Metabolic-Immune Crosstalk as a Driver of Aging and Longevity: An Insight into Drosophila Melanogaster

Authors

  • Jackson E. Onuelu Department of Pharmacology, Faculty of Allied Health Science, Delta State University, Abraka, Nigeria. Author
  • Israel O. Efejene Department of Pharmacology, Faculty of Basic Medical Sciences, Southern Delta University, Ozoro, Delta State, Nigeria. Author https://orcid.org/0009-0006-7701-8980
  • Michael E. Aisuodionoe Department of Human Physiology, Faculty of Basic Medical Sciences, Southern Delta University, Ozoro, Delta State, Nigeria. Author
  • Priestley E. Bamitale Department of Pharmacology, Faculty of Allied Health Science, Delta State University, Abraka, Nigeria. Author
  • Winifred E. Demaki Department of Pharmacology, Faculty of Allied Health Science, Delta State University, Abraka, Nigeria. Author
  • Anita O. Ayovunefe Department of Optometry, Dennis Osadebay University, Asaba, Delta State, Nigeria. Author
  • Prosper Iwhiwhu Department of Pharmacology, Faculty of Allied Health Science, Delta State University, Abraka, Nigeria. Author
  • Okunoja Marvins Department of Physiology, Faculty of Basic Medical Science, Delta State University, Abraka, Delta State, Nigeria. Author
  • Oghenevwegba P. Ishokare Department of Pharmacology, Faculty of Basic Medical Sciences, Southern Delta University, Ozoro, Delta State, Nigeria. Author

DOI:

https://doi.org/10.71637/toxicologydigest.vol5no1.50

Keywords:

Aging, Immunometabolism, Innate immunity, Longevity, Insulin signaling, TOR pathway, Drosophila melanogaster

Abstract

Background:
Aging is a complex biological process regulated by interconnected metabolic and immune pathways. Increasing evidence suggests that dysregulation of metabolic–immune crosstalk is a major driver of age-associated functional decline and reduced lifespan. Drosophila melanogaster has emerged as a powerful model system to dissect these interactions due to its conserved metabolic signaling networks and well-characterized innate immune system.

Objective:
In this context, the study focuses on pathways such as insulin/insulin-like growth factor signaling (IIS), target of rapamycin (TOR), and AMP-activated protein kinase (AMPK) closely interact with innate immune pathways, including Toll, IMD, and JAK/STAT, to influence lifespan and health span.

Methods:
This review is based on secondary data obtained from peer-reviewed literature accessed through databases including PubMed, ScienceDirect, Google Scholar, ResearchGate, and HINARI. Relevant studies evaluating Drosophila melanogaster, metabolic-immune crosstalk, aging and longevity were critically evaluated.

Results:
Age-related metabolic imbalance can lead to chronic immune activation, contributing to inflammaging, tissue dysfunction, and reduced longevity. Conversely, immune signaling can reshape metabolic homeostasis by altering nutrient allocation, mitochondrial function, and stress responses. This review highlights current advances in understanding how metabolic and immune pathways integrate to regulate aging in Drosophila melanogaster, emphasizing tissue-specific effects, environmental modulators such as diet and microbiota, and evolutionary trade-offs between immunity and longevity.

Conclusions:
Elucidating these conserved immune-metabolic mechanisms provides critical insights into the biology of aging and may inform strategies to promote healthy aging across species.

         Views | Downloads: 0 / 0

Downloads

Download data is not yet available.

References

Atsoniou, K., Giannopoulou, E., Georganta, E. M., & Skoulakis, E. M. C. (2024). Drosophila contributions towards understanding neurofibromatosis 1. Cells, 13(9), 721. https://doi.org/10.3390/cells13090721

Bolus, H., Crocker, K., Boekhoff-Falk, G., & Chtarbanova, S. (2020). Modeling neurodegenerative disorders in Drosophila melanogaster. International Journal of Molecular Sciences, 21(9), 3055. https://doi.org/10.3390/ijms21093055

Gatto, C. L., & Broadie, K. (2011). Drosophila modeling of heritable neurodevelopmental disorders. Current Opinion in Neurobiology, 21(6), 834–841. https://doi.org/10.1016/j.conb.2011.04.009

Ma, M., Moulton, M. J., Lu, S., & Bellen, H. J. (2022). “Fly-ing” from rare to common neurodegenerative disease mechanisms. Trends in Genetics, 38(10), 972–984. https://doi.org/10.1016/j.tig.2022.05.006

McGuire, S. E., Deshazer, M., & Davis, R. L. (2005). Thirty years of olfactory learning and memory research in Drosophila melanogaster. Progress in Neurobiology, 76(5), 328–347. https://doi.org/10.1016/j.pneurobio.2005.09.003

Sharma, K., Shakarad, M., Agrawal, N., Maurya, S. K., & Shweta. (2024). Drosophila glial system: An approach towards understanding molecular complexity of neurodegenerative diseases. Molecular Biology Reports, 51, 1146. https://doi.org/10.1007/s11033-024-09344-6

Simon, J. C., & Dickinson, M. H. (2010). A new chamber for studying the behavior of Drosophila. PLoS ONE, 5(1), e8793. https://doi.org/10.1371/journal.pone.0008793

Trajković, J., Makević, V., Pešić, M., Pavković-Lučić, S., Milojević, S., Cvjetković, S., Hagerman, R., Budimirovic, D. B., & Protić, D. (2022). Drosophila melanogaster as a model to study fragile X-associated disorders. Genes, 14(1), 87. https://doi.org/10.3390/genes14010087

Arrese, E. L., & Soulages, J. L. (2010). Insect fat body: Energy, metabolism, and regulation. Annual Review of Entomology, 55, 207–225. https://doi.org/10.1146/annurev-ento-112408-085356

Frappaolo, A., & Giansanti, M. G. (2023). Using Drosophila melanogaster to dissect the roles of the mTOR signaling pathway in cell growth. Cells, 12(20), 2622. https://doi.org/10.3390/cells12202622

Frappaolo, A., Karimpour-Ghahnavieh, A., Cesare, G., Fraschini, R., Vaccari, T., & Giansanti, M. G. (2022). GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila. Cell Death & Disease, 13, 1003. https://doi.org/10.1038/s41419-022-05413-5

Huang, L., & Muthuswamy, S. K. (2010). Polarity protein alterations in carcinoma: A focus on emerging roles for polarity regulators. Current Opinion in Genetics & Development, 20(1), 41–50. https://doi.org/10.1016/j.gde.2009.12.004

Naz, F., & Siddique, Y. H. (2021). Drosophila melanogaster: A versatile model of Parkinson’s disease. CNS & Neurological Disorders - Drug Targets, 20(5), 487–530. https://doi.org/10.2174/1871527320666210216150533

Parvy, J. P., Hodgson, J. A., & Cordero, J. B. (2018). Drosophila as a model system to study nonautonomous mechanisms affecting tumour growth and cell death. BioMed Research International, 2018, Article 7152962. https://doi.org/10.1155/2018/7152962

Sonoshita, M., & Cagan, R. L. (2017). Modeling human cancers in Drosophila. Current Topics in Developmental Biology, 121, 287–309. https://doi.org/10.1016/bs.ctdb.2016.07.006

Yamaguchi, M., & Yoshida, H. (2018). Drosophila as a model organism. Advances in Experimental Medicine and Biology, 1067, 1–10. https://doi.org/10.1007/978-981-13-0490-1_1

Khan, C., & Rusan, N. M. (2024). Using Drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer. Trends in Cancer, 10(4), 289–311. https://doi.org/10.1016/j.trecan.2023.11.006

Ying, L., Saavedra, P., & Perrimon, N. (2022). Cancer cachexia: Lessons from Drosophila. Disease Models & Mechanisms, 15(3), dmm049298. https://doi.org/10.1242/dmm.049298

Munnik, C., Xaba, M. P., Malindisa, S. T., Russell, B. L., & Sooklal, S. A. (2022). Drosophila melanogaster: A platform for anticancer drug discovery and personalized therapies. Frontiers in Genetics, 13, 949241.

Su, T. T. (2019). Drug screening in Drosophila: Why, when, and when not? Wiley Interdisciplinary Reviews: Developmental Biology, 8(5), e346.

Kaufman, T. C. (2017). A short history and description of Drosophila melanogaster classical genetics: Chromosome aberrations, forward genetic screens, and the nature of mutations. Genetics, 206(2), 665–689.

Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249.

Raskov, H., Søby, J. H., Troelsen, J., Bojesen, R. D., & Gögenur, I. (2020). Driver gene mutations and epigenetics in colorectal cancer. Annals of Surgery, 271(1), 75–85.

Itatani, Y., Sonoshita, M., Kakizaki, F., Okawa, K., Stifani, S., Itoh, H., Sakai, Y., & Taketo, M. M. (2016). Characterization of Aes nuclear foci in colorectal cancer cells. Journal of Biochemistry, 159(1), 133–140.

Sonoshita, M., Itatani, Y., Kakizaki, F., Sakimura, K., Terashima, T., Katsuyama, Y., Sakai, Y., & Taketo, M. M. (2015). Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO. Cancer Discovery, 5(2), 198–211.

Villegas, S. N. (2019). One hundred years of Drosophila cancer research: No longer in solitude. Disease Models & Mechanisms, 12(8), dmm039032.

Casali, A., & Batlle, E. (2009). Intestinal stem cells in mammals and Drosophila. Cell Stem Cell, 4(2), 124–127.

Bangi, E., Murgia, C., Teague, A. G., Sansom, O. J., & Cagan, R. L. (2016). Functional exploration of colorectal cancer genomes using Drosophila. Nature Communications, 7, 13615.

Smolarz, B., Łukasiewicz, H., Samulak, D., Piekarska, E., Kołaciński, R., & Romanowicz, H. (2025). Lung cancer—Epidemiology, pathogenesis, treatment and molecular aspect (Review of literature). International Journal of Molecular Sciences, 26(4), 2049.

Levine, B. D., & Cagan, R. L. (2016). Drosophila lung cancer models identify trametinib plus statin as candidate therapeutic. Cell Reports, 14(6), 1477–1487.

Das, T. K., & Cagan, R. L. (2017). KIF5B-RET oncoprotein signals through a multi-kinase signaling hub. Cell Reports, 20(10), 2368–2383.

Shergalis, A., Bankhead, A., III, Luesakul, U., Muangsin, N., & Neamati, N. (2018). Current challenges and opportunities in treating glioblastoma. Pharmacological Reviews, 70(3), 412–445.

GBD 2021 Nervous System Disorders Collaborators. (2024). Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: A systematic analysis for the Global Burden of Disease Study 2021. The Lancet Neurology, 23(4), 344–381.

Stahl, A., & Tomchik, S. M. (2024). Modeling neurodegenerative and neurodevelopmental disorders in the Drosophila mushroom body. Learning & Memory, 31(3), a053816.

Feigin, V. L., Vos, T., Nichols, E., Owolabi, M. O., Carroll, W. M., Dichgans, M., Deuschl, G., Parmar, P., Brainin, M., & Murray, C. (2020). The global burden of neurological disorders: Translating evidence into policy. The Lancet Neurology, 19(3), 255–265.

Parenti, I., Rabaneda, L. G., Schoen, H., & Novarino, G. (2020). Neurodevelopmental disorders: From genetics to functional pathways. Trends in Neurosciences, 43(8), 608–621.

O’Kane, C. J. (2011). Drosophila as a model organism for the study of neuropsychiatric disorders. Current Topics in Behavioral Neurosciences, 7, 37–60.

McGurk, L., Berson, A., & Bonini, N. M. (2015). Drosophila as an in vivo model for human neurodegenerative disease. Genetics, 201(2), 377–402.

Nitta, Y., & Sugie, A. (2022). Studies of neurodegenerative diseases using Drosophila and the development of novel approaches for their analysis. Fly, 16(1), 275–298.

Campbell, R. A., & Turner, G. C. (2010). The mushroom body. Current Biology, 20(1), R11–R12.

Ugur, B., Chen, K., & Bellen, H. J. (2016). Drosophila tools and assays for the study of human diseases. Disease Models & Mechanisms, 9(3), 235–244.

Inagaki, H. K., Kamikouchi, A., & Ito, K. (2010). Protocol for quantifying sound-sensing ability of Drosophila melanogaster. Nature Protocols, 5(1), 26–30.

Aw, D., Silva, A. B., & Palmer, D. B. (2007). Immunosenescence: Emerging challenges for an ageing population. Immunology, 120(4), 435–446. https://doi.org/10.1111/j.1365-2567.2007.02555.x

Hales, K. G., Korey, C. A., Larracuente, A. M., & Roberts, D. M. (2015). Genetics on the fly: A primer on the Drosophila model system. Genetics, 201(3), 815–842. https://doi.org/10.1534/genetics.115.183392

Johnson, R., & Cagan, R. (2010). Drosophila as a model for human disease. In M. R. Speicher, S. E. Antonarakis, & A. G. Motulsky (Eds.), Vogel and Motulsky’s human genetics (pp. 795–811). Springer. https://doi.org/10.1007/978-3-540-37654-5_51

Lusk, L., Smith, S., Martin, C., Taylor, C., & Chung, W. (1993). PACS1 neurodevelopmental disorder. In GeneReviews® [Internet]. University of Washington. https://www.ncbi.nlm.nih.gov/books/NBK559434/

Dombernowsky, S. L., Samsøe-Petersen, J., Petersen, C. H., Instrell, R., Hedegaard, A. M., Thomas, L., Atkins, K. M., Auclair, S., Albrechtsen, R., Mygind, K. J., et al. (2015). The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17. Nature Communications, 6, 7518. https://doi.org/10.1038/ncomms8518

Köttgen, M., Benzing, T., Simmen, T., Tauber, R., Buchholz, B., Feliciangeli, S., Huber, T. B., Schermer, B., Kramer-Zucker, A., Höpker, K., et al. (2005). Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation. *The EMBO Journal, 24*(4), 705–716. https://doi.org/10.1038/sj.emboj.7600551

Olson, H. E., Jean-Marçais, N., Yang, E., Heron, D., Tatton-Brown, K., van der Zwaag, P. A., Bijlsma, E. K., Krock, B. L., Backer, E., Kamsteeg, E. J., et al. (2018). A recurrent de novo PACS2 heterozygous missense variant causes neonatal-onset developmental epileptic encephalopathy, facial dysmorphism, and cerebellar dysgenesis. *American Journal of Human Genetics, 102*(5), 995–1007. https://doi.org/10.1016/j.ajhg.2018.04.008

Perveen, F. K. (2018). Introduction to Drosophila. In *Drosophila melanogaster—Model for recent advances in genetics and therapeutics*. IntechOpen. https://doi.org/10.5772/intechopen.75409

Ravindran, S. (2014). Profile of Norbert Perrimon. *Proceedings of the National Academy of Sciences of the United States of America, 111*(21), 7501–7502. https://doi.org/10.1073/pnas.1408294111

Rubin, G. M. (2023). Michael Ashburner (1942–2023). *Current Biology, 33*(18), R881–R883. https://doi.org/10.1016/j.cub.2023.07.037

Schuurs-Hoeijmakers, J. H., Oh, E. C., Vissers, L. E., Swinkels, M. E., Gilissen, C., Willemsen, M. A., Holvoet, M., Steehouwer, M., Veltman, J. A., de Vries, B. B., et al. (2012). Recurrent de novo mutations cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. *American Journal of Human Genetics, 91*(6), 1122–1127. https://doi.org/10.1016/j.ajhg.2012.10.014

Thomas, G. (2002). Furin at the cutting edge: From protein traffic to embryogenesis and disease. *Nature Reviews Molecular Cell Biology, 3*(10), 753–766. https://doi.org/10.1038/nrm934

Thomas, G., Aslan, J. E., Thomas, L., Shinde, P., Shinde, U., & Simmen, T. (2017). Caught in the act: Protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease. *Journal of Cell Science, 130*(11), 1865–1876. https://doi.org/10.1242/jcs.199349

Wan, L., Molloy, S. S., Thomas, L., Liu,G., Xiang, Y., Rybak, S. L., & Thomas, G. (1998). PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization. *Cell, 94*(2), 205–216. https://doi.org/10.1016/S0092-8674(00)81420-8

Zirin, J., Jusiak, B., Lopes, R., Ewen-Campen, B., Bosch, J. A., Risbeck, A., Forman, C., Villalta, C., Hu, Y., & Perrimon, N. (2024). Expanding the Drosophila toolkit for dual control of gene expression. *eLife, 12*, RP94073. https://doi.org/10.7554/eLife.94073

Buchon, N., Silverman, N. and Cherry, S. (2014). Immunity in Drosophila melanogaster—from microbial recognition to whole-organism physiology. *Nature Reviews Immunology, 14*(12), pp.796–810.

Ferrucci, L., & Fabbri, E. (2018). Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. *Nature Reviews Cardiology, 15*(9), 505–522. https://doi.org/10.1038/s41569-018-0064-2

Franceschi, C., & Campisi, J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. *The Journals of Gerontology: Series A, 69*(Suppl. 1), S4–S9. https://doi.org/10.1093/gerona/glu057

Franceschi, C., Garagnani, P., Parini, P., Giuliani, C., & Santoro, A. (2018). Inflammaging and immunosenescence: From mechanisms to therapeutic opportunities. *Nature Reviews Endocrinology, 14*(10), 576–590. https://doi.org/10.1038/s41574-018-0054-6

Hotamisligil, G. S. (2017). Foundations of immunometabolism and implications for metabolic health and disease. *Immunity, 47*(3), 406–420. https://doi.org/10.1016/j.immuni.2017.08.009

Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. *Nature, 493*(7432), 338–345. https://doi.org/10.1038/nature11861

Olson, H. E., Jean-Marçais, N., Yang, E., Heron, D., Tatton-Brown, K., van der Zwaag, P. A., Bijlsma, E. K., Krock, B. L., Backer, E., Kamsteeg, E. J., et al. (2018). A recurrent de novo PACS2 heterozygous missense variant causes neonatal-onset developmental epileptic encephalopathy, facial dysmorphism, and cerebellar dysgenesis. *American Journal of Human Genetics, 102*(5), 995–1007. https://doi.org/10.1016/j.ajhg.2018.04.008

Parvy, J. P., Hodgson, J. A., & Cordero, J. B. (2018). Drosophila as a model system to study nonautonomous mechanisms affecting tumour growth and cell death. *BioMed Research International, 2018*, Article 7152962. https://doi.org/10.1155/2018/7152962

Victor Atoki, A., Aja, P. M., Shinkafi, T. S., Ondari, E. N., Adeniyi, A. I., Fasogbon, I. V., Dangana, R. S., Shehu, U. U., & Akin-Adewumi, A. (2025). Exploring the versatility of *Drosophila melanogaster* as a model organism in biomedical research: A comprehensive review. *Fly, 19*(1), 2420453. https://doi.org/10.1080/19336934.2024.2420453

Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., Franceschi, C., Lithgow, G. J., Morimoto, R. I., Pessin, J. E., Rando, T. A., Richardson, A., Schadt, E. E., Wyss-Coray, T., & Sierra, F. (2014). Geroscience: Linking aging to chronic disease. *Cell, 159*(4), 709–713. https://doi.org/10.1016/j.cell.2014.10.039

Kounatidis, I., & Ligoxygakis, P. (2012). Drosophila as a model system to unravel the layers of innate immunity to infection. *Open Biology, 2*(5), 120075. https://doi.org/10.1098/rsob.120075

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. *Cell, 153*(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.039

Mathis, D., & Shoelson, S. E. (2011). Immunometabolism: An emerging frontier. *Nature Reviews Immunology, 11*(2), 81–83. https://doi.org/10.1038/nri2922

Partridge, L., Alic, N., Bjedov, I., & Piper, M. D. W. (2011). Ageing in Drosophila: The role of the insulin/IGF and TOR signalling network. *Experimental Gerontology, 46*(5), 376–381. https://doi.org/10.1016/j.exger.2010.09.003

Piper, M. D. W., & Partridge, L. (2018). Drosophila as a model for ageing. *Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1864*(9), 2707–2717. https://doi.org/10.1016/j.bbadis.2018.05.016

Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly *Drosophila melanogaster*. *Cell Metabolism, 11*(1), 35–46. https://doi.org/10.1016/j.cmet.2009.11.010

Cho, J., Hur, J. H., Walker, D. W., & Park, J. H. (2011). Mitochondrial dysfunction in Drosophila aging. *Mechanisms of Ageing and Development, 132*(11–12), 580–588. https://doi.org/10.1016/j.mad.2011.09.004

Clancy, D. J., Gems, D., Harshman, L. G., Oldham, S., Stocker, H., Hafen, E., Leevers, S. J., & Partridge, L. (2001). Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. *Science, 292*(5514), 104–106. https://doi.org/10.1126/science.1057991

Flatt, T. (2011). Survival costs of reproduction in Drosophila. *Experimental Gerontology, 46*(5), 369–375. https://doi.org/10.1016/j.exger.2010.10.008

Grönke, S., Clarke, D. F., Broughton, S., Andrews, T. D., & Partridge, L. (2010). Molecular evolution and functional characterization of Drosophila insulin-like peptides. *PLoS Genetics, 6*(2), e1000857. https://doi.org/10.1371/journal.pgen.1000857

Hwangbo, D. S., Gershman, B., Tu, M. P., Palmer, M., & Tatar, M. (2004). Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. *Nature, 429*(6991), 562–566. https://doi.org/10.1038/nature02549

Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V., & Benzer, S. (2004). Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. *Current Biology, 14*(10), 885–890. https://doi.org/10.1016/j.cub.2004.03.059

Katewa, S. D., & Kapahi, P. (2017). Dietary restriction and aging, 2009–2013. *Aging Cell, 16*(5), 969–977. https://doi.org/10.1111/acel.12630

Mair, W., Piper, M. D. W., & Partridge, L. (2005). Dietary restriction in Drosophila. *Science, 308*(5723), 1031–1034. https://doi.org/10.1126/science.1109166

Rana, A. et al., (2017). Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of *Drosophila melanogaster*. *Nature Communications, 8*, 448.

Ristow, M., & Schmeisser, K. (2014). Mitohormesis: Promoting health and lifespan by increased levels of reactive oxygen species (ROS). *Free Radical Biology and Medicine, 66*, 58–67. https://doi.org/10.1016/j.freeradbiomed.2013.06.024

Saxton, R. A., & Sabatini, D. M. (2017). mTOR signaling in growth, metabolism, and disease. *Cell, 168*(6), 960–976. https://doi.org/10.1016/j.cell.2017.02.004

Scialò, F., Fernández-Ayala, D. J. M., & Sanz, A. (2016). Mitochondrial ROS produced via reverse electron transport extend animal lifespan. *Cell Metabolism, 23*(4), 725–734. https://doi.org/10.1016/j.cmet.2016.03.009

Tatar, M., Kopelman, A., Epstein, D., Tu, M. P., Yin, C. M., & Garofalo, R. S. (2001). A mutant Drosophila insulin receptor homolog that extends lifespan and impairs neuroendocrine function. *Science, 292*(5514), 107–110. https://doi.org/10.1126/science.1057987

Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., Alroy, J., Wu, M., Py, B. F., Yuan, J., Deeney, J. T., Corkey, B. E., & Shirihai, O. S. (2008). Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. *The EMBO Journal, 27*(2), 433–446. https://doi.org/10.1038/sj.emboj.7601963

Badinloo, M., Nguyen, E., Suh, W., Alzahrani, F., Castellanos, J., Klichko, V. I., Orr, W. C., & Radyuk, S. N. (2018). Age-dependent changes in innate immune signaling in *Drosophila melanogaster*. *Aging Cell, 17*(1), e12709. https://doi.org/10.1111/acel.12709

Buchon, N., Broderick, N. A., Poidevin, M., Pradervand, S., & Lemaitre, B. (2009). Drosophila intestinal response to bacterial infection: Activation of host defense and stem cell proliferation. *Cell Host & Microbe, 5*(2), 200–211. https://doi.org/10.1016/j.chom.2009.01.0

Cao, Y., Chtarbanova, S., Petersen, A. J., & Ganetzky, B. (2013). Chronic immune activation causes neurodegeneration in Drosophila. *Cell Reports, 3*(3), 872–884. https://doi.org/10.1016/j.celrep.2013.01.028

Ferrandon, D., Imler, J. L., Hetru, C., & Hoffmann, J. A. (2007). The Drosophila systemic immune response: Sensing and signalling during bacterial and fungal infections. *Nature Reviews Immunology, 7*(11), 862–874. https://doi.org/10.1038/nri2194

Frappaolo, A., Zaccagnini, G., Riparbelli, M. G., Colotti, G., Callaini, G., & Giansanti, M. G. (2025). PACS deficiency disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype in *Drosophila melanogaster*. *Open Biology, 15*, 240267. https://doi.org/10.1098/rsob.240267

Kounatidis, I., Chtarbanova, S., Cao, Y., Hayne, M., Jayanth, D., Ganetzky, B., & Ligoxygakis, P. (2017). NF-κB immunity in the brain determines fly lifespan in healthy aging and age-related neurodegeneration. *Cell Reports, 19*(4), 836–848. https://doi.org/10.1016/j.celrep.2017.04.007

Kounatidis, I., & Ligoxygakis, P. (2012). Drosophila as a model system to unravel the layers of innate immunity to infection. *Open Biology, 2*(5), 120075. https://doi.org/10.1098/rsob.120075

Landis, G. N., Abdueva, D., Skvortsov, D., Yang, J., Rabin, B. E., Carrick, J., Tavare, S., & Tower, J. (2004). Similar gene expression patterns characterize aging and oxidative stress in *Drosophila melanogaster*. *Proceedings of the National Academy of Sciences of the United States of America, 101*(20), 7663–7668. https://doi.org/10.1073/pnas.0307605101

Lemaitre, B., & Hoffmann, J. (2007). The host defense of *Drosophila melanogaster*. *Annual Review of Immunology, 25*, 697–743. https://doi.org/10.1146/annurev.immunol.25.022106.14

Pletcher, S. D., Macdonald, S. J., Marguerie, R., Certa, U., Stearns, S. C., Goldstein, D. B., & Partridge, L. (2002). Genome-wide transcript profiles in aging and calorically restricted *Drosophila melanogaster*. *Current Biology, 12*(9), 712–723. https://doi.org/10.1016/S0960-9822(02)00808-4

Rera, M., Clark, R. I., & Walker, D. W. (2012). Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in *Drosophila*. *Proceedings of the National Academy of Sciences of the United States of America, 109*(52), 21528–21533. https://doi.org/10.1073/pnas.1215849110

Zerofsky, M., Harel, E., Silverman, N., & Tatar, M. (2005). Aging of the innate immune response in *Drosophila melanogaster*. *Aging Cell, 4*(2), 103–108. https://doi.org/10.1111/j.1474-9728.2005.00147.x

Arrese, E. L., & Soulages, J. L. (2010). Insect fat body: Energy, metabolism, and regulation. *Annual Review of Entomology, 55*, 207–225. https://doi.org/10.1146/annurev-ento-112408-085356

Becker, T., Loch, G., Beyer, M., Zinke, I., Aschenbrenner, A. C., Carrera, P., Inhester, T., Schultze, J. L., & Hoch, M. (2010). FOXO-dependent regulation of innate immune homeostasis. *Nature, 463*(7279), 369–373. https://doi.org/10.1038/nature08698

Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly *Drosophila melanogaster*. *Cell Metabolism, 11*(1), 35–46. https://doi.org/10.1016/j.cmet.2009.11.010

Chambers, M. C., Song, K. H., Schneider, D. S., & other authors. (2012). The fat body contributes to immune defense in *Drosophila*. *Developmental & Comparative Immunology, 36*(3), 532–540. https://doi.org/10.1016/j.dci.2011.03.014

Davoodi, S., Galenza, A., Panteluk, A., Deshpande, R., Ferguson, M., & Grewal, S. S. (2019). Energy metabolism regulates immune responses in *Drosophila*. *Frontiers in Physiology, 10*, 1239. https://doi.org/10.3389/fphys.2019.01239

Dionne, M. S., Pham, L. N., Shirasu-Hiza, M., & Schneider, D. S. (2006). Akt and FOXO dysregulation contribute to infection-induced wasting in *Drosophila*. *Current Biology, 16*(20), 1977–1985. https://doi.org/10.1016/j.cub.2006.08.05

Giansanti, M. G., Frappaolo, A., & Piergentili, R. (2025). *Drosophila melanogaster*: How and why it became a model organism. *International Journal of Molecular Sciences, 26*(15), 7485. https://doi.org/10.3390/ijms26157485

Martin, M., Hiroyasu, A., Guzman, R. M., Roberts, S. A., & Goodman, A. G. (2017). Rapamycin-mediated lifespan extension in *Drosophila* depends on immune modulation. *Aging Cell, 16*(5), 1102–1114. https://doi.org/10.1111/acel.12659

Slack, C., Alic, N., Foley, A., Cabecinha, M., Hoddinott, M. P., & Partridge, L. (2011). FOXO regulates lifespan and resistance to oxidative stress in *Drosophila*. *Aging Cell, 10*(4), 558–570. https://doi.org/10.1111/j.1474-9726.2011.00688.x

Varma, D., Bülow, M. H., Pesch, Y. Y., Loch, G., & Hoch, M. (2014). Nutrient sensing and immune signaling crosstalk in *Drosophila*. *Cell Host & Microbe, 16*(4), 447–458. https://doi.org/10.1016/j.chom.2014.09.001

Woodcock, K. J., Kierdorf, K., Pouchelon, C. A., Vivancos, V., Dionne, M. S., & Geissmann, F. (2015). Dysregulated lipid metabolism contributes to immune aging in *Drosophila*. *Aging Cell, 14*(4), 694–704. https://doi.org/10.1111/acel.12339

Cao, Y., Wang, C., Shen, Y., Bolton, E., & Ganetzky, B. (2019). Innate immune activation in the *Drosophila* brain disrupts neuronal function and accelerates aging. *Nature Communications, 10*, 1056. https://doi.org/10.1038/s41467-019-08929-5

Clark, R. I., Salazar, A., Yamada, R., Fitz-Gibbon, S., Morselli, M., Alcaraz, J., Rana, A., Rera, M., Pellegrini, M., Ja, W. W., & Walker, D. W. (2015). Distinct shifts in microbiota composition during *Drosophila* aging impair intestinal function and drive mortality. *Cell Reports, 12*(10), 1656–1667. https://doi.org/10.1016/j.celrep.2015.08.004

DiAngelo, J. R., Bland, M. L., Bambina, S., Cherry, S., & Birnbaum, M. J. (2009). The central role of the fat body in *Drosophila* insulin signaling and metabolism. *Developmental Cell, 16*(4), 548–557. https://doi.org/10.1016/j.devcel.2009.03.014

Doherty, J., Logan, M. A., Taşdemir, O. E., & Freeman, M. R. (2009). Glial immune signaling regulates neuronal function in *Drosophila*. *Science, 325*(5946), 1206–1210. https://doi.org/10.1126/science.1174161

Guo, L., Karpac, J., Tran, S. L., & Jasper, H. (2014). PGRP-SC2 promotes gut immune homeostasis to limit commensal dysbiosis and extend lifespan. *Cell, 156*(1–2), 109–122. https://doi.org/10.1016/j.cell.2013.12.018

Koyama, T., Mirth, C. K., & Piper, M. D. W. (2020). Chronic immune activation in the fat body promotes metabolic decline and limits lifespan in *Drosophila*. *Aging Cell, 19*(1), e13048. https://doi.org/10.1111/acel.13048

Kremer, M. C., Jung, C., Batelli, S., Rubin, G. M., & Gaul, U. (2017). Metabolic state modulates glial inflammatory responses in the aging *Drosophila* brain. *Journal of Neuroscience, 37*(34), 8359–8371. https://doi.org/10.1523/JNEUROSCI.0999-17.2017

Lee, W. J., Brey, P. T., & others. (2013). Gut immunity and homeostasis in *Drosophila*. *Developmental & Comparative Immunology, 42*(1), 22–28. https://doi.org/10.1016/j.dci.2013.04.006

Petersen, A. J., Katzenberger, R. J., & Wassarman, D. A. (2012). Insulin signaling regulates neuronal stress resistance and longevity in *Drosophila*. *Proceedings of the National Academy of Sciences of the United States of America, 109*(50), 20603–20608. https://doi.org/10.1073/pnas.1210070109

Rajan, A., & Perrimon, N. (2013). Of flies and men: Insights on organismal metabolism from *Drosophila*. *Cell Metabolism, 16*(4), 407–417. https://doi.org/10.1016/j.cmet.2013.08.011

Regan, J. C., Khericha, M., Dobson, A. J., Bolukbasi, E., Rattanavirotkul, N., & Partridge, L. (2016). Dietary restriction and gut homeostasis in aging *Drosophila*. *Cell Reports, 16*(9), 2269–2278. https://doi.org/10.1016/j.celrep.2016.07.042

Broderick, N. A., & Lemaitre, B. (2012). Gut-associated microbes of *Drosophila melanogaster*. *Gut Microbes, 3*(4), 307–321. https://doi.org/10.4161/gmic.19896

Fanson, B. G., Weldon, C. W., Pérez-Staples, D., & Taylor, P. W. (2009). Protein: Carbohydrate ratios regulate reproduction and lifespan in *Drosophila*. *Experimental Gerontology, 44*(12), 784–790. https://doi.org/10.1016/j.exger.2009.09.007

Fast, D., Duggal, A., Foley, E., & others. (2018). The gut microbiota protects against age-related inflammation in *Drosophila*. *Cell Host & Microbe, 23*(6), 829–838. https://doi.org/10.1016/j.chom.2018.05.005

Geometry Lee, K. P., Simpson, S. J., Clissold, F. J., Brooks, R., Ballard, J. W. O., Taylor, P. W., Soran, N., & Raubenheimer, D. (2008). Lifespan and reproduction in *Drosophila*: New insights from nutritional geometry. *Proceedings of the National Academy of Sciences of the United States of America, 105*(7), 2498–2503. https://doi.org/10.1073/pnas.0710787105

Lemaitre, B., Kromer-Metzger, E., Michaut, L., Nicolas, E., Meister, M., Georgel, P., Reichhart, J. M., & Hoffmann, J. A. (1995). Constitutive expression of antimicrobial peptides causes lethal tissue damage in *Drosophila*. *The EMBO Journal, 14*(3), 536–545. https://doi.org/10.1002/j.1460-2075.1995.tb07066.x

Libert, S., Chao, Y., Chu, X., & Pletcher, S. D. (2006). Trade-offs between longevity and pathogen resistance in *Drosophila*. *Cell, 125*(6), 1061–1074. https://doi.org/10.1016/j.cell.2006.05.022

Nakagawa, S., Lagisz, M., Hector, K. L., & Spencer, H. G. (2012). Comparative and meta-analytic insights into dietary restriction and lifespan. *Aging Cell, 11*(3), 401–409. https://doi.org/10.1111/j.1474-9726.2012.00798.x

Obata, F., Fons, C. O., & Gould, A. P. (2018). Diet influences host–microbiota associations and lifespan in *Drosophila*. *Cell Reports, 22*(6), 1579–1591. https://doi.org/10.1016/j.celrep.2018.01.004

Shin, S. C., Kim, S. H., You, H., Kim, B., Kim, A. C., Lee, K. A., Yoon, J. H., Ryu, J. H., & Lee, W. J. (2011). *Drosophila* microbiome modulates host developmental and metabolic homeostasis. *Science, 334*(6056), 670–674. https://doi.org/10.1126/science.1212782

Tower, J. (2015). Programmed cell death in aging. *Ageing Research Reviews, 23*, 90–100. https://doi.org/10.1016/j.arr.2015.04.002

Fabian, D. K., Garschall, K., Klepsatel, P., Santos-Matos, G., Sucena, É., Kapun, M., & Flatt, T. (2021). Metabolic regulation of innate immunity and aging in *Drosophila*. *Trends in Immunology, 42*(7), 587–601. https://doi.org/10.1016/j.it.2021.04.002

Fulop, T., Dupuis, G., Witkowski, J. M., & Larbi, A. (2018). Immunosenescence and inflamm-aging as two sides of the same coin: Friends or foes? *Frontiers in Immunology, 8*, 1960. https://doi.org/10.3389/fimmu.2017.01960

Leclerc, V., Pelte, N., El Chamy, L., Martinelli, C., Ligoxygakis, P., Hoffmann, J. A., & Reichhart, J. M. (2006). Prolonged immune activation is detrimental to *Drosophila* survival. *Journal of Immunology, 176*(4), 2062–2072. https://doi.org/10.4049/jimmunol.176.4.2062

Medzhitov, R. (2008). Origin and physiological roles of inflammation. *Nature, 454*(7203), 428–435. https://doi.org/10.1038/nature07201

Nussey, D. H., Froy, H., Lemaitre, J. F., Gaillard, J. M., & Austad, S. N. (2013). Senescence in natural populations of animals: Widespread evidence and its implications. *Science, 341*(6145), 123–128. https://doi.org/10.1126/science.1236282

Schmid-Hempel, P. (2005). Evolutionary ecology of insect immune defenses. *Annual Review of Entomology, 50*, 529–551. https://doi.org/10.1146/annurev.ento.50.071803.130420

Sheldon, B. C., & Verhulst, S. (1996). Ecological immunology: Costly parasite defences and trade-offs in evolutionary ecology. *Trends in Ecology & Evolution, 11*(8), 317–321. https://doi.org/10.1016/0169-5347(96)10039-2

Williams, G. C. (1957). Pleiotropy, natural selection, and the evolution of senescence. *Evolution, 11*(4), 398–411. https://doi.org/10.2307/2406060

Franceschi, C., Garagnani, P., Parini, P., Giuliani, C., & Santoro, A. (2018). Inflammaging and “garb-aging.” *Trends in Endocrinology & Metabolism, 29*(11), 782–792. https://doi.org/10.1016/j.tem.2018.07.005

Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of aging and age-related disease. *Nature, 493*(7432), 338–345. https://doi.org/10.1038/nature11861

Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V., & Benzer, S. (2010). Regulation of lifespan in *Drosophila* by modulation of genes in the TOR signaling pathway. *Current Biology, 16*(8), 885–890. https://doi.org/10.1016/j.cub.2004.03.059

Kundu, P., Blacher, E., Elinav, E., & Pettersson, S. (2017). Our gut microbiome: The evolving inner self. *Cell, 171*(7), 1481–1493. https://doi.org/10.1016/j.cell.2017.11.024

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. *Cell, 153*(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.039

Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., de Cabo, R., Fernandez, E., Flurkey, K., Javors, M. A., Nelson, J. F., Orihuela, C. J., Pletcher, S., Sharp, Z. D., Sinclair, D., Starnes, J. W., Wilkinson, J. E., Nadon, N. L., Strong, R., & others. (2011). Studies of caloric restriction and rapamycin in *Drosophila* and mammals: Implications for metabolic and immune aging. *Mechanisms of Ageing and Development, 132*(6–7), 283–293. https://doi.org/10.1016/j.mad.2011.04.002

Camus, M. F., Piper, M. D., & Reuter, M. (2012). Sex-specific effects of nutrition on lifespan and reproduction in *Drosophila melanogaster*. *Aging Cell, 11*(4), 640–648. https://doi.org/10.1111/j.1474-9726.2012.00822.x

Koyama, T., Mirth, C. K., & Sgrò, C. M. (2020). Chronic immune activation and metabolic decline: A tissue-specific perspective in aging *Drosophila*. *Aging Cell, 19*(1), e13048. https://doi.org/10.1111/acel.13048

Leclerc, V., O’Keefe, K., & Reichhart, J. M. (2006). Chronic immune activation reduces lifespan in *Drosophila*. *Journal of Immunology, 176*(4), 2062–2072. https://doi.org/10.4049/jimmunol.176.4.2062

Mair, W., Piper, M. D., & Partridge, L. (2005). Calories do not explain extension of lifespan by dietary restriction in *Drosophila*. *PLoS Biology, 3*(7), e223. https://doi.org/10.1371/journal.pbio.0030223

Regan, J. C., Khericha, M., Dobson, A. J., Bolukbasi, E., Rattanavirotkul, N., & Partridge, L. (2016). Sex-specific effects of diet on lifespan and gut homeostasis in *Drosophila*. *Aging Cell, 15*(4), 699–708. https://doi.org/10.1111/acel.12459

Li, Y., Hoffmann, J., Li, Y., Stephano, F., Brankatschk, M., Gutierrez, E., & others. (2020). Single-cell transcriptomics of the *Drosophila* fat body reveals immune and metabolic heterogeneity during aging. *Cell Reports, 30*(12), 4259–4272.e6. https://doi.org/10.1016/j.celrep.2020.02.091

Obata, F., Fons, C., & Gould, A. P. (2018). Early-life exposure to commensal bacteria shapes the aging gut and extends lifespan in *Drosophila*. *Cell, 174*(5), 730–743.e16. https://doi.org/10.1016/j.cell.2018.05.048

Stanley, D., Mason, L. J., Mackay, C. R., & others. (2017). Multi-omics approaches reveal molecular networks linking metabolism and immunity in aging flies. *Nature Communications, 8*, 14811. https://doi.org/10.1038/ncomms14811

Broderick, N. A., & Lemaitre, B. (2012). Gut-associated microbes of *Drosophila melanogaster*. *Gut Microbes, 3*(4), 307–321. https://doi.org/10.4161/gmic.19896

Koyama, T., Mirth, C. K., & Sgrò, C. M. (2020). Chronic immune activation and metabolic decline: A tissue-specific perspective in aging *Drosophila*. *Aging Cell, 19*(1), e13048. https://doi.org/10.1111/acel.13048

Medzhitov, R. (2008). Origin and physiological roles of inflammation. *Nature, 454*(7203), 428–435. https://doi.org/10.1038/nature07201

Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., de Cabo, R., Fernandez, E., Flurkey, K., Javors, M. A., Nelson, J. F., Orihuela, C. J., Pletcher, S., Sharp, Z. D., Sinclair, D., Starnes, J. W., Wilkinson, J. E., Nadon, N. L., Strong, R., & others. (2011). Studies of caloric restriction and rapamycin in *Drosophila* and mammals: Implications for metabolic and immune aging. *Mechanisms of Ageing and Development, 132*(6–7), 283–293. https://doi.org/10.1016/j.mad.2011.04.002

Sheldon, B. C., & Verhulst, S. (1996). Ecological immunology: Costly parasite defences and trade-offs in evolutionary ecology. *Trends in Ecology & Evolution, 11*(8), 317–321. https://doi.org/10.1016/0169-5347(96)10039-2

Downloads

Published

2026-07-09

Issue

Section

Articles

How to Cite

Onuelu, J. E., Efejene, I. O., Aisuodionoe, M. E., Bamitale, P. E., Demaki, W. E., Ayovunefe, A. O., Iwhiwhu , P., Marvins , O., & Ishokare, O. P. (2026). Metabolic-Immune Crosstalk as a Driver of Aging and Longevity: An Insight into Drosophila Melanogaster. Toxicology Digest, 5(1), 23-43. https://doi.org/10.71637/toxicologydigest.vol5no1.50

Share

Similar Articles

You may also start an advanced similarity search for this article.