Pollutants corrupt resilience pathways of aging in the nematode C. elegans

AbstractDelaying aging while prolonging health and lifespan is a major goal in aging research. While many resources have been allocated to find positive interventions with promising results, negative interventions such as pollution and their accelerating effect on age-related degeneration and disease have been mostly neglected. Here, we used the short-lived model organism C. elegans to analyze whether two candidate pollutants interfere with positive interventions by corrupting general aging pathways. We took advantage of the immense data sets describing the age-related remodeling of the proteome including increased protein insolubilities to complement our analysis. We show that the emergent pollutant silica nanoparticles (NP) and the classic xenobiotic inorganic mercury reduce lifespan and cause a premature protein aggregation phenotype. Silica NPs rescaled the longevity effect of genetic interventions targeting the IGF-1/insulin-like signaling pathway. Comparative mass spectrometry revealed that increased insolubility of proteins with important functions in proteostasis is a shared phenotype of intrinsic- and pollution-induced aging supporting the hypothesis that proteostasis is a central resilience pathway controlling lifespan and aging. The presented data demonstrate that pollutants corrupt intrinsic aging pathways, which results in premature aging phenotypes. Reducing pollution is therefore an important step to increase healthy aging and prolong life expectancies on a population level in humans and animals.

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Health and longevity studies in C. elegans: the “healthy worm database” reveals strengths, weaknesses and gaps of test compound-based studies

Biogerontology ◽

10.1007/s10522-021-09913-2 ◽

2021 ◽

Vol 22 (2) ◽

pp. 215-236

Author(s):

Nadine Saul ◽

Steffen Möller ◽

Francesca Cirulli ◽

Alessandra Berry ◽

Walter Luyten ◽

...

Keyword(s):

Healthy Aging ◽

Model Organism ◽

Research Field ◽

Aging Research ◽

Genetic Manipulations ◽

C Elegans ◽

Starting Point ◽

Health Related ◽

Phenotype Measurement ◽

Or Gene

AbstractSeveral biogerontology databases exist that focus on genetic or gene expression data linked to health as well as survival, subsequent to compound treatments or genetic manipulations in animal models. However, none of these has yet collected experimental results of compound-related health changes. Since quality of life is often regarded as more valuable than length of life, we aim to fill this gap with the “Healthy Worm Database” (http://healthy-worm-database.eu). Literature describing health-related compound studies in the aging model Caenorhabditis elegans was screened, and data for 440 compounds collected. The database considers 189 publications describing 89 different phenotypes measured in 2995 different conditions. Besides enabling a targeted search for promising compounds for further investigations, this database also offers insights into the research field of studies on healthy aging based on a frequently used model organism. Some weaknesses of C. elegans-based aging studies, like underrepresented phenotypes, especially concerning cognitive functions, as well as the convenience-based use of young worms as the starting point for compound treatment or phenotype measurement are discussed. In conclusion, the database provides an anchor for the search for compounds affecting health, with a link to public databases, and it further highlights some potential shortcomings in current aging research.

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Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans

Nature Communications ◽

10.1038/s41467-021-27803-6 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Elite Possik ◽

Clémence Schmitt ◽

Anfal Al-Mass ◽

Ying Bai ◽

Laurence Côté ◽

...

Keyword(s):

Calorie Restriction ◽

Mammalian Cells ◽

Healthy Aging ◽

Model Organism ◽

Metabolic Stress ◽

Clinical Importance ◽

C Elegans ◽

Beneficial Effects ◽

Age Related

AbstractMetabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.

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Biological Age Prediction From Wearable Device Movement Data Identifies Nutritional and Pharmacological Interventions for Healthy Aging

Frontiers in Aging ◽

10.3389/fragi.2021.708680 ◽

2021 ◽

Vol 2 ◽

Author(s):

Rebecca L. McIntyre ◽

Mizanur Rahman ◽

Siva A. Vanapalli ◽

Riekelt H. Houtkooper ◽

Georges E. Janssens

Keyword(s):

Healthy Aging ◽

Machine Learning Algorithms ◽

Biological Age ◽

Wearable Device ◽

Biological Aging ◽

Accelerometer Data ◽

Pharmacological Interventions ◽

C Elegans ◽

Movement Data ◽

Age Related

Intervening in aging processes is hypothesized to extend healthy years of life and treat age-related disease, thereby providing great benefit to society. However, the ability to measure the biological aging process in individuals, which is necessary to test for efficacy of these interventions, remains largely inaccessible to the general public. Here we used NHANES physical activity accelerometer data from a wearable device and machine-learning algorithms to derive biological age predictions for individuals based on their movement patterns. We found that accelerated biological aging from our “MoveAge” predictor is associated with higher all-cause mortality. We further searched for nutritional or pharmacological compounds that associate with decelerated aging according to our model. A number of nutritional components peak in their association to decelerated aging later in life, including fiber, magnesium, and vitamin E. We additionally identified one FDA-approved drug associated with decelerated biological aging: the alpha-blocker doxazosin. We show that doxazosin extends healthspan and lifespan in C. elegans. Our work demonstrates how a biological aging score based on relative mobility can be accessible to the wider public and can potentially be used to identify and determine efficacy of geroprotective interventions.

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Resveratrol: A Sirtuin Activator and The Fountain of Youth

The Indonesian Biomedical Journal ◽

10.18585/inabj.v7i1.16 ◽

2015 ◽

Vol 7 (1) ◽

pp. 1 ◽

Cited By ~ 1

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

Caloric Restriction ◽

Healthy Aging ◽

Myocardial Infarct ◽

Functional Decline ◽

Steady Increase ◽

Healthy Human ◽

Aging Research ◽

Human Lifespan ◽

Age Related ◽

Fountain Of Youth

BACKGROUND: An organism’s lifespan is inevitably accompanied by the aging process, which involves functional decline, a steady increase of a plethora of chronic diseases, and ultimately death. Thus, it has been an ongoing dream of mankind to improve healthspan and extend life.CONTENT: There are only a few proposed aging interventions: caloric restriction, exercise, and the use of low-molecular-weight compounds, including spermidine, metformin, resveratrol, and rapamycin. Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Resveratrol have been shown to prevent and reduce the severity of age-related diseases such as atherosclerosis, stroke, myocardial infarct, diabetes, neurodegenerative diseases, osteoarthritis, tumors and metabolic syndrome, along with their ability to extend lifespan.SUMMARY: The purpose of aging research is the identification of interventions that may avoid or ameliorate the ravages of time. In other words, the quest is for healthy aging, where improved longevity is coupled to a corresponding healthspan extension. It is only by extending the healthy human lifespan that we will truly meet the premise of the Roman poet Cicero: “No one is so old as to think that he may not live a year.”KEYWORDS: aging, caloric restriction, mimetic, healthspan, sirtuin activator

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NemaLife: A structured microfluidic culture device optimized for aging studies in crawling C. elegans

10.1101/675827 ◽

2019 ◽

Cited By ~ 4

Author(s):

Mizanur Rahman ◽

Hunter Edwards ◽

Nikolajs Birze ◽

Rebecca Gabrilska ◽

Kendra P. Rumbaugh ◽

...

Keyword(s):

Large Scale ◽

The Body ◽

Physiological Data ◽

Aging Research ◽

C Elegans ◽

Age Related ◽

Technology Platforms ◽

Aging Studies ◽

Pharyngeal Pumping ◽

Culture Maintenance

AbstractCaenorhabditis elegans is a powerful animal model in aging research. Standard longevity assays on agar plates involve the tedious task of picking and transferring animals to prevent younger progeny from contaminating age-synchronized adult populations. Large-scale studies employ progeny-blocking drugs or sterile mutants to avoid progeny contamination, but such manipulations change adult physiology and alter the influence of reproduction on normal aging. Moreover, for some agar growth-based technology platforms, such as automated lifespan machines, reagents such as food or drugs cannot be readily added/removed after initiation of the study. Current microfluidic approaches are well-suited to address these limitations, but in their liquid-based environments animals swim rather than crawl, introducing swim-induced stress in the lifespan analysis. Here we report a simple microfluidic device that we call NemaLife that features: 1) an optimized micropillar arena in which animals can crawl, 2) sieve channels that separate progeny and prevent the loss of adults from the arena during culture maintenance, and 3) ports which allow rapid accessibility to feed the adult-only population and introduce reagents as needed. Culture maintenance and liquid manipulation are performed with simple hand-held syringes to facilitate integration of our technology into general laboratory protocols. Additionally, device geometry and feeding protocols were designed to emulate the body gait, locomotion, and lifespan of animals reared on agar. We validated our approach with longevity analyses of classical aging mutants (daf-2, age-1, eat-2, and daf-16) and animals subjected to RNAi knockdown of age-related genes (age-1 and daf-16). We also showed that healthspan measures such as pharyngeal pumping and tap-induced stimulated reversals can be scored across the lifespan. Overall, the capacity to generate reliable lifespan and physiological data from the NemaLife chip underscores the potential of this device to accelerate healthspan and lifespan investigations in C. elegans.

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C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins

Biomolecules ◽

10.3390/biom10081188 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1188 ◽

Cited By ~ 1

Author(s):

Carl Alexander Sandhof ◽

Simon Oliver Hoppe ◽

Jessica Tittelmeier ◽

Carmen Nussbaum-Krammer

Keyword(s):

Neurodegenerative Diseases ◽

Model Organism ◽

Model Systems ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathies ◽

Population Demographics ◽

C Elegans ◽

Age Related ◽

Bona Fide ◽

High Degree

A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients’ families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients.

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Indoles from commensal bacteria extend healthspan

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1706464114 ◽

2017 ◽

Vol 114 (36) ◽

pp. E7506-E7515 ◽

Cited By ~ 55

Author(s):

Robert Sonowal ◽

Alyson Swimm ◽

Anusmita Sahoo ◽

Liping Luo ◽

Yohei Matsunaga ◽

...

Keyword(s):

Small Molecules ◽

Healthy Aging ◽

Commensal Bacteria ◽

Molecular Pathways ◽

Genetic Pathways ◽

C Elegans ◽

Commensal Microbiota ◽

Aryl Hydrocarbon ◽

Age Related ◽

Animal Remains

Multiple studies have identified conserved genetic pathways and small molecules associated with extension of lifespan in diverse organisms. However, extending lifespan does not result in concomitant extension in healthspan, defined as the proportion of time that an animal remains healthy and free of age-related infirmities. Rather, mutations that extend lifespan often reduce healthspan and increase frailty. The question arises as to whether factors or mechanisms exist that uncouple these processes and extend healthspan and reduce frailty independent of lifespan. We show that indoles from commensal microbiota extend healthspan of diverse organisms, including Caenorhabditis elegans, Drosophila melanogaster, and mice, but have a negligible effect on maximal lifespan. Effects of indoles on healthspan in worms and flies depend upon the aryl hydrocarbon receptor (AHR), a conserved detector of xenobiotic small molecules. In C. elegans, indole induces a gene expression profile in aged animals reminiscent of that seen in the young, but which is distinct from that associated with normal aging. Moreover, in older animals, indole induces genes associated with oogenesis and, accordingly, extends fecundity and reproductive span. Together, these data suggest that small molecules related to indole and derived from commensal microbiota act in diverse phyla via conserved molecular pathways to promote healthy aging. These data raise the possibility of developing therapeutics based on microbiota-derived indole or its derivatives to extend healthspan and reduce frailty in humans.

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The INSPIRE Bio-resource Research Platform for Healthy Aging and Geroscience: Focus on the Human Translational Research Cohort (The INSPIRE-T Cohort)

Journal of Frailty & Aging ◽

10.14283/jfa.2020.38 ◽

2020 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

S. Guyonnet ◽

Y. Rolland ◽

C. Takeda ◽

P.-J. Ousset ◽

I. Ader ◽

...

Keyword(s):

Health Care ◽

Translational Research ◽

Healthy Aging ◽

Care Pathway ◽

Integrative Approach ◽

Biological Aging ◽

Imaging Data ◽

Aging Research ◽

Age Related

Background: The Geroscience field focuses on the core biological mechanisms of aging, which are involved in the onset of age-related diseases, as well as declines in intrinsic capacity (IC) (body functions) leading to dependency. A better understanding on how to measure the true age of an individual or biological aging is an essential step that may lead to the definition of putative markers capable of predicting healthy aging. Objectives: The main objective of the INStitute for Prevention healthy agIng and medicine Rejuvenative (INSPIRE) Platform initiative is to build a program for Geroscience and healthy aging research going from animal models to humans and the health care system. The specific aim of the INSPIRE human translational cohort (INSPIRE-T cohort) is to gather clinical, digital and imaging data, and perform relevant and extensive biobanking to allow basic and translational research on humans. Methods: The INSPIRE-T cohort consists in a population study comprising 1000 individuals in Toulouse and surrounding areas (France) of different ages (20 years or over - no upper limit for age) and functional capacity levels (from robustness to frailty, and even dependency) with follow-up over 10 years. Diversified data are collected annually in research facilities or at home according to standardized procedures. Between two annual visits, IC domains are monitored every 4-month by using the ICOPE Monitor app developed in collaboration with WHO. Once IC decline is confirmed, participants will have a clinical assessment and blood sampling to investigate markers of aging at the time IC declines are detected. Biospecimens include blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. Nasopharyngeal swabs and cutaneous surface samples are collected in a large subgroup of subjects every two years. Feces, hair bulb and skin biopsy are collected optionally at the baseline visit and will be performed again during the longitudinal follow up. Expected Results: Recruitment started on October 2019 and is expected to last for two years. Bio-resources collected and explored in the INSPIRE-T cohort will be available for academic and industry partners aiming to identify robust (set of) markers of aging, age-related diseases and IC evolution that could be pharmacologically or non-pharmacologically targetable. The INSPIRE-T will also aim to develop an integrative approach to explore the use of innovative technologies and a new, function and person-centered health care pathway that will promote a healthy aging.

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High-Content C. elegans Screen Identifies Natural Compounds Impacting Mitochondria-Lipid Homeostasis and Promoting Healthspan

Cells ◽

10.3390/cells11010100 ◽

2021 ◽

Vol 11 (1) ◽

pp. 100

Author(s):

Silvia Maglioni ◽

Nayna Arsalan ◽

Anna Hamacher ◽

Shiwa Afshar ◽

Alfonso Schiavi ◽

...

Keyword(s):

Stress Response ◽

Lipid Content ◽

Model Organism ◽

Natural Compounds ◽

Extrinsic Factors ◽

Mitochondrial Stress ◽

C Elegans ◽

Stress Response Genes ◽

Age Related ◽

Kahalalide F

The aging process is concurrently shaped by genetic and extrinsic factors. In this work, we screened a small library of natural compounds, many of marine origin, to identify novel possible anti-aging interventions in Caenorhabditis elegans, a powerful model organism for aging studies. To this aim, we exploited a high-content microscopy platform to search for interventions able to induce phenotypes associated with mild mitochondrial stress, which is known to promote animal’s health- and lifespan. Worms were initially exposed to three different concentrations of the drugs in liquid culture, in search of those affecting animal size and expression of mitochondrial stress response genes. This was followed by a validation step with nine compounds on solid media to refine compounds concentration, which led to the identification of four compounds (namely isobavachalcone, manzamine A, kahalalide F and lutein) consistently affecting development, fertility, size and lipid content of the nematodes. Treatment of Drosophila cells with the four hits confirmed their effects on mitochondria activity and lipid content. Out of these four, two were specifically chosen for analysis of age-related parameters, kahalalide F and lutein, which conferred increased resistance to heat and oxidative stress and extended animals’ healthspan. We also found that, out of different mitochondrial stress response genes, only the C. elegans ortholog of the synaptic regulatory proteins neuroligins, nlg-1, was consistently induced by the two compounds and mediated lutein healthspan effects.

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Lack of Age-related Respiratory Changes in Daphnia

10.1101/2021.06.05.447222 ◽

2021 ◽

Author(s):

Cora E Anderson ◽

Millicent N Ekwudo ◽

Rachael A Jonas-Closs ◽

Yongmin Cho ◽

Leonid M Peshkin ◽

...

Keyword(s):

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane ◽

Feeding Activity ◽

Model Organism ◽

Respiratory Metabolism ◽

Aging Research ◽

Age Related ◽

Age Related Changes ◽

Pyruvate Ratio

Aging is a multifaceted process of accumulation of damages and waste in cells and tissues; age-related changes in mitochondria and in respiratory metabolism have been in the focus of aging research for decades. Here we investigated age-related changes in respiration rates, lactate/pyruvate ratio, a commonly used proxy for NAD+/NADH balance, and mitochondrial membrane potential in 4 genotypes of an emerging model organism for aging research, a cyclic parthenogen Daphnia magna. We show that total body weight-adjusted respiration rate decreases with age, although this decrease is small in magnitude and not observed in anaesthetized animals, thus likely to be accounted for by decrease in locomotion and feeding activity. Lactate/pyruvate ratio and mitochondrial membrane potential (Ψmt) showed no age-related changes, with a possible exception of mt measured in the optical lobe and in epipodites (excretory organs) in which Ψmt showed a maximum at middle age. We conclude that actuarial senescence in Daphnia is not caused by a decline in respiratory metabolism and discuss possible mechanisms of maintaining mitochondrial healthspan throughout the lifespan.

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