α- and β-Santalols Delay Aging in <i>Caenorhabditis elegans</i> via Preventing Oxidative Stress and Protein Aggregation

Mohankumar, A.; Kalaiselvi, Duraisamy; Thiruppathi, G.; Sivaramakrishnan, Muthusaravanan; Nivitha, S.; Levenson, Corey; Tawata, Shinkichi; Sundararaj, P.

doi:10.1021/acsomega.0c05006

Cited by 24 publications

(16 citation statements)

References 53 publications

(121 reference statements)

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“…Our results showed that HBA treatment could significantly reduce the accumulation of ROS in wild-type N2 (Figures 4(d) and 4(e) ) and AD model worms CL2006 (Figures 4(f) and 4(g) ). It has been reported that the oxidation of A β protein itself has been found in amyloid plaques and SOD is the main enzyme that reduces the damage of superoxide anion in the body [ 72 , 73 ]. So, we measured the SOD enzyme activity in strain CL4176.…”

Section: Resultsmentioning

confidence: 99%

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

Liu

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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The traditional Chinese medicine Gastrodia elata (commonly called “Tianma” in Chinese) has been widely used in the treatment of rheumatism, epilepsy, paralysis, headache, and dizziness. Phenolic compounds, such as gastrodin, para-hydroxybenzyl alcohol (HBA), p-hydroxybenzaldehyde, and vanillin are the main bioactive components isolated from Gastrodia elata. These compounds not only are structurally related but also share similar pharmacological activities, such as antioxidative and anti-inflammatory activities, and effects on the treatment of aging-related diseases. Here, we investigated the effect of para-hydroxybenzyl alcohol (HBA) on neurodegenerative diseases and aging in models of Caenorhabditis elegans (C. elegans). Our results showed that HBA effectively delayed the progression of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease in models of C. elegans. In addition, HBA could increase the average lifespan of N2 worms by more than 25% and significantly improve the age-related physiological functions of worms. Moreover, HBA improved the survival rate of worms under stresses of oxidation, heat, and pathogenic bacteria. Further mechanistic investigation revealed that HBA could activate FOXO/DAF-16 and SKN-1 to regulate antioxidative and xenobiotic metabolism pathway. HBA could also activate HSF-1 to regulate proteostasis maintenance pathway, mitochondrial unfolded stress response, endoplasmic stress response and autophagy pathways. The above results suggest that HBA activated multiple cellular protective pathways to increase stress resistance and protect against aging and aging-related diseases. Overall, our study indicates that HBA is a potential candidate for future development of antiaging pharmaceutical application.

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Section: Resultsmentioning

confidence: 99%

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

Liu

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Firstly, we observed that 16 µM α-santalol and 8 µM β-santalol together were the minimal dose to synergistically extend the lifespan of wild-type C. elegans by 28.0% under standard laboratory conditions ( Figure 4G ; Supplementary Figure S3 ). The combinatorial effect of santalol isomers is significantly higher (22.3%, p < 0.01) than the largest effect produced by each compound under similar conditions ( Mohankumar et al, 2018 ; Mohankumar et al, 2020 ). Interestingly, the combination of α- and β-santalol at their optimal doses (32 and 16 μM, respectively) is not synergistic and extends the mean lifespan of N2 worms by 19.0% ( Figure 4G ; Supplementary Figure S3 ).…”

Section: Resultsmentioning

confidence: 79%

“…We have previously shown that santalol isomers reduced the aggregation of toxic amyloid-β, α-synuclein, and polyglutamine proteins in C. elegans ; these proteins are involved in the key pathological events in Alzheimer’s, Parkinson’s, and Huntington’s diseases, respectively. In addition, santalol isomers extend the lifespan of C. elegans strains expressing these toxic proteins in body wall muscle cells and neurons ( Mohankumar et al, 2018 ; Mohankumar et al, 2019b ; Mohankumar et al, 2020 ). Taking into account the anti-aggregation and anti-aging potential of santalol isomers, we have tested their effects on the lifespan of worms expressing several TTR aggregates.…”

Section: Resultsmentioning

confidence: 99%

“…Lifespan was measured at 20°C as previously described ( Mohankumar et al, 2020 ). In brief, synchronized L1 stage worms (10–15 worms per plate for a total of 100–120 individuals per experiment) were raised on plates supplemented with santalol isomers and tolcapone.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study found that santalol isomers offer stress-resilience, extend healthy longevity, and retard age-related functional deficits in C. elegans ( Mohankumar et al, 2018 ; Mohankumar et al, 2019b ). Importantly, santalol isomers reduced the protein aggregates strongly associated with pathologies of Alzheimer’s, Parkinson’s, and Huntington’s diseases by activating multiple cellular signaling pathways ( Mohankumar et al, 2018 ; Mohankumar et al, 2020 ). Here, we identify santalol isomers as a potential inhibitor of TTR amyloidogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Santalol Isomers Inhibit Transthyretin Amyloidogenesis and Associated Pathologies in Caenorhabditis elegans

Mohankumar

Kalaiselvi²,

Thiruppathi³

et al. 2022

Front. Pharmacol.

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Transthyretin (TTR) is a homotetrameric protein found in human serum and is implicated in fatal inherited amyloidoses. Destabilization of native TTR confirmation resulting from mutation, environmental changes, and aging causes polymerization and amyloid fibril formation. Although several small molecules have been reported to stabilize the native state and inhibit TTR aggregation, prolonged use can cause serious side effects. Therefore, pharmacologically enhancing the degradation of TTR aggregates and kinetically stabilizing the native tetrameric structure with bioactive molecule(s) could be a viable therapeutic strategy to hinder the advancement of TTR amyloidoses. In this context, here we demonstrated α- and β-santalol, natural sesquiterpenes from sandalwood, as a potent TTR aggregation inhibitor and native state stabilizer using combined in vitro, in silico, and in vivo experiments. We found that α- and β-santalol synergize to reduce wild-type (WT) and Val30Met (V30M) mutant TTR aggregates in novel C. elegans strains expressing TTR fragments fused with a green fluorescent protein in body wall muscle cells. α- and β-Santalol extend the lifespan and healthspan of C. elegans strains carrying TTRWT::EGFP and TTRV30M::EGFP transgene by activating the SKN-1/Nrf2, autophagy, and proteasome. Moreover, α- and β-santalol directly interacted with TTR and reduced the flexibility of the thyroxine-binding cavity and homotetramer interface, which in turn increases stability and prevents the dissociation of the TTR tetramer. These data indicate that α- and β-santalol are the strong natural therapeutic intervention against TTR-associated amyloid diseases.

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Application of Caenorhabditis elegans in the evaluation of food nutrition: A review

Xiao

et al. 2023

eFood

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At present, more and more people are suffering from various diseases and it is particularly important to find a suitable biological model to evaluate the prevention and treatment effects of various drugs and active ingredients on diseases. In all biological models, Caenorhabditis elegans is a kind of organism that is easy to observe and cultivate, has a clear genetic background and a high degree of signal pathway conservation with humans. A variety of active ingredients such as polyphenols, polysaccharides, polypeptides, and vitamins exist from natural products, which has extremely high physiological functions and medicinal values. It is highly reliable to evaluate the trophic and functional properties of the active ingredients from natural products in C. elegans. The functional properties of the active ingredients from natural products such as antiaging, anti-oxidation, regulating lipid metabolism, preventing and treating Alzheimer's disease in C. elegans were clarified in this review. At the same time, its possible pathways were summarized. The literature revealed that it had great effect to evaluate the nutrition and functionality of the active ingredients from natural products in C. elegans. Finally, the shortcomings in this field and suggestions for further improvement in this field have been emphasized.

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α- and β-Santalols Delay Aging in Caenorhabditis elegans via Preventing Oxidative Stress and Protein Aggregation

Cited by 24 publications

References 53 publications

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways

Santalol Isomers Inhibit Transthyretin Amyloidogenesis and Associated Pathologies in Caenorhabditis elegans

Application of Caenorhabditis elegans in the evaluation of food nutrition: A review

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