Vascular Calcification in Chronic Kidney Disease: Targeting Cellular Senescence with Traditional Chinese Medicines

INTRODUCTION Chronic kidney disease (CKD) represents a growing public health challenge. Cardiovascular disease (CVD) is the primary contributor to mortality within this patient group. In turn, vascular aging and accelerated vascular calcification (VC) significantly exacerbate the risk of CVD in this population.[1] Although current management of VC commonly involves phosphate binders, vitamin D analogs, and calcimimetics, no therapy specifically targets the distinct pathophysiology of CKD-related VC (CKD-VC). Given this therapeutic gap, targeting cellular senescence has emerged as a promising novel strategy for preventing and treating VC in these patients. In this context, natural products and extracts derived from traditional Chinese medicines (TCMs) hold considerable potential for further investigation. An overview of VC-mediated cellular senescence in CKD pathogenesis and therapeutic strategies is summarized in Figure 1.Figure 1.: Vascular calcification-mediated cellular senescence in CKD. The prosenescent phenotype of CKD promotes the conversion of VSMCs into osteogenic phenotypes, which in turn mediate VC. Targeting cellular senescence or improving the prosenescent environment in CKD can inhibit vascular calcification. The figure was created in BioRender. Yin, X. (2026) https://BioRender.com/r1gj1mz. CKD, chronic kidney disease; VSMC, vascular smooth muscle cell; ROS, reactive oxygen species; DDR, DNA damage response; ATM, ataxia-telangiectasia; p16INK4a, cyclin-dependent kinase inhibitor 2A (CDKN2A); p21CIP1/WAF1, cyclin-dependent kinase inhibitor 1A (CDKN1A); SAβG, senescence-associated β-galactosidase; TMAO, trimethylamine N-oxide; SASP, senescence-associated secretory phenotype; GATA4, GATA binding protein 4; NF-κB, nuclear factor kappa B; GATA6, GATA binding protein 6; PQS, Panax quinquefolius saponin; DOP, dendrobium officinale polysaccharide; HMOX-1, heme oxygenase 1; D + Q, dasatinib and quercetin; GLSP, Ganoderma lucidum spore polysaccharide; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor-erythroid 2-related factor 2; Sirt6, sirtuin 6; Nkx2.5, NK2 homeobox 5.CELLULAR SENESCENCE MEDIATES VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE: A NOVEL MECHANISM Cellular senescence is marked by irreversible cessation of cell growth. It is characterized by elevated levels of senescence-associated cell cycle blockers, such as p16INK4a (cyclin-dependent kinase inhibitor 2A, CDKN2A) and p21CIP1/WAF1 (cyclin-dependent kinase inhibitor 1A, CDKN1A); chronic DNA damage response (DDR); and the proinflammatory hypersecretory state referred to as the senescence-associated secretory phenotype (SASP).[2] In CKD, microenvironmental stressors such as inflammation, oxidative stress, hyperphosphatemia, and uremic toxins drive vascular smooth muscle cells (VSMCs) into senescence. These senescent VSMCs enhance SASP release via ataxia-telangiectasia mutated (ATM)-mediated sustained DDR. Subsequently, SASP components such as bone morphogenetic protein 2 (BMP2) and interleukin-6 (IL-6) activate osteogenic signaling pathways, including upregulation of the key transcription factor runt-related transcription factor 2 (Runx2), thereby promoting the differentiation of VSMCs into osteoblast-like cells and facilitating VC.[3,4] In the context of CKD, mineral stress-exemplified by hyperphosphatemia-induces oxidative stress in VSMCs, leading to oxidative DNA damage. This activates ATM-mediated DDR, which upregulates the key senescence markers p21 and p16, thereby inducing senescence in VSMCs. Consequently, these senescent VSMCs secrete SASP enriched with proinflammatory and osteogenic factors, directly promoting osteogenic differentiation and accelerating calcification in the VSMCs. Clinical evidence demonstrates an association between higher circulation of SASP factors and aggravated vascular stiffness as well as coronary artery calcification in children with CKD.[4] Further mechanistic insight comes from animal studies. Employing a well-established CKD rat model induced by 5/6 nephrectomy, researchers showed that trimethylamine N-oxide (TMAO), a metabolite derived from gut microbiota, upregulates the expression of aorta senescence markers, including senescence-associated β-galactosidase (SAβG), p16 and p21. TMAO exerts this effect by inhibiting the degradation of the transcription factor GATA binding protein 4 (GATA4), thereby activating the nuclear factor kappa B (NF-κB) signaling pathway and enhancing SASP secretion to accelerate the senescence of VSMCs.[3] Ultimately, SASP components produced by senescent VSMCs promote senescence-associated inflammation, which in turn enhances the expression of inflammatory factors to drive osteogenic differentiation in VSMCs and ultimately VC.[4] By targeting the ATM-mediated DDR, it is possible to attenuate the SASP and subsequently mitigate VC.[4] During aortic calcification driven by DNA damage stress, the transcription factor GATA binding protein 6 (GATA6) promotes senescence and osteogenic differentiation in VSMCs by compromising ATM-mediated DDR signaling and upregulating the osteogenic marker BMP2. In contrast, the ATM inhibitor Ku55933 attenuates calcification by blocking DNA damage signaling.[5] Thus, pharmacological agents that target DNA damage signaling or eliminate senescent cells represent a potential therapeutic strategy for preventing VC in patients with advanced CKD. TARGETING CELLULAR SENESCENCE VIA MULTIPLE PATHWAYS: TRADITIONAL CHINESE MEDICINES IN THE ALLEVIATION OF VASCULAR CALCIFICATION Herbal extracts and natural products derived from TCMs, with their inherent multitarget properties, represent a promising therapeutic approach for VC driven by the prosenescent state under the complex pathological conditions of CKD, which encompass inflammation, oxidative stress, and hyperphosphatemia. Resveratrol lowers aortic calcium content and mitigates VC in uremic mice via its antioxidant activity.[6] Panax quinquefolius saponin (PQS) can effectively inhibit Pi-induced calcification in rat VSMCs by improving oxidative damage and modulating osteogenic gene expression through upregulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) expression.[7] Moreover, dendrobium officinale polysaccharide (DOP) alleviates VSMC calcification in rats through heme oxygenase 1 (HMOX-1) activation coupled with inhibition of apoptosis and inflammation.[8] Collectively, these findings indicate that the anticalcification induced by herbal extracts and natural products primarily involves the regulation of oxidative stress and inflammation. Key signaling pathways, including Nrf2/HMOX-1, appear to function as a common regulatory nexus for these agents. In addition to modulating oxidative stress and inflammation, several natural products and herbal extracts directly alleviate VC by targeting cellular senescence. Senolytic therapy using a combination of dasatinib and quercetin (D + Q) effectively eliminates senescent cells and consequently lowers the levels of associated markers in the aorta, attenuating VC.[9] Furthermore, Ganoderma lucidum spore polysaccharide (GLSP) ameliorates VC and aging phenotypes in aged mice. Its mechanism involves mitigating cell cycle arrest by downregulating key cell cycle genes, reducing DNA damage via decreased histone H2AX (H2AX) and checkpoint kinase 1 (Chk1) phosphorylation, and modulating the release of the SASP. Mechanistically, GLSP enhances sirtuin 7 (Sirt7)-mediated kelch-like ECH-associated protein 1 (Keap1) deacetylation, which facilitates its dissociation from Nrf2 and subsequent activation of the Nrf2 pathway.[10] Similarly, sirtuin 6 (Sirt6) acts by deacetylating the transcription factor NK2 homeobox 5 (Nkx2.5) to facilitate its degradation, which in turn suppresses GATA6 transcription, thereby inhibiting senescence and osteogenic differentiation in VSMCs.[5] Taken together, this evidence suggests that the TCMs’ postive effects against VC are closely associated with the modulation of sirtuin family members (such as Sirt6 and Sirt7) and their downstream pathways. This collective evidence indicates that interference with cellular senescence constitutes a key and shared mechanistic basis for combating CKD-VC. CONCLUSION AND PERSPECTIVE In summary, cellular senescence is intricately linked to the progression of CKD-VC. We have emphasized that the disordered internal environment associated with CKD, which encompasses microinflammation, oxidative stress, and uremic toxin accumulation, promotes a senescent phenotype that accelerates calcification. Notably, evidence indicates that many natural products can alleviate CKD-VC not only by directly targeting senescent cells but also by mitigating underlying pathologies, such as inflammation and oxidative stress. Therefore, the development of targeted antisenescence therapies emerges as a viable and novel therapeutic direction for combating CKD-VC. Although targeting cellular senescence represents a promising therapeutic strategy for CKD-VC, several challenges remain. A primary limitation is that most existing evidence remains correlative rather than causal. Genetic lineage tracing and inducible senolytic models should be employed to definitively establish causality between senescent cells and VC. Moreover, prevailing animal models for CKD-VC, such as those induced by adenine, 5/6 nephrectomy, or vitamin D, fail to fully recapitulate the pathogenesis of VC in CKD patients; developing vascular organoids would better recapitulate the human pathophysiological state. Furthermore, beyond the well-known SASP, other molecular signatures of senescence relevant to VC have been scarcely explored. Single-cell multi-omics and genome-wide CRISPR screens are needed to systematically map senescence beyond the SASP and identify novel targets such as metabolic reprogramming and non-coding RNA networks. Finally, the exploration of herbal extracts and natural products that attenuate VC by countering the prosenescent milieu in CKD represents a promising frontier for discovering new therapeutic targets. Financial support and sponsorship This work was supported by the Capacity Improvement Project of Xiyuan Hospital of China Academy of Chinese Medical Sciences (XYZX0405-22). Author contributions Yin XL: Conceptualization, Writing-Original draft preparation. Liu SY: Supervision and Funding. All authors have read and approved the final manuscript. Ethics approval and consent to participate Not applicable. Conflict of interest The authors declare no competing interests. Use of large language models, AI and machine learning tools None declared. Data availability statement No additional data.