Manish Chamoli - Academia.edu (original) (raw)

Papers by Manish Chamoli

Research paper thumbnail of Supplementary Figure 1 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Data from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Supplementary Figure 4 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Supplementary Figure Legends from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Abstract 66: Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment

Cancer Research, Apr 4, 2023

Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (G... more Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (Gal1) is a known modulator of tumor growth and progression in multiple cancer types including head and neck cancer (HNC). However, its contribution to the regulation of metastasis is poorly understood. Through this study we report a previously unknown role for Gal1 in modulating the STING pathway to regulate metastasis. The cGAS-STING pathway has paradoxical roles in cancer depending on the kinetics and strength of its induction, with chronic STING activation being linked to immune suppression and tumor progression while acute activation being associated with immune activation. However, little is known about the pathways that promote chronic STING activation. Using HNC and lung cancer models, we show that Gal-1 enhances STING protein stability, leading to sustained NF-κΒ activation and heightened chemokine-driven recruitment of myeloid derived suppressor cells (MDSCs). We show that Gal1-STING connection fosters the establishment of pre-metastatic niche through polymorphonuclear MDSCs (PMN-MDSCs), which modify the local lung microenvironment to support metastatic spread. Notably, RNA sequencing of MDSCs isolated from pre-metastatic lungs indicate the role of PMN-MDSCs in remodeling collagen and the extracellular matrix in the pre-metastatic compartment. Our findings reveal an unexpected role of STING activation in metastatic progression of HNC and lung cancer models and establish Gal1 as an endogenous positive regulator of STING. Citation Format: Dhanya K. Nambiar, Vignesh Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Koong, Rie Eyben, Amato Giaccia, Lingyin Li, Edgar Engleman, Quynh Thu Le. Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 66.

Research paper thumbnail of Abstract 66: Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment

Cancer Research

Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (G... more Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (Gal1) is a known modulator of tumor growth and progression in multiple cancer types including head and neck cancer (HNC). However, its contribution to the regulation of metastasis is poorly understood. Through this study we report a previously unknown role for Gal1 in modulating the STING pathway to regulate metastasis. The cGAS-STING pathway has paradoxical roles in cancer depending on the kinetics and strength of its induction, with chronic STING activation being linked to immune suppression and tumor progression while acute activation being associated with immune activation. However, little is known about the pathways that promote chronic STING activation. Using HNC and lung cancer models, we show that Gal-1 enhances STING protein stability, leading to sustained NF-κΒ activation and heightened chemokine-driven recruitment of myeloid derived suppressor cells (MDSCs). We show that Gal1-S...

Research paper thumbnail of Chamoli, M., Pandit, A., Sudharsan, M., & Mukhopadhyay, A. (2013). Novel Kinases that interact with the Insulin-IGF-1-like signaling pathway to control longevity presented in International Worm Meeting. Unpublished information; cite only with author permission

Extensive research over the past decade has identified the Insulin-IGF-1-like signaling (IIS) axi... more Extensive research over the past decade has identified the Insulin-IGF-1-like signaling (IIS) axis, predominantly a kinase cascade, as a major regulator of aging across the animal kingdom. In C. elegans, the IIS pathway regulates dauer diapause, metabolism, stress\/pathogen resistance as well as longevity. In order to identify additional kinases that may interact or cross-talk with this pathway and regulate life span, we developed a high throughput 96-well liquid RNAi screening protocol using dauer formation as the quantifiable output. We prepared a kinase mini-library that contained RNAi clones for around 400 serine-threonine kinases and screened for ones that affect dauer formation in daf-2(e1370). We identified several novel as well as previously studied modulators of the IIS pathway. Here we report characterization of two such kinases that enhanced dauer formation of an IIS pathway mutant. Although both the kinases possess activity in vitro and increased dauer formation of daf-2...

Research paper thumbnail of Mukhopadhyay, A., Chamoli, M., & Singh, A. (2013). A novel kinase regulates dietary restriction-mediated longevity in C. elegans presented in International Worm Meeting

Dietary restriction (DR) increases life span in most model systems tested. In mammals, it is asso... more Dietary restriction (DR) increases life span in most model systems tested. In mammals, it is associated with health benefits including reduced risk of cancer, cardiovascular diseases and diabetes. In spite of such positive impact, DR is easier to implement in an experimental model as compared to human beings. In this context, it will be beneficial to have an internal model of DR (iDR) where, irrespective of the calorie intake, an organism may enjoy its beneficial effects. We will discuss one such model in C. elegans. In C. elegans, DR is studied after restricting food intake by using either genetic or non-genetic manipulations. The eat-2 gene represents a well-studied genetic model of DR where a mutation in a nicotinic acetylcholine receptor subunit leaves the mutant worms with defective pharyngeal pumping and consequently, lower bacterial intake. Non-genetic methods for DR use either serial dilutions or complete deprivation of bacteria. However, these different DR regimes activate ...

Research paper thumbnail of Kinome-wide RNAi screen in Caenorhabditis elegans reveals new modulators of insulin signaling and longevity

Research paper thumbnail of Supplementary Figure 5 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Supplementary Figure 2 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Supplementary Figure 6 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan

Research paper thumbnail of Kavain suppresses human Aβ-induced paralysis in C. elegans

Figure 1: Kavain suppresses human Aβ-induced paralysis in C. elegans (A) Structure of kavain. (B)... more Figure 1: Kavain suppresses human Aβ-induced paralysis in C. elegans (A) Structure of kavain. (B) Aβ proteotoxicity in temperature-sensitive (enhanced paralysis at 25 o C) GMC101 was determined by scoring the percent of animals paralyzed following kavain and Control-DMSO treatments. Data plotted as mean ± SD, n=45 animals per trial, Control-DMSO (N=90), Kavain-50 μM (N= 135), p-value calculated using unpaired Student's t-test. Description Kavain belongs to a group of lactone-based compounds collectively known as kavalactones, present in the pepper plant kava (P. methysticum). Kavalactones have been shown to possess diverse biological activities including sedation and anxiolysis (Ooi et al., 2018). Kavain in particular has been demonstrated to show potent anti-inflammatory properties in various in vitro and animal models (

Research paper thumbnail of Aging, Parkinson’s Disease, and Models: What Are the Challenges?

Parkinson's disease (PD) is a chronic, neurodegenerative condition characterized by motor symptom... more Parkinson's disease (PD) is a chronic, neurodegenerative condition characterized by motor symptoms such as bradykinesia, rigidity, and tremor, alongside multiple nonmotor symptoms. The appearance of motor symptoms is linked to progressive dopaminergic neuron loss within the substantia nigra. PD incidence increases sharply with age, suggesting a strong association between mechanisms driving biological aging and the development and progression of PD. However, the role of aging in the pathogenesis of PD remains understudied. Numerous models of PD, including cell models, toxin-induced models, and genetic models in rodents and nonhuman primates (NHPs), reproduce different aspects of PD, but preclinical studies of PD rarely incorporate age as a factor. Studies using patient neurons derived from stem cells via reprogramming methods retain some aging features, but their characterization, particularly of aging markers and reproducibility of neuron type, is suboptimal. Investigation of age-related changes in PD using animal models indicates an association, but this is likely in conjunction with other disease drivers. The biggest barrier to drawing firm conclusions is that each model lacks full characterization and appropriate time-course assessments. There is a need to systematically investigate whether aging increases the susceptibility of mouse, rat, and NHP models to develop PD and understand the role of cell models. We propose that a significant investment in time and resources, together with the coordination and sharing of resources, knowledge, and data, is required to accelerate progress in understanding the role of biological aging in PD development and improve the reliability of models to test interventions.

Research paper thumbnail of Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in <i>Caenorhabditis elegans</i>

bioRxiv (Cold Spring Harbor Laboratory), Aug 19, 2022

The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produc... more The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food almost everywhere, from the baking industry to our everyday life. However, the Maillard reaction also takes place in all cells, from prokaryotes to eukaryotes, leading to the formation of Advanced Glycation End-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and αdicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNA-seq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGEs (MG-H1) induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream factor for increased feeding upon accumulation of AGEs by partially regulating the expression of tdc-1 and tyra-2 genes. Further, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MGO and associated AGEs. Understanding this signaling pathway is essential to modulate hedonistic overfeeding behavior observed in modern AGEs rich diets.

Research paper thumbnail of Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction

Nature Communications, Sep 25, 2020

The metabolic state of an organism instructs gene expression modalities, leading to changes in co... more The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of "Xenobiotic Detoxification Program" (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.

Research paper thumbnail of The Mitochondrial Permeability Transition Pore Activates the Mitochondrial Unfolded Protein Response and Promotes Aging

Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial... more Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear. We have found that loss OSCP in the nematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPR mt). Pharmacological or genetic inhibition of the mPTP inhibits the UPR mt and restores normal lifespan. Loss of the putative pore-forming component of F-ATP synthase extends adult lifespan, suggesting that the mPTP normally promotes aging. Our findings reveal how an mPTP/UPR mt nexus may contribute to aging and age-related diseases and how inhibition of the UPR mt may be protective under certain conditions. .

Research paper thumbnail of A cell non-autonomous FOXO/DAF-16-mediated germline quality assurance program that responds to somatic DNA damage

Research Square (Research Square), Jan 21, 2022

Germline integrity is critical for progeny fitness. Organisms deploy the DNA damage response (DDR... more Germline integrity is critical for progeny fitness. Organisms deploy the DNA damage response (DDR) signalling to protect germline from genotoxic stress, facilitating cell-cycle arrest of germ cells and DNA repair or their apoptosis. Cell-autonomous regulation of germline quality is well-studied; however, how quality is enforced cell non-autonomously on sensing somatic DNA damage is less known. Using Caenorhabditis elegans, we show that DDR disruption, only in the uterus, when insulin-IGF-1 signalling (IIS) is low, arrests germline development and induces sterility in a FOXO/DAF-16 transcription factor (TF)-dependent manner. Without FOXO/DAF-16, germ cells of the IIS mutant escape arrest to produce poor quality oocytes, showing that the TF imposes strict quality control during low IIS. In response to low IIS in neurons, FOXO/DAF-16 works cell autonomously as well as non-autonomously to facilitate the arrest. Activated FOXO/DAF-16 promotes transcription of checkpoint and DDR genes, protecting germline integrity. However, on reducing DDR during low IIS, the TF decreases ERK/MPK-1 signaling below a threshold, and transcriptionally downregulates genes involved in spermatogenesis-to-oogenesis switch as well as cdk-1/Cyclin B to promote germline arrest. Altogether, our study reveals how cell nonautonomous function of FOXO/DAF-16 promotes germline quality and progeny fitness in response to somatic DNA damage.

Research paper thumbnail of Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

bioRxiv (Cold Spring Harbor Laboratory), Jul 30, 2019

Aging is characterized by the progressive loss of physiological function in all organisms. Remark... more Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a novel target of NDGA and provide mechanistic insight into its role in longevity.

Research paper thumbnail of Supplementary Figure 1 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Data from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Supplementary Figure 4 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Supplementary Figure Legends from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Abstract 66: Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment

Cancer Research, Apr 4, 2023

Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (G... more Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (Gal1) is a known modulator of tumor growth and progression in multiple cancer types including head and neck cancer (HNC). However, its contribution to the regulation of metastasis is poorly understood. Through this study we report a previously unknown role for Gal1 in modulating the STING pathway to regulate metastasis. The cGAS-STING pathway has paradoxical roles in cancer depending on the kinetics and strength of its induction, with chronic STING activation being linked to immune suppression and tumor progression while acute activation being associated with immune activation. However, little is known about the pathways that promote chronic STING activation. Using HNC and lung cancer models, we show that Gal-1 enhances STING protein stability, leading to sustained NF-κΒ activation and heightened chemokine-driven recruitment of myeloid derived suppressor cells (MDSCs). We show that Gal1-STING connection fosters the establishment of pre-metastatic niche through polymorphonuclear MDSCs (PMN-MDSCs), which modify the local lung microenvironment to support metastatic spread. Notably, RNA sequencing of MDSCs isolated from pre-metastatic lungs indicate the role of PMN-MDSCs in remodeling collagen and the extracellular matrix in the pre-metastatic compartment. Our findings reveal an unexpected role of STING activation in metastatic progression of HNC and lung cancer models and establish Gal1 as an endogenous positive regulator of STING. Citation Format: Dhanya K. Nambiar, Vignesh Vignesh Viswanathan, Hongbin Cao, Weiruo Zhang, Li Guan, Manish Chamoli, Brittany Holmes, Christina Kong, Rachel Hildebrand, Amanda Koong, Rie Eyben, Amato Giaccia, Lingyin Li, Edgar Engleman, Quynh Thu Le. Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 66.

Research paper thumbnail of Abstract 66: Galectin-1 mediated chronic tumoral-STING activation promotes metastasisthrough MDSC recruitment

Cancer Research

Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (G... more Tumor cells alter the immune microenvironment to facilitate metastatic progression. Galectin-1 (Gal1) is a known modulator of tumor growth and progression in multiple cancer types including head and neck cancer (HNC). However, its contribution to the regulation of metastasis is poorly understood. Through this study we report a previously unknown role for Gal1 in modulating the STING pathway to regulate metastasis. The cGAS-STING pathway has paradoxical roles in cancer depending on the kinetics and strength of its induction, with chronic STING activation being linked to immune suppression and tumor progression while acute activation being associated with immune activation. However, little is known about the pathways that promote chronic STING activation. Using HNC and lung cancer models, we show that Gal-1 enhances STING protein stability, leading to sustained NF-κΒ activation and heightened chemokine-driven recruitment of myeloid derived suppressor cells (MDSCs). We show that Gal1-S...

Research paper thumbnail of Chamoli, M., Pandit, A., Sudharsan, M., & Mukhopadhyay, A. (2013). Novel Kinases that interact with the Insulin-IGF-1-like signaling pathway to control longevity presented in International Worm Meeting. Unpublished information; cite only with author permission

Extensive research over the past decade has identified the Insulin-IGF-1-like signaling (IIS) axi... more Extensive research over the past decade has identified the Insulin-IGF-1-like signaling (IIS) axis, predominantly a kinase cascade, as a major regulator of aging across the animal kingdom. In C. elegans, the IIS pathway regulates dauer diapause, metabolism, stress\/pathogen resistance as well as longevity. In order to identify additional kinases that may interact or cross-talk with this pathway and regulate life span, we developed a high throughput 96-well liquid RNAi screening protocol using dauer formation as the quantifiable output. We prepared a kinase mini-library that contained RNAi clones for around 400 serine-threonine kinases and screened for ones that affect dauer formation in daf-2(e1370). We identified several novel as well as previously studied modulators of the IIS pathway. Here we report characterization of two such kinases that enhanced dauer formation of an IIS pathway mutant. Although both the kinases possess activity in vitro and increased dauer formation of daf-2...

Research paper thumbnail of Mukhopadhyay, A., Chamoli, M., & Singh, A. (2013). A novel kinase regulates dietary restriction-mediated longevity in C. elegans presented in International Worm Meeting

Dietary restriction (DR) increases life span in most model systems tested. In mammals, it is asso... more Dietary restriction (DR) increases life span in most model systems tested. In mammals, it is associated with health benefits including reduced risk of cancer, cardiovascular diseases and diabetes. In spite of such positive impact, DR is easier to implement in an experimental model as compared to human beings. In this context, it will be beneficial to have an internal model of DR (iDR) where, irrespective of the calorie intake, an organism may enjoy its beneficial effects. We will discuss one such model in C. elegans. In C. elegans, DR is studied after restricting food intake by using either genetic or non-genetic manipulations. The eat-2 gene represents a well-studied genetic model of DR where a mutation in a nicotinic acetylcholine receptor subunit leaves the mutant worms with defective pharyngeal pumping and consequently, lower bacterial intake. Non-genetic methods for DR use either serial dilutions or complete deprivation of bacteria. However, these different DR regimes activate ...

Research paper thumbnail of Kinome-wide RNAi screen in Caenorhabditis elegans reveals new modulators of insulin signaling and longevity

Research paper thumbnail of Supplementary Figure 5 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Supplementary Figure 2 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of Supplementary Figure 6 from Galectin-1 Mediates Chronic STING Activation in Tumors to Promote Metastasis through MDSC Recruitment

Research paper thumbnail of A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan

Research paper thumbnail of Kavain suppresses human Aβ-induced paralysis in C. elegans

Figure 1: Kavain suppresses human Aβ-induced paralysis in C. elegans (A) Structure of kavain. (B)... more Figure 1: Kavain suppresses human Aβ-induced paralysis in C. elegans (A) Structure of kavain. (B) Aβ proteotoxicity in temperature-sensitive (enhanced paralysis at 25 o C) GMC101 was determined by scoring the percent of animals paralyzed following kavain and Control-DMSO treatments. Data plotted as mean ± SD, n=45 animals per trial, Control-DMSO (N=90), Kavain-50 μM (N= 135), p-value calculated using unpaired Student's t-test. Description Kavain belongs to a group of lactone-based compounds collectively known as kavalactones, present in the pepper plant kava (P. methysticum). Kavalactones have been shown to possess diverse biological activities including sedation and anxiolysis (Ooi et al., 2018). Kavain in particular has been demonstrated to show potent anti-inflammatory properties in various in vitro and animal models (

Research paper thumbnail of Aging, Parkinson’s Disease, and Models: What Are the Challenges?

Parkinson's disease (PD) is a chronic, neurodegenerative condition characterized by motor symptom... more Parkinson's disease (PD) is a chronic, neurodegenerative condition characterized by motor symptoms such as bradykinesia, rigidity, and tremor, alongside multiple nonmotor symptoms. The appearance of motor symptoms is linked to progressive dopaminergic neuron loss within the substantia nigra. PD incidence increases sharply with age, suggesting a strong association between mechanisms driving biological aging and the development and progression of PD. However, the role of aging in the pathogenesis of PD remains understudied. Numerous models of PD, including cell models, toxin-induced models, and genetic models in rodents and nonhuman primates (NHPs), reproduce different aspects of PD, but preclinical studies of PD rarely incorporate age as a factor. Studies using patient neurons derived from stem cells via reprogramming methods retain some aging features, but their characterization, particularly of aging markers and reproducibility of neuron type, is suboptimal. Investigation of age-related changes in PD using animal models indicates an association, but this is likely in conjunction with other disease drivers. The biggest barrier to drawing firm conclusions is that each model lacks full characterization and appropriate time-course assessments. There is a need to systematically investigate whether aging increases the susceptibility of mouse, rat, and NHP models to develop PD and understand the role of cell models. We propose that a significant investment in time and resources, together with the coordination and sharing of resources, knowledge, and data, is required to accelerate progress in understanding the role of biological aging in PD development and improve the reliability of models to test interventions.

Research paper thumbnail of Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in <i>Caenorhabditis elegans</i>

bioRxiv (Cold Spring Harbor Laboratory), Aug 19, 2022

The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produc... more The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food almost everywhere, from the baking industry to our everyday life. However, the Maillard reaction also takes place in all cells, from prokaryotes to eukaryotes, leading to the formation of Advanced Glycation End-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and αdicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNA-seq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGEs (MG-H1) induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream factor for increased feeding upon accumulation of AGEs by partially regulating the expression of tdc-1 and tyra-2 genes. Further, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MGO and associated AGEs. Understanding this signaling pathway is essential to modulate hedonistic overfeeding behavior observed in modern AGEs rich diets.

Research paper thumbnail of Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction

Nature Communications, Sep 25, 2020

The metabolic state of an organism instructs gene expression modalities, leading to changes in co... more The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of "Xenobiotic Detoxification Program" (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.

Research paper thumbnail of The Mitochondrial Permeability Transition Pore Activates the Mitochondrial Unfolded Protein Response and Promotes Aging

Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial... more Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear. We have found that loss OSCP in the nematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPR mt). Pharmacological or genetic inhibition of the mPTP inhibits the UPR mt and restores normal lifespan. Loss of the putative pore-forming component of F-ATP synthase extends adult lifespan, suggesting that the mPTP normally promotes aging. Our findings reveal how an mPTP/UPR mt nexus may contribute to aging and age-related diseases and how inhibition of the UPR mt may be protective under certain conditions. .

Research paper thumbnail of A cell non-autonomous FOXO/DAF-16-mediated germline quality assurance program that responds to somatic DNA damage

Research Square (Research Square), Jan 21, 2022

Germline integrity is critical for progeny fitness. Organisms deploy the DNA damage response (DDR... more Germline integrity is critical for progeny fitness. Organisms deploy the DNA damage response (DDR) signalling to protect germline from genotoxic stress, facilitating cell-cycle arrest of germ cells and DNA repair or their apoptosis. Cell-autonomous regulation of germline quality is well-studied; however, how quality is enforced cell non-autonomously on sensing somatic DNA damage is less known. Using Caenorhabditis elegans, we show that DDR disruption, only in the uterus, when insulin-IGF-1 signalling (IIS) is low, arrests germline development and induces sterility in a FOXO/DAF-16 transcription factor (TF)-dependent manner. Without FOXO/DAF-16, germ cells of the IIS mutant escape arrest to produce poor quality oocytes, showing that the TF imposes strict quality control during low IIS. In response to low IIS in neurons, FOXO/DAF-16 works cell autonomously as well as non-autonomously to facilitate the arrest. Activated FOXO/DAF-16 promotes transcription of checkpoint and DDR genes, protecting germline integrity. However, on reducing DDR during low IIS, the TF decreases ERK/MPK-1 signaling below a threshold, and transcriptionally downregulates genes involved in spermatogenesis-to-oogenesis switch as well as cdk-1/Cyclin B to promote germline arrest. Altogether, our study reveals how cell nonautonomous function of FOXO/DAF-16 promotes germline quality and progeny fitness in response to somatic DNA damage.

Research paper thumbnail of Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

bioRxiv (Cold Spring Harbor Laboratory), Jul 30, 2019

Aging is characterized by the progressive loss of physiological function in all organisms. Remark... more Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a novel target of NDGA and provide mechanistic insight into its role in longevity.