history evolution.status: publishe

Royalactine als verjongingskuur, ook voor de mens?

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Royalactin extends lifespan of C. elegans through EGF signaling

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Long live the Queen - Royalactin extends lifespan of C.elegans through epidermal growth factor (EGF) signaling

Royalactin is a glycoprotein essential for the development of long-lived queen honeybees. Only larvae fed with royal jelly, containing royalactin, develop into queens. Royalactin plays a central role in this process by switching on the epidermal growth factor (EGF) receptor signaling pathway, which ultimately leads to epigenetic changes and a long-lived queen phenotype. Recently it was shown that royalactin also extends lifespan in Drosophila melanogaster. Yet, the mechanism by which royalactin promotes longevity remains largely unknown. We set out to characterize the effects of royalactin on Caenorhabditis elegans lifespan, and clarify the possible involvement of EGF signaling in this process. We demonstrate that royalactin extends lifespan of this nematode by ~30% and that both EGF (LIN-3) and its receptor (LET-23) are essential for royalactin to exert its positive effects. Additionally, we show that royalactin enhances stress tolerance and locomotion in adult nematodes, implying that royalactin also influences healthspan. Our results support the rather novel notion that the EGF pathway, next to its important role in early development, may acts as a regulator of aging in adult animals. In short, we show that royalactin is an important lifespan-extending factor in royal jelly and acts by promoting EGF signaling in C. elegans. Further work is now being carried out to clarify which (secondary) signaling pathways are activated by royalactin, and how this ultimately translates into an extended health- and lifespan.Short oral presentation.status: publishe