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Article

Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis

by
Grit Zahn
1,*,
Hannes A. Baukmann
2,
Jasmine Wu
3,
Jens Jordan
4,
Andreas L. Birkenfeld
5,6,7,
Naomi Dirckx
3 and
Marco F. Schmidt
2
1
Eternygen GmbH, Westhafenstrasse 1, 13353 Berlin, Germany
2
biotx.ai GmbH, Am Mühlenberg 11, 14476 Potsdam, Germany
3
Department of Orthopaedics, School of Medicine, University of Maryland-Baltimore, Baltimore, MD 21201, USA
4
German Aerospace Center (DLR), Institute of Aerospace Medicine, 51147 Cologne, Germany
5
Department of Diabetology Endocrinology and Nephrology, Internal Medicine IV, University Hospital Tübingen, Eberhard Karls University Tübingen, 72074 Tübingen, Germany
6
German Center for Diabetes Research (DZD), Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Eberhard Karls University Tübingen, 72074 Tübingen, Germany
7
Department of Diabetes, Life Sciences and Medicine, Cardiovascular Medicine and Sciences, Kings College London, London WC2R 2LS, UK
*
Author to whom correspondence should be addressed.
Metabolites 2023, 13(12), 1186; https://doi.org/10.3390/metabo13121186
Submission received: 9 November 2023 / Revised: 24 November 2023 / Accepted: 1 December 2023 / Published: 6 December 2023
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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Abstract

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1–5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts’ specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.
Keywords: mINDY; SLC13A5; citrate; citrate transporter; NaCT; osteoporosis; Mendelian randomization; drug development mINDY; SLC13A5; citrate; citrate transporter; NaCT; osteoporosis; Mendelian randomization; drug development

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MDPI and ACS Style

Zahn, G.; Baukmann, H.A.; Wu, J.; Jordan, J.; Birkenfeld, A.L.; Dirckx, N.; Schmidt, M.F. Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis. Metabolites 2023, 13, 1186. https://doi.org/10.3390/metabo13121186

AMA Style

Zahn G, Baukmann HA, Wu J, Jordan J, Birkenfeld AL, Dirckx N, Schmidt MF. Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis. Metabolites. 2023; 13(12):1186. https://doi.org/10.3390/metabo13121186

Chicago/Turabian Style

Zahn, Grit, Hannes A. Baukmann, Jasmine Wu, Jens Jordan, Andreas L. Birkenfeld, Naomi Dirckx, and Marco F. Schmidt. 2023. "Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis" Metabolites 13, no. 12: 1186. https://doi.org/10.3390/metabo13121186

APA Style

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. https://doi.org/10.3390/metabo13121186

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