KYNURENINE PATHWAY INHIBITORS COMBINED WITH NAD+ PRECURSORS INCREASES LONGEVITY GENE EXPRESSION IN DROSOPHILA
Abstract With rates of aging-related functional decline rising, the need for novel intervention strategies to extend lifespan has increased. In humans, the kynurenine pathway (KP) metabolizes tryptophan and produces nicotinamide adenine dinucleotide (NAD+). KP is correlated negatively with longevity...
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| Vydáno v: | Innovation in aging Ročník 7; číslo Supplement_1; s. 1073 |
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| Hlavní autoři: | , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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Oxford University Press
21.12.2023
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| ISSN: | 2399-5300, 2399-5300 |
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| Abstract | Abstract
With rates of aging-related functional decline rising, the need for novel intervention strategies to extend lifespan has increased. In humans, the kynurenine pathway (KP) metabolizes tryptophan and produces nicotinamide adenine dinucleotide (NAD+). KP is correlated negatively with longevity and increased KP metabolite concentrations decrease the average and maximum lifespans in flies. However, genetic and pharmacological inhibition of tryptophan metabolism and dietary supplementation of NAD+ precursors increase the average and maximum lifespans in flies. To comprehensively explore the effects of KP manipulation, we fed DGRP_229 Drosophila males diets infused with ⍺-MT (KP inhibitor), nicotinamide (NAM, an NAD+ precursor), or the combination of NAM and ⍺-MT. We found that all treatments resulted in increased average and maximum lifespans, with the combination treatment displaying the greatest increase compared to the control of 30% (P< 0.0001). The combination treatment resulted in an average lifespan increase of 15% in relation to ⍺-MT alone (P< 0.0001) and 18% in comparison to NAM alone (P< 0.0001). To gain more insight into the biological mechanisms through which different treatments affect lifespan, we performed qRT-PCR on 11 longevity genes in Drosophila. We found that the combination treatment significantly increased the expression of gigas (Gig) (P=0.03), which interacts with Tsc1 to control cellular growth by regulating insulin and TOR signaling pathways, and sirtuin 1 (Sirt1) (P=0.03), an NAD+-dependent histone deacetylase. Our results demonstrate that the combined treatment of KP inhibition and NAD+ precursor elicits a transcription response similar to other lifespan-enhancing treatments and could be used as an alternative intervention method. |
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| AbstractList | With rates of aging-related functional decline rising, the need for novel intervention strategies to extend lifespan has increased. In humans, the kynurenine pathway (KP) metabolizes tryptophan and produces nicotinamide adenine dinucleotide (NAD+). KP is correlated negatively with longevity and increased KP metabolite concentrations decrease the average and maximum lifespans in flies. However, genetic and pharmacological inhibition of tryptophan metabolism and dietary supplementation of NAD+ precursors increase the average and maximum lifespans in flies. To comprehensively explore the effects of KP manipulation, we fed DGRP_229 Drosophila males diets infused with ⍺-MT (KP inhibitor), nicotinamide (NAM, an NAD+ precursor), or the combination of NAM and ⍺-MT. We found that all treatments resulted in increased average and maximum lifespans, with the combination treatment displaying the greatest increase compared to the control of 30% (P< 0.0001). The combination treatment resulted in an average lifespan increase of 15% in relation to ⍺-MT alone (P< 0.0001) and 18% in comparison to NAM alone (P< 0.0001). To gain more insight into the biological mechanisms through which different treatments affect lifespan, we performed qRT-PCR on 11 longevity genes in Drosophila. We found that the combination treatment significantly increased the expression of gigas (Gig) (P=0.03), which interacts with Tsc1 to control cellular growth by regulating insulin and TOR signaling pathways, and sirtuin 1 (Sirt1) (P=0.03), an NAD+-dependent histone deacetylase. Our results demonstrate that the combined treatment of KP inhibition and NAD+ precursor elicits a transcription response similar to other lifespan-enhancing treatments and could be used as an alternative intervention method. Abstract With rates of aging-related functional decline rising, the need for novel intervention strategies to extend lifespan has increased. In humans, the kynurenine pathway (KP) metabolizes tryptophan and produces nicotinamide adenine dinucleotide (NAD+). KP is correlated negatively with longevity and increased KP metabolite concentrations decrease the average and maximum lifespans in flies. However, genetic and pharmacological inhibition of tryptophan metabolism and dietary supplementation of NAD+ precursors increase the average and maximum lifespans in flies. To comprehensively explore the effects of KP manipulation, we fed DGRP_229 Drosophila males diets infused with ⍺-MT (KP inhibitor), nicotinamide (NAM, an NAD+ precursor), or the combination of NAM and ⍺-MT. We found that all treatments resulted in increased average and maximum lifespans, with the combination treatment displaying the greatest increase compared to the control of 30% (P< 0.0001). The combination treatment resulted in an average lifespan increase of 15% in relation to ⍺-MT alone (P< 0.0001) and 18% in comparison to NAM alone (P< 0.0001). To gain more insight into the biological mechanisms through which different treatments affect lifespan, we performed qRT-PCR on 11 longevity genes in Drosophila. We found that the combination treatment significantly increased the expression of gigas (Gig) (P=0.03), which interacts with Tsc1 to control cellular growth by regulating insulin and TOR signaling pathways, and sirtuin 1 (Sirt1) (P=0.03), an NAD+-dependent histone deacetylase. Our results demonstrate that the combined treatment of KP inhibition and NAD+ precursor elicits a transcription response similar to other lifespan-enhancing treatments and could be used as an alternative intervention method. |
| Author | Westbrook, Reyhan Said, Adam Huang, Qiao Walston, Jeremy Abadir, Peter M Wu, Yuqiong |
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| Copyright | The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. 2023 The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| DOI | 10.1093/geroni/igad104.3448 |
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With rates of aging-related functional decline rising, the need for novel intervention strategies to extend lifespan has increased. In humans, the... With rates of aging-related functional decline rising, the need for novel intervention strategies to extend lifespan has increased. In humans, the kynurenine... |
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| Title | KYNURENINE PATHWAY INHIBITORS COMBINED WITH NAD+ PRECURSORS INCREASES LONGEVITY GENE EXPRESSION IN DROSOPHILA |
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