Long-Term Kidney Disease and Aging of Body Cells

Cellular senescence can be categorized into two primary subtypes: acute and chronic. Acute cellular senescence may be induced by extracellular signals targeting specific cell populations within the tissue. This orchestrated process can yield beneficial outcomes, including the modulation of embryogenesis, the containment of tumorigenesis, the facilitation of wound healing, and the enhancement of tissue restoration [51]. Acute senescence serves as a protective reaction in response to various kidney injuries, facilitating immune clearance and tissue restoration [52]. In a timely manner, infiltrating macrophages eliminate acutely senescent cells. However, if the immune system fails to keep up with the pace of senescent cell generation and senescent cells are not promptly eliminated, they tend to accumulate over time and have the potential to develop into chronic senescence [53]. In the kidney, this immune surveillance is partly mediated by natural killer cells, which recognize and eliminate senescent renal tubular epithelial cells through NKG2D-dependent activation and perforin-mediated cytotoxicity, a process that can be impaired under immunosuppressive conditions [54].

Additionally, prolonged exposure to stressors or persistent damage can also trigger chronic senescence, which plays a key role in hindering cell renewal and repopulation [55]. It also contributes to the progression of CKD by inducing chronic inflammation and fibrotic reactions through the release of SASP factors. Primary senescent cells originate following various detrimental stimuli, including oxidative or proteostatic stress, defects in DNA repair, activation of oncogenes, and the shortening of telomeres, among others (Figure 2). In the kidney, senescence may arise through distinct mechanisms, including replicative senescence driven by telomere attrition and stress-induced premature senescence (SIPS). In largely post-mitotic or slowly proliferating renal cells, such as podocytes, senescence is more likely driven by stressors including oxidative stress, hypoxia, and uremic toxins rather than replicative exhaustion. These mechanistic differences may influence both the selection of senescence markers and the response to senotherapeutic interventions. Each of these triggers can shape the phenotype of senescent cells, and similarly, the same trigger can result in different senescent phenotypes in cells from different cell types [56].

The secretion of SASP factors by primary senescent cells can drive secondary senescence through two fundamental mechanisms [57]. The first mechanism, known as paracrine senescence, involves releasing SASP factors that propagate senescence both locally and systemically in the extracellular fluid and via the bloodstream [58]. The second mechanism, referred to as juxtacrine senescence, entails primary senescent cells inducing and reinforcing senescence in adjacent cells through direct cell-to-cell interactions, including cell fusion and intracellular protein transfer [59,60,61,62]. Consequently, secondary senescence can lead to a small subset of senescent cells expanding and spreading to distant locations, further contributing to age-related diseases.

A study has shown that the transplantation of relatively small quantities of senescent cells into the peritoneum of young mice is sufficient to induce enduring physical dysfunction and propagate cellular senescence within the host tissues. Furthermore, the transplantation of a smaller number of senescent cells yielded a similar impact in older recipients, leading to decreased survival [63]. This underscores the potency of senescent cells in diminishing both health and lifespan and indicates the potential for the spread of senescence-associated complications within different tissues.

Cellular senescence can be identified using a range of hallmarks and biomarkers, though no single marker consistently or reliably defines this complex state [64]. Senescent cells typically display an enlarged size, an increased activity of senescence-associated beta-galactosidase (SA-β-Gal), an accumulation of lipofuscin granules, and senescence-associated heterochromatin, among others [65,66]. Table 1 summarizes key markers frequently utilized to detect senescence, particularly in kidney research [17].

Among these, SA-β-Gal activity, linked to increased lysosomal content, is the most widely used marker [67,68]. However, relying solely on SA-β-Gal as a marker for senescent cells has limitations, as its activity can increase in non-senescent cells in dense cell cultures, and it is unsuitable for identifying senescent cells in paraffin-embedded tissue [67]. To address these limitations, researchers often examine additional molecular markers and pathways associated with senescence.

For example, signaling pathways leading to permanent cell cycle arrest, such as the p16/pRb and p53/p21 pathways, are critical. Early growth response 2 (Egr2), a transcriptional activator of these pathways, has been proposed as a potential senescence marker [69]. Other promising markers include tRNA-derived fragments, positive cofactor 4 (PC4), histone acetyltransferase KAT7, and Cdkn1a transcript variant 2 [70]. Elevated levels of Cyclin-Dependent Kinase (CDK) inhibitors such as p16^Ink4a (p16), p21^Cip1 (p21), p19^ARF (in mice), p14^ARF (in humans), p27^KIP1, and p15^INK4b are also indicative of senescence. DNA damage, another hallmark of senescence, is often marked by histone H2AX phosphorylation (γ-H2AX), which is associated with senescence-related alterations in DNA organization [71,72]. Additionally, nuclear changes, such as the accumulation of senescence-associated DNA damage foci (SADF) and senescence-associated heterochromatic foci (SAHF), reflect alterations in DNA structure and organization. Overexpression of SAHF-associated proteins induces senescence and represses genes related to cell proliferation [72].

Other changes include downregulation of cell proliferation markers such as Ki67 and PCNA as well as depletion of Lamin B1 (LMNB1), a structural nuclear protein [73]. Notably, the decrease in LMNB1 has been demonstrated in both apoptotic and senescent cells. However, the underlying cause for this reduction is different between these two cell states. Apoptotic cells experience LMNB1 degradation by caspases, whereas senescent cells exhibit reduced LMNB1 levels due to decreased mRNA stability [67]. Urinary clusterin has also been reported as a non-invasive biomarker of renal epithelial senescence and is associated with the progression of human kidney disease [74].

Additionally, single-cell RNA sequencing reveals that different senescent subtypes may exist, underscoring the need for a combination of markers for accurate determination of cellular senescence. A proposed three-step multi-marker workflow involves assessing SA-β-Gal activity as the first step, followed by co-staining for markers such as p16, p21, γ-H2AX, and LMNB1, and finally examining senescence markers relevant to the specific biological context [75].

In kidney disease, artificial intelligence (AI) and machine learning (ML) are increasingly applied in two complementary areas: (i) omics-based biomarker discovery and patient stratification, and (ii) imaging-based detection of senescent cells in histological samples (Table 2). These approaches differ substantially in their translational readiness and clinical applications.

Cellular senescence entails a network of signaling pathways, with the p53/p21 and p16 pathways being the primary drivers. When stressors induce DNA damage, the ATM protein kinase and p53, p21, and p16 become activated as a response [98]. Ultimately, these occurrences inhibit CDK complex phosphorylation and the retinoblastoma protein (Rb), causing cell proliferation to halt and cellular senescence to occur. The p53/p21 pathway is thought to play a part in triggering cellular senescence, whereas p16 signaling is predominantly implicated in maintaining and initiating the senescent phenotype [17].

SCAPs encompass mechanisms that are responsible for prolonging the survival of senescent cells, despite the presence of triggers that would typically lead to apoptosis, such as their own SASP [75]. SCAPs involve the activation of various factors such as the BCL-2 family, ephrin ligand B1 (EFNB1), EFNB3, Forkhead box O-4 (FOXO-4), HSP90/p-AKT, and p21/JNK, all of which play crucial roles in senescent cell survival and persistence [99,100].

Specifically, BCL-2 hinders autophagy by interacting with the autophagy protein Beclin1 and inhibiting the formation of autophagosomes [101]. FOXO-4 functions as a sequester for p53 in the nucleus, thereby restricting p53-mediated apoptosis [76]. Notably, interfering with the FOXO-4-p53 interaction leads to improved kidney function [76]. The activation of p21 prevents senescent cells from undergoing apoptosis by constraining JNK signaling and caspase activation [102]. Additionally, the stabilization of p-AKT by HSP90 contributes to the extended survival of senescent cells [103].

Klotho and sirtuin 1 (SIRT1) are intrinsic elements investigated for their anti-aging properties and their potential to prevent cellular senescence and premature aging. Klotho is a single-pass transmembrane protein mainly present in the kidney; however, our group has also shown that Klotho is expressed in the liver of naked mole rats [104,105]. Klotho also acts as a co-receptor for fibroblast growth factor 23 (FGF23), a hormone involved in phosphate metabolism that is markedly elevated in CKD, and emerging evidence suggests that dysregulation of the FGF23–Klotho axis may contribute to oxidative stress, inflammation, and pathways linked to cellular senescence [104]. Research has shown that serum levels of Klotho decline with age and in CKD, implying its possible use as a biomarker of aging [104,106]. Mice lacking Klotho display an accelerated aging phenotype, encompassing a shorter lifespan, infertility, impaired growth, diminished cognitive function, and abnormal calcification [107]. Conversely, transgenic mice overexpressing Klotho demonstrate extended lifespan and protection against age-related disorders [108]. Klotho may exert its protective effects by inhibiting the p53/p21 and Wnt/β-catenin pathways [109,110]. Specifically, Klotho was shown to protect against CKD by safeguarding aging cells from mitochondrial dysfunction and cellular senescence through the inhibition of Wnt/β-catenin signaling [111].

SIRT1 is an NAD⁺ dependent deacetylase acting on both histone and nonhistone proteins like FOXO, p53, and NF-κB. Thus, SIRT1 significantly influences central signaling pathways linked to cellular senescence and aging [112]. SIRT1 is broadly expressed in regular renal tubular cells and podocytes, but its levels diminish with the onset of renal diseases or during aging [113]. Investigations suggest that the depletion of SIRT1 in podocytes of mice results in glomerular sclerosis, a sign of aging [114]. Accordingly, the elimination of SIRT1 in endothelial cells can induce senescence via p53 acetylation, whereas overexpression of SIRT1 prevents or reverses senescence by suppressing p53 activity [115,116,117]. Moreover, research indicates that sodium tetrasulfide (Na2S4) can directly sulfhydrate SIRT1, hindering p65 NF-κB and STAT3 phosphorylation/acetylation, thus alleviating diabetic renal lesions [118].

Senescent cells have also been implicated in the disruption of NAD⁺ metabolism by secreting SASP factors which can activate the NAD⁺ consuming enzyme CD38 in macrophages. This may result in increased NAD⁺ consumption in CD38-containing tissues and result in the depletion of NAD⁺ with age [119,120]. Our group has observed an overexpression of the CD38 gene 24 h after induction of severe acute kidney injury (AKI) in rats, and this overexpression persisted continuously for 14 days post-surgery. This occurred in conjunction with the overexpression of other proinflammatory markers, even though other parameters in this model were returning to normal [106]. These findings indicate that senescent cells contribute to a decline in the level of NAD⁺, which may drive senescence-dependent age-related conditions, e.g., diabetes [121].

Recent discoveries have highlighted several additional pathways associated with kidney aging and cellular senescence, offering potential targets for therapeutic intervention. Among these, NF-κB inhibitors play a central role in regulating senescence and aging processes in the kidney. By reducing oxidative DNA damage and cellular stress, these inhibitors delay the onset of senescence. This effect is mediated through the regulation of IKKε, IKKα, and IKKβ, which are influenced by proinflammatory cytokines, pathogens, oxidative stress, and growth factors [122]. Targeted deletion of Myd88, an adapter protein in the NF-κB signaling pathway, has further demonstrated its protective role in kidney health by reducing fibrosis and preventing the accumulation of senescent tubular epithelial cells following folic acid-induced kidney injury [123]. Myd88 deletion also reduced the expression of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, TNF-α, and MCP-1, leading to improved outcomes in renal fibrosis. This suggests the involvement of innate immune signaling in cellular senescence after kidney injury [123].

In addition to intrinsic cellular pathways, immune cells may also contribute to the inflammatory milieu associated with senescence in CKD, as circulating monocytes and other immune cells can undergo functional reprogramming and promote chronic inflammatory signaling.

The Wnt/β-catenin signaling pathway has been identified as another critical contributor to age-related renal fibrosis and cellular senescence [103,104]. Activation of this pathway induces senescence, as indicated by increased levels of senescence markers like p16, p53, and p21, as well as enhanced SA-β-Gal activity in renal tubular epithelial cells [77]. In addition, the calcium-activated chloride channel accessory 1 (CLCA1), acting via the TMEM16A/Cl⁻ current pathway, has emerged as a newly recognized factor in aging-related kidney damage [124]. Interestingly, Benidipine exerts renoprotective and cardioprotective effects through the triple blockade of L-, N-, and T-type calcium channels. Moreover, this calcium channel blocker has been shown to promote the clearance of cigarette smoke-induced senescent cells and alleviate lung emphysema [125].

Another contributor to kidney aging is the cannabinoid receptor 2 (CB2), which has been linked to mitochondrial impairment in renal tubular cells. CB2 activation appears to accelerate mitochondrial dysfunction, negatively impacting renal aging and health [126].

Finally, circadian rhythm regulation also plays a pivotal role in regulating aging processes. Disruptions in circadian balance have been associated with increased senescence while maintaining proper circadian function supports cellular repair mechanisms [127]. Additionally, intestinal microbiome imbalances and microbial metabolism alterations have been shown to impair cellular reparative potential and contribute to aging processes [128,129,130,131].

Senolytic interventions can be achieved by overcoming senescent cells’ resistance to apoptosis through interference with SCAP pathways activity, thereby inducing programmed cell death [140]. Senolytics, including quercetin, a natural flavonoid found in certain fruits and vegetables, eliminate senescent vascular smooth muscle and endothelial cells in animal models [172,208]. Quercetin activates various pathways, such as AMPK, SIRT1-PINK1-mediated mitophagy, and NRF2-NF-κB signaling, to induce apoptosis in senescent cells [172,208,209,210]. It has been demonstrated that quercetin reduced senescence markers in obese mice’s kidneys and positively affected cardiac function in high-fat diet-fed mice due to its pro-angiogenic activity [211]. Additionally, in an in vitro study, quercetin significantly reduced the expression of NAMPT at the protein level. Narita et al. showed in mice that NAD⁺ stimulates components in SASP through NAMPT, the enzyme of the NAD⁺ salvage pathway [212]. Quercetin inhibited nicotinamide mononucleotide (NMN), an NAD⁺ metabolite in the salvage pathway, accumulation in mesangial cells cultured under high glucose conditions. Quercetin can also enhance the expression of SIRT1 and NMNAT; thereby, they can regulate NAD⁺ metabolite [213]. This finding suggested that inhibition of NMN accumulation may be a promising target for kidney senescence.

The combination of Dasatinib plus Quercetin (D+Q) demonstrated the ability to inhibit renal senescence and prevent the decline of renal function in both chronologically aged and transgenic aging mice [63]. This observation highlights a significant association between SCAPs and CKD. D+Q also increased α-Klotho levels in the urine, kidney, and brain of mice with an increased burden of senescent cells. In humans, D+Q elevated α-Klotho levels in the urine of patients diagnosed with idiopathic pulmonary fibrosis, a condition linked to cellular senescence [214].

The use of fisetin, another senolytic compound, reduced kidney damage in mice experiencing exacerbated atherosclerosis due to diabetes by blocking the CD36/fibrosis pathway [215,216]. Fisetin also decreased SA-β-Gal expression in senescent tubular renal cells and inhibited TGF-β-induced proliferation of renal fibroblasts [217]. In a murine model of lupus nephritis, fisetin reduced proteinuria scores and led to decreased expression of p15 in tubular epithelial cells and increased the number of proliferative Ki-67+ cells. The expression of SA-β-Gal, p53, p21, and p16 in renal tubules was reduced by fisetin in a model of cisplatin-induced murine CKD [218]. In mice with diabetes-exacerbated atherosclerosis, fisetin ameliorated the regulation of uric acid, urea, and creatinine levels, reduced morphological damages and fibrosis in the kidney, and improved glomerular function [215]. Furthermore, fisetin reduced the senescent cell burden and prevented kidney fibrosis in a telomerase-deficient progeria mouse model with elevated levels of p16 and p21 in kidney tissues [219]. This effect appeared to be mediated by induction of apoptosis in senescent cells, resulting from the inhibition of the Akt pathway through downregulation of stanniocalcin 1 (Stc1) [219]. Fisetin may also exert its senolytic effects by directly binding to and inhibiting anti-apoptotic proteins such as Bcl-xL and Bcl-2 [220,221]. These findings highlight the diverse mechanisms employed by senolytic drugs.

Other natural compounds derived from plants, such as procyanidin C1, alongside herbal extracts, demonstrate senolytic characteristics [173,222,223]. Ginsenoside, an extract sourced from ginseng, is a well-regarded anti-aging agent that hinders the aging of bone marrow rescue mesenchymal stem cells (MSC) by activating NRF2 and PI3K-Akt signaling pathways [224]. It also modulates the SASP, diminishes inflammation, sustains oxidative balance, and alleviates organ aging [225,226]. These findings suggest that targeted dietary interventions involving senolytic properties have the potential to decelerate the advancement of senescence-associated CKD.

AP20187, a synthetic dimerizer compound derived from the FK1012 system used in the INK-ATTAC transgenic model, can selectively induce apoptosis in p16-positive senescent cells by activating a caspase-based suicide mechanism in experimental mouse models [142]. In mice, targeted removal of p16 expressing senescent cells leads to a reduction in age-associated brain inflammation and stenotic kidney function and better cognitive performance [174,227]. Navitoclax (ABT-263), alongside other inhibitors of the BCL-2 family like A-1331852, A-1155463, EF24, and venetoclax, demonstrated potent senolytic impacts in aging animal models and specific types of senescent cells in laboratory investigations [175,222,228]. Particular caution may be required due to hematological side effects of some senolytics. Furthermore, inhibitors of heat shock protein 90 exhibited senolytic behavior, and radio-electric asymmetric carrier technology (REAC), a type of non-invasive therapeutic technique, was effectively used to diminish senescence in cultured stem cells [103,229].

It is important to note that certain senolytics are more specific toward particular cell types or types of senescence. Therefore, clarification is needed regarding the appropriate senolytic to use in specific contexts. To increase precision, minimize unintended impacts, and streamline the practical implementation of senolytic interventions, there is promise in utilizing strategies focused on specific organs or cells. This can be achieved through the utilization of targeted delivery technologies such as carriers, including protein-based or peptide-based systems, nanoparticles, extracellular vesicles, or alternative delivery methods. For instance, a particular approach involves attaching cytotoxic medications to antibodies that are engineered to identify the senescent cell surface marker β2-microglobulin [176]. Elevated expression of β2-microglobulin occurs through a process that is dependent on p53, indicating its correlation with senescence triggered by stress.

Another approach incorporates the activation of invariant NK T cells to enhance immune alertness and facilitate the removal of senescent cells [179]. Furthermore, senolytic impacts have been observed both in laboratory settings and within living organisms through the implementation of chimeric antigen receptor (CAR) T cells that are specifically engineered to identify the urokinase-type plasminogen activator receptor on the surface of senescent cells [180]. Moreover, encouraging outcomes have been achieved in mouse models with obesity by creating anti-aging vaccines aimed at CD153+ senescent T cells or GPNMB+ senescent endothelial cells [181].

Senomorphic drugs have gained significant attention, with metformin standing out as a well-examined example offering diverse benefits [230]. Metformin not only reduces the occurrence of age-related diseases but may also extend the lifespans of various organisms like Caenorhabditis elegans, mice, and individuals with type 2 diabetes mellitus [182]. Metformin has also been suggested to disrupt IKK/NF-κB activation, thereby preventing the emergence of the SASP [231]. Additionally, metformin may regulate the SIRT1-p300-p53-p21 pathway to prevent endothelial senescence caused by high glucose-induced metabolic memory (metabolic memory refers to the lasting effects of transient hyperglycemia, where prior high glucose levels cause persistent damage, even after glucose normalizes) [232]. Furthermore, metformin stimulates immune-mediated removal of senescent cells and reinstates effective immune surveillance against tumors [233].

Another illustration of a senomorphic drug is ruxolitinib, a JAK inhibitor that mitigates inflammation and weakness in elderly mice by suppressing inflammatory components of the SASP [183]. Additionally, mTOR inhibitors like rapamycin display senomorphic characteristics by restraining senescence and suppressing SASP in endothelial cells [184] and fibroblasts [234] through the induction of autophagy, which reduces the accumulation of damaged cellular components. Activation of mTOR leads to mitochondrial biogenesis dependent on peroxisome proliferator-activated receptor-γ coactivator 1β, production of ROS, and persistent activation of the DDR [235]. Consequently, inhibiting mTOR may prevent cellular senescence. Similarly, the anti-fibrotic drug pirfenidone has shown renoprotective and senomorphic effects in preclinical studies by dampening profibrotic and inflammatory pathways and reducing SASP factors. More broadly, TGF-β inhibitors and anti-TNF-α therapies may also modulate SASP signaling [159,185].

Various hormones also exhibit senomorphic effects. For example, melatonin hinders the expression of SASP genes by disrupting the recruitment of poly-(ADP-ribose) polymerase 1 (PARP1) by CREB-binding protein (CBP), a sensor for DNA damage [186]. Melatonin has also been demonstrated to enhance the functionality of senescent T cells [236], alleviate mitochondrial dysfunction in the heart of a mouse model with accelerated senescence [237], and rescue MSCs from senescence triggered by uremic toxins in CKD [238]. Other hormones, such as androgens [187], estrogens [188], estradiol [189], and glucocorticoids [190], can also influence the release of inflammatory cytokines. However, care should be exercised with glucocorticoids as they can induce senescence in primary human tenocytes [190].

Certain herbal compounds, including resveratrol [191] and other SIRT1-activating molecules, have been investigated as potential rejuvenating agents due to their ability to modulate oxidative stress, inflammation, and SASP signaling [135]. However, although these agents show promising effects in experimental models, their clinical efficacy and translational potential in CKD remain uncertain. Moreover, various activators of SIRT1 have been employed to prevent and treat senescence-related renal dysfunction [239]. Examples include SRT1460 [201], SRT1720 [202], SRT2183 [203], D-Pinitol [204], Isoliquiritigenin [205], and Rutin [240] (Table 4). Furthermore, other SIRT1 activators, such as NAD⁺, have been shown to exert beneficial effects on renal diseases; however, the timing of the treatment appears to be important [45].

Recent evidence reframes diabetic CKD as a systemic pro-ageing disorder driven by an integrated senescence–Klotho–sirtuin axis. SGLT-2 inhibitors and GLP-1 receptor agonists are now recognized not only as cardio-renal protective agents but also as modulators of molecular ageing pathways, with SGLT-2 inhibition showing indirect senolytic activity [28,29,30,31,32,33].

The expression of Klotho can be enhanced by reactivating endogenous Klotho or supplementing exogenous Klotho, leading to improvements in renal fibrosis and a reduction in senescence [206]. Strategies such as demethylation of the Klotho gene promoter, Klotho gene delivery, and inhibition of histone deacetylases have the potential to up-regulate Klotho [206]. Several drugs have been reported to increase endogenous Klotho levels [206], including intermedin, which can further alleviate senescence-related renal changes [241]. Additionally, the direct administration of exogenous soluble Klotho has proven effective in increasing circulating Klotho levels and preventing CKD in animal models. However, studies examining circulating Klotho levels and kidney function in CKD patients show conflicting results [242]. While several studies report reduced circulating or renal Klotho levels associated with CKD progression and worse renal outcomes [110,206], others have found weaker or inconsistent correlations in clinical cohorts [242]. This discrepancy may reflect differences in CKD stage, variability in methods used to measure soluble Klotho, and the possibility that Klotho deficiency may act both as a driver of cellular senescence and as a downstream consequence of chronic kidney injury [110,206]. Klotho deficiency may therefore amplify senescence pathways by increasing oxidative stress and profibrotic signaling.

Therefore, while rejuvenating strategies targeting metabolic and longevity pathways remain conceptually attractive, further clinical studies are required to clarify their therapeutic relevance in CKD.

Lifestyle choices can either speed up or slow down aging. Insufficient sleep may accelerate aging by triggering the DDR and the release of SASP factors [243]. On the other hand, a healthy lifestyle with regular exercise and controlled calorie intake has been proposed to slow down the aging process [244,245].

Research involving animals and humans has revealed that lifelong exercise or consistent moderate physical activity among older individuals yields positive outcomes regarding immunosenescence and age-related conditions like metabolic disorders and hepatic steatosis. These benefits are attributed to the modulation of mitochondrial function, inflammation, the SASP, and the process of lipolysis [197,198,246]. Conversely, excessive caloric intake has been linked to an expedited senescence process in mice [247], while caloric restriction has been shown to reduce senescence in dogs [199] and adipose tissue in mice [248]. These findings emphasize caloric restriction’s crucial role in extending lifespan and delaying age-related chronic conditions.

Dietary interventions impact age-related well-being through changes in epigenetic patterns and shifts in the gut microbiota. Nutrients such as betaine, choline, and folate contribute to beneficial epigenetic changes, countering age-related and CKD-related alterations by targeting the methylome or chromatin. Excessive sugar intake is linked to age-related diseases through reduced microbial diversity in animal models, among many other processes [200].

Lifetime exposure to external stressors, including temperature changes, oxygen fluctuations, and poor nutrition, triggers adaptive homeostatic mechanisms [249]. Among these mechanisms are antioxidant and anti-inflammatory responses, which are activated via the NRF2-KEAP1 signaling pathway [249]. By influencing these exposures, novel approaches can be explored to prolong the phase of healthy living, combat CKD, and potentially yield favorable effects on cellular senescence. These observations suggest that the timing of senotherapeutic intervention relative to disease stage and regenerative capacity may be a critical determinant of therapeutic success.

No new data were created or analyzed in this study. Data sharing is not applicable to this article.