Caryota maxima leaf extract extends Caenorhabditis elegans lifespan by inducing mono-unsaturated fatty acid accumulation via DAF-2 signaling

Abstract

Geroprotectors that delay aging have substantial potential for preventing and mitigating age-related diseases. Natural products derived from traditional herbal medicines are promising candidates for geroprotector discovery, because of their multi-target mechanisms and preventive health benefits. Through screening of 836 Chinese herbal medicine extracts, we identified that the leaf extract of Caryota maxima ( JM13001) significantly extended lifespan and healthspan in Caenorhabditis elegans. JM13001 increased total lipid content and upregulated mono-unsaturated fatty acids (MUFAs), which are known to contribute to longevity. JM13001 exerted its effects through DAF-2 signaling, thereby promoting lipid accumulation and extending lifespan in nematodes. Notably, the lifespan-extending effects of JM13001 were abolished after the loss of key enzymes responsible for converting saturated fatty acids to MUFAs or after oleic acid supplementation; therefore, its geroprotective effects are dependent on MUFAs. Chemical analysis revealed that JM13001 contains flavonoids such as rutin, isoquercitrin, and kaempferol-3-O-rutinoside, among which rutin alone was sufficient to reproduce the anti-aging and lipid accumulation promotion effects of JM13001 through DAF-2 signaling. This study identifies a novel geroprotective herbal extract and its active ingredient, thereby providing insights into the anti-aging mechanisms of natural geroprotectors via MUFA metabolism regulation.

Keywords

geroprotectors / Caryota maxima / Caenorhabditis elegans / mono-unsaturated fatty acids / rutin

References

[1] Guo Y, Guan T, Shafiq K, Yu Q, Jiao X, Na D, et al.: Mitochondrial Dysfunction in Aging. Ageing Research Reviews 2023, 88: 101955.

[2] Li X, Wang J, Wang L, Gao Y, Feng G, Li G, et al.: Lipid Metabolism Dysfunction Induced by Age-Dependent DNA Methylation Accelerates Aging. Signal Transduction and Targeted Therapy 2022, 7: 162.

[3] Török NJ, Adeniji NT, Fan W, Kunimoto K, Török NJ: Non-Alcoholic Fatty Liver Disease and Liver Fibrosis During Aging. Aging and Disease 2022, 13: 1239-1251.

[4] Wu Y-L, Lin ZJ, Li CC, Lin X, Shan SK, Guo B, et al.: Epigenetic Regulation in Metabolic Diseases: Mechanisms and Advances in Clinical Study. Signal Transduction and Targeted Therapy 2023, 8: 98.

[5] Mutlu AS, Duffy J, Wang MC: Lipid Metabolism and Lipid Signals in Aging and Longevity. Developmental Cell 2021, 56: 1394-1407.

[6] Ademowo OS, Wenk MR, Maier AB: Advances in Clinical Application of Lipidomics in Healthy Ageing and Healthy Longevity Medicine. Ageing Research Reviews 2024, 100: 102432.

[7] Wiley CD, Sharma R, Davis SS, Lopez-Dominguez JA, Mitchell KP, Wiley S, et al.: Oxylipin Biosynthesis Reinforces Cellular Senescence and Allows Detection of Senolysis. Cell Metabolism 2021, 33: 1124-1136.e5.

[8] Tsugawa H, Ishihara T, Ogasa K, Iwanami S, Hori A, Takahashi M, et al.: A Lipidome Landscape of Aging in Mice. Nature Aging 2024, 4: 709-726.

[9] Schroeder EA. Brunet A: Lipid Profiles and Signals for Long Life. Trends in Endocrinology & Metabolism 2015, 26: 589-592.

[10] Shmookler Reis RJ, Xu L, Lee H, Chae M, Thaden JJ, Bharill P, et al.: Modulation of Lipid Biosynthesis Contributes to Stress Resistance and Longevity of C. Elegans Mutants. Aging (Albany NY) 2011, 3: 125-147.

[11] Han S, Schroeder EA, Silva-García CG, Hebestreit K, Mair WB, Brunet A: Mono-Unsaturated Fatty Acids Link H3K4me3 Modifiers to C. Elegans Lifespan. Nature 2017, 544: 185-190.

[12] Papsdorf K, Miklas JW, Hosseini A, Cabruja M, Morrow CS, Savini M, et al.: Lipid Droplets and Peroxisomes are Co-Regulated to Drive Lifespan Extension in Response to Mono-Unsaturated Fatty Acids. Nature Cell Biology 2023, 25: 672-684.

[13] Gui R, Li W, Li Z, Wang H, Wu Y, Jiao W, et al.: Effects and Potential Mechanisms of IGF1/IGF1R in the Liver Fibrosis: A Review. International Journal of Biological Macromolecules 2023, 251: 126263.

[14] Lin C, Lin Y, Chen Y, Xu J, Li J, Cao Y, et al.: Effects of Momordica Saponin Extract on Alleviating Fat Accumulation in Caenorhabditis Elegans. Food & Function 2019, 10: 3237-3251.

[15] Wang K, Chen S, Zhang C, Huang J, Wu J, Zhou H, et al.: Enhanced ROS Production Leads to Excessive Fat Accumulation Through DAF-16 in Caenorhabditis Elegans. Experimental Gerontology 2018, 112: 20-29.

[16] Shi X, Li J, Zou X, Greggain J, Rødkær SV, Færgeman NJ, et al.: Regulation of Lipid Droplet Size and Phospholipid Composition by Stearoyl-CoA Desaturase. Journal of Lipid Research 2013, 54: 2504-2514.

[17] Ziv E, Hu D: Genetic Variation in Insulin/IGF-1 Signaling Pathways and Longevity. Ageing Research Reviews 2011, 10: 201-204.

[18] Admasu TD, Chaithanya Batchu K, Barardo D, Ng LF, Lam VYM, Xiao L, et al.: Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling. Developmental Cell 2018, 47: 67-79.e5.

[19] Kulkarni AS, Gubbi S, Barzilai N: Benefits of Metformin in Attenuating the Hallmarks of Aging. Cell Metabolism 2020, 32: 15-30.

[20] Pryor R, Norvaisas P, Marinos G, Best L, Thingholm LB, Quintaneiro LM, et al.: Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. Cell 2019, 178: 1299-1312.e29.

[21] Wang S, Lin D, Cao J, Wang L: APPA Increases Lifespan and Stress Resistance via Lipid Metabolism and Insulin/IGF-1 Signal Pathway in Caenorhabditis elegans. International Journal of Molecular Sciences 2023, 24: 13682.

[22] Wang L, Li P, Zheng F, Zhu Z, Bai F, Gao R: Collagen Peptides from Sturgeon Swim Bladder Prolong the Lifespan and Healthspan in Caenorhabditis Elegans. Journal of the Science of Food and Agriculture 2024, 104: 5244-5251.

[23] Khan J, Pernicova I, Nisar K, Korbonits M: Mechanisms of Ageing: Growth Hormone, Dietary Restriction, and Metformin. The Lancet Diabetes & Endocrinology 2023, 11: 261-281.

[24] Tang G, Li S, Zhang C, Chen H, Wang N, Feng Y: Clinical Efficacies, Underlying Mechanisms and Molecular Targets of Chinese Medicines for Diabetic Nephropathy Treatment and Management. Acta Pharmaceutica Sinica B 2021, 11: 2749-2767.

[25] Chen X-X, Feng HL, Ding YM, Chai WM, Xiang ZH, Shi Y, et al.: Structure Characterization of Proanthocyanidins from Caryota Ochlandra Hance and their Bioactivities. Food Chemistry 2014, 155: 1-8.

[26] Wang J, Liu W, Huang Y, Wang G, Guo X, Shi D, et al.: A Senomorphlytic Three-Drug Combination Discovered in Salsola Collina for Delaying Aging Phenotypes and Extending Healthspan. Advanced Science 2024, 11: e2401862.

[27] Li WJ, Wang CW, Tao L, Yan YH, Zhang MJ, Liu ZX, et al.: Insulin Signaling Regulates Longevity Through Protein Phosphorylation in Caenorhabditis Elegans. Nature Communications 2021, 12: 4568.

[28] Mao Z, Liu W, Huang Y, Sun T, Bao K, Feng J, et al.: Anti-Aging Effects of Chlorpropamide Depend on Mitochondrial Complex-II and the Production of Mitochondrial Reactive Oxygen Species. Acta Pharm Sin B 2022, 12: 665-677.

[29] Liu W, Lin H, Mao Z, Zhang L, Bao K, Jiang B, et al.: Verapamil Extends Lifespan in Caenorhabditis Elegans by Inhibiting Calcineurin Activity and Promoting Autophagy . Aging (Albany NY) 2020, 12: 5300-5317.

[30] Han B, Sivaramakrishnan P, Lin CJ, Neve IAA, He J, Tay LWR, et al.: Microbial Genetic Composition Tunes Host Longevity. Cell 2017, 169: 1249-1262.e13.

[31] Wang J, Huang Y, Shi K, Bao L, Xiao C, Sun T, et al.: Nicandra Physalodes Extract Exerts Antiaging Effects in Multiple Models and Extends the Lifespan of Caenorhabditis Elegans via DAF-16 and HSF-1 . Oxidative Medicine and Cellular Longevity 2022, 2022: 1-13.

[32] Song Z, Bao K, Liu W, Feng J, Mao Z, Bao L, et al.: Crotamiton Derivative JM03 Extends Lifespan and Improves Oxidative and Hypertonic Stress Resistance in Caenorhabditis Elegans via Inhibiting OSM-9 . Elife 2022, 11: e72410.

[33] Liu Y, Xu S, Zhang C, Zhu X, Hammad MA, Zhang X, et al.: Hydroxysteroid Dehydrogenase Family Proteins on Lipid Droplets through Bacteria, C. Elegans, and Mammals. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 2018, 1863: 881-894.

[34] Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J, et al.: Genome-Wide RNAi Analysis of Caenorhabditis Elegans fat Regulatory Genes. Nature 2003, 421: 268-272.

[35] Liu W, Guan Y, Qiao S, Wang J, Bao K, Mao Z, et al.: Antiaging Effects of Vicatia thibetica de Boiss Root Extract on Caenorhabditis Elegans and Doxorubicin-Induced Premature Aging in Adult Mice . Oxidative Medicine and Cellular Longevity 2021, 2021: 9942090.

[36] Perez CL, Van Gilst MR: A 13C Isotope Labeling Strategy Reveals the Influence of Insulin Signaling on Lipogenesis in C. elegans. Cell Metabolism 2008, 8: 266-274.

[37] Rodriguez-Colman MJ, Dansen TB, Burgering BMT: FOXO Transcription Factors as Mediators of Stress Adaptation. Nature Reviews Molecular Cell Biology 2023, 25: 46-64.

[38] Shao X, Zhang M, Chen Y, Sun S, Yang S, Li Q . Exosome-Mediated Delivery of Superoxide Dismutase for Anti-Aging Studies in Caenorhabditis Elegans. International Journal of Pharmaceutics 2023, 641: 123090.

[39] Dehghan E, Zhang Y, Saremi B, Yadavali S, Hakimi A, Dehghani M, et al.: Hydralazine Induces Stress Resistance and Extends C. Elegans Lifespan by Activating the NRF2/SKN-1 Signalling Pathway. Nature Communications 2017, 8: 2223.

[40] Zeng Q, Gong Y, Zhu N, Shi Y, Zhang C, Qin L: Lipids and Lipid Metabolism in Cellular Senescence: Emerging Targets for Age-Related Diseases. Ageing Research Reviews 2024, 97: 102294.

[41] Lau ES, Roshandelpoor A, Zarbafian S, Wang D, Guseh JS, Allen N, et al.: Eicosanoid and Eicosanoid-Related Inflammatory Mediators and Exercise Intolerance in Heart Failure with Preserved Ejection Fraction. Nature Communications 2023, 14: 7557.

[42] G gotek A, Bielawska K, Biernacki M, Dobrzy ska I, Skrzydlewska E: Time-Dependent Effect of Rutin on Skin Fibroblasts Membrane Disruption Following UV Radiation. Redox Biology 2017, 12: 733-744.

[43] Hui Y, Wen S, Lihong W, Chuang W, Chaoyun W: Molecular Structures of Nonvolatile Components in the Haihong Fruit Wine and their Free Radical Scavenging Effect. Food Chemistry 2021, 353: 129298.

[44] Li S, Li J, Pan R, Cheng J, Cui Q, Chen J, et al.: Sodium Rutin Extends Lifespan and Health Span in Mice Including Positive Impacts on Liver Health. British Journal of Pharmacology 2021, 179: 1825-1838.

[45] Liu Y, Sun Z, Dong R, Liu P, Zhang X, Li Y, et al.: Rutin Ameliorated Lipid Metabolism Dysfunction of Diabetic NAFLD via AMPK/SREBP1 Pathway. Phytomedicine 2024, 126: 155437.