Caenorhabditis Elegans and Probiotics Interactions from a Prolongevity Perspective

Probiotics exert beneficial effects on host health through different mechanisms of action, such as production of antimicrobial substances, competition with pathogens, enhancement of host mucosal barrier integrity and immunomodulation. In the context of ageing, which is characterized by several physiological alterations leading to a low grade inflammatory status called inflammageing, evidences suggest a potential prolongevity role of probiotics. Unraveling the mechanisms underlying anti-ageing effects requires the use of simple model systems. To this respect, the nematode Caenorhabditis elegans represents a suitable model organism for the study of both host-microbe interactions and for ageing studies, because of conserved signaling pathways and host defense mechanisms involved in the regulation of its lifespan. Therefore, this review analyses the impact of probiotics on C. elegans age-related parameters, with particular emphasis on oxidative stress, immunity, inflammation and protection from pathogen infections. The picture emerging from our analysis highlights that several probiotic strains are able to exert anti-ageing effects in nematodes by acting on common molecular pathways, such as insulin/insulin-like growth factor-1 (IIS) and p38 mitogen-activated protein kinase (p38 MAPK). In this perspective, C. elegans appears to be advantageous for shedding light on key mechanisms involved in host prolongevity in response to probiotics supplementation.

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Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽

10.3390/biology10020163 ◽

2021 ◽

Vol 10 (2) ◽

pp. 163

Author(s):

Swapnil Gupta ◽

Panpan You ◽

Tanima SenGupta ◽

Hilde Nilsen ◽

Kulbhushan Sharma

Keyword(s):

Dna Repair ◽

Neurodegenerative Diseases ◽

3D Models ◽

Model Systems ◽

Spinocerebellar Ataxias ◽

C Elegans ◽

Cellular Processes ◽

Age Related ◽

Damage Response ◽

Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

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Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Nature Communications ◽

10.1038/s41467-020-20269-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mercedes M. Pérez-Jiménez ◽

José M. Monje-Moreno ◽

Ana María Brokate-Llanos ◽

Mónica Venegas-Calerón ◽

Alicia Sánchez-García ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Caenorhabditis Elegans ◽

Protein Aggregation ◽

Steroid Hormones ◽

Sensory Neurons ◽

Environmental Cues ◽

Steroid Sulfatase ◽

Loss Of Function ◽

C Elegans ◽

Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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Graptopetalum paraguayense Extract Ameliorates Proteotoxicity in Aging and Age-Related Diseases in Model Systems

Nutrients ◽

10.3390/nu13124317 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4317

Author(s):

Yan-Xi Chen ◽

Phuong Thu Nguyen Le ◽

Tsai-Teng Tzeng ◽

Thu-Ha Tran ◽

Anh Thuc Nguyen ◽

...

Keyword(s):

Model Systems ◽

Wild Type ◽

Nematode Caenorhabditis Elegans ◽

Cancer Cell Growth ◽

C Elegans ◽

Age Related ◽

Ampk Activity ◽

Β Amyloid ◽

Amp Activated Protein Kinase ◽

U87 Cells

Declines in physiological functions are the predominant risk factors for age-related diseases, such as cancers and neurodegenerative diseases. Therefore, delaying the aging process is believed to be beneficial in preventing the onset of age-related diseases. Previous studies have demonstrated that Graptopetalum paraguayense (GP) extract inhibits liver cancer cell growth and reduces the pathological phenotypes of Alzheimer’s disease (AD) in patient IPS-derived neurons. Here, we show that GP extract suppresses β-amyloid pathology in SH-SYS5Y-APP695 cells and APP/PS1 mice. Moreover, AMP-activated protein kinase (AMPK) activity is enhanced by GP extract in U87 cells and APP/PS1 mice. Intriguingly, GP extract enhances autophagy in SH-SYS5Y-APP695 cells, U87 cells, and the nematode Caenorhabditis elegans, suggesting a conserved molecular mechanism by which GP extract might regulate autophagy. In agreement with its role as an autophagy activator, GP extract markedly diminishes mobility decline in polyglutamine Q35 mutants and aged wild-type N2 animals in C. elegans. Furthermore, GP extract significantly extends lifespan in C. elegans.

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Metaflammation: Tissue-Specific Alterations of the NLRP3 Inflammasome Platform in Metabolic Syndrome

Current Medicinal Chemistry ◽

10.2174/0929867324666170407123522 ◽

2018 ◽

Vol 25 (11) ◽

pp. 1294-1310 ◽

Cited By ~ 23

Author(s):

Raffaella Mastrocola ◽

Manuela Aragno ◽

Giuseppe Alloatti ◽

Massimo Collino ◽

Claudia Penna ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Advanced Glycation Endproducts ◽

Low Grade ◽

Advanced Glycation ◽

Added Sugars ◽

Physiological Ageing ◽

Glycation Endproducts ◽

Inflammatory Status ◽

Age Related

In the last decades, the extension of life expectancy and the increased consumption of foods rich in saturated fats and added sugars have exposed the general population to emerging health problems. The prevalence of metabolic syndrome (MS), composed of a cluster of factors as obesity, dyslipidemia, hyperglycemia, and hypertension, is rapidly increasing in industrialized and developing countries leading to precocious onset of age-related diseases. Indeed, oxidative stress, accumulation of advanced glycation endproducts, and a chronic low-grade inflammation are common features of MS and physiological ageing. In particular, the entire set of MS factors contributes to the development of an inflammatory status named metaflammation, which has been associated with activation of early innate immune response through the assembling of the multiprotein complex inflammasome. The most investigated family of inflammasome platforms is the NOD-like receptor pyridine containing (NLRP) 3, which is activated by several exogenous and endogenous stimuli, leading to the sequential cleavage of caspase-1 and IL-1β, followed by secretion of active IL-1β. We here collect the most recent findings on NLRP3 activation in MS providing evidence of its central role in disease progression and organ dysfunction in target tissues of metaflammation, in particular in cardiovascular, hepatic and renal complications, with a focus on oxidative stress and advanced glycation endproducts. A wide overview of the most promising strategies for the modulation of NLRP3 activation and related metabolic repercussions is also provided, since the finding of specific pharmacological tools is an urgent requirement to reduce the social and economic burden of MS- and elderly-associated diseases.

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Ferrous-glutathione coupling mediates ferroptosis and frailty in Caenorhabditis elegans

10.1101/594408 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nicole L. Jenkins ◽

Simon A. James ◽

Agus Salim ◽

Fransisca Sumardy ◽

Terence P. Speed ◽

...

Keyword(s):

Cell Death ◽

Caenorhabditis Elegans ◽

Ferrous Iron ◽

Somatic Tissue ◽

Glutathione Depletion ◽

Death Process ◽

C Elegans ◽

Regulated Cell Death ◽

Age Related ◽

Ageing Rate

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis1, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in the Caenorhabditis elegans model of ageing2. Here we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan in C. elegans. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant ageing rate. Because excess age-related iron elevation in somatic tissue, particularly in brain3–5, is thought to contribute to degenerative disease6, 7, our data indicate that post-developmental interventions to limit ferroptosis may promote healthy ageing.

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Rubidium chloride increases lifespan through an AMPK/FOXO-dependent pathway in Caenorhabditis elegans

The Journals of Gerontology Series A ◽

10.1093/gerona/glab329 ◽

2021 ◽

Author(s):

Mengjiao Hao ◽

Zhikang Zhang ◽

Yijun Guo ◽

Huihao Zhou ◽

Qiong Gu ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Stress Responses ◽

Aging Effect ◽

Stress Effect ◽

Neuroprotective Effects ◽

C Elegans ◽

Cycle Arrest ◽

Age Related ◽

Promising Target ◽

Amp Activated Protein Kinase

Abstract AMP-activated protein kinase (AMPK) is involved in life span maintenance, stress responses, and germ cell cycle arrest upon dauer entry. AMPK is currently considered a promising target for preventing age-related diseases. Rubidium is one of the trace elements in human body. As early as the 1970s, RbCl has been was reported to have neuroprotective effects. In this work, we report the anti-aging effect of RbCl in Caenorhabditis elegans. Specifically, we reveal that (1) RbCl does increase the lifespan and enhance stress resistance in C. elegans without disturbing their fecundity. (2) RbCl induces superoxide dismutase (SOD) expression, which is essential for its anti-aging and anti-stress effect. (3) AAK-2 and DAF-16 are essential to the anti-aging efficacy of RbCl, and RbCl can promote DAF-16 translocating into the nucleus, suggesting that RbCl delays aging through regulating AMPK/FOXO pathway. RbCl can be a promising agent against aging related diseases.

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Secoisolariciresinol Diglucoside Delays the Progression of Aging-Related Diseases and Extends the Lifespan of Caenorhabditis elegans via DAF-16 and HSF-1

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/1293935 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Min Lu ◽

Lin Tan ◽

Xiao-Gang Zhou ◽

Zhong-Lin Yang ◽

Qing Zhu ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Body Movement ◽

Mrna Level ◽

Secoisolariciresinol Diglucoside ◽

Neuroprotective Effects ◽

Sesame Seeds ◽

C Elegans ◽

Age Related ◽

6 Hydroxydopamine ◽

And Oxidative Stress

Secoisolariciresinol diglucoside (SDG) is a phytoestrogen and rich in food flaxseed, sunflower seeds, and sesame seeds. Among the beneficial pharmacological activities of SDG on health, many are age related, such as anticancer, antidiabetes, antioxidant, and neuroprotective effects. Thus, we investigated if SDG had an effect on antiaging in Caenorhabditis elegans (C. elegans). Our results showed that SDG could extend the lifespan of C. elegans by up to 22.0%, delay age-related decline of body movement, reduce the lethality of heat and oxidative stress, alleviate dopamine neurodegeneration induced by 6-hydroxydopamine (6-OHDA), and decrease the toxicity of Aβ protein in C. elegans. SDG could increase the expression of the downstream genes of DAF-16, DAF-12, NHR-80, and HSF-1 at mRNA level. SDG could not extend the lifespan of mutants from genes daf-16, hsf-1, nhr-80, daf-12, glp-1, eat-2, and aak-2. The above results suggested that SDG might enhance the stress resistance, delay the progression of aging-related diseases, and extend the lifespan of C. elegans via DAF-16 and HSF-1.

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Neuroligin dependence of social behaviour in Caenorhabditis elegans provides a model to investigate an autism-associated gene

Human Molecular Genetics ◽

10.1093/hmg/ddaa232 ◽

2020 ◽

Author(s):

Helena Rawsthorne ◽

Fernando Calahorro ◽

Emily Feist ◽

Lindy Holden-Dye ◽

Vincent O’Connor ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Genetic Variants ◽

Social Behaviour ◽

Animal Studies ◽

Model Organism ◽

Autism Spectrum ◽

C Elegans ◽

Important Regulator ◽

Human Mutation ◽

The Impact

Abstract Autism spectrum disorder (ASD) is characterized by a triad of behavioural impairments including social behaviour. Neuroligin, a trans-synaptic adhesion molecule, has emerged as a penetrant genetic determinant of behavioural traits that signature the neuroatypical behaviours of autism. However, the function of neuroligin in social circuitry and the impact of genetic variation to this gene is not fully understood. Indeed, in animal studies designed to model autism, there remains controversy regarding the role of neuroligin dysfunction in the expression of disrupted social behaviours. The model organism, Caenorhabditis elegans, offers an informative experimental platform to investigate the impact of genetic variants on social behaviour. In a number of paradigms, it has been shown that inter-organismal communication by chemical cues regulates C. elegans social behaviour. We utilize this social behaviour to investigate the effect of autism-associated genetic variants within the social domain of the research domain criteria. We have identified neuroligin as an important regulator of social behaviour and segregate the importance of this gene to the recognition and/or processing of social cues. We also use CRISPR/Cas9 to edit an R-C mutation that mimics a highly penetrant human mutation associated with autism. C. elegans carrying this mutation phenocopy the behavioural dysfunction of a C. elegans neuroligin null mutant, thus confirming its significance in the regulation of animal social biology. This highlights that quantitative behaviour and precision genetic intervention can be used to manipulate discrete social circuits of the worm to provide further insight into complex social behaviour.

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Allostatic load and ageing: linking the microbiome and nutrition with age-related health

Biochemical Society Transactions ◽

10.1042/bst20190110 ◽

2019 ◽

Vol 47 (4) ◽

pp. 1165-1172 ◽

Cited By ~ 9

Author(s):

Paul G. Shiels ◽

Sarah Buchanan ◽

Colin Selman ◽

Peter Stenvinkel

Keyword(s):

Allostatic Load ◽

Nutritional Risk ◽

Inflammatory Factors ◽

Low Grade ◽

Methyl Donors ◽

Inflammatory Status ◽

Persistent Inflammation ◽

Age Related ◽

Metabolic Capability ◽

Lifestyle Disease

Abstract Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome. Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the ‘diseasome’ of ageing. Additionally, it can be influenced by the ‘foodome’, via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

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ESPO/ BIOLOGICAL SCIENCES SECTION SYMPOSIUM: EMERGING INSIGHTS IN INTERACTIONS AND NETWORKS IN THE BIOLOGY OF AGING DEVELOPING C. ELEGANS TO STUDY AGE-RELATED EXTRACELLULAR VESICLE SIGNALS

Innovation in Aging ◽

10.1093/geroni/igz038.1583 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S424-S424

Author(s):

Joshua Russell ◽

Matt Kaeberlein

Keyword(s):

Biological Sciences ◽

Mammalian Cell Culture ◽

Extracellular Vesicle ◽

Model Systems ◽

C Elegans ◽

Physiological Processes ◽

Age Related ◽

Powerful Approach ◽

Invertebrate Model ◽

Biology Of Aging

Abstract All cells release vesicles into their extracellular environment. These extracellular vesicles (EVs) contain multiple classes of molecules, including nucleic acids, proteins, and lipids. EV-signaling has been shown to be impacted by many age-related physiological processes such as inflammation, mitochondrial stress, and autophagy as well as directly mediate critical functions in cellular senescence and aging. The isolation and analysis of EV cargos from mammalian cell culture and liquid biopsy samples has become a powerful approach for uncovering the messages that are packaged into these organelles. Caenorhabditis elegans is a premier model for dissecting the genetics of aging however, EV analysis has not been tenable in invertebrate model systems due to lack of methods for obtaining sufficient amounts of pure EVs. We developed a method for isolating pure EVs from C. elegans with yields sufficient for mass spectrometry and RNAseq. Here we present the analysis of the genetic and protein cargos of EVs collected from wild type and long-lived mutants collected at different time points across their lifespans. As the first investigation of age-related EV signals in an invertebrate model system we believe these results will provide insights into cell non-autonomous mechanisms of aging.

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