A comparative study of metformin and nicotinamide riboside in alleviating tissue aging in rats
Lingling Geng, Bin Zhang, Haisong Liu, Si Wang, Yusheng Cai, Kuan Yang, Zhiran Zou, Xiaoyu Jiang, Zunpeng Liu, Wei Li, Zeming Wu, Xiaoqian Liu, Qun Chu, Guang-Hui Liu, Jing Qu, Weiqi Zhang
A comparative study of metformin and nicotinamide riboside in alleviating tissue aging in rats
Metformin (MET) and nicotinamide riboside (NR) have both been reported to exert geroprotective effects in multiple species. However, the mechanism by which MET and NR regulate the aging program and delay aging in multiple tissues remains unclear. Here, we demonstrated that MET and NR attenuate aging features in human mesenchymal stem cells. Moreover, by systematically investigating the pathophysiological changes in different tissues from aged rats after oral administration of MET and NR, we showed that both MET and NR treatment alleviated various aging-related characteristics in multiple tissues, including inflammation, fibrosis, and protein aggregates. Consistently, MET or NR treatment partially rescued aging-related gene expression changes in aged rats. Collectively, we report that both MET and NR attenuate senescence phenotypes in human stem cells in vitro and in a variety of rodent tissues in vivo, thus providing a valuable resource and foundation for further evaluation of these two compounds against aging.
metformin / nicotinamide riboside / aging / senescence / inflammation
[1] |
Campisi J, Kapahi P, Lithgow GJ, et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 2019;571:183–92.
CrossRef
Google scholar
|
[2] |
Mahmoudi S, Xu L, Brunet A. Turning back time with emerging rejuvenation strategies. Nat Cell Biol 2019;21:32–43.
CrossRef
Google scholar
|
[3] |
Finkel T. The metabolic regulation of aging. Nat Med 2015;21:1416–23.
CrossRef
Google scholar
|
[4] |
Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013;153:1194–217.
CrossRef
Google scholar
|
[5] |
Sacks D, Baxter B, Campbell BCV, et al. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int J Stroke 2018;13:612–32.
CrossRef
Google scholar
|
[6] |
Cai Y, Song W, Li J, et al. The landscape of aging. Sci China Life Sci 2022;65:2354–454.
CrossRef
Google scholar
|
[7] |
Ren R, Ocampo A, Liu G-H, et al. Regulation of stem cell aging by metabolism and epigenetics. Cell Metab 2017;26:460–74.
CrossRef
Google scholar
|
[8] |
Sun Y, Li Q, Kirkland JL. Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging. Life Med 2022;1:103–19.
CrossRef
Google scholar
|
[9] |
Barzilai N, Crandall JP, Kritchevsky SB, et al. Metformin as a tool to target aging. Cell Metab 2016;23:1060–5.
CrossRef
Google scholar
|
[10] |
Fang J, Yang J, Wu X, et al. Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell 2018;17:e12765.
CrossRef
Google scholar
|
[11] |
Zhang H, Ryu D, Wu Y, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 2016;352:1436–43.
CrossRef
Google scholar
|
[12] |
Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab 2020;32:15–30.
CrossRef
Google scholar
|
[13] |
Lei Y, Yi Y, Liu Y, et al. Metformin targets multiple signaling pathways in cancer. Chin J Cancer 2017;36:17.
CrossRef
Google scholar
|
[14] |
Ma T, Tian X, Zhang B, et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 2022;603:159–65.
CrossRef
Google scholar
|
[15] |
Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds. Nat Rev Mol Cell Biol 2016;17:679–90.
CrossRef
Google scholar
|
[16] |
Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun 2013;4:2192.
CrossRef
Google scholar
|
[17] |
Cai Y, Wang S, Qu J, et al. Rejuvenation of tissue stem cells by intrinsic and extrinsic factors. Stem Cells Transl Med 2022;11:231–8.
CrossRef
Google scholar
|
[18] |
Singh SR. Stem cell niche in tissue homeostasis, aging and cancer. Curr Med Chem 2012;19:5965–74.
CrossRef
Google scholar
|
[19] |
Zhu Q, Ding L, Yue R. Skeletal stem cells: a game changer of skeletal biology and regenerative medicine? Life Med 2022;1:294–306.
CrossRef
Google scholar
|
[20] |
Zhang W, Li J, Suzuki K, et al. Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 2015;348:1160–3.
CrossRef
Google scholar
|
[21] |
Shan H, Geng L, Jiang X, et al. Large-scale chemical screen identifies Gallic acid as a geroprotector for human stem cells. Protein Cell 2022;13:532–9.
CrossRef
Google scholar
|
[22] |
Wang S, Min Z, Ji Q, et al. Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction. Protein Cell 2020;11:1–22.
CrossRef
Google scholar
|
[23] |
Yoshino J, Baur JA, Imai SI. NAD(+) Intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab 2018;27:513–28.
CrossRef
Google scholar
|
[24] |
Choe SS, Huh JY, Hwang IJ, et al. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front Endocrinol 2016;7:30.
CrossRef
Google scholar
|
[25] |
Aging Atlas C. Aging Atlas: a multi-omics database for aging biology. Nucleic Acids Res 2021;49:D825–30.
CrossRef
Google scholar
|
[26] |
Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun 2018;9:1286.
CrossRef
Google scholar
|
[27] |
Chen YW, Harris RA, Hatahet Z, et al. Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities. Proc Natl Acad Sci USA 2015;112:E4556–64.
CrossRef
Google scholar
|
[28] |
Le Pelletier L, Mantecon M, Gorwood J, et al. Metformin alleviates stress-induced cellular senescence of aging human adipose stromal cells and the ensuing adipocyte dysfunction. eLife 2021;10:e62635.
CrossRef
Google scholar
|
[29] |
Li X, Li J, Wang L, et al. The role of metformin and resveratrol in the prevention of hypoxia-inducible factor 1α accumulation and fibrosis in hypoxic adipose tissue. Br J Pharmacol 2016;173:2001–15.
CrossRef
Google scholar
|
[30] |
Karnewar S, Neeli PK, Panuganti D, et al. Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: relevance in age-associated vascular dysfunction. Biochim Biophys Acta Mol Basis Dis 2018;1864:1115–28.
CrossRef
Google scholar
|
[31] |
Park JW, Park JE, Kim SR, et al. Metformin alleviates ionizing radiation-induced senescence by restoring BARD1-mediated DNA repair in human aortic endothelial cells. Exp Gerontol 2022;160:111706.
CrossRef
Google scholar
|
[32] |
Fielder E, Wan T, Alimohammadiha G, et al. Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice. eLife 2022;11:e75492.
CrossRef
Google scholar
|
[33] |
Li X, Wang L, Yang X, et al. Metformin attenuates ischemia-reperfusion injury of fatty liver in rats through inhibition of the TLR4/NF-κB axis. Balkan Med J 2020;37:196–202.
CrossRef
Google scholar
|
[34] |
Xu L, Hu G, Xing P, et al. Paclitaxel alleviates the sepsis-induced acute kidney injury via lnc-MALAT1/miR-370-3p/HMGB1 axis. Life Sci 2020;262:118505.
CrossRef
Google scholar
|
[35] |
Serrano A, Asnani-Kishnani M, Couturier C, et al. DNA Methylation changes are associated with the programming of white adipose tissue browning features by Resveratrol and Nicotinamide Riboside neonatal supplementations in mice. Nutrients 2020;12:461.
CrossRef
Google scholar
|
[36] |
de Castro JM, Stein DJ, Medeiros HR, et al. Nicotinamide riboside neutralizes hypothalamic inflammation and increases weight loss without altering muscle mass in obese rats under calorie restriction: a preliminary investigation. Front Nutr 2021;8:648893.
CrossRef
Google scholar
|
[37] |
Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 2021;372:1224–9.
CrossRef
Google scholar
|
[38] |
Ma S, Sun S, Geng L, et al. Caloric restriction reprograms the single- cell transcriptional landscape of Rattus Norvegicus aging. Cell 2020;180:984–1001.e1022.
CrossRef
Google scholar
|
[39] |
Chen J, Ou Y, Li Y, et al. Metformin extends C. elegans lifespan through lysosomal pathway. eLife 2017;6:e31268.
CrossRef
Google scholar
|
[40] |
Smith DL, Jr., Elam CF Jr., Mattison JA, et al. Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci 2010;65:468–74.
CrossRef
Google scholar
|
[41] |
Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab 2014;16:1165–73.
CrossRef
Google scholar
|
[42] |
Kharitonenkov A, Shiyanova TL, Koester A, et al. FGF-21 as a novel metabolic regulator. J Clin Investig 2005;115:1627–35.
CrossRef
Google scholar
|
[43] |
Liu Z, Li W, Geng L, et al. Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor. Cell Discov 2022;8:6.
CrossRef
Google scholar
|
[44] |
Ma S, Sun S, Li J, et al. Single-cell transcriptomic atlas of primate cardiopulmonary aging. Cell Res 2021;31:415–32.
CrossRef
Google scholar
|
[45] |
Cai Y, Zhou H, Zhu Y, et al. Elimination of senescent cells by beta-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell Res 2020;30:574–89.
CrossRef
Google scholar
|
[46] |
Debacq-Chainiaux F, Erusalimsky JD, Campisi J, et al. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protocols 2009;4:1798–806.
CrossRef
Google scholar
|
[47] |
Geng L, Liu Z, Zhang W, et al. Chemical screen identifies a geroprotective role of quercetin in premature aging. Protein Cell 2019;10:417–35.
CrossRef
Google scholar
|
[48] |
Wang S, Zheng Y, Li J, et al. Single-cell transcriptomic atlas of primate ovarian aging. Cell 2020;180:585–600.e519.
CrossRef
Google scholar
|
[49] |
Wang W, Zheng Y, Sun S, et al. A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence. Sci Transl Med 2021;13:eabd2655.
CrossRef
Google scholar
|
[50] |
Li W, Zou Z, Cai Y, et al. Low-dose chloroquine treatment extends the lifespan of aged rats. Protein Cell 2022;13:454–61.
CrossRef
Google scholar
|
[51] |
Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods 2015;12:357–60.
CrossRef
Google scholar
|
[52] |
Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics (Oxford, England) 2015;31:166–9.
CrossRef
Google scholar
|
[53] |
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15:550.
CrossRef
Google scholar
|
[54] |
Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019;10:1523.
CrossRef
Google scholar
|
[55] |
Subramanian A, Kuehn H, Gould J, et al. GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics (Oxford, England) 2007;23:3251–3.
CrossRef
Google scholar
|
/
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