INDY (I’m Not Dead, Yet)

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INDY (acronym I’m Not Dead, Yet) is a longevity gene originally found in the fruit fly Drosophila melanogaster, which encodes a plasma membrane Krebs cycle intermediate transporter.[1] Defects in this gene can lead to production of a protein that renders metabolism less efficient; as a result the body functions as if the fruit fly were dieting as in calorie restriction regimen, even though its eating habits are unchanged. In natural populations of flies individuals heterozygous for the Hoppel transposon insertion variant in the first intron of the Indy gene have lower Indy mRNA levels, higher fecundity and fitness advantage providing them life span extension.[2] Such mutations in the Indy gene in the heterozygous state result in an 80–100% increase in the average lifespan of both adult male and female fruitflies without sacrificing fertility or physical activity.[3] Heterozygous long-lived Indy females continued to produce viable adult offspring for an average of 40% longer than control flies (23.2 days versus 16.5 days).[3] Indy long-lived flies show several phenotypes that are shared by long-lived calorie restriction flies, including decreased insulin-like signaling, lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity.[4]

The molecular mechanism, by which the heterozygote advantage of Indy on longevity is mediated, involves modulation of Indy transcription[3][4]

Indy homologues

mINDY targeted interventions to promote a healthier and longer life. According to Mishra et al. 2021[5]

Indy homologues have been identified in bacteria, worms, mice, rats, dogs, rabbits, monkeys, chimpanzees, zebrafish, pigs and humans.[5][6]

SLC13A5

As a crucial energy sensor regulating cytosolic citrate levels, the homolog of the mammalian INDY gene (mINDY) also known as SLC13A5 gene or Na+/citrate cotransporter (NaCT), plays crucial metabolic roles maintaining energy homeostasis in the liver, brain, and several other tissues.[7][8] Though both Drosophila INDY and mammalian INDY transport citrate and, to a lesser extent, succinate, malate, or fumarate, their structures differ as evident from only ~35% identity in amino acid sequence.[9] The SLC13A5 gene, in addition to citrate transport, influences bile acid synthesis, nucleotide metabolism, as well as transport and synthesis of fatty acids. [10] In humans though beneficial effects of INDY deficiency are retained to a large extent, there is evidence for significant negative consequences, such as the devastating neurological disease known as Early Infantile Epileptic Encephalopathy-25 (EIEE-25).[11] The effect of mINDY on health depends on age. Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads besides epileptic encephalopathy to developmental delay, thinning of tooth enamel.[12][13][14]

Loss of mINDY in MINDY-/- mice increases energy expenditure associated with increased hepatic fat oxidation and reduces hepatic lipogenesis, while surprisingly, calorie intake in MINDY-/- mice is not reduced.[15][16] This reduces obesity, prevents lipid accumulation in the liver and skeletal muscle, and increases insulin sensitivity under conditions of high fat diets and during aging.[15][8] Similar to what is seen in dietary restriction animals, systemic deletion of the SLC13A5 gene (mIndy knockout [KO]) significantly improves memory performance and motor coordination of mice. In addition, mice with systemic or nervous system deletion of SLC13A5 exhibit increased hippocampal neurogenesis and dendritic spine formation in dentate granule cells that also demonstrate a critical role for brain-derived mIndy in the regulation of memory function in animals.[17][10]

Interleukin 6 (IL-6) can stimulate mIndy expression by binding to its cognate receptor, which induces mIndy transcription by activating the STAT3 (signal transducer and activator of transcription 3) mediator protein.[18] Thus, activation of the IL-6 and STAT3 signal, stimulating mIndy expression, enhances cytoplasmic citrate influx and enhances hepatic lipogenesis in vivo.[18]

Although SLC13A5 deficiency protects adults from obesity and diabetes, in young organisms this deficiency leads to epileptic encephalopathy and developmental delay, thinning of tooth enamel.[19][20][21]

Inhibitors of SLC13a5

Studies using antisense oligonucleotides to suppress mIndy in rats have demonstrated an improvement in insulin sensitivity, which has been attributed to improved hepatic glucose production and insulin sensitivity.[22]

Obesity and type-2 diabetes are strong risk factors for metabolically associated fatty liver disease (MAFLD), also known as Non-alcoholic fatty liver disease (NAFLD).[23] Increased mIndy mRNA expression in the liver is strongly associated with obesity, insulin resistance, and fatty liver disease in humans.[18] So, one of approaches to treating human NAFLD, obesity and metabolic syndrome via influences on host metabolism and energy is targeting in the liver the activity of the SLC13a5 gene by inhibition with RNAi,[24] aptamers,[22] compound 2 (PF-06649298),[25] compound 4a,[26] BI01383298[27][18] A selective, human- and multi-species-active, non-competitive, non-substrate-like inhibitor of Slc13a5/mINDY activity, called ETG-5773, has also been developed.[28] Diet-induced obesity mouse model treated with 15 mg/kg of compound ETG-5773 twice daily within a month had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Mechanistic investigation in the seven-day study showed increased plasma β-hydroxybutyrate and activated hepatic AMPK (adenosine monophosphate-activated protein kinase), reflecting findings from Indy (−/−) knockout mice.[28] So, by blocking the absorption of citrate, ETG-5773 is able to combat hepatic steatosis and fatty deposits, and therefore can be used in the future for the prevention and treatment of diet-induced obesity and non-alcoholic fatty liver disease due to metabolic disorders.[28]

Pharmacological SLC13A5 inhibition could have utility in preventing or treating osteoporosis.[29]

See also

References

  1. ↑ Knauf, F., Mohebbi, N., Teichert, C., Herold, D., Rogina, B., Helfand, S., ... & Aronson, P. S. (2006). The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochemical Journal, 397(1), 25-29.
  2. ↑ Zhu, C. T., Chang, C., Reenan, R. A., & Helfand, S. L. (2014). Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion. Aging (Albany NY), 6(1), 58. PMID: 24519859 PMC:3927810 DOI: 10.18632/aging.100634
  3. ↑ 3.0 3.1 3.2 Rogina, B., Reenan, R. A., Nilsen, S. P., & Helfand, S. L. (2000). Extended life-span conferred by cotransporter gene mutations in Drosophila. Science, 290(5499), 2137-2140. PMID: 11118146 DOI: 10.1126/science.290.5499.2137
  4. ↑ 4.0 4.1 Wang, P. Y., Neretti, N., Whitaker, R., Hosier, S., Chang, C., Lu, D., ... & Helfand, S. L. (2009). Long-lived Indy and calorie restriction interact to extend life span. Proceedings of the National Academy of Sciences, 106(23), 9262-9267.
  5. ↑ 5.0 5.1 Mishra, D., Kannan, K., Meadows, K., Macro, J., Li, M., Frankel, S., & Rogina, B. (2021). INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans. Frontiers in Aging, 73. Doi:10.3389/fragi.2021.782162
  6. ↑ Kannan, K., & Rogina, B. (2021). The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis. Metabolites, 11(10), 705. Doi:10.3390/metabo11100705
  7. ↑ Mycielska, M. E., James, E. N., & Parkinson, E. K. (2022). Metabolic Alterations in Cellular Senescence: The Role of Citrate in Ageing and Age-Related Disease. International Journal of Molecular Sciences, 23(7), 3652. PMID: 35409012 PMC:8998297 DOI:10.3390/ijms23073652
  8. ↑ 8.0 8.1 Li, Z., & Wang, H. (2021). Molecular Mechanisms of the SLC13A5 Gene Transcription. Metabolites, 11(10), 706. PMID: 34677420 PMC:8537064 DOI: 10.3390/metabo11100706
  9. ↑ Jaramillo-Martinez, V., Sivaprakasam, S., Ganapathy, V., & Urbatsch, I. L. (2021). Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions. Metabolites, 11(10), 669. PMID: 34677384 PMC:8537002 DOI: 10.3390/metabo11100669
  10. ↑ 10.0 10.1 Milosavljevic, S., Glinton, K. E., Li, X., Medeiros, C., Gillespie, P., Seavitt, J. R., ... & Elsea, S. H. (2022). Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis. Metabolites, 12(4), 351. PMID 35448538 PMC:9032242 doi:10.3390/metabo12040351
  11. ↑ Kopel, J. J., Bhutia, Y. D., Sivaprakasam, S., & Ganapathy, V. (2021). Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier. Biochemical Journal, 478(3), 463-486. PMID: 33544126 PMC:7868109 DOI: 10.1042/BCJ20200877
  12. ↑ Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:5023510 doi:10.2119/molmed.2016.0007
  13. ↑ Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:8625967 doi:10.3390/metabo11110746
  14. ↑ Goodspeed, K., Liu, J. S., Nye, K. L., Prasad, S., Sadhu, C., Tavakkoli, F., ... & Bailey, R. M. (2022). SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes, 13(9), 1655. PMID: 36140822 PMC:9498415 DOI: 10.3390/genes13091655
  15. ↑ 15.0 15.1 Birkenfeld, A. L., Lee, H. Y., Guebre-Egziabher, F., Alves, T. C., Jurczak, M. J., Jornayvaz, F. R., ... & Shulman, G. I. (2011). Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell metabolism, 14(2), 184-195. PMID: 21803289 PMC:3163140 DOI: 10.1016/j.cmet.2011.06.009
  16. ↑ Rogina, B. (2017). INDY—A New Link to Metabolic Regulation in Animals and Humans. Frontiers in Genetics, 8, 66. PMID: 28596784 PMC:5442177 DOI: 10.3389/fgene.2017.00066
  17. ↑ Fan, S. Z., Sung, C. W., Tsai, Y. H., Yeh, S. R., Lin, W. S., & Wang, P. Y. (2021). Nervous system deletion of mammalian INDY in mice mimics dietary restriction-induced memory enhancement. The Journals of Gerontology: Series A, 76(1), 50-56. PMID:32808644 DOI:10.1093/gerona/glaa203
  18. ↑ 18.0 18.1 18.2 18.3 von Loeffelholz, C., Lieske, S., Neuschäfer‐Rube, F., Willmes, D. M., Raschzok, N., Sauer, I. M., … & Birkenfeld, A. L. (2017). The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism. Hepatology, 66(2), 616—630. PMID 28133767 PMC:5519435 doi:10.1002/hep.29089
  19. ↑ Klotz, J., Porter, B. E., Colas, C., Schlessinger, A., & Pajor, A. M. (2016). Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Molecular medicine, 22(1), 310-321. PMID 27261973 PMC:5023510 doi:10.2119/molmed.2016.00077
  20. ↑ Brown, T. L., Nye, K. L., & Porter, B. E. (2021). Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder. Metabolites, 11(11), 746. PMID 34822404 PMC:8625967 doi:10.3390/metabo11110746
  21. ↑ Irizarry, A. R., Yan, G., Zeng, Q., Lucchesi, J., Hamang, M. J., Ma, Y. L., & Rong, J. X. (2017). Defective enamel and bone development in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient mice. PloS one, 12(4), e0175465. PMID 28406943 PMC:5391028 doi:10.1371/journal.pone.0175465
  22. ↑ 22.0 22.1 Pesta, D. H., Perry, R. J., Guebre-Egziabher, F., Zhang, D., Jurczak, M., Fischer-Rosinsky, A., … & Birkenfeld, A. L. (2015). Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). Aging (Albany NY), 7(12), 1086. PMID 26647160 PMC:4712334 DOI:10.18632/aging.100854
  23. ↑ Stefan, N., & Cusi, K. (2022). A global view of the interplay between non-alcoholic fatty liver disease and diabetes. The Lancet Diabetes & Endocrinology. 10(4), 284-296 DOI:10.1016/S2213-8587(22)00003-1
  24. ↑ Brachs, S., Winkel, A. F., Tang, H., Birkenfeld, A. L., Brunner, B., Jahn-Hofmann, K., ... & Spranger, J. (2016). Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Molecular metabolism, 5(11), 1072-1082. PMID: 27818933 PMC:5081411 DOI: 10.1016/j.molmet.2016.08.004
  25. ↑ EL-AGROUDY, N. E. R. M. E. E. N., ZAHN, G., HERRMANN, C., MINGRONE, G., ALVES, T. C., & BIRKENFELD, A. L. (2022). 839-P: Pharmacological Inhibition of Mammalian INDY Ameliorates Western Diet–Induced NASH in Mice: Possible Implication of FgfMPK Signaling. Diabetes, 71(Supplement_1). https://doi.org/10.2337/db22-839-P
  26. ↑ Willmes, D. M., Kurzbach, A., Henke, C., Schumann, T., Zahn, G., Heifetz, A., … & Birkenfeld, A. L. (2018). The longevity gene INDY (I’m Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology & therapeutics, 185, 1-11. PMID 28987323 Doi:10.1016/j.pharmthera.2017.10.003
  27. ↑ Higuchi, K., Kopel, J. J., Sivaprakasam, S., Jaramillo-Martinez, V., Sutton, R. B., Urbatsch, I. L., & Ganapathy, V. (2020). Functional analysis of a species-specific inhibitor selective for human Na±coupled citrate transporter (NaCT/SLC13A5/mINDY). Biochemical Journal, 477(21), 4149-4165. PMID 33079129 PMC:7657661 doi:10.1042/BCJ20200592
  28. ↑ 28.0 28.1 28.2 Zahn, G., Willmes, D. M., El-Agroudy, N. N., Yarnold, C., Jarjes-Pike, R., Schaertl, S., ... & Birkenfeld, A. L. (2022). A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity. Metabolites, 12(8), 732.PMID: 36005604 PMC:9413491 DOI: 10.3390/metabo12080732
  29. ↑ Zahn, G., Baukmann, H. A., Wu, J., Jordan, J., Birkenfeld, A. L., Dirckx, N., & Schmidt, M. F. (2023). Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis. Metabolites, 13(12), 1186. PMID: 38132868 PMC10744747 DOI: 10.3390/metabo13121186
  30. ↑ Pesta, D., & Jordan, J. (2022). INDY as a Therapeutic Target for Cardio-Metabolic Disease. Metabolites, 12(3), 244. PMID: 35323687 PMCID: PMC8949283 DOI: 10.3390/metabo12030244
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