
==== Front
Ren Fail
Ren Fail
Renal Failure
0886-022X
1525-6049
Taylor & Francis

39248407
10.1080/0886022X.2024.2398712
2398712
Version of Record
Review Article
Chronic Kidney Disease and Progression
Podocyte senescence: from molecular mechanisms to therapeutics
Q. Zhao et al.
Zhao Qian a#
Huang Yongzhang a#
Fu Ningying a#
Cui Caixia b
Peng Xuan c
Kang Haiyan a
Xiao Jie a
https://orcid.org/0000-0002-1525-6143
Ke Guibao a
a Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
b Department of Nephrology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
c Department of Nephrology, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu, China
# Qian Zhao, Yongzhang Huang and Ningying Fu contributed equally to this work as first authors.

CONTACT Jie Xiao 13600097893@163.com
Guibao Ke gbke@outlook.com Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang West Road, Guangzhou, China.
9 9 2024
2024
9 9 2024
46 2 239871221 12 2023
25 8 2024
26 8 2024
KnowledgeWorks Global Ltd.6 9 2024
published online in a building issue6 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

As an important component of the glomerular filtration membrane, the state of the podocytes is closely related to kidney function, they are also key cells involved in aging and play a central role in the damage caused by renal aging. Therefore, understanding the aging process of podocytes will allow us to understand their susceptibility to injury and identify targeted protective mechanisms. In fact, the process of physiological aging itself can induce podocyte senescence. Pathological stresses, such as oxidative stress, mitochondrial damage, secretion of senescence-associated secretory phenotype, reduced autophagy, oncogene activation, altered transcription factors, DNA damage response, and other factors, play a crucial role in inducing premature senescence and accelerating aging. Senescence-associated-β-galactosidase (SA-β-gal) is a marker of aging, and β-hydroxybutyric acid treatment can reduce SA-β-gal activity to alleviate cellular senescence and damage. In addition, CCAAT/enhancer-binding protein-α, transforming growth factor-β signaling, glycogen synthase kinase-3β, cycle-dependent kinase, programmed cell death protein 1, and plasminogen activator inhibitor-1 are closely related to aging. The absence or elevation of these factors can affect aging through different mechanisms. Podocyte injury is not an independent process, and injured podocytes interact with the surrounding epithelial cells or other kidney cells to mediate the injury or loss of podocytes. In this review, we discuss the manifestations, molecular mechanisms, biomarkers, and therapeutic drugs for podocyte senescence. We included elamipretide, lithium, calorie restriction, rapamycin; and emerging treatment strategies, such as gene and immune therapies. More importantly, we summarize how podocyte interact with other kidney cells.

Keywords

Podocyte senescence
molecular mechanisms
biomarkers
intervention targets
Guangdong Basic and Applied Basic Research Foundation 10.13039/501100021171 2023A1515012474 Guangzhou City Science and Technology Project 2023A03J0344 202201020508 Chengdu Medical Research Project 202303053935 This study was supported by Guangdong Basic and Applied Basic Research Foundation (No. 2023A1515012474), Guangzhou City Science and Technology Project (No. 2023A03J0344 and No. 202201020508), and Chengdu Medical Research Project (No. 202303053935).
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pmcBackground

Characteristics and role of podocytes

Together with endothelial cells and the glomerular basement membrane, podocytes form the glomerular filtration barrier and therefore play a key role in maintaining the blood-urine barrier for high molecular weight proteins. Podocytes are terminally differentiated glomerular epithelial cells. In mature glomeruli, podocytes do not readily proliferate under normal conditions or in response to multiple injuries; therefore, the loss of podocytes cannot be compensated by regenerative proliferation [1,2].

Podocyte senescence

Senescence

Senescence is a programmed biological process that occurs in response to various stressors, including telomere uncapping, oncogene activity, oxidative stress, and so on [3,4]. Senescence induces stable growth arrest to effectively ensure that damaged or transformed cells do not perpetuate their genomes and is usually accompanied by substantial phenotypic changes, including chromatin remodeling and metabolic reprogramming [5,6]. When the podocytes enter senescence, they undergo a series of morphological and metabolic changes [7]. Age-dependent glomerulosclerosis and the accompanying decline in glomerular filtration rate are parallel to changes in the structure, number, and function of all four resident glomerular cell types: podocytes, mesangial cells, endothelial cells, and mural epithelial cells [8–10].

Identifying the site of cellular senescence in the kidney

Molecular mechanisms and epidemiological and clinical evidence of renal aging suggest that aging is a major cause of the increased incidence of acute kidney injury and chronic kidney disease [11]. Identification of the site of senescence can help guide the use of anti-aging drugs to treat kidney injury, and early identification of podocyte senescence allows us to take measures to mitigate or interrupt senescence, reduce glomerular damage, and protect residual kidney function. In patients with hypertension, urinary extracellular vesicles(EVs)levels may help identify sites of intrarenal cellular senescence, and in patients with relatively preserved renal function, substantial podocyte senescence or extracellular vesicle shedding of senescent podocytes is associated with glomerular damage, as direct glomerular damage is marked by an increase in podocyte-specific EVs. However, we cannot exclude the presence of some non-renal-derived extracellular vesicles in urine [12,13].

Podocyte senescence and its core role

Podocytes are key cells involved in aging [14] and play a central role in the damage caused by renal aging [15]. Age-dependent glomerulosclerosis has been considered a podocyte disease [16]. The number and density of podocytes decrease with age [17], and aged podocytes undergo senescence [18], stress [19], and decrease in slit diaphragm proteins [17]. This is manifested by the accumulation of senescence markers in podocytes, structural instability, impaired function, increased extracellular matrix synthesis, and increased albuminuria [15]. Therefore, understanding the normal aging process of podocytes will allow us to understand their susceptibility to injury and identify targeted protective mechanisms [17].

Mechanisms of podocyte senescence

Senescent cells accumulate with increasing chronological age

In podocytes, senescence increases with healthy aging (Figure 1a) [17,20–22] in which metabolism and inflammatory pathways are activated. Although senescent cells are in a growth-arrested state, they remain metabolically active and exhibit a hypersecretory phenotype called senescence-associated secretory phenotype (SASP) [23]. In tissues with cellular senescence, pro-inflammatory cytokines (e.g., interleukin −1(IL-1), IL-2, IL-6, IL-8, tumor necrosis factor-α (TNF-α)) and anti-inflammatory cytokines (e.g., IL-1 receptor antagonist, transforming growth factor-β (TGF-β)) are secreted simultaneously. NOD-like receptor 3 (NLRP3) inflammasome, which acts as a mediator in SASP induction, and its downstream effector caspase-1 increase in the aged podocytes, which further produce pro-inflammatory cytokines IL-1β and IL-18 that accelerate podocyte senescence[23,24]. What is more, in normal and healthy aging processes, pro-inflammatory cytokines and anti-inflammatory cytokines are in a delicate balance, when this balance is disrupted, cellular senescence is accelerated [14,15,20,22,25,26]. Many involved proteins in podocyte disappearance in different clinical settings are also altered during aging [17,27,28].

Figure 1. Mechanisms of podocyte senescence. Several mechanisms lead to podocyte aging: (a) The physiological aging process induces cellar senescence. (b) SASP components enhance senescence through autocrine and paracrine pathways, whereas senescent podocytes can secrete pro-inflammatory cytokines, growth factors, proteases, and extracellular matrix components through SASP, which leads to their detachment and loss. (c) Podocytes experience damage resembling an aging phenotype if they fail to undergo autophagy. (d) Selective chemical inhibition of the mitochondrial function and depletion of mitochondrial sirtuins trigger senescence. (e) There is a notable downregulation in many candidate transcription factors, their regulators, and their downstream targets in senescent podocytes, such as NOTCH1, which induces production of the SASP pro-inflammatory cytokines IL-1, IL-6, and IL-8 in profoundly senescent cells. Other factors include GRHL2 and PDCD 1. On the other hand, Pod-Sirt1RNAi, the transcription factor p53, and PD-1 are upregulated. (f) When telomere shortening reaches a critical size, it leads to aging by activating the DNA damage response. (g) The DNA damage response is activated by DNA double-strand breaks, which activate tumor suppressor p53 while stimulating the expression of p21, mediating aging-related cell cycle arrest. (h) SAHF is a heterochromatin domain that enhances DDR-resistant heterochromatin structure and inhibits DDR signaling. (i) Some oncogenes induce cellular senescence by inducing NADPH oxidase to produce ROS, promoting the initial hyperproliferative phase associated with altered DNA replication and DNA damage accumulation.

Podocyte senescence with SASP

Senescence is mediated by the cell cycle-dependent kinase inhibitors p21WAF1, p16INK4a, or p15INK4b, which induce permanent blockade of the cell cycle [29,30]. This block is coupled with the secretion of molecules of the SASP [31]. SASP is usually secreted by senescent cells through autocrine/paracrine pathways (Figure 1b), which is a hallmark of senescent cells [24,26]. EVs have been identified as key mediators of the paracrine aging effect of the SASP and its native properties [32,33]. A variety of SASP effectors that are released as soluble molecules or EVs [34,35] or are enriched in the plasma during human aging and age-related diseases [36]. In fact, SASP is a common feature of various types of aging [15]. The cell type undergoing senescence and how senescence is triggered determines the composition of the SASP [24]. An example is the increased secretion of multiple damage-associated molecular patterns (DAMPs), including calreticulin and high mobility group box 1, by senescent fibroblasts under all senescence inducers. But, the secretion of central DAMPs was significantly reduced or unchanged by senescent renal epithelial cells, demonstrating that some defining soluble SASP components vary depending on cell type. In addition, dysfunctional mitochondria cause a distinct senescence response, termed mitochondrial dysfunction-associated senescence, which lacks the IL-1-dependent proinflammatory arm of the SASP [34,37]. Podocyte senescence may have similar mechanisms in disease and aging processes but produce different SASP components, leading to different phenotypes [38]. Senescent podocytes have been found to secrete proteases, growth factors, pro-inflammatory cytokines, and extracellular matrix components through the SASP [6,39], contributing to their detachment and loss [38].

In terms of SASP regulation, the establishment and secretion of SASP factors can be modulated by inhibiting heat shock protein 90, a ubiquitously expressed molecular chaperone that plays an important role in protein stabilization and degradation [40,41]. Rapamycin can regulate mammalian target of rapamycin (mTOR) activity and autophagy, attenuate the expression of SASP factors, and extend health span in vivo [42,43]. Furthermore, in the colons of mice and healthy humans, calorie restriction reduces p16 levels and the transcriptional expression of genes associated with cellular senescence, including SASP (Table 1) [44].

Table 1. Drugs/interventions against podocyte senescence.

Drugs/Interventions	Mechanism	Ref.	
Calorie Restriction	Calorie restriction play a role in podocytes by regulating autophagy.

Calorie restriction can reduce p16 levels and the transcriptional expression of genes associated with cellular senescence, including SASP, and in mice, it can reduce DDR and improve the telomere.

	[44]	
Elamipretide (SS-31)	It is associated with SIRT1, which improve mitochondrial function by improving OXPHOS coupling, increasing ATP synthesis, enhancing electron transfer through cytochrome c, and reducing ROS production.	[27]	
HDAC inhibitor	Low-dose HDAC inhibitors can reduce CCFs and inhibit SASP.

HDAC4 inhibitor TMP269 can inhibit the phosphorylation of p53 induced by folic acid and ischemia / reperfusion, and maintain the expression of E-cadherin, BMP7, Klotho and Bcl-2 in the injured kidney.

	[45,46]	
Anti-PD-1 antibody	Improve the metabolic state of the podocytes, reduce intracellular inflammation, decrease the SASP in aging podocytes, reduce stress, enhance autophagy, and improve survival.	[20]	
β-hydroxybutyrate	Reducing senescence-associated staining for β-galactosidase activity, reducing the expression of key mediators of senescence signaling, such as p16INK4a and p21, and preserving synaptophysin expression.

Selectively activating Nrf2 and enhancing antioxidant response.

	[25]	
Dasatinib + quercetin	Inhibiting a broad spectrum of protein kinases and tyrosine kinases and reducing markers of aging.

Administration of dasatinib and quercetin improve kidney function, increased expression of WT1, and decreased p16 levels.

Decreasing mRNA levels of genes encoding proinflammatory cytokines: IL-1β, TNF-α, has an anti-inflammatory effect and reduces chronic inflammation.

Quercetin is potent antioxidant that substantially increase the expression of anti-aging marker protein SMP30.

	[3,47–51]	
Lithium	Targeted inhibition of GSK3β in podocytes.

Leukocyte telomeres in humans taking lithium over long periods were approximately 35% longer than non–lithium-treated controls.

	[22,52]	
Rapamycin	Inhibiting mTOR signaling pathway, and regulate many essential cellular processes, including translation, transcription, and autophagy, it can also attenuate the expression of SASP factors, and reverse podocyte hypertrophy in the presence of injury

Increasing Nrf2 levels, which activates autophagy, and reduces induction of cellular senescence in vitro.

	[42,43,53]	
MCC950	In middle-aged mice using the NLRP3 inhibitor MCC950 have a higher podocyte density and higher levels of health span markers, reduced podocyte senescence, and SASP.	[21]	
Magnesium lithospermate B(MLB)	MLB is extracted from Salviae miltiorrhizae, it can ameliorate renal oxidative stress through reduction of reactive oxygen species.
MLB can decrease the level of senescence-related proteins such as p16, ADP-ribosylation factor 6, p53, and p21, furthermore, significantly attenuate the age-related increase in serum urea nitrogen, up-regulate podocyte structural proteins, and reduce renal structural injury.	[54]	
Note: SIRT1 sirtuin 1, OXPHOS oxidative phosphorylation, ROS reactive oxygen species, GSK3β Glycogen synthase kinase 3β, NLRP3 NOD-like receptor3, DDR DNA damage response, WT-1 Wilms’ tumor protein-1, IL-1β Interleukin-1β, TNF-α tumor necrosis factor α, SMP30 senescence marker protein 30, mTOR mammalian target of rapamycin, Nrf2 nuclear factor erythroid 2-related factor 2, NLRP3 NOD-like receptor3, MCC950 a NLRP3 inhibitor, SASP senescence-associated secretory phenotype, HDAC histone deacetylase, CCFs cytoplasmic chromatin fragments, TMP269 a selective HDAC4 inhibitor, BMP7 bone morphogenetic protein 7, PD-1 programmed cell death protein.

Autophagy reduction

Podocytes have an extremely high basal autophagic activity, which is essential for energy homeostasis. If podocytes fail to autophagy, damage resembling the aging phenotype occurs (Figure 1c). Reduced autophagy increases the extent of damage in podocyte diseases, such as focal segmental glomerulosclerosis (FSGS), and may also increase podocyte damage in elderly patients with podocyte diseases [55].

Many proteins and genes are involved in regulating aging through autophagy. Autophagy-associated gene 5 (Atg5) is a key regulator of autophagy. The Atg5-specific deletion phenotype exhibits reduced autophagy and enhanced senescence, which is characterized by a decreased number of podocytes and accumulation of damaged organelles and protein aggregates (Table 2) [55]. What is more, sirtuins mediate the beneficial effects of calorie restriction by regulating autophagy [14].

Table 2. Critical genes / proteins contributing to podocyte senescence.

Critical proteins/Genes	Mechanism/expression change	Ref.	
Sirtuins	Sirtuins are implicated in DNA repair, cellular metabolism, mitochondrial function, and inflammation.SIRT-1 regulates cellular senescence and multiple aging-related cellular processes, including:SIRT1/Keap1/Nrf2/HO-1 and SIRT1/PI3K/Akt/GSK-3β mediated oxidative stress

SIRT1/NF-kB and SIRT1/NLRP3 regulated inflammatory response

SIRT1/PGC-1α/eIF2α/ATF4/CHOP and SIRT1/PKD1/CREB controlled phosphorylation

SIRT1/PINK1/Parkin mediated mitochondrial damage

SIRT1/FOXO mediated autophagy

SIRT1/FOXG1/CREB/BDNF/Trkbcatenin mediated neuroprotective effects.

SIRT7-deficient cells experience replication stress and impaired DDR.

	[56]	
NOTCH1	Drives a TGF-β-rich secretome, whilst suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBP β.	[57]	
Atg5	A key regulator of autophagy.	[55]	
p53	Upregulated	[14]	
p16	Upregulated	[58]	
p21	Upregulated	[58]	
Note: Keap1 Kelch-like ECH associated protein1, Nrf2 nuclear factor erythroid 2-related factor 2, HO-1 heme oxygenase-1, PI3K phosphoinositide 3-kinase, Akt protein kinase B, GSK-3β glycogen synthase kinase 3β, NF- κB nuclear factor-kappa B, NLRP3 NOD-like receptor protein 3, PGC-1α proliferator-activated receptor gamma coactivator 1α, eIF2α eukaryotic initiation factor 2α, ATF4 activating transcription factor 4, CHOP C/EBP homologous protein, PKD-1 polycystic kidney disease, CREB cAMP response element binding protein, PINK1 PTEN-induced kinase 1, FOXO fork head box O, FOXG fork head box transcription factor G, BDNF brain-derived neurotrophic factor, C/EBP β CCAAT/enhancer-binding protein β, NOTCH1 notch receptor 1, TGF-β transforming growth factor β, Agt5 angiotensinogen 5.

In addition, mTOR activity was higher in the podocytes of aged mice. The mTOR complex pathway has been shown to inhibit autophagy [59]. The increase in mTOR signaling in podocytes contributes to disease and aggravates injury, whereas the specific decrease in mTOR signaling in podocytes can limit injury[60]. In physiological processes, the number and density of podocytes decrease with age, and when podocytes are injured, they undergo several cellular processes including hypertrophy [17,23,61]. Rapamycin is mTOR inhibitor that has no effect on podocyte density in elderly mice. Besides, inhibition of mTOR signaling can also reverse podocyte hypertrophy in the presence of injury [62,63].

Mitochondrial dysfunction, oxidative stress, and reduced metabolism

Specific characteristics of senescent cells include changes in mitochondrial mass, morphology, and membrane potential. The important role of mitochondria is supported by the causal link between mitochondrial dysfunction and age-related senescence. Dysfunctional mitochondria may play a vital role in the establishment of senescence, because the selective chemical inhibition of mitochondrial function and the depletion of mitochondrial sirtuins, an evolutionarily conserved set of proteins that regulate aging in different species, trigger senescence [37,64,65].

Sirtuins deficiency

Sirtuins are ubiquitously expressed as deacetylases. They have been implicated in several cellular activities including mitochondrial function, cellular metabolism, DNA repair, and inflammation (Table 2). If their expression fails, the integrity of the genome will decline, leading to the devastating consequences for cell health and eventually leading to organismal aging [66].

SIRT7

Age-dependent upregulation of SIRT7 was the only change in sirtuins between aged and young podocytes, SIRT7 deficiency may be associated with age-associated aging of podocytes, as SIRT7-deficient cells experience replication stress and impaired DNA damage response (DDR). Moreover, SIRT7-deficient mice also display an accelerated aging phenotype in other tissues [67].

SIRT1

SIRT1 is a gene associated with cellular longevity as it protects podocytes from damage caused by various cellular stressors. Due to its crucial role in podocyte homeostasis, it has been referred to as a longevity gene [18,56]. The overall consequences of reduced SIRT1 levels are caused by increased oxidative stress and mitochondrial damage (Table 2) [68]. Reduced SIRT1 expression increases podocyte aging (Figure 1d). In mouse podocytes, knockdown of SIRT1 leads to an overall reduction in podocyte numbers, increased glomerulosclerosis and albuminuria, and a decrease in key podocyte protein levels. In adriamycin-induced glomerular injury, SIRT1 knockout mice showed substantial mitochondrial damage, proteinuria, glomerulosclerosis, and impaired mitochondrial autophagy [18].

Accumulation of mitochondrial dysfunction is associated with increased oxidative stress in senescent cells [37,44]. The mitochondrial antioxidant, elamipretide (SS-31) (Table 1), is also associated with an increase in SIRT1 levels, which improve mitochondrial function by improving oxidative phosphorylation (OXPHOS) coupling, enhancing electron transfer through cytochrome c, increasing adenosine triphosphate (ATP) synthesis, and reducing reactive oxygen species (ROS) production, thus protects podocyte against senescence [27,69].

Transcriptional change

The transcriptional profile of senescence differs from that of other renal diseases [17]. Consistent with DNA damage in aging podocytes, the transcription factor p53 (Table 2) is upregulated compared to most other transcription factors that are reduced in aged podocytes [14]. For example, in profoundly senescent cells, reduced levels of NOTCH1 (Table 2) induced the production of the SASP pro-inflammatory cytokines IL-1, IL-6, and IL-8 [57]. Besides, Granule head-like transcription factor 2 (GRHL2) and its key targets were substantially downregulated and may regulate the declining function of senescent podocytes (Figure 1e) [17].

A marked reduction in transcription factors and their downstream targets may be the main cause of morphological and physiological changes in senescent podocytes [14]. For example, Pod-SIRT1RNAi (an shRNA targeting SIRT1) glomeruli are associated with reduced activation of the transcription factor peroxisome proliferator-activated receptor (PPAR)-gamma coactivador-1α (PGC-1α)/PPARγ, forkhead box O (FOXO)3, FOXO4, and p65 nuclear factor-kappaB (NF-κB) via SIRT1-mediated deacetylation[18], decreased SIRT1 expression in podocytes increases podocyte loss in the kidneys of aging mice, partly owing to dysregulation of PGC-1α, FOXO3, FOXO4, and NF-κB mediated pathways.

In contrast, PDCD 1 (gene name for human programmed cell death protein 1), which is correlated with a lower estimated glomerular filtration rate and greater segmental glomerulosclerosis and vascular arteriolar intima-tubular ratio, is increased with age in micro-dissected human glomeruli. Programmed cell death protein (PD-1) signaling plays a key role in cell survival and the induction of SASP. More than 40% of the genes regulated by PD-1 are involved in natural podocyte aging[20]. Programmed cell death protein ligand 1 (PD-L1) expression is associated with higher levels of SASP, and increased levels of PD-1 in podocytes lead to apoptosis in the healthy lifespan, loss of PD-1 in podocytes may prolong kidney health by preventing podocyte-induced injury [20,70,71].

DNA damage

Senescence is induced by abnormal DNA replication and accumulation of DNA damage [44]. Nuclear DNA damage is often considered a common underlying cause of aging, mainly in the form of double-stranded DNA breaks, which activate the DDR pathway [72]. DDR regulates the SASP through multiple pathways and may be one of the driving pathways of senescence-associated inflammation. DDR stops cell cycle progression and prevents the propagation of damaged genetic information in daughter cells. At the end of the DDR cascade, the tumor suppressor p53 is activated and stimulates the expression of the cytokine-dependent kinase (CDK) inhibitor p21, an important mediator of senescence-associated cell cycle arrest (Figure 1g) [44]. The CDK inhibitor p21cip1 may play a key role in podocyte cell cycle arrest in response to DNA damage and the regulation of DNA damage response effectors [62].

Senescence can be triggered by various stimuli [5], the most classic being the shortening of telomeres at each cell division owing to the lack of specific repair mechanisms. Telomere shortening in the kidney [73] explains the impaired regenerative capacity [74], which is one of the primary mechanisms that induce cellular senescence [44], but may not drive the senescence phenotype per se [74]. When telomere shortening reaches a critical size, the DNA damage response is activated and leads to senescence (Figure 1 f and g) [5,75]. In fact, one or a few DDR-signaling telomeres are sufficient to trigger replicative cellular senescence [76], whereas forced expression of telomerase can prevent cellular senescence and promote unlimited cell proliferation [77]. Calorie restriction in mice can reduce DDR and improved telomere maintenance without increased telomerase activity [78]. Lithium is also known to have potent anti-aging activity, and leukocyte telomeres in people taking lithium for a long time are approximately 35% longer than those in controls not taking lithium [52,79], suggesting that preventing telomere shortening is a key mechanism in stopping cellular senescence.

Chromatin changes

Aging can be accompanied by substantial phenotypic alterations, including metabolic reprogramming and chromatin remodeling [5,6]. Metabolic reprogramming of aging cells refers to the cells’ ability to alter their metabolism in response to aging-related stimuli and stress. The pathways of metabolic reprogramming are closely linked to cell aging and function, involving processes such as autophagy, oxidative stress, chronic inflammation, and more. Chromatin reorganization plays a key role in the aging process; however, the exact mechanism remains unknown [38].

Most senescent cells exhibit profound changes in the epigenome and chromatin organization. Senescence-associated heterochromatin foci (SAHF) are spatially organized heterochromatin domains that enhance DDR-resistant heterochromatin structures that inhibit DDR signaling (Figure 1, g and h). Owing to its function in regulating DNA damage and preventing premature aging, expression of podocyte histone deacetylase (HDAC) during development is essential for maintaining a normal glomerular filtration barrier [38]. The absence of HDAC1/2 may prevent podocyte quiescence by maintaining open chromatin, which in turn leads to greater susceptibility to DNA breaks and prevents successful repair of DNA damage, leading to senescence (Figure 2). Mice with a podocyte-specific deletion of HDAC1/2 develop severe proteinuria, renal failure, and collapsing glomerulopathy [38]. However, TMP269, a potent and selective class IIA HDAC (including HDAC4, 5, 7, 9) inhibitor, inhibits renal tubular cell injury and apoptosis, and promotes renal tubular cell proliferation and cellular autophagy [45]. HDAC4 is highly expressed in podocytes of mice with diabetic nephropathy (DN), knocking down this HDAC isoform alleviates podocyte damage and proteinuria, suggesting the importance of HDAC4 in mediating podocyte injury [80]. This indicates the significant role of HDAC4 in causing damage to podocytes. In addition, loss of cytosolic membranes in the cytoplasm of senescent cells can lead to the release of cytoplasmic chromatin fragments (CCFs) [81–83]. If low-dose HDAC inhibitors are used, CCFs can be reduced, and SASP can be inhibited (Table 1) [46].

Figure 2. Loss of HDAC1/2 in podocytes results in DNA damage and senescence. Deletion of HDAC1/2 in podocytes results in sustained DNA double-strand breaks (DSBs), which may be attributed to chromatin opening and anti-phospho-ataxia telangiectasia mutated phosphorylation. Phosphorylated histone H2AX (γH2AX)is a sensitive molecular marker of DSBs. Upon loss of HDAC1/2, ATM phosphorylation initiates DNA damage repair and activates downstream effector proteins, p53, whereas p21 mediates podocyte cell-cycle arrest in the G1 phase. Immunofluorescence of HDAC1/2 double KO (DKO) kidneys showed increased expression of cell cycle protein D in the nucleus of podocytes, suggesting cell cycle activation. Ki67 is a biomarker for detecting proliferating cells in the G1, S, G2, and M phases of the cell cycle in both collapsing glomerulopathy (CG) and DKO kidneys; however, no Ki67 expression was seen in the G0 phase. The DKO podocytes showed Ki67 expression, confirming the proliferative phenotype. HDAC1/2 knockout podocytes have detached peduncles, lipofuscin droplets accumulate in the podocytes in vivo, and increased SA-β-gal activity is observed in approximately 80% of DKO podocytes. These features suggest cellular senescence. Through the senescence secretion-associated phenotype (SASP), damaged podocytes secrete pro-inflammatory cytokines, growth factors, and matrix metalloproteinases, leading to subsequent detachment and loss of podocytes, as evidenced by podocyte senescence in urine.

Oncogenes induce aging

Oncogene expression triggers an initiation of a hyperproliferative phase, which is intrinsically linked to oncogene-induced DNA replication stress and oncogene-induced accumulation of telomeric dysfunction, ultimately participating in the DDR pathway and leading to senescence (Figure 1 g and i) [84].

In tumors, ROS act as DNA-damaging agents and signaling molecules that activate pro-mitogenic oncogenes. By promoting the initial excessive proliferative phase associated with altered DNA replication and DNA damage accumulation, oncogene-induced ROS production by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase induces cellular senescence [85]. A deficiency in tumor suppressor expression can also induce proliferative arrest, such as phosphatase and tensin homolog deficiency-induced cellular senescence [44].

The anticancer drugs, quercetin and dasatinib, inhibit broad-spectrum tyrosine kinases and protein kinases and reduce markers of aging [86–88]. For example, the administration of dasatinib and quercetin in a diabetic model of aging increased Wilms’ tumor gene 1(WT1) expression, decreased p16 levels, and improved renal function [47]. WT1 is an important gene for podocyte function [17], and p16-positive cell clearance prevents podocyte loss [73]. Obese individuals treated with dasatinib and quercetin showed reduced p16INK4a cells, microalbuminuria, and improved renal podocyte function in the renal cortex [47].

Biomarkers and therapeutic drugs of podocyte senescence

Biomarkers of podocyte senescence

Many aging-related biomarkers have been identified during kidney aging. Understanding these biomarkers can help us to evaluate the degree of aging of kidney cells and can also help us find methods to prevent kidney aging.

SA-β-gal

Senescence-associated-β-galactosidase (SA-β-gal) is a common marker of aging [89]. Persistently high glucose (HG) increases SA-β-gal activity, increases the expression of aging-associated proteins p21 and p16INK4a, while activating telomerase and shortening telomere length [89,90]. Compared to podocytes in healthy non-aged glomeruli, the classical senescence markers, p16INK4 and SA-β-gal, are substantially increased in healthy aged and non-aged kidneys with superimposed glomerular disease or DN [91–93].

CDK inhibitors

Increased levels of CDK inhibitors are another distinguishing feature of senescent cells [44]. Proliferation is harmful to the normal biological function of podocytes and may be controlled by a decrease in CDK inhibitors [62]. The induction of p16INK4a and p21Cip1 inhibits the cyclin-dependent kinases CDK4, CDK6 that are necessary for promoting cell cycle progression [24]. The CDK inhibitor p16INK4a plays an important role in the accumulation of senescent cells during senescence, as it is specifically activated in senescent cells and suppresses CDK4/6, thereby inducing senescence-associated cell cycle arrest in the G0/1 phase [44]. Additionally, mechanical stretching restrains podocyte proliferation and induces cells to adopt a hypertrophic phenotype, which is ameliorated by the CDK inhibitor p21Cip1 [94]. In conclusion, it can be inferred that if the levels of CDK inhibitors are reduced in podocytes, they slow down the aging process.

C/EBP α deficiency

C/EBP α is highly expressed in podocytes [15]. It controls a wide range of cellular processes, which include energy metabolism, cellular proliferation and differentiation, autoimmunity, and inflammation [95]. It also helps maintain podocyte integrity both in vivo and in vitro in experimental FSGS models [96]. C/EBPα knockdown exacerbates podocyte senescence by means of the adenosine monophosphate-activated protein kinase/mTOR pathway, manifested by accumulation of senescence markers in podocytes, increased synthesis of extracellular matrix, structural instability (podocyte foot processes effacement), increased albuminuria, and impaired function [15]. Podocyte-specific C/EBP α knockdown not only exacerbates the development of glomerulosclerosis in the context of chronic aging but also triggers the development of tubulointerstitial damage. This may be associated with chronologically aging animals and premature aging, and these findings may provide new ways to prevent renal injury during aging.

TGF-β1

Senescent cells release TGF-β, a major regulator of fibrosis [97], and promote renal tubular interstitial fibrosis, podocyte apoptosis, and hypertrophy [98]. The importance of TGF-β1 signaling has been emphasized in the regulation of senescence both in vitro and in vivo [99–101]. The results showed that podocyte-specific TGF-β1 overexpressing mice showed mesangial expansion, diffuse foot process disappearance, glomerular basal thickening, substantial increase in β-galactosidase activity in the glomeruli, and up-regulation of senescence-related proteins Rb2 and p27. p21 and p16 are the main molecules responsible for cellular senescence, inhibiting the cell cycle protein-dependent kinase CKD, and regulating the blockade of senescence (Table 2) [58]. Podocyte TGF-β1 could upregulate p21 expression and affect the behavior of p16 in glomerular endothelial cells in vivo and in vitro, further TGF-β1 induces oxidative stress-induced activation of the p53/p21 pathway and senescence [58,102].

Gsk3β

Glycogen synthase kinase 3β (GSK3β) is overexpressed and overactive in glomerular podocytes with age, and associated with functional and histological signs of renal aging [22]. GSK3β is a universally expressed serine/threonine kinase, while phosphorylation of p16INK4a and p53 at serine 152 and 37, respectively, is required for the pro-senescence signaling activities. Mechanistically, the beneficial effects of GSK3β knockout appear to be achieved by inhibiting aging signals, as shown by reduced expression of p16INK4a, p53, and p21, and decreased expression of fibrogenic SASP factors PAI-1 and fibronectin. Gene or drug-targeted inhibition of GSK3β in podocytes can reduce glomerular senescence and SASP in the glomeruli. In addition, targeted inhibition of GSK3β by low dose lithium can reduce aging signal and renal senescence in mice, which make GSK3β potentially important in the treatment and intervention of delaying renal senescence [22].

Anti-PD-1 antibody

PD-1 and its ligands, PD-L1 and PD-L2, constitute a group of immune checkpoints that play a crucial role in preventing autoimmunity [70]. Senescent cells heterogeneously express the immune checkpoint protein PD-L1, and PD-L1 senescent cells build up in vivo with age [71]. Podocytes isolated from aged mice exhibit increased expression of the PD-1 surface receptor and its two ligands (PD-L1 and PD-L2) [20].

Aging podocytes exhibit a remarkable inflammatory transcriptome profile [17]. Anti-PD-1 antibodies improve the metabolic state of the podocytes, reduce intracellular inflammation, decrease the SASP in aging podocytes, reduce stress, enhance autophagy, and improve survival (Table 1). When anti-PD-1 antibodies are injected into aged mice, podocyte genes, functions, and transcription factors are restored, and the lifespan of glomerular podocytes is extended. In addition, the same anti-PD-1 antibody administered to young mice with experimental FSGS reduced proteinuria and increased podocyte counts [20]. GSK3β is a key upstream kinase regulating PD-1 expression, and its inhibition in vivo blocks PD-1 expression [103]. Therefore, it is speculated that GSK3β and PD-1 are likely to regulate podocyte senescence through analogous pathways [70].

As suggested by related studies, because heterogeneous expression of PD-L1 plays an important role in the accumulation of senescent cells and inflammation associated with aging, upstream regulation of the SASP and elimination of PD-L1 senescent cells by immune checkpoint blockade may be a valuable future avenue for anti-aging therapy [20,71].

Podocyte-specific signaling

The activity of many podocyte-specific signals decreases in aging podocytes, which likely leads to reduced functioning. The levels of the epidermal growth factor receptor (EGFR/ErBB1) and ErBB4 receptors and many of their ligands that promote kidney injury are significantly reduced. Other critical signaling pathways that decreased include vascular endothelial growth factor (VEGF), WNT, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and slit guidance ligand 2/roundabout guidance receptor 2, which might lead to a decrease in podocyte function. Augmenting these diminished signaling pathways may have a protective effect on the aging kidney [17,104].

Therapeutic drugs for podocyte senescence

Anti-aging drugs have been developed for drug therapy, an important part of anti-aging therapy, plays an important role in delaying podocyte and kidney senescence. At present, known anti-aging drugs mainly include HDAC inhibitor, β-hydroxybutyrate, senolytics, elamipretide, lithium, rapamycin. Additional information on these is provided in Table 1.

β-hydroxybutyrate

DN is clinically characterized by glomerular destruction leading to podocyte senescence and progressive albuminuria. In podocytes exposed to a diabetic environment in vitro, β-hydroxybutyrate treatment largely attenuated cellular senescence and damage by reducing senescence-associated staining for β-galactosidase activity, reducing the expression of key mediators of senescence signaling, such as p16INK4a and p21, and preserving synaptophysin expression. In addition to reducing cell senescence and damage by reducing the β-galactosidase activity of senescence-related staining, β-hydroxybutyrate treatment was also associated with enhanced antioxidant response of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Selective Nrf2 activation is adequate for the anti-aging and podocyte-protective effect of β-hydroxybutyric acid.[25]

Senolytics

Senolytics are a class of drugs that selectively remove senescent cells. Early pilot trials on senolytics have suggested that they reduce inflammation, decrease senescent cells, and alleviate frailty in humans [105]. Bioinformatic analyses have identified 46 compounds that target senescent cell anti-apoptotic pathways as potentially senolytic [106]. First-generation senolytics, such as dasatinib and quercetin (Table 1), are drugs that target a number of pathways and preferentially induce apoptosis in senescent cells and have been tested in several preclinical models of aging and diseases [106]. For example, high-fat diets induced senescent mouse kidney cells are linked to functional impairment and renal fibrosis, quercetin treatment reduces SASP marker expression and senescent cell burden, improves kidney function and alleviates renal fibrosis [107]. Over 20 clinical trials of senolytic therapies have been completed, ongoing, or planned. Patients with diabetic kidney disease using dasatinib and quercetin can decrease the adipose tissue senescent cell burden, fibrosis, inflammation, and circulating SASP factors [108]. Large randomized controlled trials to assess and ensure the safety, benefits, and target engagement of senolytics are needed to validate preliminary results from early phase clinical trials.

The method used to discover the anti-aging effects of dasatinib and quercetin (Bcl-xl pro-survival regulators) can be used to discover other cell type-specific anti-aging drugs to increase the variety of anti-aging drugs. For example, the Bcl-2 family inhibitor, navitoclax, targets Bcl-2, Bcl-xl, and Bcl-w and has anti-aging effects on certain types of senescent cells [109].

Elamipretide

Age-related podocyte deterioration involves remodeling of the cytoskeleton. Regardless of the underlying cause of glomerular dysfunction, the initial signs of podocyte deterioration are characterized by the retraction of foot processes, leading to impaired filtration slits. Changes in the morphology of foot processes are associated with alterations in the fundamental actin cytoskeleton. Dysregulation of the actin cytoskeleton and subsequent podocyte injury contribute to the progression of kidney damage [110]. The mitochondria-targeting peptide, elamipretide, does not affect the density of podocytes but reduces markers of podocyte damage (junctional proteins) and improves cytoskeletal integrity (synaptic podoproteins) (Table 1) [27].

Recently, elamipretide was used in domestic pigs with atherosclerotic renal artery stenosis (ARAS). It has been confirmed that mitochondrial protection by elamipretide improves renal function and fibrosis in aging stenotic kidneys in ARAS and partially alleviates cell senescence. However, it has not been applied clinically and its subsequent aging efffects needs to be considered.

Lithium

By the middle of the nineteenth century, lithium carbonate was used as a medical treatment for a range of disorders, including cancer; however, it is now mainly used to treat bipolar disorder. In Drosophila, lithium prolongs lifespan in a dose-dependent manner, and the higher the dose, the greater the toxicity to survival [111]. As mentioned above, lithium can prevent cell aging by preventing telomere shortening, and low doses of lithium targeting GSK3β can reduce aging signals and kidney aging in mice (Table 1) [22].

Rapamycin

Rapamycin is a macromolecular lipid compound with immunosuppressive and antiproliferative effects on mammalian cells [112,113]. Rapamycin treatment slows down or even reverses various age-related changes in mice [114]. Rapamycin protein complex 1(mTORC1) integrates growth factors, nutrition, stress and other input signals to phosphorylate many targets and regulate cell growth and various cellular processes, including autophagy, nucleotide synthesis and so on [115]. Abnormal activation of mTORC1 has been documented as a feature of various renal diseases, leading to endoplasmic reticulum stress and apoptosis [116]. As mentioned above, rapamycin can regulate aging by reducing the production of SASP via inhibition of the mTOR signaling pathway.

Currently, the clinical application of rapamycin is limited by its side effects, including hyperlipidemia and nephrotoxicity. Strategies to reduce the risks associated with mTORC1 inhibition include improving existing rapalog (the analogs of rapamycin) administration regimens, using rapalogs in combination with kinase inhibitors, and developing new rapamycin variants with mTORC1/mTORC2 specificity. More human studies are needed, but the balance of data suggests that reducing mTORC1 signaling may be a feasible strategy for extending the life span of humans (Table 1) [115].

Emerging treatment strategy

Progress has been made in the treatment of podocyte senescence, which mainly includes gene therapy and immunotherapy. The emergence of these new treatments has rekindled hope of delaying the progression of aging diseases, particularly gene therapy, which has made significant progress in the treatment of podocyte diseases [117].

Gene therapy

Gene therapy has emerged as a powerful tool for treating age-associated diseases by transferring specific genes into target cell populations. Gene therapy techniques allow for editing and epigenetic modifications such as inhibition, activation, and demethylation of target genes [117].

Clinical application targets for aging-related genes include telomerase. Telomerase activator (TA) can improve the expression of (telomerase reverse transcriptase) TERT and plays a therapeutic role. For example, feeding TA-65 to transgenic mice overexpressing human wild-type α-synuclein can induce Parkinson disease with increased expression of TERT and autophagy. Moreover, with an expression of TERT increased, no malignant tendencies were found in the above studies, which laid the foundation for further exploration and promotion of clinical trials [117,118].

Potential targets of aging-related genes for clinical applications include KLB、KL 、 FGF family, FOXOs, SIRT, and VEGF [117].

The KLB that encodes β-Klotho is mainly expressed in adipocytes, testis, stomach, and liver, but this gene or its protein has been poorly understood. The KL that encodes α-Klotho is especially high in the kidneys, and highly present in the distal tubules and proximal tubules. It can inhibit aging by inhibiting p53/p21 pathway, making it the main regulator of cell aging [119,120]. However, the level of Klotho decreases with age in humans, which contributes to the gradual loss of age-related renal function [121–125]. In addition, FGF may be at the core of the anti-aging effects of Klotho [126]. Preclinical evidence has demonstrated that Klotho has broad therapeutic potential for treating various aging-related diseases, although no interventional clinical trials have been conducted to assess the clinical potential of KL and Klotho.

The FOXO protein family comprises transcription factors that are activated under stressful circumstances, including oxidative stress, DNA damage, starvation, and energy deficiency, which promote post-translational modifications, such as monoubiquitination, phosphorylation, methylation, and glycosylation [127]. Current studies on FOXOs have focused on the mechanisms underlying aging-related diseases, and some preclinical studies are underway [128,129].

Vegf is negatively associated with aging, and high Vegf expression has a protective effect on the cardiovascular system [130–132]. Increased lifespans and physiological functions have been reported after transgenic VEGF and adeno-associated virus (AAV)–assisted VEGF transduction. However, many studies have identified it as a promoting factor for malignant tumors. Therefore, whether it induces cancer when applied in anti-aging gene therapy remains a concern.[133].

Studies on SIRT have shifted from familiarity with signaling pathways to utilization in mammalian models of nephropathy, cardiovascular diseases, and neurodegeneration [134–136]. Correspondingly, drugs that regulate these signaling pathways have emerged and have been evaluated in clinical trials [137,138]. Researchers have established a Tie2-Cre (a gene that can induce progerin expression, accelerate aging, and shorten life span)-induced conditional progesterone knock-in model for Hutchinson-Gilford progeria syndrome. Research based on this model has shown that SIRT7 loaded into cells by recombinant adeno-associated virus serotype 1 (rAAV1) can reduce the disease phenotype and prolong the lifespan of mice with progeria [139]. These experimental data emphasize that gene therapy is a potential strategy for the clinical treatment of age-related diseases.

Gene therapy has been controversial since its first proposal. Considering its safety and feasibility, the current recombinant rAAV-mediated gene replacement strategy seems to be the most suitable for the clinical application of treating aging-related diseases [117]. Recent studies have used AAV-based gene therapy to reduce genetic defects in human and mouse disease models by referring to NPHS2 mutations in the podocyte gene that encodes globin. In addition, there have been successful cases in which AAV 2/9 targets mouse podocytes and improves the vector to treat mouse albuminuria, whereas the synthetic capsid AAV-LK03 can effectively transfect human podocytes. Although there are still many challenges to overcome before this study can be translated to humans, this work demonstrates the first step in AAV gene therapy for podocyte monogenic diseases [54]. Recent research has demonstrated that nanoplexes-nanoliposomes capable of encapsulating RNA to protect it from enzymatic degradation-can effectively load microRNA (miRNA)-30a mimics and deliver them to podocytes in a HG environment. MiRNAs are essential for the regulation of gene expression and normal renal function. MiRNA-30a is mainly responsible for podocyte homeostasis, in diabetic nephropathy, miRNA-30a is directly and mainly inhibited by Notch signal pathway induced by hyperglycemia kidney, which leads to podocyte injury and apoptosis. These nanoplexes upregulate the expression of miRNA-30a and inhibit Notch-1 signal transduction in podocytes exposed to HG [140].

Immune therapy

Immunotherapy is another approach for clearing senescent cells by increasing their capacity to target senescent cells. Different immune cell-based therapeutic approaches have been used to treat diseases, and these approaches may be enhanced to target senescent cells [141]. Recently, a cell surface protein, urokinase-type plasminogen activator receptor (uPAR), was found to be highly induced in senescent cells. Chimeric antigen receptor T-cells, which are designed to target uPAR proteins, can eliminate senescent cells both in vivo and in vitro [142]. Moreover, natural killer cells also target senescent cells [143]. Other immune cells also play various roles in cellular senescence, and these cells have the potential to develop novel therapeutic approaches, as explained previously [144]. Currently, different types of immunotherapies are being developed, and the transformation of these immune cells into senotherapeutics is a new and promising research field that may pave the way for treating various cellular senescence-related diseases, including podocyte senescence.

Podocyte interactions with other glomerular cells

Podocyte interactions with senescent endothelial cells

The glomeruli are composed of different cell types, including thylakoid cells, podocytes, and endothelial cells [73]. In pathological settings characterized by glomerular lesions, such as DN, glomerulonephritis, or focal segmental glomerulosclerosis, senescence has been demonstrated to be related to thylakoid, endothelial, podocyte, or mural epithelial cells [145].

There is a deleterious crosstalk between senescent endothelial cells and podocytes. Plasminogen activator inhibitor-1 (PAI-1) is an important mediator of endothelial and podocyte interactions in the vicinity of endothelial cells [73]. PAI-1 may lead to β-1 integrin endocytosis by interacting with a complex of uPAR, which in turn triggers podocyte detachment (Figure 3) [146].

Figure 3. Podocyte interactions with endothelial cells. Damaged podocytes inhibit the expression of VEGF, leading to dysfunction of the endothelial cells. Damaged endothelial cells produce and secrete PAI-1, which binds to circulating uPAs on capillaries or podocyte surfaces, and then forms a PAI-1/uPA/uPAR complex with uPAR on the podocytes surface. The complex can bind β1-integrins (a strong assembler of podocyte-glomerular basement membrane attachment). With the help of the large endocytic receptor, LDL receptor-related protein, on the surface of the podocyte, β1-integrinin is translocated to the podocytoplasm by endocytosis with the PAI-1/uPA/uPAR complex. Finally, primary healthy podocytes that have lost β1-integrin are detached from the GBM.

Thus, PAI-1 may be both a prognostic marker and a therapeutic target for prolonging renal survival during aging [73]. In vivo, selective inactivation of PAI-1 in endothelial cells protected against podocyte loss and lesion development in the glomeruli of aged mice. In vitro, blocking PAI-1 in the supernatant of senescent endothelial cells prevented podocyte apoptosis [73]. Similarly, it has been shown that podocytes signal to glomerular endothelial cells in a paracrine manner via VEGF, angiopoietin, or endothelin [147,148]. VEGF expression is inhibited in damaged podocytes, resulting in dysfunction of the epithelial cells, which produce PAI-1 and mediate podocyte loss from the basement membrane through a range of mechanisms.

Crosstalk between podocytes and mesangial cells

Glomerular mesangial cells play an important role in facilitating the production of podocyte-specific VEGF-A and promoting proper maturation of glomerular endothelial cells. Over-expression of VEGF-A derived from podocytes and the activation of mTORC1 mRNA in podocytes can induce mesangial expansion [149,150]. In addition to this, compared to normal conditions, mesangial cell-derived EVs secreted more TGF-β1 under HG conditions, significantly upregulated the expression of TGF-β1 receptor in podocytes, and inhibited cell adhesion and led to podocyte apoptosis through TGF-β1- phosphoinositide 3-kinase (PI3K)/Akt signaling pathway [151].

Upon diabetic insult, podocytes are subjected to obvious stress and injury and show a senescence-like phenotype. Approximately 60% of the podocytes age after diabetic damage [25]. Whether these interaction pathways between kidney cells are also operative in aging kidney cells requires further exploration. Despite the complexity of cellular crosstalk during aging, the development of anti-aging drugs that target the pathways and targets involved in these interactions is promising. Efforts should be made to elucidate these complex processes and relationships and further exploration in this area is imperative.

Summary and outlook

There is no doubt that technological progress has promoted in-depth understanding of podocyte senescence-related disease. With a more comprehensive understanding of the mechanism of podocyte senescence, obtaining drugs to prevent podocyte senescence is challenging but promising. In future, it will be feasible to overcome the shortcomings of existing drugs/interventions or further explore new drugs with better safety and fewer side effects. In addition, starting with the current potential aging-related genes such as KL, KLB and FGF family, FOXOs, VEGF, SIRT, and in-depth studies in gene therapy may be a breakthrough to delay the senescence of podocytes or other kidney cells.

Podocyte senescence significantly contributes to the progression of kidney diseases and has garnered considerable attention as a critical factor in kidney aging. After decades of work, the key mechanisms of understanding podocyte senescence have been progressively revealed: the first is the production of SASP as a marker of aging, which induces and accelerates aging; the second is the decrease of autophagy leading to the appearance of a podocyte senescence phenotype; the third is the senescence caused by mitochondrial functional damage, which involves sirtuins regulating mitochondrial damage to induce podocyte senescence; and the fourth is transcriptional changes as in podocyte senescence that involves up-regulation of transcription factor p53 and down-regulation of other transcription factors. Senescent podocytes are also manifest by a significant increase in PD-1 surface receptor and its two ligands, which is considered to be related to a higher level of SASP. The fifth is DNA damage, when a telomere shortens to a critical size, DNA damage will activate DNA damage response leading to aging. The DNA damage response cascade finally regulates senescence-related cell cycle arrest through p53/p21 pathway. Chromatin change is an important part of the aging process, and the expression of HDAC plays an important role in regulating chromatin structure and DNA damage, and it may be able to prevent cell senescence. Finally, oncogene expression triggers senescence, and the activation of oncogenes ultimately leads to aging through DDR.

Various possible mechanisms for alleviating podocyte senescence have been gradually proposed, and various drugs for improving podocyte senescence have achieved results in various animal experiments or clinical trials. Some of the anti-aging drugs currently under study include β-hydroxybutyrate, senolytics, elamipretide, lithium, and rapamycin. Research on the anti-aging properties of β-hydroxybutyrate, elamipretide, and lithium is in the animal research stage, while research on senolytics and rapamycin has progressed to the clinical trial stage. However, further trials are necessary to assess and demonstrate their safety and benefits. In contrast, gene therapy has made great progress in the treatment of podocyte diseases, and different types of immunotherapies may pave the way for curing various cellular senescence-related diseases, including podocyte senescence.

Authors’ contributions

Guibao Ke and Jie Xiao conceptualized the ideas. Qian Zhao and Yongzhang Huang wrote the first draft of the manuscript. Caixia Cui prepared the figures. Ningying Fu, Xuan Peng, and Haiyan Kang revised the manuscript. All the authors approved the final version of the manuscript.

Disclosure statement

The authors declared no competing interests for this work.
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