How Aging Affects Kidney Filter Cells and Possible Treatments for Related Diseases

Cellular senescence, a key hallmark of aging, critically contributes to the functional deterioration of podocytes [14]. Senescent podocytes exhibit permanent cell cycle arrest, resistance to apoptosis, and distinct morphological and biochemical alterations, including hypertrophy and cytoskeletal simplification [6,14] (Figure 1). A primary driver of podocyte aging is telomere attrition [15]. Repeated cell division and oxidative stress cause telomeres to shorten over time. This eventually triggers a persistent DNA damage response (DDR) [16]. In podocytes, telomere dysfunction induces genomic instability and potently activates the p53-p21^Cip1 and p16^INK4a-Rb pathways, enforcing irreversible cell cycle arrest [3,6].

Additionally, senescent podocytes acquire an SASP, characterized by hypersecretion of pro-inflammatory cytokines, chemokines, growth factors, and matrix-remodeling enzymes [17]. The SASP fosters a pro-fibrotic and pro-inflammatory microenvironment within the glomerulus, exacerbating tissue injury and accelerating disease progression [7,18]. In aging kidneys, glomeruli exhibit elevated expression of senescence markers, including p16^INK4a and senescence-associated β-galactosidase (SA-β-gal), which correlates with reduced podocyte density and albuminuria [6]. Notably, the DDR not only sustains the senescent state but also perpetuates SASP signaling through persistent activation of ATM/ATR kinases and downstream NF-κB transcription factors [17].

Collectively, telomere shortening, DDR activation, and SASP propagate a self-amplifying circuit that exacerbates podocyte dysfunction and significantly contributes to the pathogenesis of age-related glomerulopathies.

Mitochondrial dysfunction constitutes a hallmark feature of senescent podocytes (Figure 1). Pronounced mitochondrial structural damage, including cristae dissolution and outer membrane rupture, was revealed in the glomeruli of aged mice. This was accompanied by upregulated expression of reactive oxygen species (ROS)-producing enzymes and diminished levels of oxidative phosphorylation complexes I–IV [19,20]. Metabolic profiling of senescent podocytes demonstrates a shift from mitochondrial respiration toward glycolytic dependence and impaired fatty acid oxidation [19]. Mechanistically, defects in the electron transport chain coupled with NADPH oxidase hyperactivity propel excessive ROS production [21]. Elevated mitochondrial ROS (mtROS) inflict damage to mitochondrial DNA (mtDNA), lipids, and proteins, precipitating mitochondrial permeability transition pore (mPTP) opening, cytochrome c release, caspase activation, and podocyte apoptosis [22].

Key regulators of mitochondrial integrity, including sirtuin 1 (SIRT1), PPARγ coactivator-1α (PGC-1α), and mitochondrial transcription factor A (TFAM), exhibit downregulation in senescent podocytes [23,24]. In aldosterone-infusion models and human nephropathies, reduced ATP production, collapsed mitochondrial membrane potential, decreased mtDNA copy number, and ultrastructural abnormalities precede podocyte loss [21,25]. Pharmacological activation of peroxisome proliferator-activated receptor Gamma (PPARγ) or SIRT1 restores mitochondrial function and attenuates ROS generation, preserving podocyte viability [25,26].

In summary, podocyte mitochondrial dysfunction manifests as compromised bioenergetics, oxidative stress, impaired quality control, and activation of cell death pathways, establishing a self-amplifying cycle that accelerates glomerular aging.

Autophagy serves as an essential quality-control mechanism in terminally differentiated podocytes, facilitating the clearance of damaged proteins and organelles to maintain cellular homeostasis [27,28] (Figure 1). Genetic ablation of the core autophagy gene autophagy-related 5 (Atg5) in podocytes induces proteinuria and accelerates glomerulosclerosis. It also leads to hallmark aging phenotypes, including lipofuscin accumulation and ubiquitinated protein aggregates [29,30]. This confirms that impaired autophagy compromises cytoplasmic renewal and directly precipitates progressive podocyte aging.

Furthermore, lysosomal dysfunction results in autophagosome accumulation, endoplasmic reticulum stress (ERS), FPE, and premature lethality in murine models [31,32]. Similarly, podocyte-specific knockout of the prorenin receptor or lysosomal proteases contributes to albuminuria, cytoskeletal disruption, and eventual glomerulosclerosis, underscoring the critical importance of lysosomal integrity to podocyte [33,34].

The autophagy-lysosome pathway exhibits functional crosstalk with the ubiquitin-proteasome system (UPS) [35]. Autophagy deficiency initially upregulates proteasomal activity, but ultimately leads to the accumulation of cytotoxic protein aggregates, exacerbating podocyte injury [32]. Intriguingly, selective induction or enhancement of autophagy via rapamycin or AMP-activated protein kinase (AMPK)/SIRT1 activators exerts protective effects on podocytes. However, excessive autophagic activity may exert detrimental effects in specific contexts [36,37].

In summary, compromised autophagic flux and lysosomal dysfunction in podocytes establish a vicious cycle characterized by misfolded protein accumulation, chronic stress response activation, cytoskeletal destabilization, and cell death.

Podocytes undergo profound epigenetic remodeling during aging and in disease states, significantly impacting gene expression, chromatin architecture, and cellular identity [38] (Figure 1). These alterations encompass DNA methylation dynamics, histone post-translational modifications, and chromatin remodeling events, collectively disrupting podocyte homeostasis [39].

Histone modifications critically influence podocyte fate. Aged podocytes exhibit reduced trimethylation of histone H3 lysine 27 (H3K27me3), attributable to decreased expression of the methyltransferase enhancer of zeste homolog 2 (EZH2). This imbalance drives transcriptional derepression of pro-senescence and pro-fibrotic genes, contributing to oxidative stress, FPE, and podocyte injury [40,41]. Dysregulation of histone deacetylases (HDACs), particularly HDAC1/2 and SIRT1/6, further exacerbates genomic instability. Podocyte-specific ablation of Hdac1/2 or Sirt1 induces proteinuria and accelerates glomerulosclerosis [42,43,44].

DNA methylation alterations prominently feature in podocyte pathology [45]. Under hyperglycemic or oxidative stress, DNA methyltransferases (DNMTs) are recruited to promoters of essential podocyte genes, inducing transcriptional silencing that disrupts SD integrity and promotes proteinuria [39]. DNMT1-mediated repression may establish an epigenetic memory, perpetuating injury responses and impairing regenerative capacity [46]. Chromatin architecture is progressively destabilized with aging. Senescent podocytes exhibit loss of constitutive heterochromatin and form senescence-associated heterochromatin foci, driven by altered histone landscapes and diminished HDAC activity. This reorganization compromises genomic integrity and reinforces SASP [42].

In summary, aging- and disease-induced epigenetic dysregulation, manifested through histone/DNA methylation defects and chromatin disorganization, disrupts core podocyte transcriptional networks, promoting senescence, dedifferentiation, and attrition of podocytes.

Podocyte foot processes rely on a precisely regulated actin cytoskeleton, anchored by SD complexes and integrin-based adhesions, to withstand hemodynamic stress and maintain GFB integrity [47]. Under the condition of aging and diseases, this actin network undergoes destabilization, precipitating FPE and weakened adhesion to the GBM, and eventually podocyte detachment [48,49] (Figure 1).

A core mechanism involves diminished expression of SD proteins, notably nephrin (NPHS1) and podocin (NPHS2) [50]. Transcriptional downregulation of these canonical genes in aged podocytes attenuates critical linkages between the SD, focal adhesions, and the actin cytoskeleton [51]. FPE, a hallmark of aging and glomerulopathies, results from dynamic actin reorganization and synaptopodin disassembly, reflecting compromised cytoskeletal stability [52].

Genetic and acquired defects in actin-regulating proteins, such as α-actinin-4 (ACTN4), inverted formin-2 (INF2), and non-muscle myosin heavy chain 9 (MYH9), contribute to aberrant actin architecture [50]. For instance, ACTN4 and INF2 mutations impair actin filament crosslinking and resilience, diminishing podocyte capacity to recover from mechanical stretch and promoting detachment under physiological stress [53,54].

Podocyte–GBM adhesion, mediated primarily by α3β1 integrins and focal adhesion components like integrin-linked kinase (ILK), is disrupted in aging. Consequently, this cascade impairs focal adhesion turnover, stress fiber formation, and lamellipodial dynamics, culminating in podocyte detachment and proteinuria [49]. Furthermore, integrin downregulation and loss of adhesion receptors progressively weaken podocyte anchorage to the GBM [55].

Collectively, aging drives progressive structural deterioration of SD complexes, actin filament organization, and adhesion machinery, ultimately manifesting as FPE and podocyte loss.

FSGS is a heterogeneous podocytopathy characterized by podocyte loss, FPE, and segmental glomerular scarring, often progressing to proteinuria and end-stage kidney disease [56]. Genetic causes, complement-mediated injury, hemodynamic and metabolic stress, and aberrant signaling pathways all converge to injure podocytes, rendering them vulnerable to senescence and detachment [56,57].

Mitochondrial dysfunction and metabolic derangement are central to podocyte aging in FSGS [21]. High-risk apolipoprotein L1 (APOL1) variants impair mitochondrial fatty acid oxidation, causing lipid intermediate accumulation, ATP depletion, and increased susceptibility to cytoskeletal instability and detachment. In addition, APOL1-mediated mitochondrial membrane disruption induces mPTP opening and mtROS overproduction, leading to oxidative damage of mtDNA and respiratory chain components [58]. This oxidative stress activates redox-sensitive pathways and enforces permanent cell cycle arrest. Meanwhile, sustained hyperactivation of rapamycin complex 1 (mTORC1), reflected by increased S6K1 and 4E-BP1 phosphorylation, promotes podocyte hypertrophy and anabolic overload by aggravating mitochondrial stress, ERS, and proteotoxicity [59].

Autophagy impairment and aberrant cell cycle reentry are key drivers of podocyte aging in FSGS [27]. Hyperactivation of the rapamycin (mTOR)/S6K1 axis by methyltransferase-like 14 (METTL14)-mediated m⁶A methylation suppresses SIRT1, a central regulator of autophagy and mitochondrial quality control [60]. Consequently, defective autophagosome formation hampers the clearance of damaged mitochondria, oxidized proteins, and cytoskeletal aggregates, leading to chronic ERS and enhanced DDR, which reinforce senescence signaling. In parallel, aberrant expression of mitotic arrest deficient 2-like protein 2 (MAD2B) induces forced cell cycle reentry, culminating in mitotic catastrophe and ultimately podocyte loss [61].

Inflammatory and complement-mediated mechanisms critically reinforce podocyte aging in FSGS. Activation of the complement component C5a/C5a receptor 1 (C5aR1) axis promotes inflammation, apoptosis, and a senescence-like phenotype, driving podocyte detachment and GFB disruption, while C5aR1 inhibition alleviates injury and disease progression [62]. Similarly, podocyte protease receptor 1 (PAR-1) stimulation induces stress, cell cycle dysregulation, and senescence signaling, leading to podocyte dysfunction and glomerulosclerosis [63]. In addition, inflammatory cues upregulate C–C chemokine receptor type 2 (CCR2) in podocytes, enhancing monocyte/macrophage recruitment, chronic inflammation, and local immune infiltration [64]. This inflammatory burden exacerbates podocyte injury, redox imbalance, and DDR, thereby consolidating the senescent phenotype.

Cytoskeletal disruption and mechano-transductive stress exacerbate podocyte fragility. Loss of key structural proteins, including α3β1 integrin, Crumbs homolog 2 (Crb2), and FAM40A, together with dysfunction of actin regulators such as Rho-associated coiled-coil containing protein kinase 2 (ROCK2) and focal adhesion kinase (FAK), disrupts cytoskeletal organization and SD stability [52,65,66]. In parallel, nuclear exclusion of yes-associated protein (YAP), often induced by biomechanical stress, suppresses gene programs required for cytoskeletal repair and mechanosensing, leading to FPE, SD breakdown, and weakened GBM adhesion [67]. This structural vulnerability exposes podocytes to aberrant mechanical forces, which activate senescence-related pathways, impair repair capacity, and accelerate podocyte detachment and senescence [52].

Epigenetic and post-translational dysregulation consolidate podocyte senescence in FSGS. METTL14-mediated m⁶A modification of SIRT1 transcripts represses this longevity-associated deacetylase, impairing oxidative stress resistance, DNA repair, and mitochondrial function, and disrupting chromatin maintenance [60]. Under chronic glomerular stress, transient receptor potential canonical 6 (TRPC6) activation with downstream S6 kinase phosphorylation drives compensatory hypertrophy, which imposes excessive metabolic and biosynthetic load, exacerbating replication stress and senescence [59]. Collectively, these events reshape podocyte transcriptional and chromatin landscapes, locking cells into a senescent state that perpetuates glomerular injury.

In FSGS, podocyte aging arises from mitochondrial dysfunction, autophagy blockade, inflammation–complement activation, cytoskeletal disassembly, and epigenetic reprogramming (Figure 2 and Figure 3). Recognition of these intersecting mechanisms underscores potential interventions to delay podocyte aging and slow FSGS progression.

MCD is an idiopathic podocytopathy and the leading cause of nephrotic syndrome, characterized by proteinuria, edema, and profound FPE [68]. Recent discoveries suggest an autoimmune component beyond classical podocyte injury [69,70,71,72].

Podocyte aging is central to the pathogenesis of MCD. Oxidative stress and lipid-driven inflammation activate the cluster of differentiation 36 (CD36)–NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome–pyroptosis cascade, elevating interleukin-18 (IL-18) and ox-LDL levels [73]. Nephrin autoantibody binding at the SD triggers nephrin phosphorylation and cytoskeletal remodeling, perpetuating podocyte stress [69]. Interleukin-33 (IL-33), via group 2 innate lymphoid cells (ILC2)-mediated type 2 T helper cells (Th2) cytokines, may exert protective effects but also contribute to inflammation and podocyte imbalance [71]. Dysregulated cluster of differentiation 80 (CD80)–cytotoxic T-lymphocyte antigen 4 (CTLA4) signaling further promotes cell cycle arrest, cytoskeletal disorganization, and mitochondrial dysfunction [70]. Collectively, these mechanisms enforce podocyte senescence, disrupt the GFB, and underlie the relapsing nature of MCD.

MN is an immune complex-mediated podocytopathy characterized by subepithelial immune deposits and complement activation, particularly C3 and C5b-9, which form the membrane attack complex (MAC) on podocytes and drive proteinuria [74,75]. Primary antigens such as phospholipase A2 receptor (PLA2R) drive this cascade, further exacerbated by C3a/C3aR-mediated podocyte injury [76,77].

Complement-mediated mitochondrial dysfunction initiates podocyte pyroptosis, dependent on ROS, caspase-1, Gasdermin D (GSDMD), and NLRP3 activation, which amplifies inflammatory signaling, SASP, and permanent cell cycle arrest [78]. In MN, impaired autophagy is driven by PLA2R and secretory phospholipase A2 group IB (sPLA2-IB) through p38MAPK/mTOR signaling, which phosphorylates unc-51 like autophagy activating kinase 1 (ULK1) at Ser757 and blocks AMPK–ULK1 interaction to inhibit autophagy initiation [79]. Insufficient autophagic flux causes accumulation of damaged mitochondria and misfolded proteins, aggravating oxidative stress and senescence. C5b-9 and lysosomal dysfunction further block autophagy, promoting cytoskeletal injury, SD disassembly, and podocyte detachment [80]. These events form a vicious cycle that accelerates podocyte aging and glomerular damage in MN.

Unlike FSGS, where metabolic stress dominates, podocyte senescence in MCD and MN is primarily shaped by immune dysregulation and complement activation, underscoring inflammatory-immune pathways as the main drivers (Figure 2 and Figure 3).

Podocyte aging is a key pathological event in DKD. Podocytes from type 2 DKD patients show elevated senescence markers, correlating with proteinuria and hyperglycemia, indicating accelerated cellular senescence in the diabetic milieu [81,82].

Mitochondrial dysfunction and oxidative stress are fundamental drivers of podocyte aging in DKD. Hyperglycemia induces mtROS via the NADPH oxidase 4 (NOX4)/TRPC6 axis, causing oxidative stress, mtDNA damage, and ATP loss [83]. Dysregulation of mitochondrial regulators, including A-kinase anchoring protein 1 (AKAP1), uncoupling proteins 2 (UCP2), acyl-coenzyme A:lyso-cardiolipin acyltransferase-1 (ALCAT1), and mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), collectively disrupts mitochondrial integrity and energy metabolism. AKAP1 deficiency impairs mtDNA biogenesis [84]; UCP2 loss increases ROS and impairs autophagy [85]; pathological ALCAT1 upregulation generates peroxidized cardiolipin, promoting membrane instability and cytochrome c release [86]; and mGPDH loss disrupts the glycerophosphate shuttle and oxidative phosphorylation [87]. Protective progranulin (PGRN) normally facilitates mitophagy and biogenesis, but its loss causes damaged mitochondria to accumulate [88]. In parallel, reduced signaling regulatory protein α (SIRPα) enhances pyruvate kinase M2 (PKM2) nuclear translocation, shifting metabolism from oxidative phosphorylation to aerobic glycolysis, aggravating mitochondrial dysfunction and SASP activation [89]. Together, these mechanisms compromise podocyte viability, diminish regenerative capacity, and enforce senescence.

In DKD, autophagy impairment and lysosomal dysfunction drive podocyte aging. High glucose activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mTORC1 pathway, inhibiting the ULK1/autophagy-related 13 (ATG13) complex and blocking autophagosome formation [90]. Concurrently, TRPC6-mediated calcium influx and calpain activation disrupt autophagic flux by impairing vesicle trafficking and lysosomal fusion [91]. YAP inhibition reduces Wilms tumor 1 (WT1) expression, suppressing autophagy-related genes [92], while noncoding RNAs such as circ-0000953 and CircHIPK3 interact with miR-665-3p to further repress autophagy networks [93,94]. These defects lead to the accumulation of dysfunctional mitochondria and p62-positive aggregates, compromising proteostasis and accelerating podocyte senescence [95].

Epigenetic and transcriptional dysregulation increase podocyte susceptibility to senescence in DKD. Accumulation of advanced glycation end-products (AGEs) suppresses EZH2, reducing H3K27me3 and activating pro-senescent transcriptional programs, while restoring EZH2 mitigates injury [96]. Methyltransferase-like 3 (METTL3)-mediated m⁶A modification stabilizes tissue inhibitor of metalloproteinases 2 (TIMP2) mRNA, enhancing stress signaling and podocyte injury, which is alleviated by METTL3 silencing [97]. Downregulation of disruptor of telomeric silencing 1-like (DOT1L) alters H3K79 methylation, therefore compromising genomic integrity [98]. Epigenetic upregulation of regulator of calcineurin 1 (RCAN1) activates calcineurin–nuclear factor of activated T cell (NFAT) signaling, promoting oxidative stress, inflammation, and cell cycle arrest [99]. LncRNAs, such as plasmacytoma variant translocation 1 (PVT1), HOXB3OS, and ENST00000436340, modulate pro-apoptotic transcripts, SIRT1 stability, and vesicular stress, respectively [100,101,102]. Additionally, glycogen synthase kinase 3 β (GSK3β) activation impairs β-catenin and nuclear factor erythroid 2-Related Factor 2 (NRF2) to weaken antioxidant defenses [103]. Increased Src homology region 2 domain-containing phosphatase-1 (SHP-1) activity reduces podocin SUMOylation, compromising SD integrity and cytoskeletal architecture [104]. Collectively, these alterations disrupt homeostasis and enforce podocyte senescence.

In DKD, podocyte aging is accelerated by lipotoxicity and chronic inflammation. Excess lipid accumulation, driven by dysregulated lipid transport and metabolism, disrupts mitochondrial β-oxidation and energy homeostasis and induces ERS. G protein-coupled receptor 43 (GPR43) activation enhances lipid uptake and triggers extracellular signal-regulated kinase (ERK)/early growth response 1 (EGR1) signaling, whereas its deficiency improves insulin sensitivity via AMPKα [105,106]. Loss of carnitine palmitoyltransferase-1A (CPT1A) further exacerbates lipotoxic stress and apoptosis [107]. Lipid overload activates the NLRP3 inflammasome, which is modulated by junctional adhesion molecule-like protein (JAML) and C–X–C chemokine ligand 16 (CXCL16), leading to IL-1β, IL-6, and TNF-α release and a pro-inflammatory microenvironment [108,109,110]. These cytokines activate downstream death pathways, including PANoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and death receptor 5, and apoptotic signaling amplified by retinoic acid receptor responder protein-1 (RARRES1) [111,112].

Compared with FSGS, DKD features additional systemic metabolic insults from hyperglycemia and lipid overload, which amplify oxidative stress and inflammatory signaling, highlighting the interplay between systemic metabolic derangements and podocyte senescence (Figure 2 and Figure 3).

LN features accelerated podocyte aging driven by immune complex deposition, complement activation, and chronic inflammation [113]. Sublytic assembly of C5b-9 on the membrane of podocyte induces mtROS generation and oxidative DNA damage, triggering irreversible cell cycle arrest [114,115].

In LN, impaired autophagy drives podocyte senescence and injury [116]. Nestin, an intermediate filament protein specific to podocytes, enhances mitophagy, clearing damaged mitochondria and reducing mtROS, thereby protecting podocytes from oxidative stress [117]. Conversely, CD36 upregulation suppresses autophagic flux, weakening cellular defenses [118]. While inflammatory stimuli such as interferon-α (IFN-α) and pathogenic antibodies can induce protective autophagy [119], inhibition or overwhelming of autophagy renders podocytes highly susceptible to irreversible senescence.

Inflammasome activation contributes to podocyte aging in LN [120]. CD36 inhibits autophagy and activates the NLRP3 inflammasome, promoting IL-1β release and SASP-driven local inflammation, which induces paracrine senescence in neighboring glomerular cells [118]. C5a/C5aR1 triggers mitochondrial stress and amplifies inflammation, synergizing with NLRP3 to accelerate podocyte aging [121].

Mitochondrial dysfunction is a key driver of podocyte aging in LN. C5a/C5aR1 promotes dynamin-related protein 1 (DRP1) phosphorylation, causing excessive mitochondrial fragmentation, ROS accumulation, oxidative DNA damage, and activation of senescence pathways [122]. Conversely, Nestin preserves mitochondrial integrity via mitophagy, reducing ROS and cellular injury [117].

Loss of cytoskeletal integrity contributes to podocyte aging in LN. Upregulated Piezo1 responds to mechanical stress by increasing Ca²⁺ influx, activating Rac1 and paxillin signaling, and driving cytoskeletal remodeling, FPE, and GFB disruption. Concurrent nephrin downregulation or mislocalization further impairs podocyte function, promotes senescence, and exacerbates proteinuria and glomerular injury [123].

In LN, podocyte aging is driven by impaired autophagy, inflammasome activation, mitochondrial dysfunction, and cytoskeletal disintegration (Figure 2 and Figure 3). Unlike DKD, where metabolic stress dominates, or MCD/MN, where adaptive immune responses are key, LN emphasizes autoimmunity-induced inflammasome activation and complement-mediated mitochondrial injury as the central drivers of senescence.

Hypertension and obesity impose unique stressors on podocytes, driving premature podocyte aging through convergent molecular pathways, manifesting as elevated p21^Cip1, p53, and SASP expression independent of chronological age [124].

In hypertensive nephropathy (HN), podocyte aging is driven by mechanical stress, redox imbalance, aberrant protein modifications, and proteostasis disruption [125,126]. Upregulated Piezo1 transduces biomechanical strain via Ca²⁺ influx, activating Rac1 and downstream cytoskeletal remodeling and leading to FPE. While four-and-a-half LIM domains protein 2 (FHL2) amplifies Rac1 activity, destabilizing the actin cytoskeleton [127,128,129]. Concurrent angiotensin II overactivation impairs anaerobic glycolysis, causing energy deficits, mitochondrial dysfunction, and activation of senescence signaling [130]. Post-translational modifications further contribute. Ubiquitin-specific protease 22 (USP22) stabilizes high mobility group box 1 (HMGB1), enhancing angiotensin II-induced inflammation, oxidative stress, and apoptosis [131], whereas sirtuin 2 (SIRT2) preserves cytoskeletal integrity by deacetylating Septin4 [132]. Hypertensive stimuli also suppress heat shock protein 70 (Hsp70), compromising proteostasis, inducing protein aggregation and ERS, and accelerating senescence [133]. Together, these alterations impair podocyte integrity and regenerative potential, promoting chronic aging in HN.

In obesity-related glomerulopathy (ORG), podocyte aging is driven by lipid overload, chronic inflammation, and mitochondrial stress [134]. Excess lipids are internalized via CD36, intensified by phosphatase and tensin homolog (PTEN) downregulation, leading to lipotoxicity and activation of the ROS/NF-κB/NLRP3 inflammasome axis [135,136]. Chronic inflammation causes cytoskeletal disarray, mitochondrial damage, and cell cycle arrest, while reduced adiponectin further weakens antioxidant and anti-inflammatory defenses [137]. Mediators such as purinergic 2X7 (P2X7) and acid sphingomyelinase enhance inflammasome activity and propagate paracrine injury via inflammatory exosomes [138,139]. Compensatory WT1 upregulation partially maintains podocyte identity but cannot prevent progressive podocyte loss [140,141]. Dysregulated Wnt/β-catenin signaling, overactivated by aldosterone, drives dedifferentiation, mesenchymal transition, and senescence-associated gene expression [142].

Podocyte aging in HN and ORG arises from overlapping stress pathways. In contrast to FSGS and DKD, where intracellular metabolic or hyperglycemic stress predominates, HN and ORG highlight biomechanical strain and lipid-induced inflammation as the main drivers of premature podocyte aging (Figure 2 and Figure 3).

Genetic podocytopathies such as Alport syndrome (AS) and Fabry disease (FD) drive premature podocyte aging through hereditary defects that impair structural integrity and intracellular homeostasis [143,144] (Figure 2 and Figure 3).

In AS, podocyte aging arises from inherited GBM structural defects due to COL4A3, COL4A4, or COL4A5 mutations, which disrupt type IV collagen networks and impose chronic stress on overlying podocytes [145,146,147]. Disease progression further drives aging through oxidative stress, DNA damage, cytoskeletal disruption, and lipid stress. Key mediators include NOX4, amplifying mtROS, and matrix metalloproteinase-2 (MMP-2), degrading extracellular matrix (ECM) and weakening podocyte–GBM adhesion, leading to DDR and cell cycle arrest [148,149,150]. Loss of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) disrupts cytoskeletal integrity and membrane dynamics, increasing susceptibility to detachment and apoptosis [151], while p53 overactivation promotes premature senescence [152]. Vascular endothelial growth factor A (VEGFA) accumulation in the GBM and discoidin domain receptor 1 (DDR1) activation link matrix abnormalities to lipid-mediated injury, further exacerbating mitochondrial damage, ERS, and autophagic impairment [153,154]. Together, inherited structural fragility and acquired stress-induced mechanisms converge to drive podocyte senescence in AS.

FD, an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leads to globotriaosylceramide (GL-3) accumulation in podocytes, driving aging through multiple interrelated pathways [155,156,157]. Progressive GL-3 buildup correlates with podocyte loss, structural damage, and proteinuria, particularly in female heterozygous carriers [158,159]. FD podocytes exhibit ERS, chronic inflammation, and impaired autophagy, notably disrupted autophagosome–lysosome fusion, causing accumulation of damaged mitochondria and undegraded substrates, which exacerbate oxidative stress and trigger senescence [160,161,162]. Furthermore, ceria–zirconia nanoparticles have been shown to restore autophagic flux and reduce GL-3 accumulation in FD, highlighting the potential of autophagy-targeting strategies [163]. α-Synuclein accumulation contributes to cytoskeletal disorganization and FPE, while ferroptosis-related pathways enhance susceptibility to oxidative injury [164,165,166]. Integrin α3β1 dysfunction further impairs adhesion, promoting detachment and mechanical instability [167]. Collectively, GL-3 accumulation initiates a self-reinforcing cascade of autophagy impairment, cytoskeletal collapse, ferroptotic signaling, and adhesion loss, leading to sustained podocyte aging and progression of Fabry nephropathy.

Unlike acquired podocytopathies, genetic diseases feature primary hereditary defects that predispose podocytes to chronic stress, making ECM disruption and lysosomal substrate accumulation key triggers of premature aging.

Senolytic therapy has emerged as a promising approach to alleviate podocyte aging. In both animal models and human studies, the senolytic combination of dasatinib and quercetin (D + Q) effectively eliminates senescent cells, reduces the SASP, and improves kidney structure and function [168] (Table 1).

Mechanistically, D + Q therapy alleviates podocyte aging by modulating key signaling pathways associated with aging and cellular stress. Quercetin, a flavonoid with antioxidant and anti-inflammatory properties, promotes autophagic clearance of damaged organelles and misfolded proteins in aged podocytes by activating AMPK signaling and inhibiting mTOR signaling [169]. In DKD models, the D + Q combination specifically activates autophagy and inhibits Notch pathway overactivation, a known inducer of podocyte dedifferentiation and senescence, thereby preserving podocyte identity and reducing proteinuria. Additionally, D + Q reduces the expression of senescence markers (p16^INK4a and p21^CIP1) and improves mitochondrial integrity, thereby reinforcing cellular resilience under metabolic stress [170].

Beyond diabetic models, senolytic therapy has shown beneficial effects in acute and chronic kidney injury contexts, suggesting its broader applicability across podocytopathies [171]. In murine models of ischemia–reperfusion injury and renal fibrosis, D + Q treatment reduced senescent cells in renal tubules and glomeruli, facilitated tissue repair, and attenuated progression to CKD. These outcomes underscore the dual benefit of senolytics: both halting maladaptive aging responses and reactivating regenerative programs [172,173]. Importantly, senolytic therapy is under clinical investigation for renal aging, and combining it with autophagy enhancers or anti-fibrotics may improve outcomes in age-related podocytopathies [174]. However, a key knowledge gap remains regarding the long-term safety, optimal dosing, and tissue-specific targeting of senolytic therapy in podocytes, which must be addressed before its widespread clinical application can be made.

Podocyte regeneration represents a novel and promising strategy to counteract podocyte aging and loss in podocytopathies. Unlike terminally differentiated podocytes, renal progenitors, including parietal epithelial cells (PECs), can differentiate into new podocytes under certain conditions [175] (Table 1).

Drug repurposing offers a pragmatic and efficient avenue to identify therapies that mitigate podocyte aging, particularly by leveraging the known safety profiles of existing compounds. Several widely used medications have demonstrated anti-aging and renoprotective effects in preclinical models of podocytopathies (Table 1).