Targeting cellular senescence in kidney diseases and aging: A focus on mesenchymal stem cells and their paracrine factors

Similar to differentiation, apoptosis, and replication, senescence can manifest at any stage of life, indicating irreversible growth arrest and resistance to apoptosis. Senescent cells have a distinctive secretome called the senescence-associated secretory phenotype (SASP) including profibrotic and proinflammatory factors with endocrine, paracrine, and autocrine activities [8]. There are also alterations in the morphology of these cells such as abnormal organelles, granularity in the cytoplasm, and flattened cell bodies.

Cell senescence can occur either as replicative senescence (due to the reduced telomerase activity and loss of telomeres) or stress-induced senescence. Stress-induced senescence can be promoted by DNA damage, oxidative stress, reactive oxygen species (ROS), or inflammation [9, 10]. ROS production results in premature senescence by upregulation of p21 and p16 [11]. Immediately after ischemia/reperfusion (I/R) injury, kidney expression of β-galactosidase, a biomarker of elevated autophagy in senescent cells, is induced by an overexpression of p21 [12]. Moreover, both senescence and overexpressed p21 produce TGF-β that leads to fibrosis [13].

Senescence is accompanied by elevated secretion of EVs [14] and these vesicles perform key roles in senescent cells [15, 16], inducing autocrine and paracrine senescence in their adjacent cells [16]. Malfunctioned exosome secretion leads to DNA damage response (DDR) in all cells [17]. The surrounding environment and adjacent cells are also impacted by the SASP and the presence of cytokines, proteases, growth and hemostatic factors, laminin, fibronectin, and collagens (extracellular matrix proteins) [18] .

During the aging procedure, the immune system also becomes dysfunctional, and consequently senescent cells are not removed in time, inducing chronic inflammation and fibrosis [5]. The performance and outcome of SASP can be different based on the factors that cause cell aging. In the chronically induced aging process, it can activate pathogenic reactions through the accumulation of macrophages and the stimulation of malignant cells in the surrounding environment [19]. Instead, in the transient presence of senescent cells, SASP plays a physiological role and exerts a beneficial effect, limiting fibrosis in response to damage by induction of fibroblast senescence, in successful tissue homeostasis and embryonic organogenesis, healing, or repairing [20]. Thus, senescent cells provide a mechanism that avoids the proper proliferation of injured cells but continues to be metabolically active and remains viable.

Another feature of senescent cells is their ability to resist apoptosis. Various mechanisms facilitate the sustenance of senescent cells (Table 1), including the induction of the unfolded protein response, metabolic reprogramming, and strategies for evading the detection of the immune system (reviewed in Ref [21]).

Cellular senescence has a reparative role in kidney injury and promots tissue repair and regeneration. These cells can secrete various factors that may enhance local inflammation and recruit immune cells necessary for tissue repair. Specific markers, such as p21 and p16, can indicate a protective response that helps limit damage and promote healing after kidney injury. Conversely, persistent senescence can lead to detrimental effects, particularly when senescent cells accumulate over time. This accumulation can contribute to chronic inflammation, fibrosis, and further decline in renal function [35, 36].

Various insults trigger the senescence in different kidney cells via distinct pathways. Stress factors, kidney diseases, and physiologically kidney aging can activate cell senescence signaling pathways. Kidney cellular senescence can act as both a cause, through triggering cellular senescence mechanisms, and a consequence of kidney disease, as a result of the progression of AKI and CKD [37]. Cell senescence in kidney cells induces microscopic and macroscopic changes, implying changes in kidney function. The accumulation of senescent cells in the kidneys also leads to structural changes such as glomerulosclerosis and tubular atrophy, common in aging kidneys (Fig. 1). In aged populations, AKI increases the risk of progression to CKD, underscoring a significant association between acute injury and chronic disease via mechanisms that encompass cellular senescence [36]. In the following sections, we will first cast light on the current understanding of the molecular mechanisms involved in kidney cell senescence, and then elucidate the mutual interactions between cellular senescence, kidney diseases, and aging.

Tubular epithelial cells (TECs) are considered the main location for kidney senescence and aging, exerting a significant impact on the physiological and pathological functions of the kidneys. These cells have abundant mitochondria, indicating their heightened energy and metabolic requirements. Kidney TECs are predominantly located in regions of the kidney with restricted blood flow and oxygen availability, making them intrinsically more susceptible to injury, reviewed comprehensively elsewhere [38]. Different insults such as ischemia, high glucose, radiation, nephrotoxic drugs, and contrast agents result in tubular cell injury and senescence by the disruption of the cytoskeleton, degradation of DNA, and damage in TEC’s membrane, culminating in tubular necrosis, apoptosis, and ferroptosis. Additionally, under AKI, TECs are susceptible to oxidative stress, mitochondrial dysfunction, and disruptions in energy metabolism and autophagy, leading to stress-induced cellular senescence (Fig. 2). Hyperglycemia by triggering endoplasmic reticulum stress through activating ATF4-p16 signaling [29] and sodium-glucose cotransporter 2 (SGLT2) /p21-dependent pathway [39] can trigger tubular senescence. Likewise, SGLT2 is activated by hedgehog interacting protein, promoting TEC senescence in a type 1 diabetes model [40]. TEC senescence can be also induced by the overexpression of Wnt9a [41], activation of the Wnt–β-catenin pathway [42], and inhibition of AMPK–mTOR signaling [43]. Moreover, TEC senescence is regulated by Myd88 through Toll-like receptor signaling [6]. The senescence of TECs correlates with a decline in the rate of renal recovery after kidney injury, maladjusted repair, kidney dysfunction, and development of CKD, and is accompanied by renal fibrosis progression [44].

Podocytes are terminally differentiated kidney cells that are crucial in maintaining the proper functioning of the filtration barrier within the glomerulus. Podocyte senescence is a process implicated in kidney injury and aging. According to some research, podocyte damage induces senescence, thereby hastening glomerular aging in young mice and cultured cells [45]. Floge et al. initially identified the pivotal role of podocytes in age-related glomerulosclerosis [46]. Research on human beings has further emphasized the significance of podocytes as a crucial cell type impacted by aging since advanced age presents itself by podocyte depletion in people lacking evidence of renal pathology [47].

A combination of environmental, systemic, common aging-related factors [hypertension, diabetes, and obesity], and podocyte-specific factors [alterations in definite transcription factors such as Grhl2 (Grainyhead-like2)] contribute to podocyte senescence (Fig. 3A-B). Senescence signaling pathways in podocytes involve key mediators like p16^INK4A, p21, and p53, influencing cellular senescence, degeneration, and the expression of fibrogenic factors [48, 49]. Besides cellular senescence, the phenotype of aging podocyte is distinguished by alterations in ultrastructure and functionality, oxidative, cellular, and endoplasmic reticulum stress, and hypertrophy, alongside diminished autophagy, and the heightened manifestation of genes associated with aging.

The downregulation of sirtuin 1 and C/EBPα has been identified in the aged podocytes. Sirtuin1 is a gene associated with longevity that serves to protect podocytes from inflammation and oxidative stress and controls the function of numerous transcription factors. C/EBPα is a transcription factor that manages autoimmunity, inflammation, and energy metabolism in podocytes. C/EBPα deficiency in podocytes has been shown to aggravate podocyte senescence and kidney damage through the AMPK/mTOR pathway (mechanisms associated with metabolism) in aging mice. On the other hand, the upregulation of podocyte-specific programmed cell death 1 (PD-1) and glycogen synthase kinase 3β (GSK3β) is connected with the senescence of podocytes, giving rise to a decline in the function and histology observed with age. The upregulation of PD-1 in aged podocytes evades detection by immune cells, affecting surrounding cells through the SASP [50]. GSK3β and PD-1 might regulate senescent podocytes via a comparable pathway since GSK3β is a pivotal upstream kinase, regulating PD-1 expression [51]. Beyond aging, ischemia, radiation, nephrotoxic drugs, and unilateral ureteral obstruction (UUO) can induce podocyte senescence through the inhibition of C/EBPα, reduction in AMPK-mTOR signaling, and activation of Wnt-β-catenin signaling, which inhibits autophagy (Fig. 3A, B). In the aging kidney, podocyte senescence has been connected with the induction of glomerulosclerosis [52].

The notion of vascular senescence and early vascular aging stands as a crucial risk factor for the premature emergence of cardiovascular complications. The senescence of glomerular endothelial cells plays a critical role in age-related kidney disease, particularly in the development of glomerulosclerosis through mechanisms involving plasminogen activator inhibitor-1 (PAI-1) [53]. TGF-β1 can also induce nuclear translocation of p16, contributing to endothelial cellular senescence in the glomeruli [54]. As research indicates, endothelial cells and macrophages are prominent sources of SASP components in hyperglycemic renal tissue [55]. High glucose levels can cause macrophage infiltration, the activation of NOX1-PKC signaling, and mitochondrial dysfunction, culminating in increased ROS levels and senescence of endothelial cells. Radiation triggers the onset of cellular senescence in glomerular endothelial cells by stimulating the NF-κB signaling [56], accumulation of M1 macrophage, and increasing ROS and p38 MAPK signaling [57]. Angiopoietin-1 is reported to prevent H₂O₂-induced glomerular endothelial cells by the ERK1/2 pathway [58]. Aged podocytes may stimulate alterations in the endothelial cells and vice versa. Senescent glomerular endothelial cells drive podocyte damage by promoting the F-actin cytoskeleton reorganization by expression of PAI-1, reducing the number of focal adhesions, and stimulating podocyte apoptosis and detachment [53], (Fig. 3C).

Hypertrophy of the intima and media, sclerosis of the vascular wall, and the formation of atheromatous plaques are structural changes in the renal vessels due to aging, similar to the changes observed in vessels in other organs of the body. Increased tortuosity and loss of glomerular integrity, creation of direct shunt between afferent and efferent vessels, hypertrophy of the vascular wall, and reduction of the lumen diameter of afferent arteries are changes that occur mainly in the aging processes [59].

Kidney mesangial cells exert a central role in preserving the function and structure of the glomerulus. High levels of glucose induce mesangial cell senescence via AGE-STAT5 signaling, inhibiting autophagy, and the accumulation of injured mitochondria and ROS. Senescence of kidney scattered tubular-like cells is induced by ischemic renovascular that weakens their reparative capacity [60]. In a study on renal transplant biopsies, all cases had a positive P16^INK4A nucleus staining in their distal tubules and collecting ducts, accompanied by vascular smooth muscle cells (VSMCs), parietal epithelium of glomeruli, podocytes, and interstitial cells positive staining in some cases [61].

Life-threatening AKI is mainly triggered by surgeries, ischemia, and nephrotoxic stimuli [34, 62]. During the occurrence of AKI, the kidney is subjected to various forms of stress and challenges [38, 63], which can readily induce cellular senescence. There is a mounting body of evidence indicating a close association between cellular senescence and the underlying pathophysiology of AKI, as they both exhibit a cell cycle arrest at the G2/M phase, heightened oxidative stress, an increase in cyclin-dependent kinase inhibitors, telomere shortening, and an exacerbated in the fibrotic processes. The reduction of klotho expression in the context of AKI might also facilitate the onset of senescence and hinder the recovery mechanisms following an episode of AKI [64]. Furthermore, the activation of Notch signaling has been observed in I/R-induced AKI models, subsequently triggering the activation of p21 and p16^INK4a and intensifying interstitial fibrosis development [65]. On the other hand, emerging evidence indicates that senescent TECs contribute to the development of AKI and the transition from AKI to CKD [66, 67].

In cases of mild and moderate AKI, approximately 70% of quiescent tubular cells can re-enter the cell cycle from a dormant state within the first 24 h, engaging in regeneration and proliferation, thereby facilitating the recovery of kidney function and structure [68]. However, during maladaptive repair after severe AKI, TECs can undertake a senescence-like phenotype due to telomere shortening, elevated levels of cyclin kinase inhibitors (mainly p21), and downregulated in Klotho expression. In a paracrine manner, senescent TECs give rise to senescence in surrounding cells [69]. The profibrotic and proinflammatory mediators of SASP stimulate the infiltration of immune cells and tubular cell damage generating in persistent tubulointerstitial inflammation, the proliferation of fibroblasts, and extreme extracellular matrix deposition augmenting kidney damage and the progression to CKD. Senescent immune cells, such as CD14⁺ CD16⁺ monocytes and CD28⁻ T cells also exacerbate kidney ROS production and chronic inflammation, promoting CKD progression [44].

The selective removal of senescent cells significantly alleviates physical dysfunction and a healthy lifespan in mice. In a contrast-induced AKI model, paricalcitol pre-treatment could reduce tissue damage and cellular senescence [66]. Likewise, Lipoxin A4 by blocking crosstalk between premature senescence and inflammation could restore kidney function in septic-induced AKI mice [67]. These data support that cellular senescence can be a new target for AKI management and restoring its balance could have prospective benefits.

CKD serves as a clinical model of premature and enhanced kidney aging. Individuals with CKD experience a substantially hastened aging process described by cardiovascular diseases, osteoporosis, muscle wasting, persistent uremic inflammation, and frailty, even before reaching end-stage renal failure. All of these complications share similar pathological features associated with senescent cells. However, due to the complex correlation between CKD and senescence, it is challenging to judge if the senescent kidney cells are a consequence or a trigger of CKD.

Evidence indicates that kidney senescence participates in the progression and pathogenesis of CKD. For example, in kidney allografts undergoing the transition from AKI to CKD, the level of p21 is elevated [70]. Moreover, in an elderly I/R injury mouse model of CKD, microvascular rarefaction and inflammation are more significant compared to young controls [71]. Increased levels of senescence markers and senescent cells have been documented in the I/R injury and UUO models, as well as in kidney biopsy from patients with CKD [72]. In these studies, senescent cells were predominantly identified as tubular epithelial cells [42], implying that kidney diseases progress in the context of senescence within these specific cells.

The CKD-associated activation of anti-aging (e.g. reduced expression of klotho, loss of autophagy) and aging-promoting (e.g. inflammation, oxidative stress, uremic toxins, overactivation of the RAS, hyperphosphatemia) factors make important contributions to an elevated cellular senescence in CKD. The SASP in senescent cells shares similarities with the CKD-associated secretory phenotype [35]. Both involve the secretion of profibrotic and pro-inflammatory factors that can lead to further tissue damage and dysfunction. For instance, in a renal fibrosis model following I/R injury, higher levels of TNF-α and MCP-1 were reported [71]. Moreover, elevated levels of MCP-1, epidermal growth factor, IL-1α, IL-6, and VEGF are seen in the blood samples of patients with early CKD [73]. Additionally, urine studies of CKD patients were in favor of elevated TGF-β1, MCP-1, and IL-8 [74]. Cellular senescence in aged kidneys with CKD shows reduced function and elevated vulnerability to AKI [71, 75–78].

Senescence of TECs is also involved in glomerular diseases including diabetic nephropathy, IgA nephropathy (IgAN), UUO, focal segmental glomerulosclerosis [79], and lupus nephritis (LN) [80]. Moreover, studying tubular TECs of healthy living kidney donors and patients with glomerular disease using P16^INK4A staining revealed that senescence was more present in cases compared to controls (80% vs. 21%) [80]. Furthermore, kidneys with IgAN are associated with elevated P21^CIP1 and P16^INK4A protein expression in tubular cells [72]. Studies showed that telomere shortening and aging biomarkers especially accompanying the progression of IgAN were not significant in other glomerular diseases [81]. Renal TECs in patients with IgAN displayed features of augmented senescence similar to mechanisms accompanying normal aging [72]. Cellular senescence has a key role in LN pathogenesis by accumulating p16^INK4a-positive cells [82]. There is a clear association between the accumulation of this type of cells in the biopsy of all patients with lupus and the severity of kidney involvement [83].

Senescent podocyte, endothelial, and mesangial cells may contribute to DN. Recent studies have shown that proximal TECs are the main target for diminished glucose-induced metabolic disarrays in DN. High glucose levels by increasing miR‐378i expression, an impending biomarker of renal impairment, can prompt the senescence of TECs. In the tubular, meningeal, and podocyte cells of patients with type 2 diabetes, the level of p16 expression and senescence-associated beta-galactosidase (SA‑β‑gal) activity is increased, establishing a straight connection between hyperglycemia and the initiation of senescence [84].

The kidney has various metabolic roles, hence, metabolic syndrome has important effects on the kidney by aggravating kidney damage [85]. It has been shown that the intensity of allograft, diabetes, and IgAN is correlated with the severity of the senescence [72, 86, 87], which is seen in all of these diseases [72, 88]. However, diabetes is the most known condition in terms of cellular senescence in the renal system. Furthermore, the degree of senescence before kidney transplantation is capable of predicting the patients’ outcome regarding graft success [89], indicating that targeting senescent cells may be an efficient therapeutic strategy in renal diseases, and various studies have reported improved renal function and attenuated kidney fibrosis following decreased senescent cells. For instance, inhibition of p53 based on small interfering RNAs is related to reducing cellular senescence and renal fibrosis in rats [90]. This is believed to be partially in association with the function of cell cycle-arrested tubules (at G2/M) that have a part in the production of increased amounts of renal fibrosis-related [91] SASP components such as TGF-β and CCN2 [92, 93]. Renal exposure to hyperglycemic conditions in patients with DM2 drastically enhances the burden of cellular senescence, which is particularly seen among TECs and podocytes [87]. In one study, seven days of exposure to streptozotocin-induced hyperglycemia in mice caused an increase in the renal burden of cellular senescence through SASP [55]. In another study, an increase in aggregation of senescent cells in hyperglycemic rats took only 10 days, which was mostly seen in cortical cells [94]. Surprisingly, the decreased burden of cellular senescence in an obesity-induced metabolic dysfunction model improved glucose homeostasis and insulin sensitivity that was accompanied by declined microalbuminuria and enhanced podocyte function [95].

Senescent epithelial cells initiate maladaptive repair following aging and injury, contributing to the development of kidney fibrosis [44]. In addition, the extent of renal fibrosis in mice is directly related to the level of senescence markers [71]. Although the exact underlying mechanism is not clear, multiple studies have supported the concept of senescence’s role in renal fibrosis progression through transgenic or pharmacological elimination of senescent cells in animal models [96–98]. The investigation of post-injury renal tissue has revealed senescence-mediated progressive fibrosis, decreased vascular density, and organ malfunction through SASP activation. Moreover, the elevated levels of senescent cells were related to poorer renal function and outcome [99]. This is in line with the previously found evidence that indicates prolonged exposure to SASP (such as stemness induction) impairs tissue regeneration [100].

The role of senescence in kidney fibrosis has been approved by a decline in fibrosis in mice lacking p16 expression after I/R injury [41, 101]. Although most of these studies are animal studies, some studies have indicated the role of senescence in human renal fibrosis. Multiple reports have shown that the burden of senescent cells predicts the transplant renal function and is positively associated with the extent of tubular atrophy and fibrosis [89, 102–104].

Given the scenario of kidney cell senescence in kidney aging and diseases, the main question is how to avoid the senescence process and whether AKI and CKD can be repaired. Targeting anti-aging signaling pathways by interventional strategies can be clarified for reversing and/or avoiding cellular senescence over time. These interventions could be alterations in lifestyle [105], modulating SASP, probiotics, antioxidants, inhibitors of NF-κB and mTOR, and activators of Nrf2, sirtuins, and AMPK, as well as senolytic drugs. Maique indicated that klotho inhibits aging induced by high phosphate in the proximal tubular epithelial cells [106]. In another study, klotho could also inhibit mitochondrial cellular aging, DNA injury, and oxidative stress in a mouse with immune complex-mediated glomerulonephritis and thereby increase animal survival, maintain kidney function, improving tubulointerstitial and glomerular injury [107]. Therefore, it is suggested that klotho supplementation may serve as a proper therapeutic approach for the management of CKD and other age-related diseases [108].

Senotherapeutic agents are useful for attenuating aging and age-related disease footprint. These agents are categorized as senolytics (selective killers of senescent cells), senomorphics (blockers of SASP), and senoinflammation (immunity-mediated removers of senescent cells, also called inflammaging) [109]. MSCs and their paracrine factors can be other sources of anti-senescence interventions that modify the characteristics of senescent cells or delete them (Fig. 4).

The first senolytic agents including Quercetin and Dasatinib were introduced by Zhu et al. in 2015. Quercetin, a plant flavonoid effective, was used against senescent human bone marrow-derived MSCs (BM-MSCs) and endothelial cells of mice, both of which led to a decrease in senescent cell burden [110]. It was shown that Dasatinib and Quercetin treatment could inhibit several age-associated mice disorders including CKD [111] and it has been applied in a human clinical trial with unpublished results (NCT02848131↗) [7, 112]. Since then, seven types of senolytic agents have been introduced so far, consisting of kinase inhibitors, histone deacetylase (HDAC) inhibitors, heat shock protein 90 (HSP90) inhibitors, p53 binding inhibitors, Bcl-2 family inhibitors, and UBX0101 [113]. In addition, it was reported that oral apigenin could diminish increased expression levels of SASP and IκBζ in old rat kidneys [114].

Senostatics can prevent elements of the senescent phenotype without removing the cells. Drugs familiar to nephrologists including rapamycin (sirolimus) and metformin by improving mitochondrial function and activating autophagy can extend lifespan [115]. Metformin also decreased aging in the TECs [116].

Natural compounds.

Quercetin, fisetin, piperlongumine (PL), and natural phytochemicals present senolytic potentials in in vitro studies. In senesced human WI-38 fibroblasts, PL selectively induces apoptosis through ionizing radiation, H-Ras activation, or replicative exhaustion [117]. Fisetin preferentially removes irradiation-induced senescent HUVECs. However, no effect on IMR90 or pre-adipocytes has been established [118].

UBX0101 is a small molecule with senolytic potential that inhibits the interaction between MDM2 and p53 [119]. Intra-articular injection of this agent has been associated with decreased accumulated senescent cells in the synovium and articular cartilage of aged mice induced by apoptosis, leading to attenuated osteoarthritis (OA) following trauma [119]. UBX0101 is also capable of improving the cartilage-rejuvenation capacity of chondrocytes within human OA tissue [119]. The first senolytic agent, UBX0101, has entered a phase-1 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03513016↗).

Forkhead box protein O4 (FOXO4) is a key protein with a pivotal role in keeping senescent cells alive. Bioinformatic studies of RNA sequences of senescent cells induced by I/R suggested that FOXO4-DRI (fork head box O transcription factor 4-D-retro-inverso) peptide is a novel agent with senolytic potential that blocks the interplay between p53 and FOXO4 in senescent IMR90 cells and HUVECs leading to apoptosis in these cells [97]. FOXO4-DRI is also effective in fitness, hair density, and kidney function improvement in aged mice [97].

Although, there is a wide variety of target proteins for senolytic agents for instance p53, Bcl-xL, Bcl-2, HSP90, and a tyrosine kinase, the discovery of novel targets for these agents is of great importance. Moreover, the cell-specific activity of senolytics suggests that cellular senescence is differentially regulated within different types of cells making it difficult to develop a single effective agent for all types of cells [109].

Senomorphics are diverse agents with regulatory features in senescent cells with indirect induction of apoptosis. Treatment of senescent cells with senomorphics modifies the phenotype conversion of these cells to young normal cells through SASP, senescence-related signal pathways, and interference with senoinflammation. Among well-known senomorphic compounds, telomerase activators [120], caloric restriction diets [121] and mimetics [122], proteasome activators [123], autophagy activators [124], antioxidants [125], mTOR inhibitors [126], sirtuin activators [127], and anti-inflammatory agents targeting inflammaging /senoinflammation [128] can be mentioned.

ssKU-60,019 induces the practical recovery of the autophagy/lysosome axis, accompanied by metabolic replanning and restoration of mitochondrial function [129]. This agent is an inhibitor of Ataxia-telangiectasia mutated (ATM) kinase activated through DNA double-stranded breaks and is involved in senescent cell regulation [130].

JH4 is another small molecule with senomorphic features that interferes with the junction between progerin and lamin [131]. Progerin is a shortened lamin protein related to the Hutchitson-Gilford progeria syndrome (HGPS) which accumulates by cumulative shortening of telomere throughout fibroblast cells senescence [132]. JH4 could alleviate the deformation of the nucleus and cellular senescence, and return aging biomarkers like growth arrest SA-β-Gal activity, and HGPS [131]. The administration of JH4 significantly reduced multiple age-related disorders [131]. Plant-derived natural compounds, consisting of quercetagetin 3,4′-dimethyl ether [133], (−)-loliolide [134], quercetin-3-O-β-D-glucuronide [135], and juglanin [136] are recognized as agents with senomorphic potential that decline the level of p53 and SAβG in senescent HUVECs and HDFs.

mTOR activity significantly increases in normal senescent kidneys. Although activated mTOR increases p21 expression levels followed by SASP release and cell cycle arrest in senescent cells, rapamycin could block the proinflammatory phenotype as a senomorphic agent [137].

Senoinflammation (also called inflammaging) indicates the long-lasting, sterile, low-grade, and unresolved inflammatory situation accompanied by aging [138, 139]. NF-κB present in an active form in the elderly, is a principal transcription protein involved in senoinflammation and its activity is connected to common aging regulators, including DNA damage, mTOR, SIRT, FOXO, and IGF-1 [140]. As a result, the prevention of NF-κB has been proposed as a probable target of senomorphics. A peptide with IKK-inhibiting features, the NF-κB-activating kinase, decreased cellular senescence [141]. Furthermore, SASP has also a prominent part in the senoinflammation of senescent cells. Thus, targeting SASP in these cells could be a feasible target of senomorphics. The Janus kinase (JAK)/STAT pathway can modulate SASP and drugs with inhibitory effects on JAK alleviate senoinflammation in senescent cells, mitigate age-related organ malfunction, and improve physical activity in elder mice [142].

Not only are tissue senescent cells capable of contributing to both innate and acquired immunity, but also immune responses clear senescent cells form tissues, maintaining tissue homeostasis mostly via the DNA damage feedback [143]. However, inadequate removal of senescent cells as a consequence of senescent immunosurveillence results in facilitated aggregation of senescent cells in aged tissues and ARDs [143]. Dipeptidyl peptidase 4 (DPP4) is an enhanced glycoprotein in the plasma membrane of senescent fibroblasts, resulting in antibody and NK cell-mediated removal of DPP4-positive senescent cells [144]. CD4⁺ T cells, macrophages, and NK cells also play a vital role in the elimination of senescent cells, malignancy development prevention [144], and embryonic development [145].

Antibody-mediated targeted therapy of senescent cells is an alternative immunotherapeutic strategy to fight senescence. Since CD9 is increased in the plasma membrane of senescent cells [146], CD9 antibody-conjugated nanoparticles are developed to selectively deliver drugs to senescent cells and suppress their phenotype in HDFs [147, 148]. Despite the discovery of new senescent cell-specific cell surface proteins with senescent cells-targeting potential, the essence of new proteins’ discovery is inevitable, whose identification would help improve the development of new strategies for immunity-mediated elimination of senescent cells.

Senolytic agents carried by nanomedicines (e.g. conjugates and liposomes) have great potential for targeting and treatment of aged kidney cells especially proximal tubular cells [149]. Some studies reported that megalin and folate receptor 1α could be beneficial for targeting the proximal tubular cells [150, 151]. Small interfering RNA (siRNA) might also be another therapeutic agent against aged kidneys. Molitoris showed that the intravenous injection of p53 siRNA decreases cellular p53 and apoptosis in ischemic- and cisplatin-induced AKI models [90]. Other kidney cells (i.e. podocytes, mesangial [152, 153], and endothelial cells) have also the potential to be targeted via other surface receptors (using liposomes or nanoparticles) [154–156].

MSCs are multipotent cells with proliferative, anti-inflammatory, anti-oxidative, antimicrobial, antifibrotic, antitumor, and proangiogenic effects, contributing to tissue homeostasis and regeneration. Only recently has the clinical importance of MSCs therapy for aging commenced [157]. Preclinical and clinical studies have revealed the beneficial effects of MSC therapy in different kidney diseases [158–160]. Due to the engraftment of MSCs, recent evidence suggests that major trophic effects of MSCs are attributed to their paracrine biofactors [161]. Owing to the cell-free sources, MSC-derived products have numerous advantages over MSC therapy including low immunogenicity, no risk of tumor formation, and easy transfer into recipient cells.

MSC-derived EV therapy can improve renal outcomes in multiple animal models of AKI and CKD (Reviewed in Ref [162, 163]). The renoprotective, regenerative, anti-apoptotic, antifibrotic, anti-inflammatory, mitochondrial hemostasis, and immunomodulatory effects of MSC-EVs have been reported in these studies [161] that are mediated by a variety of mechanisms [158]. Moreover, MSC-EVs can inhibit cell apoptosis, stimulate tubular epithelial cell proliferation, and recover kidneys in plenty of AKI and CKD models, indicating their regenerative effects [158–160, 164]. Furthermore, MSC-derived factors can modulate the senescent phenotype and its associated secretory profile by targeting cellular senescence in kidney cells [165]. In the following sections, we highlight the role of MSCs and their products on senescent and aging kidneys during AKI and CKD.

It should be noted that the MSCs’ therapeutic impacts might rely on their senescence status, whether derived from young donors or not [165]. Evidence shows that young donor-derived MSCs are more effective in alleviating kidney aging than older ones [165]. The presence of longer telomeres and some regenerative factors (such as microRNAs) in younger cells may be responsible for their effectiveness. Moreover, it has been revealed that UC-MSCs are effective in decreasing the cell-cycle inhibitors’ expression compared to AD- or BM-MSCs [198]. These results propose that the impacts of MSCs are context and cell-type-dependent. Overall, MSC therapy enhances kidney function, inflammation, and fibrosis and declines IL-6 overexpression and senescence-associated β-Galactosidase activity.

Due to their immunomodulatory and therapeutic potency, MSCs are now the base of cellular and cell-free therapies in the management of many kidney diseases but MSCs are also not immune to aging. Following either the process of aging in older individuals, uremic milieu, or prolonged in vitro expansion, MSCs encounter cellular senescence [199]. It is reported that ROS production, ischemia, inflammation, cellular microenvironment, poor control of the disease, and pathophysiological uremic milieu induced by CKD/AKI can decrease the efficacy of MSC therapy due to premature cellular senescence, contributing to their poor regenerative potential [188, 200]. The senescence of MSCs-induced by CKD/AKI results in the modification of their secretory profile and a decline in their differentiation and proliferation capabilities [201]. The presence of certain senescence markers may also impair the immunomodulatory effect of MSCs, reducing their effectiveness in therapeutic contexts.

Given the failure of cell culture conditions to inverse the MSC phenotype following exposure to uremic circumstances, it is reasonable to hypothesize that epigenetic alterations, resembling those detected in aging MSCs, are prompted by CKD and this could potentially explain what has been referred to as uremic memory based on clinical clarifications. Multiple uremic factors have been identified as potential causes of MSC impairment. P-cresol and indoxyl sulfate have been shown to reduce MSC proliferation in mice. Furthermore, diabetes constructs an adverse microenvironment for MSCs, rendering their survival, and migration to infected tissue, and make functional performance more challenging. MSCs exhibit low viability and proliferation ability, accompanied by decreased glycosaminoglycans and proteoglycans in the surrounding tissues [202]. Advanced glycosylated end-products production initiates apoptosis and ROS generation, further preventing the proliferation of MSCs. Additionally, under hypoxic conditions, oxidative stress adversely affects the paracrine effects of MSCs in diabetic individuals. The elevated levels of superoxide in hypoxic MSCs impede the production of angiogenic growth factors [203, 204]. Moreover, MSCs exhibit impaired migration ability under hyperglycemic conditions [205]. Other factors that promote MSC aging and contribute to damage in stem cells include mitochondrial dysfunction, non-coding RNAs, EVs, genetic abnormality, pro-inflammatory molecules, and angiotensin II, all of which are present in kidney diseases.

Other significant challenges include MSC cell sources, the safety of MSCs, and the development of effective isolation methods. Different sources of MSCs (e.g., adipose tissue, bone marrow) show variability in their functional capabilities and aging characteristics. This heterogeneity complicates the selection of optimal MSC populations for therapy, as older or more senescent cells may not provide the desired regenerative effects. Understanding how these factors influence MSC behavior will provide insights into optimizing MSC-based therapies for kidney diseases.

There is a significant demand for the development of innovative research endeavors aimed at deepening the understanding of cellular senescence and facilitating the discovery of novel approaches to counteract senescence under pathophysiological contexts. Preconditioning of MSCs prolongs their lifespan and expands their functionality. Kim et al. suggested that metformin preconditioning MSCs could improve vessel repair and functional recovery, proliferative potential of MSCs, and inhibit CKD-induced DNA damage and senescence of MSCs. Pretreatment with metformin was found to mitigate oxidative stress and senescence in an ischemic disease model associated with CKD [206]. Metformin acts on MSCs by activating AMP-activated protein kinase (AMPK), reducing oxidative stress, modulating inflammatory pathways, and inducing autophagy, thereby maintaining cellular homeostasis and enhancing MSC longevity. Likewise, melatonin can defend CKD-MSCs against senescence by improving mitochondrial function, cell proliferation, glycolytic metabolism [207] and their regenerative potential [208]. Melatonin regulates MSCs via paracrine mechanisms, controls ROS generation, promotes cell proliferation by inducing the expression of SRY-box transcription factor 2, and modulates immune responses, all contributing to enhanced MSC survival and function. Additionally, MSCs treated with fucoidan can augment angiogenesis, regeneration, and cell proliferation in an ischemia CKD model [209]. Fucoidan exerts its effects through strong antioxidant properties, modulation of inflammatory pathways, and promotion of MSC proliferation and differentiation. Preconditioning with Tinospora cordifolia and Withania somnifera (herbal extracts) has been found to delay senescence in Wharton’s jelly MSCs [210]. These pre-conditioning strategies may contribute to maintaining the regenerative potential of MSCs and delaying the onset of senescence.

Rejuvenating MSCs can reverse aging-associated phenotypes as it is a result of cellular senescence. Preconditioning with miscellaneous pharmacological compounds, mTOR inhibitors, antioxidants, resveratrol, and Metformin can enhance the stemness and therapeutic potency of MSCs [211, 212]. Hypoxic and Serum-free medium preconditioning rejuvenates MSCs and their secreted profile [213] and it can be applied in targeting kidney senescent cells under physiological and pathological circumstances.

This study was approved by Tabriz University of Medical Sciences, Tabriz, Iran (Ethical code: IR.TBZMED.REC.1402.472).

Not applicable.

The authors declare no competing interests.

This is a review article, no new data were created or analyzed in this study.