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

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity by a still not fully understood mechanism. We find that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones and increases longevity. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) and is not additive to the longevity of germline-less mutants. Noteworthy, sul-2 mutations do not affect fertility. Thus, STS inactivation affects the germline signalling process regulating longevity. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of germline longevity by environmental cues. We also demonstrate that treatment with the specific STS inhibitor STX64, reproduces the longevity phenotype of sul-2 mutants. Remarkably, STS inhibition by either mutation or drug treatment ameliorates protein aggregation diseases in C. elegans models of Parkinson, Huntington and Alzheimer, as well as Alzheimer disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors for the treatment of aging and aging related diseases.

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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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A complement factor H homolog, heparan sulfation, and syndecan maintain inversin compartment boundaries in C. elegans cilia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2016698118 ◽

2021 ◽

Vol 118 (16) ◽

pp. e2016698118

Author(s):

Natalie Acker ◽

Harold Smith ◽

Claire Devine ◽

Sharon L. Oltjen ◽

Sofia Tsiropoulou ◽

...

Keyword(s):

Sensory Neurons ◽

Disease Risk ◽

The Elderly ◽

Factor H ◽

Age Related Macular Degeneration ◽

Complement Factor H ◽

Complement Factor ◽

Loss Of Function ◽

C Elegans ◽

Age Related

Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. Canonical disease models suggest that defective interactions between complement factor H (CFH) and cell surface heparan sulfate (HS) result in increased alternative complement pathway activity, cytolytic damage, and tissue inflammation in the retina. Although these factors are thought to contribute to increased disease risk, multiple studies indicate that noncanonical mechanisms that result from defective CFH and HS interaction may contribute to the progression of AMD as well. A total of 60 ciliated sensory neurons in the nematode Caenorhabditis elegans detect chemical, olfactory, mechanical, and thermal cues in the environment. Here, we find that a C. elegans CFH homolog localizes on CEP mechanosensory neuron cilia where it has noncanonical roles in maintaining inversin/NPHP-2 within its namesake proximal compartment and preventing inversin/NPHP-2 accumulation in distal cilia compartments in aging adults. CFH localization and maintenance of inversin/NPHP-2 compartment integrity depend on the HS 3-O sulfotransferase HST-3.1 and the transmembrane proteoglycan syndecan/SDN-1. Defective inversin/NPHP-2 localization in mouse and human photoreceptors with CFH mutations indicates that these functions and interactions may be conserved in vertebrate sensory neurons, suggesting that previously unappreciated defects in cilia structure may contribute to the progressive photoreceptor dysfunction associated with CFH loss-of-function mutations in some AMD patients.

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The Anaphase-Promoting Complex (APC) ubiquitin ligase affects chemosensory behavior inC. elegans

PeerJ ◽

10.7717/peerj.2013 ◽

2016 ◽

Vol 4 ◽

pp. e2013 ◽

Cited By ~ 1

Author(s):

Julia Wang ◽

Alexandra K. Jennings ◽

Jennifer R. Kowalski

Keyword(s):

Sensory Neurons ◽

Ubiquitin Ligase ◽

Isoamyl Alcohol ◽

Sensory Function ◽

Anaphase Promoting Complex ◽

Loss Of Function ◽

Wild Type ◽

C Elegans ◽

The Difference ◽

Hypomorphic Alleles

The regulation of fundamental aspects of neurobiological function has been linked to the ubiquitin signaling system (USS), which regulates the degradation and activity of proteins and is catalyzed by E1, E2, and E3 enzymes. The Anaphase-Promoting Complex (APC) is a multi-subunit E3 ubiquitin ligase that controls diverse developmental and signaling processes in post-mitotic neurons; however, potential roles for the APC in sensory function have yet to be explored. In this study, we examined the effect of the APC ubiquitin ligase on chemosensation inCaenorhabditis elegansby testing chemotaxis to the volatile odorants, diacetyl, pyrazine, and isoamyl alcohol, to which wild-type worms are attracted. Animals with loss of function mutations in either of two alleles (g48andye143) of the gene encoding the APC subunit EMB-27 APC6 showed increased chemotaxis towards diacetyl and pyrazine, odorants sensed by AWA neurons, but exhibited normal chemotaxis to isoamyl alcohol, which is sensed by AWC neurons. The statistically significant increase in chemotaxis in theemb-27 APC6mutants suggests that the APC inhibits AWA-mediated chemosensation inC. elegans. Increased chemotaxis to pyrazine was also seen with mutants lacking another essential APC subunit, MAT-2 APC1; however,mat-2 APC1mutants exhibited wild type responses to diacetyl. The difference in responsiveness of these two APC subunit mutants may be due to differential strength of these hypomorphic alleles or may indicate the presence of functional sub-complexes of the APC at work in this process. These findings are the first evidence for APC-mediated regulation of chemosensation and lay the groundwork for further studies aimed at identifying the expression levels, function, and targets of the APC in specific sensory neurons. Because of the similarity between human andC. elegansnervous systems, the role of the APC in sensory neurons may also advance our understanding of human sensory function and disease.

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Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species

10.1101/2021.09.08.459547 ◽

2021 ◽

Author(s):

Osvaldo Villa ◽

Nicole L. Stuhr ◽

Chia-An Yen ◽

Eileen M. Crimmins ◽

Thalida Em Arpawong ◽

...

Keyword(s):

Stress Responses ◽

Predictive Biomarker ◽

Loss Of Function ◽

C Elegans ◽

Muscle Aging ◽

Age Related ◽

The Us ◽

Muscle Health ◽

Human Participants ◽

Long Term Impact

Environmental stress can negatively impact organismal aging, however, the long-term impact of endogenously derived reactive oxygen species from normal cellular metabolism remains less clear. Here we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a biomarker for age-related changes in muscle health by combining C. elegans genetics and a gene-wide association study (GeneWAS) from aged human participants of the US Health and Retirement Study (HRS)1–4. In a screen for mutations that activate SKN-1-dependent oxidative stress responses in the muscle of C. elegans5–7, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. These genetic mutations map across the ALH-6 polypeptide, which lead to age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 differentially impact age-related muscle function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component of normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

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ACaenorhabditis elegansPheromone Antagonizes Volatile Anesthetic Action Through a Go-Coupled Pathway

Genetics ◽

10.1093/genetics/161.1.109 ◽

2002 ◽

Vol 161 (1) ◽

pp. 109-119 ◽

Cited By ~ 1

Author(s):

Bruno van Swinderen ◽

Laura B Metz ◽

Laynie D Shebester ◽

C Michael Crowder

Keyword(s):

Sensory Neurons ◽

Volatile Anesthetic ◽

Loss Of Function ◽

Wild Type ◽

C Elegans ◽

Pheromone Activity ◽

Dauer Formation ◽

Anesthetic Action ◽

Nervous System Function ◽

Type C

AbstractVolatile anesthetics (VAs) disrupt nervous system function by an ill-defined mechanism with no known specific antagonists. During the course of characterizing the response of the nematode C. elegans to VAs, we discovered that a C. elegans pheromone antagonizes the VA halothane. Acute exposure to pheromone rendered wild-type C. elegans resistant to clinical concentrations of halothane, increasing the EC50 from 0.43 ± 0.03 to 0.90 ± 0.02. C. elegans mutants that disrupt the function of sensory neurons required for the action of the previously characterized dauer pheromone blocked pheromone-induced resistance (Pir) to halothane. Pheromone preparations from loss-of-function mutants of daf-22, a gene required for dauer pheromone production, lacked the halothane-resistance activity, suggesting that dauer and Pir pheromone are identical. However, the pathways for pheromone’s effects on dauer formation and VA action were not identical. Not all mutations that alter dauer formation affected the Pir phenotype. Further, mutations in genes not known to be involved in dauer formation completely blocked Pir, including those altering signaling through the G proteins Goα and Gqα. A model in which sensory neurons transduce the pheromone activity through antagonistic Go and Gq pathways, modulating VA action against neurotransmitter release machinery, is proposed.

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Trigonelline Extends the Lifespan of C. Elegans and Delays the Progression of Age-Related Diseases by Activating AMPK, DAF-16, and HSF-1

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/7656834 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Wen-Yu Zeng ◽

Lin Tan ◽

Cong Han ◽

Zhuo-Ya Zheng ◽

Gui-Sheng Wu ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Neurodegenerative Diseases ◽

Stress Resistance ◽

Aging Effect ◽

Loss Of Function ◽

Asian Countries ◽

C Elegans ◽

Age Related ◽

Anti Oxidant ◽

Pathogenic Effects

Trigonelline is the main alkaloid with bioactivity presented in fenugreek, which was used in traditional medicine in Asian countries for centuries. It is reported that trigonelline has anti-inflammatory, anti-oxidant, and anti-pathogenic effects. We are wondering whether trigonelline have anti-aging effect. We found that 50 μM of trigonelline had the best anti-aging activity and could prolong the lifespan of Caenorhabditis elegans (C. elegans) by about 17.9%. Trigonelline can enhance the oxidative, heat, and pathogenic stress resistance of C. elegans. Trigonelline could also delay the development of neurodegenerative diseases, such as AD, PD, and HD, in models of C. elegans. Trigonelline could not prolong the lifespan of long-lived worms with loss-of-function mutations in genes regulating energy and nutrition, such as clk-1, isp-1, eat-2, and rsks-1. Trigonelline requires daf-16, hsf-1, and aak-2 to extend the lifespan of C. elegans. Trigonelline can also up-regulate the expression of daf-16 and hsf-1 targeted downstream genes, such as sod-3, gst-4, hsp-16.1, and hsp-12.6. Our results can be the basis for developing trigonelline-rich products with health benefits, as well as for further research on the pharmacological usage of trigonelline.

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Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage in C. elegans

10.1101/456863 ◽

2018 ◽

Author(s):

Chia-An Yen ◽

Dana L. Ruter ◽

Christian D. Turner ◽

Shanshan Pang ◽

Sean P. Curran

Keyword(s):

Flavin Adenine Dinucleotide ◽

Sperm Quality ◽

Mitochondrial Dynamics ◽

Sperm Function ◽

Loss Of Function ◽

C Elegans ◽

Age Related ◽

Proline Catabolism ◽

A Cell ◽

The Impact

ABSTRACTExposure to environmental stress is clinically established to influence male reproductive health, but the impact of normal cellular metabolism on sperm quality is less well-defined. Here we show that impaired mitochondrial proline catabolism, reduces energy-storing flavin adenine dinucleotide (FAD) levels, alters mitochondrial dynamics toward fusion, and leads to age-related loss of sperm quality (size and activity), which reduces competitive fitness. Loss of the 1-pyrroline-5-carboxylate dehydrogenase enzyme alh-6 that catalyzes the second step in mitochondrial proline catabolism, leads to premature male reproductive senescence. Reducing the expression of the proline catabolism enzyme alh-6 or FAD biosynthesis pathway genes in the germline is sufficient to recapitulate the sperm-related phenotypes observed in alh-6 loss-of-function mutants. These sperm-specific defects are suppressed by feeding diets that restore FAD levels. Our results define a cell autonomous role for mitochondrial proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically reverse these defects.

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Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage in C. elegans

eLife ◽

10.7554/elife.52899 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 9

Author(s):

Chia-An Yen ◽

Dana L Ruter ◽

Christian D Turner ◽

Shanshan Pang ◽

Sean P Curran

Keyword(s):

Flavin Adenine Dinucleotide ◽

Sperm Quality ◽

Mitochondrial Dynamics ◽

Sperm Function ◽

Loss Of Function ◽

C Elegans ◽

Age Related ◽

Proline Catabolism ◽

A Cell ◽

The Impact

Exposure to environmental stress is clinically established to influence male reproductive health, but the impact of normal cellular metabolism on sperm quality is less well-defined. Here we show that impaired mitochondrial proline catabolism, reduces energy-storing flavin adenine dinucleotide (FAD) levels, alters mitochondrial dynamics toward fusion, and leads to age-related loss of sperm quality (size and activity), which diminishes competitive fitness of the animal. Loss of the 1-pyrroline-5-carboxylate dehydrogenase enzyme alh-6 that catalyzes the second step in mitochondrial proline catabolism leads to premature male reproductive senescence. Reducing the expression of the proline catabolism enzyme alh-6 or FAD biosynthesis pathway genes in the germline is sufficient to recapitulate the sperm-related phenotypes observed in alh-6 loss-of-function mutants. These sperm-specific defects are suppressed by feeding diets that restore FAD levels. Our results define a cell autonomous role for mitochondrial proline catabolism and FAD homeostasis on sperm function and specify strategies to pharmacologically reverse these defects.

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Twitchy, the Drosophila orthologue of the ciliary gating protein FBF1/dyf-19, is required for coordinated locomotion and male fertility

Biology Open ◽

10.1242/bio.058531 ◽

2021 ◽

Author(s):

Suzanne H Hodge ◽

Amy Watts ◽

Richard Marley ◽

Richard A Baines ◽

Ernst Hafen ◽

...

Keyword(s):

Sensory Neurons ◽

Primary Cilia ◽

Loss Of Function ◽

Transmembrane Receptors ◽

C Elegans ◽

Male Germline ◽

Sensory Cilia ◽

Import And Export ◽

Flagellar Axoneme

Primary cilia are compartmentalised from the rest of the cell by a ciliary gate comprising transition fibres and a transition zone. The ciliary gate allows the selective import and export of molecules such as transmembrane receptors and transport proteins. These are required for the assembly of the cilium, its function as a sensory and signalling centre and to maintain its distinctive composition. Certain motile cilia can also form within the cytosol as exemplified by human and Drosophila sperm. The role of transition fibre proteins has not been well described in the cytoplasmic cilia. Drosophila have both compartmentalized primary cilia, in sensory neurons, and sperm flagella that form within the cytosol. Here, we describe phenotypes for twitchy the Drosophila orthologue of a transition fibre protein, mammalian FBF1/C. elegans dyf-19. Loss-of-function mutants in twitchy are adult lethal and display a severely uncoordinated phenotype. Twitchy flies are too uncoordinated to mate but RNAi-mediated loss of twitchy specifically within the male germline results in coordinated but infertile adults. Examination of sperm from twitchy RNAi-knockdown flies shows that the flagellar axoneme forms, elongates and is post-translationally modified by polyglycylation but the production of motile sperm is impaired. These results indicate that twitchy is required for the function of both sensory cilia that are compartmentalized from the rest of the cell and sperm flagella that are formed within the cytosol of the cell. Twitchy is therefore likely to function as part of a molecular gate in sensory neurons but may have a distinct function in sperm cells.

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Potential immunotherapy for Alzheimer disease and age-related dementia

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2019.21.1/mischwartz ◽

2019 ◽

Vol 21 (1) ◽

pp. 21-25 ◽

Cited By ~ 1

Keyword(s):

Immune System ◽

Alzheimer Disease ◽

Cross Talk ◽

Immune Checkpoint ◽

Short Review ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

New Approach ◽

Age Related ◽

The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

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