Healthspan Enhancement by Olive Polyphenols in C. elegans Wild Type and Parkinson’s Models

Parkinson’s disease (PD) is the second most prevalent late-age onset neurodegenerative disorder, affecting 1% of the population after the age of about 60 years old and 4% of those over 80 years old, causing motor impairments and cognitive dysfunction. Increasing evidence indicates that Mediterranean diet (MD) exerts beneficial effects in maintaining health, especially during ageing and by the prevention of neurodegenerative disorders. In this regard, olive oil and its biophenolic constituents like hydroxytyrosol (HT) have received growing attention in the past years. Thus, in the current study we test the health-promoting effects of two hydroxytyrosol preparations, pure HT and Hidrox® (HD), which is hydroxytyrosol in its “natural” environment, in the established invertebrate model organism Caenorhabditis elegans. HD exposure led to much stronger beneficial locomotion effects in wild type worms compared to HT in the same concentration. Consistent to this finding, in OW13 worms, a PD-model characterized by α-synuclein expression in muscles, HD exhibited a significant higher effect on α-synuclein accumulation and swim performance than HT, an effect partly confirmed also in swim assays with the UA44 strain, which features α-synuclein expression in DA-neurons. Interestingly, beneficial effects of HD and HT treatment with similar strength were detected in the lifespan and autofluorescence of wild-type nematodes, in the neuronal health of UA44 worms as well as in the locomotion of rotenone-induced PD-model. Thus, the hypothesis that HD features higher healthspan-promoting abilities than HT was at least partly confirmed. Our study demonstrates that HD polyphenolic extract treatment has the potential to partly prevent or even treat ageing-related neurodegenerative diseases and ageing itself. Future investigations including mammalian models and human clinical trials are needed to uncover the full potential of these olive compounds.

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Healthspan Maintenance and Prevention of Parkinson’s-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans

International Journal of Molecular Sciences ◽

10.3390/ijms21072588 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2588 ◽

Cited By ~ 23

Author(s):

Giovanni Brunetti ◽

Gabriele Di Rosa ◽

Maria Scuto ◽

Manuela Leri ◽

Massimo Stefani ◽

...

Keyword(s):

Olive Oil ◽

Dopaminergic Neurons ◽

Model Organism ◽

Full Potential ◽

Detoxifying Enzymes ◽

C Elegans ◽

Beneficial Effects ◽

Underlying Causes ◽

Invertebrate Model ◽

Rotenone Exposure

Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer’s and Parkinson’s disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism Caenorhabditis elegans was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different C. elegans PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.

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Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model

10.1101/2020.02.12.946004 ◽

2020 ◽

Cited By ~ 1

Author(s):

Sanjib Guha ◽

Sarah Fischer ◽

Gail VW Johnson ◽

Keith Nehrke

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Model ◽

Neurodegenerative Disorder ◽

Model Organism ◽

Single Copy ◽

Mitochondrial Stress ◽

C Elegans ◽

Touch Receptor Neurons ◽

New Perspective

ABSTRACTBackgroundA defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer’s disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include phosphorylation at Threonine 231 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is recognized to play a central role in pathogenesis of AD, the precise mechanisms by which these abnormal PTMs contribute to the neural toxicity of tau is unclear.MethodsHuman 0N4R tau (wild type) was expressed in touch receptor neurons of the genetic model organism C. elegans through single-copy gene insertion. Defined mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 genome editing. These mutations included T231E and T231A, to mimic phosphorylation and phospho-ablation of a commonly observed pathological epitope, respectively, and K274/281Q, to mimic disease-associated lysine acetylation. Stereotypical touch response assays were used to assess behavioral defects in the transgenic strains as a function of age, and genetically-encoded fluorescent biosensors were used to measure the morphological dynamics and turnover of touch neuron mitochondria.ResultsUnlike existing tau overexpression models, C. elegans single-copy expression of tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited reduced touch sensation and morphological abnormalities that increased with age. In addition, the PTM-mimetic mutants lacked the ability to engage mitophagy in response to mitochondrial stress.ConclusionsLimiting the expression of tau results in a genetic model where pathological modifications and age result in evolving phenotypes, which may more closely resemble the normal progression of AD. The finding that disease-associated PTMs suppress compensatory responses to mitochondrial stress provides a new perspective into the pathogenic mechanisms underlying AD.

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Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model

Molecular Neurodegeneration ◽

10.1186/s13024-020-00410-7 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Sanjib Guha ◽

Sarah Fischer ◽

Gail V. W. Johnson ◽

Keith Nehrke

Keyword(s):

Genetic Model ◽

Neurodegenerative Disorder ◽

Model Organism ◽

Single Copy ◽

Neuronal Morphology ◽

Mitochondrial Morphology ◽

Mitochondrial Stress ◽

C Elegans ◽

Touch Receptor Neurons ◽

New Perspective

Abstract Background A defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer’s disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include phosphorylation at Threonine 231 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is recognized to play a central role in pathogenesis of AD, the precise mechanisms by which these abnormal PTMs contribute to the neural toxicity of tau is unclear. Methods Human 0N4R tau (wild type) was expressed in touch receptor neurons of the genetic model organism C. elegans through single-copy gene insertion. Defined mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 genome editing. These mutations included T231E, to mimic phosphorylation of a commonly observed pathological epitope, and K274/281Q, to mimic disease-associated lysine acetylation – collectively referred as “PTM-mimetics” – as well as a T231A phosphoablation mutant. Stereotypical touch response assays were used to assess behavioral defects in the transgenic strains as a function of age. Genetically-encoded fluorescent biosensors were expressed in touch neurons and used to measure neuronal morphology, mitochondrial morphology, mitophagy, and macro autophagy. Results Unlike existing tau overexpression models, C. elegans single-copy expression of tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited reduced touch sensation and neuronal morphological abnormalities that increased with age. In addition, the PTM-mimetic mutants lacked the ability to engage neuronal mitophagy in response to mitochondrial stress. Conclusions Limiting the expression of tau results in a genetic model where modifications that mimic pathologic tauopathy-associated PTMs contribute to cryptic, stress-inducible phenotypes that evolve with age. These findings and their relationship to mitochondrial stress provides a new perspective into the pathogenic mechanisms underlying AD.

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Supplemental Cellular Protection by a Carotenoid Extends Lifespan via Ins/IGF-1 Signaling inCaenorhabditis elegans

Oxidative Medicine and Cellular Longevity ◽

10.1155/2011/596240 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 26

Author(s):

Koumei Yazaki ◽

Chinatsu Yoshikoshi ◽

Satoru Oshiro ◽

Sumino Yanase

Keyword(s):

Model Organism ◽

Lifespan Extension ◽

Cell Organelle ◽

Wild Type ◽

Marine Animals ◽

Cellular Protection ◽

C Elegans ◽

Expression Of Genes ◽

Genes Encoding ◽

In The Wild

Astaxanthin (AX), which is produced by some marine animals, is a type of carotenoid that has antioxidative properties. In this study, we initially examined the effects of AX on the aging of a model organismC. elegansthat has the conserved intracellular pathways related to mammalian longevity. The continuous treatments with AX (0.1 to 1 mM) from both the prereproductive and young adult stages extended the mean lifespans by about 16–30% in the wild-type and long-lived mutantage-1ofC. elegans. In contrast, the AX-dependent lifespan extension was not observed even in adaf-16null mutant. Especially, the expression of genes encoding superoxide dismutases and catalases increased in two weeks after hatching, and the DAF-16 protein was translocated to the nucleus in the AX-exposed wild type. These results suggest that AX protects the cell organelle mitochondria and nucleus of the nematode, resulting in a lifespan extension via an Ins/IGF-1 signaling pathway during normal aging, at least in part.

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Expression of β-1,4-galactosyltransferases during Aging in Caenorhabditis elegans

Gerontology ◽

10.1159/000510722 ◽

2020 ◽

Vol 66 (6) ◽

pp. 571-581

Author(s):

Jennifer Kremer ◽

Cornelia Brendel ◽

Elisabeth Karin Maria Mack ◽

Hildegard Isolde Dietlinde Mack

Keyword(s):

Caenorhabditis Elegans ◽

Model Organism ◽

Mrna Levels ◽

Germline Stem Cells ◽

Wild Type ◽

Activity Increase ◽

C Elegans ◽

Targeted Analysis ◽

Age Dependent ◽

Plasma Activity

Background: Altered plasma activity of β-1,4-galactosyltransferases (B4GALTs) is a novel candidate biomarker of human aging. B4GALT1 is assumed to be largely responsible for this activity increase, but how it modulates the aging process is unclear at present. Objectives: To determine how expression of B4GALT1 and other B4GALT enzymes changes during aging of an experimentally tractable model organism, Caenorhabditis elegans. Methods: Targeted analysis of mRNA levels of all 3 C. elegans B4GALT family members was performed by qPCR in wild-type and in long-lived daf-2 (insulin/IGF1-like receptor)-deficient or germline-deficient animals. Results: bre-4 (B4GALT1/2/3/4) is the only B4GALT whose expression increases during aging in wild-type worms. In addition, bre-4 levels also rise during aging in long-lived daf-2-deficient worms, but not in animals that are long-lived due to the lack of germline stem cells. On the other hand, expression of sqv-3 (B4GALT7) and of W02B12.11 (B4GALT5/6) appears decreased or constant, respectively, in all backgrounds during aging. Conclusions: The age-dependent bre-4 mRNA increase in C. elegans parallels the age-dependent B4GALT activity increase in humans and is consistent with C. elegans being a suitable experimental organism to define potentially conserved roles of B4GALT1 during aging.

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Anti-aging and Anti-aggregation Properties of Polyphenolic Compounds in C. elegans

Current Pharmaceutical Design ◽

10.2174/1381612824666180515145652 ◽

2018 ◽

Vol 24 (19) ◽

pp. 2107-2120 ◽

Cited By ~ 7

Author(s):

Nikoletta Papaevgeniou ◽

Niki Chondrogianni

Keyword(s):

Oxidative Stress ◽

Model Organism ◽

Protective Role ◽

Polyphenolic Compounds ◽

Nematode Caenorhabditis Elegans ◽

C Elegans ◽

Beneficial Effects ◽

Age Related ◽

Anti Oxidant ◽

Main Model

Polyphenols constitute a group of compounds that have been highly investigated for their beneficial effects against various pathologic and non-pathologic conditions and diseases. Among their multi-faceted properties, their anti-oxidant potential nominates them as ideal protective candidates for conditions characterized by elevated levels of oxidative stress, including aging and age-related diseases. The nematode Caenorhabditis elegans is a multicellular model organism that is highly exploited in studies related to aging and age-associated pathologies. In this review, we will summarize studies where polyphenolic compounds have been tested for their anti-aging potential and their protective role against the progression of age-related diseases using C. elegans as their main model.

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Tart Cherry Increases Lifespan in Caenorhabditis elegans by Altering Metabolic Signaling Pathways

Nutrients ◽

10.3390/nu12051482 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1482

Author(s):

Shasika Jayarathne ◽

Latha Ramalingam ◽

Hunter Edwards ◽

Siva A. Vanapalli ◽

Naima Moustaid-Moussa

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Mitochondrial Function ◽

Antioxidant Properties ◽

Wild Type ◽

Tart Cherry ◽

C Elegans ◽

Beneficial Effects ◽

The Mean ◽

And Oxidative Stress

Aging and healthspan are determined by both environmental and genetic factors. The insulin/insulin-like growth factor-1(IGF-1) pathway is a key mediator of aging in Caenorhabditis elegans and mammals. Specifically, DAF-2 signaling, an ortholog of human IGF, controls DAF-16/FOXO transcription factor, a master regulator of metabolism and longevity. Moreover, mitochondrial dysfunction and oxidative stress are both linked to aging. We propose that daily supplementation of tart cherry extract (TCE), rich in anthocyanins with antioxidant properties may exert dual benefits for mitochondrial function and oxidative stress, resulting in beneficial effects on aging in C. elegans. We found that TCE supplementation at 6 μg or 12 μg/mL, increased (p < 0.05) the mean lifespan of wild type N2 worms, respectively, when compared to untreated control worms. Consistent with these findings, TCE upregulated (p < 0.05) expression of longevity-related genes such as daf-16 and aak-2 (but not daf-2 or akt-1 genes) and genes related to oxidative stress such as sod-2. Further, we showed that TCE supplementation increased spare respiration in N2 worms. However, TCE did not change the mean lifespan of daf-16 and aak-2 mutant worms. In conclusion, our findings indicate that TCE confers healthspan benefits in C. elegans through enhanced mitochondrial function and reduced oxidative stress, mainly via the DAF-16 pathway.

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Head-to-Head Comparison of Three Methods of Quantifying Competitive Fitness in C. elegans

10.1101/371831 ◽

2018 ◽

Author(s):

Timothy A. Crombie ◽

Sayran Saber ◽

Ayush Shekhar Saxena ◽

Robyn Egan ◽

Charles F. Baer

Keyword(s):

Model Organism ◽

Experimental Population ◽

Wild Type ◽

Experimental Conditions ◽

Competitive Fitness ◽

C Elegans ◽

Tenfold Increase ◽

Different Types ◽

Multicellular Organisms ◽

Automated Methods

AbstractOrganismal fitness is relevant in many contexts in biology. The most meaningful experimental measure of fitness is competitive fitness, when two or more entities (e.g., genotypes) are allowed to compete directly. In theory, competitive fitness is simple to measure: an experimental population is initiated with the different types in known proportions and allowed to evolve under experimental conditions to a predefined endpoint. In practice, there are several obstacles to obtaining robust estimates of competitive fitness in multicellular organisms, the most pervasive of which is simply the time it takes to count many individuals of different types from many replicate populations. Methods by which counting can be automated in high throughput are desirable, but for automated methods to be useful, the bias and technical variance associated with the method must be (a) known, and (b) sufficiently small relative to other sources of bias and variance to make the effort worthwhile.The nematode Caenorhabditis elegans is an important model organism, and the fitness effects of genotype and environmental conditions are often of interest. We report a comparison of three experimental methods of quantifying competitive fitness, in which wild-type strains are competed against GFP-marked competitors under standard laboratory conditions. Population samples were split into three replicates and counted (1) “by eye” from a saved image, (2) from the same image using CellProfiler image analysis software, and (3) with a large particle flow cytometer (a “worm sorter”). From 720 replicate samples, neither the frequency of wild-type worms nor the among-sample variance differed significantly between the three methods. CellProfiler and the worm sorter provide at least a tenfold increase in sample handling speed with little (if any) bias or increase in variance.

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Experimental investigation using micro-PIV of the effect of microRNA-1 deficiency on motility in Caenorhabditis elegans

10.1101/2020.06.16.119396 ◽

2020 ◽

Author(s):

S. Ravikumar ◽

M. Fedrizzi ◽

R. Prabhakar ◽

R. Pocock ◽

M. K. O’Bryan ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Swimming Speed ◽

Model Organism ◽

The Body ◽

Wild Type ◽

Mean Power ◽

C Elegans ◽

Micro Piv ◽

Image Velocimetry ◽

Beating Frequency

AbstractCaenorhabditis elegans is a microscopic nematode used extensively as a model organism in studies of neuromuscular function and neurodegenerative disorders. A mutation in mir-1 affects signalling at the neuromuscular junction. We investigate the effect of this mutation on the propulsive power exerted by nematodes as they grow in size with age. We compare the motility of wild-type and mir-1(gk276) mutant nematodes in a Newtonian fluid using a two-component, two dimensional (2C-2D) Digital Microscopic Particle Image Velocimetry (µ-PIV) technique. Beating amplitudes of the head and tail, the wavelength of undulatory waves and the swimming speed scale linearly with size in both the wild-type and mutant strains. The beating frequency is independent of size or position along the body. Differences in the magnitudes of these kinematic parameters between the two strains, however, grow systematically with age. The swimming speed scales linearly with the wave speed of the neuromuscular undulation in both nematode strains with a conserved ratio. The magnitude of mean power and mean local fluid circulation in the mutant is significantly lower compared to those of the wild-type animals of the same age. This indicates that a mutation in mir-1 adversely affects motility in C. elegans.

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Promoters of the dhs-21 gene encoding dicarbonyl/l-xylulose reductase in Caenorhabditis elegans

Vietnam Journal of Biotechnology ◽

10.15625/1811-4989/15/2/12353 ◽

2018 ◽

Vol 15 (2) ◽

pp. 359-365

Author(s):

Lê Thọ Sơn ◽

Joohong Ahnn ◽

Jeong Hoon Cho ◽

Nguyễn Huy Hoàng

Keyword(s):

Caenorhabditis Elegans ◽

Model Organism ◽

Biological Research ◽

Loss Of Function ◽

Wild Type ◽

C Elegans ◽

Larval Stages ◽

Vital Functions

Dicarbonyl/L-xylulose (DCXR) was identified as a dehydrogenase. This type of enzyme was presented in various forms of lives including bacteria, fungi, plants and animals. Generally, it converts L-xylulose to xylitol in the presence of either cofactor NADH or NADPH in vitro. Previous studies reported the biochemistry properties and crystal structure but largely uncovered biological roles of DCXRs. It was impossible to dissect the functions in mice or human cells that had many DCXR homologs in their genomes. Interestingly, the wild-type Caenorhabditis elegans, a well-known model organism in biological research, has only nuclear genomic dhs-21 that encodes a unique homologous DCXR. Thus Ce.dhs-21 and the host C. elegans were relevant for investigation of the physiologically-vital functions of the DCXR. This research aimed to the expression of dhs-21 in vivo. We defined three promoters , manipulated three relative reporter-constructs that conjugated the dhs-21 gene and Green Flouresent Protein (known as GFP) one. The construct vectors were transferred into wild-type C. elegans N2 and as well as the hermaphroditic loss of function dhs-21(jh129) by microinjection. In the results, we found that the expression pattern of dhs-21 under the only p2-promoter construct was stable and similar to immunogold Electric Microscopy (EM) images. The dhs-21 gene was expressed in both sexes of at all larval stages till the deaths of worms. DHS-21 was expressed in the cytosol of the intestinal, gonad sheath and uterous seam cell (utse).

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