Uric acid is known to act as an antioxidant, and one hypothesis posits that certain primates, including humans, increased their uric acid levels during evolution to extend lifespan. To test whether genetically altering the activity of endogenous uric acid synthesis affects organismal lifespan, we generated transgenic Caenorhabditis elegans overexpressing the xanthine dehydrogenase XDH-1, an enzyme involved in uric acid production. These transgenic animals displayed an 11–15% increase in lifespan. They also exhibited enhanced resistance to the oxidative stress–inducing agent paraquat, implying that the lifespan extension might be linked to the antioxidant effects of uric acid.
","acknowledgements":"pNTN036 was provided by Dr. A. Kuhara. RB2379 was provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing"],"email":"m2117068ca@ug.jwu.ac.jp","firstName":"Asuka","lastName":"Chino","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan"],"departments":["Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["investigation","writing_originalDraft"],"email":"sa3030g@gmail.com","firstName":"Ayaka","lastName":"Sugiyama","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing","fundingAcquisition"],"email":"onoh@fc.jwu.ac.jp","firstName":"Hayao","lastName":"Ohno","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"326356964"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":null,"extendedData":[],"funding":"Japan Society for the Promotion of Science (JSPS) KAKENHI 23K05644 and grants from the Mitsubishi Foundation, the Lotte Foundation, the Koyanagi Foundation, the Takeda Science Foundation, the G-7 Scholarship Foundation, the Mishima Kaiun Memorial Foundation to HO.
","image":{"url":"https://portal.micropublication.org/uploads/2f2263c1cd8133c40fda7a6c667679ec.jpg"},"imageCaption":"(A) Lifespans of WT animals and transgenic animals expressing xdh-1 driven by the eft-3 promoter (Ex[eft-3p::xdh-1]). Number of animals analyzed: WT, n = 48; Ex[eft-3p::xdh-1], n = 48. p = 0.0018 (log-rank (Mantel-Cox) test). (B) Lifespans of WT and xdh-1(ok3234) animals. Number of animals analyzed: WT, n = 43; xdh-1(ok3234), n = 39. p = 0.9195 (log-rank (Mantel-Cox) test). (C) Pharyngeal pumping rate of WT and Ex[eft-3p::xdh-1]. Bars represent mean ± SEM. Number of animals analyzed: n = 16. p = 0.8329 (two-tailed t test). n.s., not significant. (D, E) Fraction of L4 or adult WT and Ex[eft-3p::xdh-1] animals in the presence of 0.02 mM (D) and 0.04 mM (E) paraquat. Bars represent mean ± SEM. n = 3 assays. Two-tailed t test. n.s., not significant.
","imageTitle":"Overexpression of xdh-1 in a WT background results in lifespan extension and enhanced resistance to paraquat
","methods":"For pDEST-xdh-1, the SalI-KpnI fragment from pNTN036 (a gift from A. Kuhara), which contains the xdh-1 cDNA (Takagaki et al., 2020), was subcloned into the XhoI-KpnI site of pPD-DEST2-exman (a gift from H. Kunitomo). The PCR-amplified eft-3 promoter (2,852 bp) was cloned into pDONR201 through BP reaction (site-specific recombination) to create pENTR-eft-3p. The expression constructs of pG-eft-3p::xdh-1 was created by LR reaction between pENTR-eft-3p and pDEST-xdh-1.
Germ-line transformations were performed using standard microinjection methods. For the CAT33 strain, pG-eft-3p::xdh-1 was injected at 20 ng/µL along with the co-injection marker pG-myo-3p::venus (15 ng/µL) and the carrier DNA plasmid pPD49.26 (65 ng/µL).
Lifespan assays and pharyngeal pumping assays were performed as described previously (Ohno et al., 2017), with exception that the lifespan assay plates were incubated at 20°C.
For paraquat assays, nematode growth medium (NGM) plates containing paraquat (0.2 or 0.4 mM) were prepared by diluting a 1 M paraquat stock solution into molten NGM prior to dispensing. Plates were seeded with E. coli HB101. Gravid adults were placed on the plates and allowed to lay eggs overnight; adults were removed the following day (day 1). The proportion of animals that had reached the L4 larval stage was scored on days 4, 5, 7, and 8.
Five different plates containing paraquat (0, 0.1, 0.2, 0.3, 0.4 mM) were made and seeded with HB101. Gravid adults were placed on the plates to lay eggs, and then the adults were removed the next day. The number of animals that reached the L4 larval stage was counted daily.
Statistic analyses were performed using Prism v.10 (GraphPad software, San Diego, CA).
","reagents":"Strains used in this study:
Caenorhabditis elegans wild isolate. | |
Ex[myo-3p::venus]. (marker only) | |
(a) RB2379 was outcrossed to N2 five times in our lab before use.
","patternDescription":"Uric acid is generated through the oxidation of xanthine catalyzed by xanthine dehydrogenase (XDH) or xanthine oxidase (XO) (Chung et al., 1997; Bortolotti, 2021). It constitutes the terminal metabolite of purine nucleotide catabolism in humans and in many other species it serves as a primary nitrogenous excretion product. Uric acid exhibits potent antioxidant activity and has been implicated in influencing organismal lifespan (Ames et al., 1981; Glantzounis et al., 2005). A positive correlation has been reported between primate species' maximum lifespan and plasma uric acid concentration (Cutler, 1991), and it has been proposed that evolutionary alterations in uric acid metabolism—such as the loss of uricase—have contributed to lifespan changes in species including humans (Álvarez-Lario & Macarrón-Vicente, 2010).
It has been reported that addition of uric acid to the culture medium extends the lifespan of Caenorhabditis elegans (Wan et al., 2020). However, this effect may be indirect: uric acid could adversely affect the bacterial food source, producing calorie-restriction–like conditions (Lakowski & Hekimi, 1998; Lee et al., 2006) or altering bacterial growth activity (Fukushima et al., 2025; Garsin et al., 2001), which can affect worm lifespan. The C. elegans gene xdh-1 encodes XDH-1, the worm homolog of xanthine dehydrogenase (Yoshina et al., 2022). XDH-1 functions in AIN and AVJ neurons to regulate cold tolerance (Takagaki et al., 2020), and loss of xdh-1 activity promotes formation of xanthine stones (Snoozy et al., 2025).
In the present study, we generated a transgenic C. elegans line that overexpresses xdh-1 and measured lifespan to address whether altering the activity of the endogenous uric-acid synthesis pathway changes organismal lifespan. The xdh-1 cDNA was placed under the eft-3 promoter (eft-3p) to drive strong, ubiquitous expression and introduced into wild-type animals. The resulting transgenic line was designated CAT33. CAT33 exhibited an approximately 15% increase in lifespan compared with wild type (Fig. 1A; mean lifespan: wild type 24.2 days, CAT33 27.7 days). To confirm reproducibility, lifespan was measured again one month later; this experiment again showed an extension of about 11% (mean lifespan: wild type 23.5 days, CAT33 26.2 days; n = 21; Log-rank (Mantel–Cox) test, p = 0.0516). An independently obtained transgenic line carrying the same construct (CAT118) also showed lifespan extension (mean lifespan: wild type 24.2 days, CAT118 26.4 days; n = 48 and n = 59, respectively; Log-rank (Mantel–Cox) test, p = 0.0276). By contrast, the xdh-1 mutant xdh-1(ok3234) showed no change in lifespan relative to wild-type (N2) animals (Fig. 1B; mean lifespan: wild type 25.6 days, xdh-1(ok3234) 25.3 days). Together, these results indicate that appropriately altering activity in the uric acid synthesis pathway can potentially extend lifespan.
The feeding rate of CAT33 did not differ from that of wild-type animals (Fig. 1C), suggesting that dietary restriction is unlikely to account for the observed lifespan extension. To assess whether CAT33 exhibits increased oxidative stress resistance, we cultured worms on media containing the oxidative stressor paraquat; in the presence of 0.4 mM paraquat, CAT33 showed enhanced resistance (Fig. 1D and 1E). It is conceivable that uric acid, elevated by XDH-1 overexpression, could act as an antioxidant and thereby extend lifespan. However, whether XDH-1 overexpression actually increases uric acid levels, whether any increase in uric acid is causally responsible for lifespan extension, which tissues XDH-1 acts in to modulate lifespan, and whether optimizing the level or site of XDH-1 expression could further extend longevity remain open questions for future study.
","references":[{"reference":"Chung HY, Baek BS, Song SH, Kim MS, Huh JI, Shim KH, Kim KW, Lee KH. 1997. Xanthine dehydrogenase/xanthine oxidase and oxidative stress. Age (Omaha) 20(3): 127-40.
","pubmedId":"23604305","doi":""},{"reference":"Bortolotti M, Polito L, Battelli MG, Bolognesi A. 2021. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol 41: 101882.
","pubmedId":"33578127","doi":""},{"reference":"Ames BN, Cathcart R, Schwiers E, Hochstein P. 1981. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 78(11): 6858-62.
","pubmedId":"6947260","doi":""},{"reference":"Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. 2005. Uric acid and oxidative stress. Curr Pharm Des 11(32): 4145-51.
","pubmedId":"16375736","doi":""},{"reference":"Cutler RG. 1991. Antioxidants and aging. Am J Clin Nutr 53(1 Suppl): 373S-379S.
","pubmedId":"1985414","doi":""},{"reference":"Álvarez-Lario B, Macarrón-Vicente J. 2010. Uric acid and evolution. Rheumatology (Oxford) 49(11): 2010-5.
","pubmedId":"20627967","doi":""},{"reference":"Wan QL, Fu X, Dai W, Yang J, Luo Z, Meng X, et al., Zhou Q. 2020. Uric acid induces stress resistance and extends the life span through activating the stress response factor DAF-16/FOXO and SKN-1/NRF2. Aging (Albany NY) 12(3): 2840-2856.
","pubmedId":"32074508","doi":""},{"reference":"Lakowski B, Hekimi S. 1998. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 95(22): 13091-6.
","pubmedId":"9789046","doi":""},{"reference":"Lee GD, Wilson MA, Zhu M, Wolkow CA, de Cabo R, Ingram DK, Zou S. 2006. Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 5(6): 515-24.
","pubmedId":"17096674","doi":""},{"reference":"Garsin DA, Sifri CD, Mylonakis E, Qin X, Singh KV, Murray BE, Calderwood SB, Ausubel FM. 2001. A simple model host for identifying Gram-positive virulence factors. Proc Natl Acad Sci U S A 98(19): 10892-7.
","pubmedId":"11535834","doi":""},{"reference":"Yoshina S, Izuhara L, Kamatani N, Mitani S. 2022. Regulation of aging by balancing mitochondrial function and antioxidant levels. J Physiol Sci 72(1): 28.
","pubmedId":"36380272","doi":""},{"reference":"Takagaki N, Ohta A, Ohnishi K, Kawanabe A, Minakuchi Y, Toyoda A, Fujiwara Y, Kuhara A. 2020. The mechanoreceptor DEG-1 regulates cold tolerance in Caenorhabditis elegans. EMBO Rep 21(3): e48671.
","pubmedId":"32009302","doi":""},{"reference":"Snoozy J, Bhattacharya S, Johnson B, Fettig RR, Van Asma A, Brede C, et al., Warnhoff K. 2025. XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell. PLoS Biol 23(9): e3003410.
","pubmedId":"40991662","doi":""},{"reference":"Ohno H, Yoshida M, Sato T, Kato J, Miyazato M, Kojima M, Ida T, Iino Y. 2017. Luqin-like RYamide peptides regulate food-evoked responses in C. elegans. Elife 6: pii: e28877. 10.7554/eLife.28877.
","pubmedId":"28847365","doi":""}],"title":"Overexpression of xanthine dehydrogenase extends lifespan in C. elegans
","reviews":[{"reviewer":{"displayName":"Kurt Warnhoff"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"664815ab-8209-40e9-b333-79188bc9f4ce","decision":"revise","abstract":"Uric acid is known to act as an antioxidant, and one hypothesis posits that certain primates, including humans, increased their uric acid levels during evolution to extend lifespan. To test whether genetically altering the activity of endogenous uric acid synthesis affects organismal lifespan, we generated transgenic Caenorhabditis elegans overexpressing the xanthine dehydrogenase XDH-1, an enzyme involved in uric acid production. These transgenic animals displayed a 9–15% increase in lifespan. They also exhibited enhanced resistance to the oxidative stress–inducing agent paraquat, implying that the lifespan extension might be linked to the antioxidant effects of uric acid.
","acknowledgements":"pNTN036 was provided by Dr. A. Kuhara. FX33446 and FX33448 were provided by the National Bioresource Project (NBRP)-Japan. RB2379 was provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing"],"email":"m2117068ca@ug.jwu.ac.jp","firstName":"Asuka","lastName":"Chino","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan"],"departments":["Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["investigation","writing_originalDraft"],"email":"sa3030g@gmail.com","firstName":"Ayaka","lastName":"Sugiyama","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing","fundingAcquisition"],"email":"onoh@fc.jwu.ac.jp","firstName":"Hayao","lastName":"Ohno","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"326356964"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Japan Society for the Promotion of Science (JSPS) KAKENHI 26K09212 and grants from the Mitsubishi Foundation, the Lotte Foundation, the Koyanagi Foundation, the Takeda Science Foundation, the G-7 Scholarship Foundation, the Mishima Kaiun Memorial Foundation to HO.
","image":{"url":"https://portal.micropublication.org/uploads/50680a1c18ca985e1015e1c35ec8befe.jpg"},"imageCaption":"(A) Lifespans of WT animals and transgenic animals expressing xdh-1 driven by the eft-3 promoter (Ex[eft-3p::xdh-1]). Number of animals analyzed and P values are shown in Table 1A, Experiment 1. (B) Lifespans of WT and xdh-1(ok3234) animals. Number of animals analyzed and P value are shown in Table 1B, Experiment 1. (C) Pharyngeal pumping rate of WT and Ex[eft-3p::xdh-1] (CAT33). Bars represent mean ± SEM. Number of animals analyzed: n = 16. P = 0.8329 (two-tailed t test). n.s., not significant. (D, E) Fraction of WT and Ex[eft-3p::xdh-1] animals grown to L4 or adult stages in the presence of 0.2 mM (D) and 0.4 mM (E) paraquat. Bars represent mean ± SEM. n = 3 assays. The total numbers of animals analyzed in all assays are shown in parentheses. Two-tailed t test. n.s., not significant. Table 1. Results of lifespan analysis: (A, B) LS, lifespan. Statistical analyses were conducted using Log-rank (Mantel-Cox) test.
","imageTitle":"Overexpression of xdh-1 in a WT background results in lifespan extension and enhanced resistance to paraquat
","methods":"For pDEST-xdh-1, the SalI-KpnI fragment from pNTN036 (a gift from A. Kuhara), which contains the xdh-1 cDNA (Takagaki et al., 2020), was subcloned into the XhoI-KpnI site of pPD-DEST2-exman (a gift from H. Kunitomo). The PCR-amplified eft-3 promoter (2,852 bp) was cloned into pDONR201 through BP reaction (site-specific recombination) to create pENTR-eft-3p. The expression constructs of pG-eft-3p::xdh-1 was created by LR reaction between pENTR-eft-3p and pDEST-xdh-1. Details of the system are available at the following web site:
http://molecular-ethology.biochem.s.u-tokyo.ac.jp/Gateway/Gateway_overview1.html
Germ-line transformations were performed using standard microinjection methods. For the CAT33 strain, pG-eft-3p::xdh-1 was injected at 20 ng/µL along with the co-injection marker pG-myo-3p::venus (15 ng/µL) and the carrier DNA plasmid pPD49.26 (65 ng/µL).
Lifespan assays and pharyngeal pumping assays were performed as described previously (Ohno et al., 2017), with exception that the lifespan assay plates were incubated at 20°C.
For paraquat assays, nematode growth medium (NGM) plates containing paraquat (0.2 or 0.4 mM) were prepared by diluting a 1 M paraquat stock solution into molten NGM prior to dispensing. Plates were seeded with E. coli HB101. Gravid adults were placed on the plates and allowed to lay eggs overnight; adults were removed the following day (day 1). The proportion of animals that had reached the L4 larval stage was scored on days 4, 5, 7, and 8.
Statistic analyses were performed using Prism v.10 (GraphPad software, San Diego, CA).
","reagents":"Strains used in this study:
N2 | Caenorhabditis elegans wild isolate. |
RB2379 | xdh-1(ok3234) IV. (a) |
FX33446 | xdh-1(tm9909) IV. (b) |
FX33448 | xdh-1(tm9911) IV. (b) |
CAT117 | Ex[myo-3p::venus]. (marker only) |
CAT33 | Ex[eft-3p::xdh-1, myo-3p::venus]. |
CAT118 | Ex[eft-3p::xdh-1, myo-3p::venus]. |
(a) RB2379 was outcrossed to N2 five times in our lab before use.
(b) Outcrossed twice in National Bioresource Project (NBRP)-Japan.
","patternDescription":"Uric acid is generated through the oxidation of xanthine catalyzed by xanthine dehydrogenase (XDH) or xanthine oxidase (XO) (Chung et al., 1997; Bortolotti, 2021). It constitutes the terminal metabolite of purine nucleotide catabolism in humans and in many other species it serves as a primary nitrogenous excretion product. Uric acid exhibits potent antioxidant activity and has been implicated in influencing organismal lifespan (Ames et al., 1981; Glantzounis et al., 2005). A positive correlation has been reported between primate species’ maximum lifespan and plasma uric acid concentration (Cutler, 1991), and it has been proposed that evolutionary alterations in uric acid metabolism—such as the loss of uricase—have contributed to lifespan changes in species including humans (Álvarez-Lario & Macarrón-Vicente, 2010).
It has been reported that addition of uric acid to the culture medium extends the lifespan of Caenorhabditis elegans (Wan et al., 2020). However, this effect may be indirect: uric acid could adversely affect the bacterial food source, producing calorie-restriction–like conditions (Lakowski & Hekimi, 1998; Lee et al., 2006) or altering bacterial growth activity, which can affect worm lifespan (Fukushima et al., 2025; Garsin et al., 2001). The C. elegans gene xdh-1 encodes XDH-1, the worm homolog of xanthine dehydrogenase (Yoshina et al., 2022). XDH-1 functions in AIN and AVJ neurons to regulate cold tolerance (Takagaki et al., 2020), and loss of xdh-1 activity promotes formation of xanthine stones (Snoozy et al., 2025).
In the present study, we generated a transgenic C. elegans line that overexpresses xdh-1 and measured lifespan to address whether altering the activity of the endogenous uric-acid synthesis pathway changes organismal lifespan. The xdh-1 cDNA was placed under the eft-3 (also known as eef-1A.1) promoter (eft-3p) to drive strong, ubiquitous expression and introduced into wild-type animals; the resulting transgenic line was designated CAT33. Although eft-3p has been employed in previous investigations of lifespan (e.g., Tuckowski et al., 2025; Morphis et al., 2022), its introduction per se has not been reported to affect lifespan. In addition, the xdh-1 cDNA has been confirmed to be functionally active (Takagaki et al., 2020). CAT33 exhibited an approximately 15% increase in lifespan compared with wild type (Fig. 1A and Table 1A). To confirm reproducibility, lifespan was measured again one month later; this experiment again showed an extension of about 11% (Table 1A). An independently obtained transgenic line carrying the same construct (CAT118) also showed lifespan extension (Table 1A). By contrast, three xdh-1 loss-of-function mutants, xdh-1(ok3234), xdh-1(tm9909), and xdh-1(tm9911), showed no change in lifespan relative to wild-type (N2) animals, suggesting that overexpression of xdh-1 is sufficient for lifespan extension but xdh-1 is not necessary for normal lifespan (Fig. 1B and Table 1B). Together, these results indicate that appropriately altering activity in the uric acid synthesis pathway can potentially extend lifespan.
The pharyngeal pumping rate of CAT33 did not differ from that of wild-type animals (Fig. 1C), suggesting that dietary restriction is unlikely to account for the observed lifespan extension. To assess whether CAT33 exhibits increased oxidative stress resistance, we cultured worms on media containing the oxidative stressor paraquat; in the presence of 0.4 mM paraquat, CAT33 showed enhanced resistance (Fig. 1D and 1E). It is conceivable that uric acid, elevated by XDH-1 overexpression, could act as an antioxidant and thereby extend lifespan. However, whether XDH-1 overexpression actually increases uric acid levels, whether any increase in uric acid is causally responsible for lifespan extension, which tissues XDH-1 acts in to modulate lifespan, and whether optimizing the level or site of XDH-1 expression could further extend longevity remain open questions for future study.
","references":[{"reference":"Álvarez-Lario B, Macarrón-Vicente J. 2010. Uric acid and evolution. Rheumatology (Oxford) 49(11): 2010-5.
","pubmedId":"20627967","doi":""},{"reference":"Ames BN, Cathcart R, Schwiers E, Hochstein P. 1981. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 78(11): 6858-62.
","pubmedId":"6947260","doi":""},{"reference":"Bortolotti M, Polito L, Battelli MG, Bolognesi A. 2021. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol 41: 101882.
","pubmedId":"33578127","doi":""},{"reference":"Chung HY, Baek BS, Song SH, Kim MS, Huh JI, Shim KH, Kim KW, Lee KH. 1997. Xanthine dehydrogenase/xanthine oxidase and oxidative stress. Age (Omaha) 20(3): 127-40.
","pubmedId":"23604305","doi":""},{"reference":"Cutler RG. 1991. Antioxidants and aging. Am J Clin Nutr 53(1 Suppl): 373S-379S.
","pubmedId":"1985414","doi":""},{"reference":"Fukushima Y, Kagami A, Sonoda H, Shimokawa K, Suico MA, Kai H, Shuto T. 2025. Dietary state and impact of DMSO on Caenorhabditis elegans aging: Insights from healthspan analysis. Biochem Biophys Res Commun 742: 151156.
","pubmedId":"39657354","doi":""},{"reference":"Garsin DA, Sifri CD, Mylonakis E, Qin X, Singh KV, Murray BE, Calderwood SB, Ausubel FM. 2001. A simple model host for identifying Gram-positive virulence factors. Proc Natl Acad Sci U S A 98(19): 10892-7.
","pubmedId":"11535834","doi":""},{"reference":"Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. 2005. Uric acid and oxidative stress. Curr Pharm Des 11(32): 4145-51.
","pubmedId":"16375736","doi":""},{"reference":"Lakowski B, Hekimi S. 1998. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 95(22): 13091-6.
","pubmedId":"9789046","doi":""},{"reference":"Lee GD, Wilson MA, Zhu M, Wolkow CA, de Cabo R, Ingram DK, Zou S. 2006. Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 5(6): 515-24.
","pubmedId":"17096674","doi":""},{"reference":"Morphis AC, Edwards SL, Erdenebat P, Kumar L, Li J. 2022. Auxin-Inducible Degron System Reveals Temporal-Spatial Roles of HSF-1 and Its Transcriptional Program in Lifespan Assurance. Front Aging 3: 899744.
","pubmedId":"35899092","doi":""},{"reference":"Ohno H, Yoshida M, Sato T, Kato J, Miyazato M, Kojima M, Ida T, Iino Y. 2017. Luqin-like RYamide peptides regulate food-evoked responses in C. elegans. Elife 6: pii: e28877. 10.7554/eLife.28877.
","pubmedId":"28847365","doi":""},{"reference":"Snoozy J, Bhattacharya S, Johnson B, Fettig RR, Van Asma A, Brede C, et al., Warnhoff K. 2025. XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell. PLoS Biol 23(9): e3003410.
","pubmedId":"40991662","doi":""},{"reference":"Takagaki N, Ohta A, Ohnishi K, Kawanabe A, Minakuchi Y, Toyoda A, Fujiwara Y, Kuhara A. 2020. The mechanoreceptor DEG-1 regulates cold tolerance in Caenorhabditis elegans. EMBO Rep 21(3): e48671.
","pubmedId":"32009302","doi":""},{"reference":"Tuckowski AM, Beydoun S, Kitto ES, Bhat A, Howington MB, Sridhar A, et al., Leiser SF. 2025. fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans. Elife 13: 10.7554/eLife.99971.
","pubmedId":"39951337","doi":""},{"reference":"Wan QL, Fu X, Dai W, Yang J, Luo Z, Meng X, et al., Zhou Q. 2020. Uric acid induces stress resistance and extends the life span through activating the stress response factor DAF-16/FOXO and SKN-1/NRF2. Aging (Albany NY) 12(3): 2840-2856.
","pubmedId":"32074508","doi":""},{"reference":"Yoshina S, Izuhara L, Kamatani N, Mitani S. 2022. Regulation of aging by balancing mitochondrial function and antioxidant levels. J Physiol Sci 72(1): 28.
","pubmedId":"36380272","doi":""}],"title":"Overexpression of xanthine dehydrogenase extends lifespan in C. elegans
","reviews":[{"reviewer":{"displayName":"Kurt Warnhoff"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"08f8fc34-4fa9-4adc-80b8-0e091bcdaeb1","decision":"edit","abstract":"Uric acid is known to act as an antioxidant, and one hypothesis posits that certain primates, including humans, increased their uric acid levels during evolution to extend lifespan. To test whether genetically altering the activity of endogenous uric acid synthesis affects organismal lifespan, we generated transgenic Caenorhabditis elegans overexpressing the xanthine dehydrogenase XDH-1, an enzyme involved in uric acid production. These transgenic animals displayed a 9–15% increase in lifespan. They also exhibited enhanced resistance to the oxidative stress–inducing agent paraquat, implying that the lifespan extension might be linked to the antioxidant effects of uric acid.
","acknowledgements":"pNTN036 was provided by Dr. A. Kuhara. FX33446 and FX33448 were provided by the National Bioresource Project (NBRP)-Japan. RB2379 was provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing"],"email":"m2117068ca@ug.jwu.ac.jp","firstName":"Asuka","lastName":"Chino","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan"],"departments":["Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["investigation","writing_originalDraft"],"email":"sa3030g@gmail.com","firstName":"Ayaka","lastName":"Sugiyama","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing","fundingAcquisition"],"email":"onoh@fc.jwu.ac.jp","firstName":"Hayao","lastName":"Ohno","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"326356964"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Japan Society for the Promotion of Science (JSPS) KAKENHI 26K09212 and grants from the Mitsubishi Foundation, the Lotte Foundation, the Koyanagi Foundation, the Takeda Science Foundation, the G-7 Scholarship Foundation, the Mishima Kaiun Memorial Foundation to HO.
","image":{"url":"https://portal.micropublication.org/uploads/50680a1c18ca985e1015e1c35ec8befe.jpg"},"imageCaption":"(A) Lifespans of WT animals and transgenic animals expressing xdh-1 driven by the eft-3 promoter (Ex[eft-3p::xdh-1]). Number of animals analyzed and P values are shown in Table 1A, Experiment 1. (B) Lifespans of WT and xdh-1(ok3234) animals. Number of animals analyzed and P value are shown in Table 1B, Experiment 1. (C) Pharyngeal pumping rate of WT and Ex[eft-3p::xdh-1] (CAT33). Bars represent mean ± SEM. Number of animals analyzed: n = 16. P = 0.8329 (two-tailed t test). n.s., not significant. (D, E) Fraction of WT and Ex[eft-3p::xdh-1] animals grown to L4 or adult stages in the presence of 0.2 mM (D) and 0.4 mM (E) paraquat. Bars represent mean ± SEM. n = 3 assays. The total numbers of animals analyzed in all assays are shown in parentheses. Two-tailed t test. n.s., not significant. Table 1. Results of lifespan analysis: (A, B) LS, lifespan. Statistical analyses were conducted using Log-rank (Mantel-Cox) test.
","imageTitle":"Overexpression of xdh-1 in a WT background results in lifespan extension and enhanced resistance to paraquat
","methods":"For pDEST-xdh-1, the SalI-KpnI fragment from pNTN036 (a gift from A. Kuhara), which contains the xdh-1 cDNA (Takagaki et al., 2020), was subcloned into the XhoI-KpnI site of pPD-DEST2-exman (a gift from H. Kunitomo). The PCR-amplified eft-3 promoter (2,852 bp) was cloned into pDONR201 through BP reaction (site-specific recombination) to create pENTR-eft-3p. The expression constructs of pG-eft-3p::xdh-1 was created by LR reaction between pENTR-eft-3p and pDEST-xdh-1. Details of the system are available at the following web site:
http://molecular-ethology.biochem.s.u-tokyo.ac.jp/Gateway/Gateway_overview1.html
Germ-line transformations were performed using standard microinjection methods. For the CAT33 strain, pG-eft-3p::xdh-1 was injected at 20 ng/µL along with the co-injection marker pG-myo-3p::venus (15 ng/µL) and the carrier DNA plasmid pPD49.26 (65 ng/µL).
Lifespan assays and pharyngeal pumping assays were performed as described previously (Ohno et al., 2017), with exception that the lifespan assay plates were incubated at 20°C. Note: For preparation of NGM plates used in lifespan assays, N1000 Nematode Growth Medium (USBiological, Swampscott, MA, USA) was used in Table 1A, Experiments 1 and 2 and Table 1B, Experiment 1, whereas HIPOLYPEPTON SHIOTANI (SHIOTANI M.S., Hyogo, Japan) was used in Table 1B, Experiments 2 and 3. The latter formulation supports more robust microbial growth; this difference may have contributed to the shortened mean lifespan observed in Table 1B, Experiments 2 and 3.
For paraquat assays, nematode growth medium (NGM) plates containing paraquat (0.2 or 0.4 mM) were prepared by diluting a 1 M paraquat stock solution into molten NGM prior to dispensing. Plates were seeded with E. coli HB101. Gravid adults were placed on the plates and allowed to lay eggs overnight; adults were removed the following day (day 1). The proportion of animals that had reached the L4 larval stage was scored on days 4, 5, 7, and 8.
Statistic analyses were performed using Prism v.10 (GraphPad software, San Diego, CA).
","reagents":"Strains used in this study:
N2 | Caenorhabditis elegans wild isolate. |
RB2379 | xdh-1(ok3234) IV. (a) |
FX33446 | xdh-1(tm9909) IV. (b) |
FX33448 | xdh-1(tm9911) IV. (b) |
CAT117 | Ex[myo-3p::venus]. (marker only) |
CAT33 | Ex[eft-3p::xdh-1, myo-3p::venus]. |
CAT118 | Ex[eft-3p::xdh-1, myo-3p::venus]. |
(a) RB2379 was outcrossed to N2 five times in our lab before use.
(b) Outcrossed twice in National Bioresource Project (NBRP)-Japan.
","patternDescription":"Uric acid is generated through the oxidation of xanthine catalyzed by xanthine dehydrogenase (XDH) or xanthine oxidase (XO) (Chung et al., 1997; Bortolotti, 2021). It constitutes the terminal metabolite of purine nucleotide catabolism in humans and in many other species it serves as a primary nitrogenous excretion product. Uric acid exhibits potent antioxidant activity and has been implicated in influencing organismal lifespan (Ames et al., 1981; Glantzounis et al., 2005). A positive correlation has been reported between primate species’ maximum lifespan and plasma uric acid concentration (Cutler, 1991), and it has been proposed that evolutionary alterations in uric acid metabolism—such as the loss of uricase—have contributed to lifespan changes in species including humans (Álvarez-Lario & Macarrón-Vicente, 2010).
It has been reported that addition of uric acid to the culture medium extends the lifespan of Caenorhabditis elegans (Wan et al., 2020). However, this effect may be indirect: uric acid could adversely affect the bacterial food source, producing calorie-restriction–like conditions (Lakowski & Hekimi, 1998; Lee et al., 2006) or altering bacterial growth activity, which can affect worm lifespan (Fukushima et al., 2025; Garsin et al., 2001). The C. elegans gene xdh-1 encodes XDH-1, the worm homolog of xanthine dehydrogenase (Yoshina et al., 2022). XDH-1 functions in AIN and AVJ neurons to regulate cold tolerance (Takagaki et al., 2020), and loss of xdh-1 activity promotes formation of xanthine stones (Snoozy et al., 2025).
In the present study, we generated a transgenic C. elegans line that overexpresses xdh-1 and measured lifespan to address whether altering the activity of the endogenous uric-acid synthesis pathway changes organismal lifespan. The xdh-1 cDNA was placed under the eft-3 (also known as eef-1A.1) promoter (eft-3p) to drive strong, ubiquitous expression and introduced into wild-type animals; the resulting transgenic line was designated CAT33. Although eft-3p has been employed in previous investigations of lifespan (e.g., Tuckowski et al., 2025; Morphis et al., 2022), its introduction per se has not been reported to affect lifespan. In addition, the xdh-1 cDNA has been confirmed to be functionally active (Takagaki et al., 2020). CAT33 exhibited an approximately 15% increase in lifespan compared with wild type (Fig. 1A and Table 1A). To confirm reproducibility, lifespan was measured again one month later; this experiment again showed an extension of about 11% (Table 1A). An independently obtained transgenic line carrying the same construct (CAT118) also showed lifespan extension (Table 1A). By contrast, three xdh-1 loss-of-function mutants, xdh-1(ok3234), xdh-1(tm9909), and xdh-1(tm9911), showed no change in lifespan relative to wild-type (N2) animals, suggesting that overexpression of xdh-1 is sufficient for lifespan extension but xdh-1 is not necessary for normal lifespan (Fig. 1B and Table 1B). Together, these results indicate that appropriately altering activity in the uric acid synthesis pathway can potentially extend lifespan.
The pharyngeal pumping rate of CAT33 did not differ from that of wild-type animals (Fig. 1C), suggesting that dietary restriction is unlikely to account for the observed lifespan extension. To assess whether CAT33 exhibits increased oxidative stress resistance, we cultured worms on media containing the oxidative stressor paraquat; in the presence of 0.4 mM paraquat, CAT33 showed enhanced resistance (Fig. 1D and 1E). It is conceivable that uric acid, elevated by XDH-1 overexpression, could act as an antioxidant and thereby extend lifespan. However, whether XDH-1 overexpression actually increases uric acid levels, whether any increase in uric acid is causally responsible for lifespan extension, which tissues XDH-1 acts in to modulate lifespan, and whether optimizing the level or site of XDH-1 expression could further extend longevity remain open questions for future study.
","references":[{"reference":"Álvarez-Lario B, Macarrón-Vicente J. 2010. Uric acid and evolution. Rheumatology (Oxford) 49(11): 2010-5.
","pubmedId":"20627967","doi":""},{"reference":"Ames BN, Cathcart R, Schwiers E, Hochstein P. 1981. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 78(11): 6858-62.
","pubmedId":"6947260","doi":""},{"reference":"Bortolotti M, Polito L, Battelli MG, Bolognesi A. 2021. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol 41: 101882.
","pubmedId":"33578127","doi":""},{"reference":"Chung HY, Baek BS, Song SH, Kim MS, Huh JI, Shim KH, Kim KW, Lee KH. 1997. Xanthine dehydrogenase/xanthine oxidase and oxidative stress. Age (Omaha) 20(3): 127-40.
","pubmedId":"23604305","doi":""},{"reference":"Cutler RG. 1991. Antioxidants and aging. Am J Clin Nutr 53(1 Suppl): 373S-379S.
","pubmedId":"1985414","doi":""},{"reference":"Fukushima Y, Kagami A, Sonoda H, Shimokawa K, Suico MA, Kai H, Shuto T. 2025. Dietary state and impact of DMSO on Caenorhabditis elegans aging: Insights from healthspan analysis. Biochem Biophys Res Commun 742: 151156.
","pubmedId":"39657354","doi":""},{"reference":"Garsin DA, Sifri CD, Mylonakis E, Qin X, Singh KV, Murray BE, Calderwood SB, Ausubel FM. 2001. A simple model host for identifying Gram-positive virulence factors. Proc Natl Acad Sci U S A 98(19): 10892-7.
","pubmedId":"11535834","doi":""},{"reference":"Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. 2005. Uric acid and oxidative stress. Curr Pharm Des 11(32): 4145-51.
","pubmedId":"16375736","doi":""},{"reference":"Lakowski B, Hekimi S. 1998. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 95(22): 13091-6.
","pubmedId":"9789046","doi":""},{"reference":"Lee GD, Wilson MA, Zhu M, Wolkow CA, de Cabo R, Ingram DK, Zou S. 2006. Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 5(6): 515-24.
","pubmedId":"17096674","doi":""},{"reference":"Morphis AC, Edwards SL, Erdenebat P, Kumar L, Li J. 2022. Auxin-Inducible Degron System Reveals Temporal-Spatial Roles of HSF-1 and Its Transcriptional Program in Lifespan Assurance. Front Aging 3: 899744.
","pubmedId":"35899092","doi":""},{"reference":"Ohno H, Yoshida M, Sato T, Kato J, Miyazato M, Kojima M, Ida T, Iino Y. 2017. Luqin-like RYamide peptides regulate food-evoked responses in C. elegans. Elife 6: pii: e28877. 10.7554/eLife.28877.
","pubmedId":"28847365","doi":""},{"reference":"Snoozy J, Bhattacharya S, Johnson B, Fettig RR, Van Asma A, Brede C, et al., Warnhoff K. 2025. XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell. PLoS Biol 23(9): e3003410.
","pubmedId":"40991662","doi":""},{"reference":"Takagaki N, Ohta A, Ohnishi K, Kawanabe A, Minakuchi Y, Toyoda A, Fujiwara Y, Kuhara A. 2020. The mechanoreceptor DEG-1 regulates cold tolerance in Caenorhabditis elegans. EMBO Rep 21(3): e48671.
","pubmedId":"32009302","doi":""},{"reference":"Tuckowski AM, Beydoun S, Kitto ES, Bhat A, Howington MB, Sridhar A, et al., Leiser SF. 2025. fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans. Elife 13: 10.7554/eLife.99971.
","pubmedId":"39951337","doi":""},{"reference":"Wan QL, Fu X, Dai W, Yang J, Luo Z, Meng X, et al., Zhou Q. 2020. Uric acid induces stress resistance and extends the life span through activating the stress response factor DAF-16/FOXO and SKN-1/NRF2. Aging (Albany NY) 12(3): 2840-2856.
","pubmedId":"32074508","doi":""},{"reference":"Yoshina S, Izuhara L, Kamatani N, Mitani S. 2022. Regulation of aging by balancing mitochondrial function and antioxidant levels. J Physiol Sci 72(1): 28.
","pubmedId":"36380272","doi":""}],"title":"Overexpression of xanthine dehydrogenase extends lifespan in C. elegans
","reviews":[{"reviewer":{"displayName":"Kurt Warnhoff"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"44090843-6e63-49bf-b12f-291cac1506b5","decision":"accept","abstract":"Uric acid is known to act as an antioxidant, and one hypothesis posits that certain primates, including humans, increased their uric acid levels during evolution to extend lifespan. To test whether genetically altering the activity of endogenous uric acid synthesis affects organismal lifespan, we generated transgenic Caenorhabditis elegans overexpressing the xanthine dehydrogenase XDH-1, an enzyme involved in uric acid production. These transgenic animals displayed a 9–15% increase in lifespan. They also exhibited enhanced resistance to the oxidative stress–inducing agent paraquat, implying that the lifespan extension might be linked to the antioxidant effects of uric acid.
","acknowledgements":"pNTN036 was provided by Dr. A. Kuhara. FX33446 and FX33448 were provided by the National Bioresource Project (NBRP)-Japan. RB2379 was provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing"],"email":"m2117068ca@ug.jwu.ac.jp","firstName":"Asuka","lastName":"Chino","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan"],"departments":["Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["investigation","writing_originalDraft"],"email":"sa3030g@gmail.com","firstName":"Ayaka","lastName":"Sugiyama","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing","fundingAcquisition"],"email":"onoh@fc.jwu.ac.jp","firstName":"Hayao","lastName":"Ohno","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"326356964"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Japan Society for the Promotion of Science (JSPS) KAKENHI 26K09212 and grants from the Mitsubishi Foundation, the Lotte Foundation, the Koyanagi Foundation, the Takeda Science Foundation, the G-7 Scholarship Foundation, the Mishima Kaiun Memorial Foundation to HO.
","image":{"url":"https://portal.micropublication.org/uploads/50680a1c18ca985e1015e1c35ec8befe.jpg"},"imageCaption":"(A) Lifespans of WT animals and transgenic animals expressing xdh-1 driven by the eft-3 promoter (Ex[eft-3p::xdh-1]). Number of animals analyzed and P values are shown in Table 1A, Experiment 1. (B) Lifespans of WT and xdh-1(ok3234) animals. Number of animals analyzed and P value are shown in Table 1B, Experiment 1. (C) Pharyngeal pumping rate of WT and Ex[eft-3p::xdh-1] (CAT33). Bars represent mean ± SEM. Number of animals analyzed: n = 16. P = 0.8329 (two-tailed t test). n.s., not significant. (D, E) Fraction of WT and Ex[eft-3p::xdh-1] animals grown to L4 or adult stages in the presence of 0.2 mM (D) and 0.4 mM (E) paraquat. Bars represent mean ± SEM. n = 3 assays. The total numbers of animals analyzed in all assays are shown in parentheses. Two-tailed t test. n.s., not significant. Table 1. Results of lifespan analysis: (A, B) LS, lifespan. Statistical analyses were conducted using Log-rank (Mantel-Cox) test.
","imageTitle":"Overexpression of xdh-1 in a WT background results in lifespan extension and enhanced resistance to paraquat
","methods":"For pDEST-xdh-1, the SalI-KpnI fragment from pNTN036 (a gift from A. Kuhara), which contains the xdh-1 cDNA (Takagaki et al., 2020), was subcloned into the XhoI-KpnI site of pPD-DEST2-exman (a gift from H. Kunitomo). The PCR-amplified eft-3 promoter (2,852 bp) was cloned into pDONR201 through BP reaction (site-specific recombination) to create pENTR-eft-3p. The expression constructs of pG-eft-3p::xdh-1 was created by LR reaction between pENTR-eft-3p and pDEST-xdh-1. Details of the system are available at the following web site:
http://molecular-ethology.biochem.s.u-tokyo.ac.jp/Gateway/Gateway_overview1.html
Germ-line transformations were performed using standard microinjection methods. For the CAT33 strain, pG-eft-3p::xdh-1 was injected at 20 ng/µL along with the co-injection marker pG-myo-3p::venus (15 ng/µL) and the carrier DNA plasmid pPD49.26 (65 ng/µL).
Lifespan assays and pharyngeal pumping assays were performed as described previously (Ohno et al., 2017), with exception that the lifespan assay plates were incubated at 20°C. Note: For preparation of NGM plates used in lifespan assays, N1000 Nematode Growth Medium (USBiological, Swampscott, MA, USA) was used in Table 1A, Experiments 1 and 2 and Table 1B, Experiment 1, whereas HIPOLYPEPTON SHIOTANI (SHIOTANI M.S., Hyogo, Japan) was used in Table 1B, Experiments 2 and 3. The latter formulation supports more robust microbial growth; this difference may have contributed to the shortened mean lifespan observed in Table 1B, Experiments 2 and 3.
For paraquat assays, nematode growth medium (NGM) plates containing paraquat (0.2 or 0.4 mM) were prepared by diluting a 1 M paraquat stock solution into molten NGM prior to dispensing. Plates were seeded with E. coli HB101. Gravid adults were placed on the plates and allowed to lay eggs overnight; adults were removed the following day (day 1). The proportion of animals that had reached the L4 larval stage was scored on days 4, 5, 7, and 8.
Statistic analyses were performed using Prism v.10 (GraphPad software, San Diego, CA).
","reagents":"Strains used in this study:
Caenorhabditis elegans wild isolate. | |
Ex[myo-3p::venus]. (marker only) | |
(a) RB2379 was outcrossed to N2 five times in our lab before use.
(b) Outcrossed twice in National Bioresource Project (NBRP)-Japan.
","patternDescription":"Uric acid is generated through the oxidation of xanthine catalyzed by xanthine dehydrogenase (XDH) or xanthine oxidase (XO) (Chung et al., 1997; Bortolotti, 2021). It constitutes the terminal metabolite of purine nucleotide catabolism in humans and in many other species it serves as a primary nitrogenous excretion product. Uric acid exhibits potent antioxidant activity and has been implicated in influencing organismal lifespan (Ames et al., 1981; Glantzounis et al., 2005). A positive correlation has been reported between primate species' maximum lifespan and plasma uric acid concentration (Cutler, 1991), and it has been proposed that evolutionary alterations in uric acid metabolism—such as the loss of uricase—have contributed to lifespan changes in species including humans (Álvarez-Lario & Macarrón-Vicente, 2010).
It has been reported that addition of uric acid to the culture medium extends the lifespan of Caenorhabditis elegans (Wan et al., 2020). However, this effect may be indirect: uric acid could adversely affect the bacterial food source, producing calorie-restriction–like conditions (Lakowski & Hekimi, 1998; Lee et al., 2006) or altering bacterial growth activity, which can affect worm lifespan (Fukushima et al., 2025; Garsin et al., 2001). The C. elegans gene xdh-1 encodes XDH-1, the worm homolog of xanthine dehydrogenase (Yoshina et al., 2022). XDH-1 functions in AIN and AVJ neurons to regulate cold tolerance (Takagaki et al., 2020), and loss of xdh-1 activity promotes formation of xanthine stones (Snoozy et al., 2025).
In the present study, we generated a transgenic C. elegans line that overexpresses xdh-1 and measured lifespan to address whether altering the activity of the endogenous uric-acid synthesis pathway changes organismal lifespan. The xdh-1 cDNA was placed under the eft-3 (also known as eef-1A.1) promoter (eft-3p) to drive strong, ubiquitous expression and introduced into wild-type animals; the resulting transgenic line was designated CAT33. Although eft-3p has been employed in previous investigations of lifespan (e.g., Tuckowski et al., 2025; Morphis et al., 2022), its introduction per se has not been reported to affect lifespan. In addition, the xdh-1 cDNA has been confirmed to be functionally active (Takagaki et al., 2020). CAT33 exhibited an approximately 15% increase in lifespan compared with wild type (Fig. 1A and Table 1A). To confirm reproducibility, lifespan was measured again one month later; this experiment again showed an extension of about 11% (Table 1A). An independently obtained transgenic line carrying the same construct (CAT118) also showed lifespan extension (Table 1A). By contrast, three xdh-1 loss-of-function mutants, xdh-1(ok3234), xdh-1(tm9909), and xdh-1(tm9911), showed no change in lifespan relative to wild-type (N2) animals, suggesting that overexpression of xdh-1 is sufficient for lifespan extension but xdh-1 is not necessary for normal lifespan (Fig. 1B and Table 1B). Together, these results indicate that appropriately altering activity in the uric acid synthesis pathway can potentially extend lifespan.
The pharyngeal pumping rate of CAT33 did not differ from that of wild-type animals (Fig. 1C), suggesting that dietary restriction is unlikely to account for the observed lifespan extension. To assess whether CAT33 exhibits increased oxidative stress resistance, we cultured worms on media containing the oxidative stressor paraquat; in the presence of 0.4 mM paraquat, CAT33 showed enhanced resistance (Fig. 1D and 1E). It is conceivable that uric acid, elevated by XDH-1 overexpression, could act as an antioxidant and thereby extend lifespan. However, whether XDH-1 overexpression actually increases uric acid levels, whether any increase in uric acid is causally responsible for lifespan extension, which tissues XDH-1 acts in to modulate lifespan, and whether optimizing the level or site of XDH-1 expression could further extend longevity remain open questions for future study.
","references":[{"reference":"Álvarez-Lario B, Macarrón-Vicente J. 2010. Uric acid and evolution. Rheumatology (Oxford) 49(11): 2010-5.
","pubmedId":"20627967","doi":""},{"reference":"Ames BN, Cathcart R, Schwiers E, Hochstein P. 1981. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 78(11): 6858-62.
","pubmedId":"6947260","doi":""},{"reference":"Bortolotti M, Polito L, Battelli MG, Bolognesi A. 2021. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol 41: 101882.
","pubmedId":"33578127","doi":""},{"reference":"Chung HY, Baek BS, Song SH, Kim MS, Huh JI, Shim KH, Kim KW, Lee KH. 1997. Xanthine dehydrogenase/xanthine oxidase and oxidative stress. Age (Omaha) 20(3): 127-40.
","pubmedId":"23604305","doi":""},{"reference":"Cutler RG. 1991. Antioxidants and aging. Am J Clin Nutr 53(1 Suppl): 373S-379S.
","pubmedId":"1985414","doi":""},{"reference":"Fukushima Y, Kagami A, Sonoda H, Shimokawa K, Suico MA, Kai H, Shuto T. 2025. Dietary state and impact of DMSO on Caenorhabditis elegans aging: Insights from healthspan analysis. Biochem Biophys Res Commun 742: 151156.
","pubmedId":"39657354","doi":""},{"reference":"Garsin DA, Sifri CD, Mylonakis E, Qin X, Singh KV, Murray BE, Calderwood SB, Ausubel FM. 2001. A simple model host for identifying Gram-positive virulence factors. Proc Natl Acad Sci U S A 98(19): 10892-7.
","pubmedId":"11535834","doi":""},{"reference":"Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. 2005. Uric acid and oxidative stress. Curr Pharm Des 11(32): 4145-51.
","pubmedId":"16375736","doi":""},{"reference":"Lakowski B, Hekimi S. 1998. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 95(22): 13091-6.
","pubmedId":"9789046","doi":""},{"reference":"Lee GD, Wilson MA, Zhu M, Wolkow CA, de Cabo R, Ingram DK, Zou S. 2006. Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 5(6): 515-24.
","pubmedId":"17096674","doi":""},{"reference":"Morphis AC, Edwards SL, Erdenebat P, Kumar L, Li J. 2022. Auxin-Inducible Degron System Reveals Temporal-Spatial Roles of HSF-1 and Its Transcriptional Program in Lifespan Assurance. Front Aging 3: 899744.
","pubmedId":"35899092","doi":""},{"reference":"Ohno H, Yoshida M, Sato T, Kato J, Miyazato M, Kojima M, Ida T, Iino Y. 2017. Luqin-like RYamide peptides regulate food-evoked responses in C. elegans. Elife 6: pii: e28877. 10.7554/eLife.28877.
","pubmedId":"28847365","doi":""},{"reference":"Snoozy J, Bhattacharya S, Johnson B, Fettig RR, Van Asma A, Brede C, et al., Warnhoff K. 2025. XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell. PLoS Biol 23(9): e3003410.
","pubmedId":"40991662","doi":""},{"reference":"Takagaki N, Ohta A, Ohnishi K, Kawanabe A, Minakuchi Y, Toyoda A, Fujiwara Y, Kuhara A. 2020. The mechanoreceptor DEG-1 regulates cold tolerance in Caenorhabditis elegans. EMBO Rep 21(3): e48671.
","pubmedId":"32009302","doi":""},{"reference":"Tuckowski AM, Beydoun S, Kitto ES, Bhat A, Howington MB, Sridhar A, et al., Leiser SF. 2025. fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans. Elife 13: 10.7554/eLife.99971.
","pubmedId":"39951337","doi":""},{"reference":"Wan QL, Fu X, Dai W, Yang J, Luo Z, Meng X, et al., Zhou Q. 2020. Uric acid induces stress resistance and extends the life span through activating the stress response factor DAF-16/FOXO and SKN-1/NRF2. Aging (Albany NY) 12(3): 2840-2856.
","pubmedId":"32074508","doi":""},{"reference":"Yoshina S, Izuhara L, Kamatani N, Mitani S. 2022. Regulation of aging by balancing mitochondrial function and antioxidant levels. J Physiol Sci 72(1): 28.
","pubmedId":"36380272","doi":""}],"title":"Overexpression of xanthine dehydrogenase extends lifespan in C. elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":"1782841578773"}]},{"id":"958d5545-5580-4710-b5ce-926101c751f5","decision":"publish","abstract":"Uric acid is known to act as an antioxidant, and one hypothesis posits that certain primates, including humans, increased their uric acid levels during evolution to extend lifespan. To test whether genetically altering the activity of endogenous uric acid synthesis affects organismal lifespan, we generated transgenic Caenorhabditis elegans overexpressing the xanthine dehydrogenase XDH-1, an enzyme involved in uric acid production. These transgenic animals displayed a 9–15% increase in lifespan. They also exhibited enhanced resistance to the oxidative stress–inducing agent paraquat, implying that the lifespan extension might be linked to the antioxidant effects of uric acid.
","acknowledgements":"pNTN036 was provided by Dr. A. Kuhara. FX33446 and FX33448 were provided by the National Bioresource Project (NBRP)-Japan. RB2379 was provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
","authors":[{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing"],"email":"m2117068ca@ug.jwu.ac.jp","firstName":"Asuka","lastName":"Chino","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan"],"departments":["Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["investigation","writing_originalDraft"],"email":"sa3030g@gmail.com","firstName":"Ayaka","lastName":"Sugiyama","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Japan Women's University, Tokyo, Japan","Japan Women's University, Tokyo, Japan"],"departments":["Division of Material and Biological Sciences, Graduate School of Science","Department of Chemical and Biological Sciences, Faculty of Science"],"credit":["conceptualization","investigation","writing_originalDraft","writing_reviewEditing","fundingAcquisition"],"email":"onoh@fc.jwu.ac.jp","firstName":"Hayao","lastName":"Ohno","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"326356964"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Japan Society for the Promotion of Science (JSPS) KAKENHI 26K09212 and grants from the Mitsubishi Foundation, the Lotte Foundation, the Koyanagi Foundation, the Takeda Science Foundation, the G-7 Scholarship Foundation, the Mishima Kaiun Memorial Foundation to HO.
","image":{"url":"https://portal.micropublication.org/uploads/50680a1c18ca985e1015e1c35ec8befe.jpg"},"imageCaption":"(A) Lifespans of WT animals and transgenic animals expressing xdh-1 driven by the eft-3 promoter (Ex[eft-3p::xdh-1]). Number of animals analyzed and P values are shown in Table 1A, Experiment 1. (B) Lifespans of WT and xdh-1(ok3234) animals. Number of animals analyzed and P value are shown in Table 1B, Experiment 1. (C) Pharyngeal pumping rate of WT and Ex[eft-3p::xdh-1] (CAT33). Bars represent mean ± SEM. Number of animals analyzed: n = 16. P = 0.8329 (two-tailed t test). n.s., not significant. (D, E) Fraction of WT and Ex[eft-3p::xdh-1] animals grown to L4 or adult stages in the presence of 0.2 mM (D) and 0.4 mM (E) paraquat. Bars represent mean ± SEM. n = 3 assays. The total numbers of animals analyzed in all assays are shown in parentheses. Two-tailed t test. n.s., not significant. Table 1. Results of lifespan analysis: (A, B) LS, lifespan. Statistical analyses were conducted using Log-rank (Mantel-Cox) test.
","imageTitle":"Overexpression of xdh-1 in a WT background results in lifespan extension and enhanced resistance to paraquat
","methods":"For pDEST-xdh-1, the SalI-KpnI fragment from pNTN036 (a gift from A. Kuhara), which contains the xdh-1 cDNA (Takagaki et al., 2020), was subcloned into the XhoI-KpnI site of pPD-DEST2-exman (a gift from H. Kunitomo). The PCR-amplified eft-3 promoter (2,852 bp) was cloned into pDONR201 through BP reaction (site-specific recombination) to create pENTR-eft-3p. The expression constructs of pG-eft-3p::xdh-1 was created by LR reaction between pENTR-eft-3p and pDEST-xdh-1. Details of the system are available at the following web site:
http://molecular-ethology.biochem.s.u-tokyo.ac.jp/Gateway/Gateway_overview1.html
Germ-line transformations were performed using standard microinjection methods. For the CAT33 strain, pG-eft-3p::xdh-1 was injected at 20 ng/µL along with the co-injection marker pG-myo-3p::venus (15 ng/µL) and the carrier DNA plasmid pPD49.26 (65 ng/µL).
Lifespan assays and pharyngeal pumping assays were performed as described previously (Ohno et al., 2017), with exception that the lifespan assay plates were incubated at 20°C. Note: For preparation of NGM plates used in lifespan assays, N1000 Nematode Growth Medium (USBiological, Swampscott, MA, USA) was used in Table 1A, Experiments 1 and 2 and Table 1B, Experiment 1, whereas HIPOLYPEPTON SHIOTANI (SHIOTANI M.S., Hyogo, Japan) was used in Table 1B, Experiments 2 and 3. The latter formulation supports more robust microbial growth; this difference may have contributed to the shortened mean lifespan observed in Table 1B, Experiments 2 and 3.
For paraquat assays, nematode growth medium (NGM) plates containing paraquat (0.2 or 0.4 mM) were prepared by diluting a 1 M paraquat stock solution into molten NGM prior to dispensing. Plates were seeded with E. coli HB101. Gravid adults were placed on the plates and allowed to lay eggs overnight; adults were removed the following day (day 1). The proportion of animals that had reached the L4 larval stage was scored on days 4, 5, 7, and 8.
Statistic analyses were performed using Prism v.10 (GraphPad software, San Diego, CA).
","reagents":"Strains used in this study:
Caenorhabditis elegans wild isolate. | |
Ex[myo-3p::venus]. (marker only) | |
(a) RB2379 was outcrossed to N2 five times in our lab before use.
(b) Outcrossed twice in National Bioresource Project (NBRP)-Japan.
","patternDescription":"Uric acid is generated through the oxidation of xanthine catalyzed by xanthine dehydrogenase (XDH) or xanthine oxidase (XO) (Chung et al., 1997; Bortolotti, 2021). It constitutes the terminal metabolite of purine nucleotide catabolism in humans and in many other species it serves as a primary nitrogenous excretion product. Uric acid exhibits potent antioxidant activity and has been implicated in influencing organismal lifespan (Ames et al., 1981; Glantzounis et al., 2005). A positive correlation has been reported between primate species' maximum lifespan and plasma uric acid concentration (Cutler, 1991), and it has been proposed that evolutionary alterations in uric acid metabolism—such as the loss of uricase—have contributed to lifespan changes in species including humans (Álvarez-Lario & Macarrón-Vicente, 2010).
It has been reported that addition of uric acid to the culture medium extends the lifespan of Caenorhabditis elegans (Wan et al., 2020). However, this effect may be indirect: uric acid could adversely affect the bacterial food source, producing calorie-restriction–like conditions (Lakowski & Hekimi, 1998; Lee et al., 2006) or altering bacterial growth activity, which can affect worm lifespan (Fukushima et al., 2025; Garsin et al., 2001). The C. elegans gene xdh-1 encodes XDH-1, the worm homolog of xanthine dehydrogenase (Yoshina et al., 2022). XDH-1 functions in AIN and AVJ neurons to regulate cold tolerance (Takagaki et al., 2020), and loss of xdh-1 activity promotes formation of xanthine stones (Snoozy et al., 2025).
In the present study, we generated a transgenic C. elegans line that overexpresses xdh-1 and measured lifespan to address whether altering the activity of the endogenous uric-acid synthesis pathway changes organismal lifespan. The xdh-1 cDNA was placed under the eft-3 (also known as eef-1A.1) promoter (eft-3p) to drive strong, ubiquitous expression and introduced into wild-type animals; the resulting transgenic line was designated CAT33. Although eft-3p has been employed in previous investigations of lifespan (e.g., Tuckowski et al., 2025; Morphis et al., 2022), its introduction per se has not been reported to affect lifespan. In addition, the xdh-1 cDNA has been confirmed to be functionally active (Takagaki et al., 2020). CAT33 exhibited an approximately 15% increase in lifespan compared with wild type (Fig. 1A and Table 1A). To confirm reproducibility, lifespan was measured again one month later; this experiment again showed an extension of about 11% (Table 1A). An independently obtained transgenic line carrying the same construct (CAT118) also showed lifespan extension (Table 1A). By contrast, three xdh-1 loss-of-function mutants, xdh-1(ok3234), xdh-1(tm9909), and xdh-1(tm9911), showed no change in lifespan relative to wild-type (N2) animals, suggesting that overexpression of xdh-1 is sufficient for lifespan extension but xdh-1 is not necessary for normal lifespan (Fig. 1B and Table 1B). Together, these results indicate that appropriately altering activity in the uric acid synthesis pathway can potentially extend lifespan.
The pharyngeal pumping rate of CAT33 did not differ from that of wild-type animals (Fig. 1C), suggesting that dietary restriction is unlikely to account for the observed lifespan extension. To assess whether CAT33 exhibits increased oxidative stress resistance, we cultured worms on media containing the oxidative stressor paraquat; in the presence of 0.4 mM paraquat, CAT33 showed enhanced resistance (Fig. 1D and 1E). It is conceivable that uric acid, elevated by XDH-1 overexpression, could act as an antioxidant and thereby extend lifespan. However, whether XDH-1 overexpression actually increases uric acid levels, whether any increase in uric acid is causally responsible for lifespan extension, which tissues XDH-1 acts in to modulate lifespan, and whether optimizing the level or site of XDH-1 expression could further extend longevity remain open questions for future study.
","references":[{"reference":"Álvarez-Lario B, Macarrón-Vicente J. 2010. Uric acid and evolution. Rheumatology (Oxford) 49(11): 2010-5.
","pubmedId":"20627967","doi":""},{"reference":"Ames BN, Cathcart R, Schwiers E, Hochstein P. 1981. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 78(11): 6858-62.
","pubmedId":"6947260","doi":""},{"reference":"Bortolotti M, Polito L, Battelli MG, Bolognesi A. 2021. Xanthine oxidoreductase: One enzyme for multiple physiological tasks. Redox Biol 41: 101882.
","pubmedId":"33578127","doi":""},{"reference":"Chung HY, Baek BS, Song SH, Kim MS, Huh JI, Shim KH, Kim KW, Lee KH. 1997. Xanthine dehydrogenase/xanthine oxidase and oxidative stress. Age (Omaha) 20(3): 127-40.
","pubmedId":"23604305","doi":""},{"reference":"Cutler RG. 1991. Antioxidants and aging. Am J Clin Nutr 53(1 Suppl): 373S-379S.
","pubmedId":"1985414","doi":""},{"reference":"Fukushima Y, Kagami A, Sonoda H, Shimokawa K, Suico MA, Kai H, Shuto T. 2025. Dietary state and impact of DMSO on Caenorhabditis elegans aging: Insights from healthspan analysis. Biochem Biophys Res Commun 742: 151156.
","pubmedId":"39657354","doi":""},{"reference":"Garsin DA, Sifri CD, Mylonakis E, Qin X, Singh KV, Murray BE, Calderwood SB, Ausubel FM. 2001. A simple model host for identifying Gram-positive virulence factors. Proc Natl Acad Sci U S A 98(19): 10892-7.
","pubmedId":"11535834","doi":""},{"reference":"Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. 2005. Uric acid and oxidative stress. Curr Pharm Des 11(32): 4145-51.
","pubmedId":"16375736","doi":""},{"reference":"Lakowski B, Hekimi S. 1998. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A 95(22): 13091-6.
","pubmedId":"9789046","doi":""},{"reference":"Lee GD, Wilson MA, Zhu M, Wolkow CA, de Cabo R, Ingram DK, Zou S. 2006. Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 5(6): 515-24.
","pubmedId":"17096674","doi":""},{"reference":"Morphis AC, Edwards SL, Erdenebat P, Kumar L, Li J. 2022. Auxin-Inducible Degron System Reveals Temporal-Spatial Roles of HSF-1 and Its Transcriptional Program in Lifespan Assurance. Front Aging 3: 899744.
","pubmedId":"35899092","doi":""},{"reference":"Ohno H, Yoshida M, Sato T, Kato J, Miyazato M, Kojima M, Ida T, Iino Y. 2017. Luqin-like RYamide peptides regulate food-evoked responses in C. elegans. Elife 6: pii: e28877. 10.7554/eLife.28877.
","pubmedId":"28847365","doi":""},{"reference":"Snoozy J, Bhattacharya S, Johnson B, Fettig RR, Van Asma A, Brede C, et al., Warnhoff K. 2025. XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell. PLoS Biol 23(9): e3003410.
","pubmedId":"40991662","doi":""},{"reference":"Takagaki N, Ohta A, Ohnishi K, Kawanabe A, Minakuchi Y, Toyoda A, Fujiwara Y, Kuhara A. 2020. The mechanoreceptor DEG-1 regulates cold tolerance in Caenorhabditis elegans. EMBO Rep 21(3): e48671.
","pubmedId":"32009302","doi":""},{"reference":"Tuckowski AM, Beydoun S, Kitto ES, Bhat A, Howington MB, Sridhar A, et al., Leiser SF. 2025. fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans. Elife 13: 10.7554/eLife.99971.
","pubmedId":"39951337","doi":""},{"reference":"Wan QL, Fu X, Dai W, Yang J, Luo Z, Meng X, et al., Zhou Q. 2020. Uric acid induces stress resistance and extends the life span through activating the stress response factor DAF-16/FOXO and SKN-1/NRF2. Aging (Albany NY) 12(3): 2840-2856.
","pubmedId":"32074508","doi":""},{"reference":"Yoshina S, Izuhara L, Kamatani N, Mitani S. 2022. Regulation of aging by balancing mitochondrial function and antioxidant levels. J Physiol Sci 72(1): 28.
","pubmedId":"36380272","doi":""}],"title":"Overexpression of xanthine dehydrogenase extends lifespan in C. elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]}]}},"species":{"species":[{"value":"acer saccharum","label":"Acer saccharum","imageSrc":"","imageAlt":"","mod":"TreeGenes","modLink":"https://treegenesdb.org","linkVariable":""},{"value":"achillea millefolium","label":"Achillea millefolium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"acinetobacter baylyi","label":"Acinetobacter baylyi","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"actinobacteria bacterium","label":"Actinobacteria bacterium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"adelges tsugae","label":"Adelges tsugae","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"adenocaulon chilense","label":"Adenocaulon chilense","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"aedes 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