Abstract
Cellular senescence is a ubiquitous process with roles in tissue remodelling, including wound repair and embryogenesis. However, prolonged senescence can be maladaptive, leading to cancer development and age-related diseases. Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21; however, few markers have high sensitivity and specificity. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence might have beneficial roles during development and recovery from injury, but can also contribute to the progression of acute kidney injury and chronic kidney disease. Therapies that target senescence, including senolytic and senomorphic drugs, stem cell therapies and other interventions, have been shown to extend lifespan and reduce tissue injury in various animal models. Early clinical trials confirm that senotherapeutic approaches could be beneficial in human disease. However, larger clinical trials are needed to translate these approaches to patient care.
Key points
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Cellular senescence regulates physiological and homeostatic processes, particularly during embryonic development and wound healing, but can also be a pathological process that contributes to ageing, various diseases and metabolic disorders.
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Senescent cells are characterized by morphological alterations including large, flat bodies and organelle abnormalities, as well as loss of physiological functions, an inability to proliferate and the senescence-associated secretory phenotype.
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SABG, p21 and p16 are the most commonly used senescence markers but have limitations; novel non-invasive approaches are needed to detect cellular senescence with high sensitivity and specificity in vitro.
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Cellular senescence is involved in the pathogenesis of chronic kidney disease and acute kidney injury, but also seems to have a protective role in the early stages of acute kidney injury.
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Senescence-targeting interventions, including senolytic drugs conjugated to antibodies against β2-microglobulin, chimeric antigen receptor T cells and anti-ageing vaccines, show promise for clinical application.
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Clinical trials are needed to assess the safety and efficacy of senotherapeutic approaches, optimize treatment regimens and develop more individualized and standardized treatment strategies.
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Introduction
The phenomenon of cellular senescence was discovered in the 1960s in human diploid cell strains that had exhausted their replicative potential1. Senescence is characterized by cell-cycle arrest in the G1 or possibly G2 phase, which prevents the proliferation of damaged cells2,3. By contrast, cellular quiescence, a reversible growth arrest state secondary to scarce nutrition and growth factors, takes place in the G0 phase4. Cellular senescence occurs during embryonic development and can be induced by cellular impairment, including DNA damage, telomere shortening or dysfunction, oncogene activation or loss of tumour suppressor functions, epigenetic changes and organelle damage5.
The principal cause of senescent stress is DNA damage6, which activates the DNA damage response (DDR) and the canonical p53–p21 pathway7 (Fig. 1). P21 (also known as cyclin-dependent kinase inhibitor 1) inhibits cyclin–cyclin-dependent kinase complexes that block the formation of the DREAM complex, which represses cell-cycle genes by binding their homology region8. Unlike DDR-induced senescence, epigenetic alterations cause senescence mainly via the p16–RB pathway9. p16 (also known as cyclin-dependent kinase inhibitor 2A) can inhibit the formation of cyclin D–CDK4/6 complexes and thereby prevent phosphorylation of RB and promote formation of the RB–E2F complex, which inhibits the transcription of cell-cycle genes8. Evidence suggests that p21 is mainly activated early during the evolution of senescence, whereas p16 maintains cellular senescence10.
The senescence-associated secretory phenotype (SASP) is an important feature of senescent cells that comprises the release of numerous cytokines, chemokines, growth factors and proteases11, which are sometimes enclosed within microparticles, into the extracellular environment. Many cell types also release extracellular vesicles, which contain cellular contents, including proteins, lipids and nucleic acids. Extracellular vesicles have a role in inter-cellular communication, and altered extracellular vesicle cargoes are important components of the SASP12. Through the release of SASP factors, senescence can modulate pathways in neighbouring cells and tissues as well as at remote sites. Notably, senescent cells that are induced by different stress stimuli may manifest distinctive SASP components13.
Cellular senescence has beneficial biological functions in the regulation of embryonic development, wound healing, resolution of fibrosis and tumour suppression. However, prolonged senescence can result in deleterious sequelae, including tumour development, chronic inflammation, immune deficit and stem cell exhaustion. Interest in cellular senescence and in senescence-modulating interventions is increasing owing to observations that in addition to driving ageing, cellular senescence has important roles in the pathogenesis of chronic diseases, including osteoporosis, metabolic syndrome, type 2 diabetes mellitus, cancer, reproductive ageing, atherosclerosis, neurodegeneration, glaucoma and chronic kidney disease (CKD). In this Review, we describe the mechanisms, hallmarks and consequences of cellular senescence, as well as the therapeutic potential of senescence-targeting interventions.
Senescence in physiology and pathology
Diverse types of stimuli trigger senescence, reflecting its spectrum of roles under different conditions (Table 1). Developmental senescence and replicative senescence (which occurs secondary to telomere shortening) occur under physiological conditions during embryogenesis and ageing, respectively, whereas other types of senescence are often induced by pathological stressors, including tumorigenesis, diabetes mellitus, chemotherapy or radiation.
Embryogenesis and development
In 2006, a transcript of INK4b, which encodes a cyclin-dependent kinase (CDK) inhibitor that blocks progression of the cell cycle beyond the G1 phase, was detected in the roof plate of the develo** chicken hindbrain14, implicating senescence in the regulation of embryonic development. Subsequently, p66Shc, which regulates oxidative stress-induced senescence, was found to mediate early cleavage arrest in failed bovine embryonic development, suggesting that cellular senescence might fine-tune embryogenesis to prevent the continued development of poor-quality embryos15.
In the mammalian embryo, senescence occurs at multiple locations, including the limbs, nervous system and gut endoderm16. In the develo** kidney, accumulation of senescent cells signals immune cells to facilitate mesonephros regression through macrophage-mediated phagocytosis of these senescent cells17. Markers of senescence, including senescence-associated β-galactosidase (SABG), p21, p27 (encoded by CDKN1B) and p15 (encoded by CDKN2B), were detected in mouse mesonephros at embryonic day 12.5 to 14.5 (ref.17). Knocking down p21 in mouse embryos results in developmental abnormalities16. Senescence has also been shown to regulate the development of multiple tissues in zebrafish embryos18.
Importantly, senescent decidual cells in the mammalian endometrium can secrete multiple canonical implantation factors and form a suitable environment for embryonic implantation19. Cellular senescence may therefore have roles in pruning and remodelling develo** systems and modulating their microenvironment, and is thus required to ensure fetal integrity.
Wound healing
Wound healing is a physiological response for repairing tissue injury that involves inflammation, new tissue formation and tissue remodelling. Cellular senescence has an important role throughout the wound-healing process. In cutaneous wound healing, the matricellular protein CCN1 can induce fibroblast or myofibroblast senescence and thereby reduce fibrosis via activation of the DDR and ROS–p16 signalling20. Similarly, in corneal wound healing, fibroblast senescence manifests as an anti-fibrogenic phenotype, with reduced responses to fibroblast growth factor 2 (FGF2; also known as basic FGF) and platelet-derived growth factor-BB, and increased expression of MMP1, MMP3 and MMP13 (ref.21).
Conversely, cellular senescence can interfere with wound healing. For example, inflammation-mediated cellular senescence decreases fibroblast proliferation and migration, which is vital during new tissue formation22. Tenovin-1 treatment induced senescence of cultured astrocytes and thereby impaired their wound-healing activity23. Moreover, senescent lung fibroblasts induced G2/M cell-cycle arrest of alveolar epithelial cells, leading to aberrant wound repair and re-epithelialization24. Senescent mesenchymal stem cell (MSC)-derived extracellular vesicles also inhibit wound healing via a mechanism that involves downregulation of miR-146a25. In diabetes, oxidative stress activates caveolin 1–PTRF signalling, which leads to induction of cellular senescence via the p53–p21 pathway26. The resulting diabetes-induced senescence26, together with a CXCR2-enriched SASP27, impair wound healing. These findings indicate that although transient cellular senescence can promote tissue repair, the prolonged presence of senescent cells can hamper this process.
Cancer
Cellular senescence can have beneficial and detrimental effects in cancer (Fig. 2). Oncogene activation, loss of anti-oncogenes and irreparable DNA damage not only induce apoptosis but also elicit cellular senescence to prevent tumour initiation. Transient insults may result in cell-cycle arrest, which can prevent carcinogenic mutations from being passed on to the next generation of cells and accelerate immune clearance.
DDR signalling is the main mechanism of oncogene-induced senescence. Oncogene activation or irreparable DNA damage induce activation of ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2), leading to phosphorylation of histone H2AX and p53 and activation of p53–p21 signalling28. Additional pathways, including NLRP6–NF-κB–p14ARF–MDM2 and miR-203–ITPKA–MDM2, can also activate p53–p21 signalling. In breast carcinoma cells, overexpression of oncogenic ERBB2 elicits senescence by upregulating p21 independently of p53 (ref.29). Loss of anti-oncogenes such as PTEN can induce senescence through the Akt–mTOR–p53 and p19ARF–MDM2–p53 signalling pathways30.
Depletion of CSN5 induced senescence in p53-null cells, suggesting that alternative pathways of senescence exist31. Further studies demonstrated that the p16–RB and TAp63–p21–RB pathways are involved in oncogene-induced senescence and suppression of tumorigenesis32,33. In mice, inactivation of heat shock factor 4 (HSF4) enhanced senescence and suppressed tumorigenesis independently of p53 via a mechanism that is dependent on p21 and p27 (ref.34). Reactive oxygen species (ROS)-induced senescence in cancer cells is dependent on p16INK4A, p21Waf1/Cip1 and/or p27Kip1, but does not require p53 (ref.35).
The high-mobility group box-containing protein 1 (HBP1) transcription factor is a novel activator of p21 (and thereby senescence) that acts by attenuating degradation of p53 or by regulating Wnt–β-catenin–EZH2 signalling independently of p53 (ref.36). Wnt signalling also has a role in inducing the senescence of thyroid cancer cells146 and cell density might influence SABG staining regardless of cell proliferation status147. These findings suggest that SABG is not a sufficiently robust and specific marker of senescent cells.
Gene and protein components of senescence-related signalling pathways such as p16 and p21 are canonical markers of senescence148,149. Expression of Met is also considered to be a marker of cellular senescence150 and the accumulation of nuclear globular actin accumulation has been reported to be a more sensitive marker of cellular senescence than SABG activity151. Other markers of senescence include telomere shortening152, the DNA double-strand-break marker H2AX153, typical chromatin changes such as senescence-associated heterochromatin foci154, cytosolic double-stranded DNA and miR-146a155,156. Decreased cellular proliferation potential (which can be measured using BrdU or EdU incorporation assays) and increased apoptosis resistance (for example, as a result of upregulation of BCL proteins) also occur in some types of senescent cells157.
Potential blood or urine biomarkers of senescence include plasma angiopoietin-like 2, growth/differentiation factor 15, stanniocalcin 1 and serine protease inhibitors, serum T-kininogen and urinary 8-oxoguanosine11,158,159,160. Activin A is normally only expressed during embryonic development, but is copiously expressed in injured and senescent kidneys and can be detected in the plasma and urine of patients with kidney disease161. SASP signatures enable the detection and characterization of cellular senescence in vivo but need to be defined in specific biological contexts as they might overlap with inflammatory profiles that are not associated with senescence. Extracellular vesicles can be isolated from urine or peripheral blood and analysed as an index of parent cell senescence; for example, increased levels of urinary URAT1+p16+ extracellular vesicles reflect increased proximal tubular cell senescence162.
Several markers characterize specific senescent tissues or cells. For example, loss of EPC1 expression is a marker of senescence in human dermal fibroblasts163. In T cells, expression of NKG2D, KLRG1, CD57 and CD28 might reflect senescence64,164,165. NKG2D166 and activin A161 are potential markers of senescence in kidney tissue. Spectrin–phaemoglobin crosslinking is an important feature of senescence in red blood cells167, SRSF1 has been postulated to be a key marker of endothelial senescence168 and maspin is a marker of senescence in oral premalignant lesions169.
Endogenous autofluorescence of MSCs is considered to be a useful marker to rapidly determine their senescent status in vitro170. However, the small number of senescent cells relative to quiescent cells, robust tissue autofluorescence, and low penetration of fluorescence signals hamper the detection of senescent cells in vivo using fluorescence-based imaging. Near-infrared imaging methods are not clinically applicable because of the limited availability of high-performance second near-infrared region (NIR-II) fluorophores with high brightness and biocompatibility as well as the long-term health risks of using non-biodegradable quantum dots and lanthanide-doped nanoparticles. Positron emission tomography-based methods of detecting senescent cells are being investigated in animal studies but will require the development of sensitive clinical probes171. Advances in non-invasive imaging methods may enable the detection and spatial allocation of senescence-prone regions that warrant intervention.
Senescence in kidney diseases
Kidney cell senescence was first described in 1992 (ref.172). In addition to its role in physiological kidney ageing, senescence has important roles in the development of CKD and acute kidney injury (AKI) (Fig. 3). Interventions that clear senescent cells, including senolytic drugs, are therefore promising novel treatments for kidney diseases.
Acute kidney injury
Emerging evidence indicates that senescence contributes to the progression of AKI and that senescence inhibition can promote kidney recovery. For example, inhibition of tubular cell senescence using lipoxin A4 restored renal function in a rat model of septic shock-induced AKI173. Similarly, in a rat model of contrast-induced AKI, pre-treatment with paricalcitol before contrast medium administration reduced cellular senescence (that is, expression of SABG and p16INK4A) and tissue damage and prevented kidney dysfunction174. Notably, patients aged over 70 years have a 3.5-fold higher incidence of AKI than younger individuals175. This increased incidence has been linked to immunosenescence, amplification of the SASP176, and/or downregulation of the geroprotective protein α-Klotho177. Urine and plasma levels of p21 correlate with renal cortical expression of this protein and could be a useful non-invasive biomarker of AKI and kidney ageing178.
The complement system (C5a), DNA methylation, Wnt4–β-catenin signalling and ROS have been implicated in the development of cellular senescence in AKI179,180. Senescence has been shown to reduce the regenerative capacity of tubular, glomerular and interstitial cells181 and to delay recovery from AKI induced by ischaemia–reperfusion injury (IRI) in mice182. Following IRI, markers of kidney cell senescence (Bax and p16 mRNA) peaked at day 12, suggesting an increase in senescent cells in the chronic phase after AKI that might contribute to maladaptive repair and progression to CKD183. Treatment with nicotinamide mononucleotide reduced tubular cell DNA damage and senescence and attenuated renal fibrosis in mouse models of ischaemic AKI184. Increasing evidence suggests that cellular senescence might also have beneficial effects in AKI. A small-molecule inhibitor of CDK4 and CDK6 induced proximal tubule cell-cycle arrest and ameliorated kidney injury in a mouse IRI model185. Moreover, we found that inhibition of senescence within the first week after induction of renal ischaemia in a mouse model impeded functional recovery (measured using renal perfusion and plasma cystatin-c levels)186, suggesting a protective role early in the process of AKI. Delineating the time course of kidney injury and the role of cellular senescence during each phase might identify a therapeutic time window to target senescence and interrupt the development of AKI.
Chronic kidney disease
CKD is increasingly recognized to mimic age-related diseases and senescence and the SASP are important drivers of CKD progression187 (Fig. 4). CKD can accelerate the senescence of immune, endothelial and vascular smooth muscle cells via a process known as uraemia-associated ageing188,189, potentially constituting a feed-forward mechanism of cellular damage. Immunosenescence in CKD manifests as an increased proportion of terminally differentiated T cells, telomere shortening of mononuclear cells, low thymic output189 and reduced immune-mediated clearance of senescent kidney cells, which promotes CKD progression.
The mechanisms that underlie CKD-induced senescence include hyperphosphataemia, a common complication of CKD that elicits senescence in myoblasts190, endothelial cells191 and aorta smooth muscle cells192 and contributes to sarcopenia and vascular calcification. Furthermore, uraemic toxins have been implicated in the senescence of proximal tubular cells193. Tubular epithelial cell senescence can be induced by inhibition of AMPK–mTOR signalling194, activation of the Wnt–β-catenin pathway195 or overexpression of Wnt9a196, and promotes epithelial to mesenchymal transition and consequent fibrosis. α-Klotho, an endogenous antagonist of Wnt–β-catenin signalling, was downregulated in unilateral ureteral obstruction, adriamycin nephropathy, and IRI models of fibrotic kidney disease197. Senolytic combination therapy with dasatinib and quercetin alleviated kidney fibrosis in mouse models of chronic renal ischaemia186 and abrogated the progression of AKI to CKD in mouse models of IRI and cisplatin-induced injury198.
Podocyte senescence induces glomerulosclerosis in the ageing kidney via AMPK–mTOR signalling199, whereas DKD or overfeeding can induce renal cellular senescence by decreasing sirtuin 1 expression200. In patients with DKD, the circulating senescence marker activin A is elevated161 and p16 is upregulated in tubular epithelial cells201. In mice with streptozotocin-induced diabetes, glomerular endothelial senescence is driven by M1 macrophages and largely dependent on intracellular ROS202. High blood glucose also induces mesangial cell senescence by activating RAGE–STAT5 signalling, which inhibits autophagy203 and therefore leads to accumulation of injured mitochondria and ROS, which are important inducers of senescence.
We detected cellular senescence (upregulation of p16, p19 and p21) in the kidneys of mice186, pigs204 and patients186 with renal artery stenosis and observed that ischaemic renovascular disease induces senescence of renal scattered tubular-like cells, which impairs their reparative capacity205. Senescence of renal tubular epithelial cells promotes progression of immunoglobulin A (IgA) nephropathy206 and the presence of p16INK4a-positive cells in kidney biopsy samples from patients with lupus nephritis is associated with renal injury and a worse prognosis207. Elevated gene expression of the senescence markers Tp16, Tp19 and Tp53 was also observed in mice with obesity-induced kidney injury208 and p16 expression was strikingly increased in biopsy samples from patients with glomerular disease209. Exposure of kidney cells to nephrotoxic factors including radiation125, TNF210, hypoxia or glucose oxidase211,212 can induce cell-cycle arrest in vitro. Replicative senescence is also involved in the development of chronic allograft nephropathy213. The complement factor H-related genes CFHR1 and CFHR3 have been implicated in tubular cell senescence in allografts in transplant recipients with IgA nephropathy214.
Extensive basic and clinical studies are required to elucidate the complex mechanisms of cellular senescence in CKD. Although these mechanisms are shared across many forms of kidney disease, the extent and unique features of cellular senescence likely vary with the severity and underlying aetiology of CKD.
Interventions targeting senescence
As cellular senescence has key roles in many age-related diseases, interventions targeting senescence, known as senotherapeutics, are potential therapies for these diseases (Table 2). The promise of such approaches is underscored by the observation that genetic animal models of senescent cell deficiency show improved recovery from kidney injury215 and extended lifespan128. Existing senotherapeutic approaches include drugs that selectively eliminate senescent cells, known as senolytics, drugs that inhibit the SASP, known as senomorphics, exogenous cell-based products and non-pharmacological therapies.
Senolytic interventions
Senolytic drugs were developed to overcome the characteristic resistance to apoptosis of senescent cells by inducing pre-programmed cell death216. Quercetin, a natural flavonoid found in some fruit and vegetables, has been shown to eliminate senescent vascular smooth muscle and endothelial cells in animal models by inducing apoptosis through activation of AMPK217,218, sirtuin 1–PINK1-mediated mitophagy219 and NRF2–NF-κB220 signalling. We found that quercetin blunted the expression of senescence markers in the kidneys of obese mice208 and had beneficial, senescence-independent effects on cardiac function in mice fed a high-fat diet owing to pro-angiogenic activity221, highlighting the multiple modes of action of senolytic drugs.
The plant flavonoid fisetin222,223 and procyanidin C1, which is a flavonoid found in grape seeds, are also senolytics224. Herbal extracts can also have senolytic activity. For example, one of the best-known anti-ageing drugs, ginsenoside, is an extract of ginseng that prevents senescence of bone marrow MSCs by activating NRF2 and PI3K–Akt signalling225. Ginsenoside can also modulate the SASP, reduce inflammation, balance redox status and attenuate organ ageing226,227. These observations suggest that selected dietary interventions with senolytic effects could potentially halt the progression of senescence-associated CKD.
AP20187, an FK1012 analogue, selectively induced apoptosis of p16Ink4a‐expressing senescent cells in various mouse models, resulting in improvements in age‐related brain inflammation, cognitive function and stenotic kidney function186,228. Navitoclax (also known as ABT-263) is an inhibitor of anti-apoptotic BCL-2 family proteins that induces apoptosis and exerts potent senolytic effects in ageing animal models and in some types of senescent cells in vitro229,230. Other BCL-2 family inhibitors, including A-1331852, A-1155463, EF24 and venetoclax, are also effective senolytics6,231,232. In addition, heat shock protein 90 inhibitors have senolytic activity233 and radio-electric asymmetric conveyer technology was shown to be effective in reducing the senescence of cultured stem cells234. Notably, these interventions do not selectively target senescent cells, and thus can be associated with off-target adverse effects, such as abnormal embryo development, dysregulated wound healing and tumorigenesis.
Organ-targeted or cell-targeted approaches using protein-based or peptide-based carriers, nanoparticles, extracellular vesicles or other vehicles could increase the specificity, decrease the off-target effects and facilitate the clinical translation of senolytic interventions. Current strategies to selectively target senescent cells include conjugating toxic drugs to antibodies against the senescent membrane marker β2-microglobulin235, which is upregulated via a p53-dependent mechanism, suggesting that it is a marker of stress-induced senescence. Another strategy involves activation of invariant NK T cells to improve immunosurveillance and removal of senescent cells236. Moreover, chimeric antigen receptor T cells that were engineered to specifically recognize the urokinase-type plasminogen activator receptor on the surface of senescent cells had senolytic effects in vitro and in vivo237. Finally, anti-ageing vaccines have been developed to target CD153+ senescent T cells or GPNMB+ senescent endothelial cells with promising results in obese mouse models238.
Senomorphic drugs
One of the best-studied senomorphic drugs is metformin, which reduces the incidence of age-related diseases and expands the lifespan of Caenorhabditis elegans, mice and patients with type 2 diabetes mellitus239. Metformin also enhances the anticancer efficacy of CDK4 and CDK6 inhibitors by modulating the SASP240, inhibits endothelial senescence caused by high glucose-induced metabolic memory by regulating the sirtuin 1–p300–p53–p21 pathway241, triggers immune‐mediated clearance of senescent cells and restores tumour immunosurveillance242.
Other senomorphic drugs include ruxolitinib, a JAK inhibitor that reduces inflammation and alleviates frailty in aged mice by suppressing inflammatory SASP factors243. mTOR inhibitors, such as rapamycin, inhibit senescence and suppress the SASP in endothelial cells244 and fibroblasts245 by inducing autophagy, thereby reducing the accumulation of damaged organelles. Activation of mTOR leads to peroxisome proliferator-activated receptor-γ coactivator 1β-dependent mitochondrial biogenesis, ROS production and persistent activation of the DDR246. Thus, inhibition of mTOR ameliorates cellular senescence.
Several herb extracts, such as resveratrol247, also show anti-SASP activity. Furthermore, the small molecule ML324 that inhibits KDM4, which is involved in the epigenetic regulation of SASP genes, was shown to decrease the SASP in senescent tumour stromal cells248. However, this approach needs to be used cautiously to avoid adverse effects given the sometimes incongruent behaviours of tumour and stromal microenvironments249 and possibly other cellular niches.
Some hormones also have senomorphic effects. For example, melatonin suppresses SASP gene expression by interrupting the recruitment of CREB-binding protein (CBP) by poly-(ADP-ribose) polymerase 1 (PARP1), which is a sensor of DNA damage250. Melatonin improves senescent T cell activity251, alleviated cardiac mitochondrial dysfunction in a mouse model of accelerated senescence252, and rescued MSCs from uraemic toxin-induced senescence in CKD253. Other hormones, including androgens254, oestrogens255, oestradiol256 and glucocorticoids257, can also modulate the release of inflammatory cytokines. However, glucocorticoids need to be used with caution as they can induce senescence in primary human tenocytes257.
Stem cells and extracellular vesicles
In addition to many other salutary effects, stem cells and their extracellular vesicles can exert senolytic activity. For example, bone-marrow-derived MSCs decreased senescence and improved cardiac function in aged mice258, pluripotent stem cells prevented stress-induced senescence in cardiomyocyte-derived cells259 and human umbilical cord-derived MSCs protected rat kidneys from AKI-induced senescence180. We observed relatively modest senolytic efficacy of adipose-derived MSCs in post-stenotic mouse and human kidneys260. In contrast to these senolytic effects, human umbilical cord-derived MSCs increased splenic CD4+ T cell senescence and alleviated symptoms of lupus in mice261. These differing findings suggest that the effects of MSCs are likely cell type and context dependent.
Stem cell extracellular vesicles have robust anti-senescence activity and might be less prone to rejection or tumour formation than their parent stem cells. MSC-derived extracellular vesicles inhibited oxidative stress-induced senescence in endothelial cells, promoted wound closure in ageing diabetic mice162, but methods for their harvesting and characterization require standardization. Clinical end-points and indices of the therapeutic success of senotherapeutics are required for clinical trials. In the future, novel biomarkers of senescence could potentially be used to direct the management of patients who might benefit from attenuation of cellular senescence.
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Acknowledgements
The authors’ work was supported by National Institutes of Health grant numbers DK120292, DK122734, AG062104, AG013925 and AG61456, the Connor Fund, Robert P. and Arlene R. Kogod, Robert J. and Theresa W. Ryan, and the Noaber Foundation.
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W.H. researched the data for the article and wrote the text. W.H. and L.O.L contributed substantially to discussion of the content. All authors reviewed and/or edited the manuscript before submission.
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L.O.L. is an adviser to AstraZeneca, CureSpec, Beren, Ribocure Pharmaceuticals and Butterfly Biosciences. Patents on senolytic drugs and their uses are held by the Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. The other authors declare no conflicts of interest.
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Glossary
- DREAM complex
-
A multisubunit complex formed by the assembly of p130 and p107 with their dimerization partner, E2F4/5, and a multi-vulva class-B core complex.
- Somatic hypermutation
-
A programmed process of adaptation to new foreign elements (such as microbes) whereby changes are introduced to the nucleotide sequences of immunoglobulin genes during B cell development.
- Efferocytosis
-
The process by which apoptotic cells are removed by phagocytic cells.
- Ramified
-
Used to describe cells that have long branch-like processes.
- Geroprotective protein
-
A protein that has anti-ageing effects.
- Radio-electric asymmetric conveyer technology
-
A technology delivering very low-intensity radio-electric emission to generate microcurrents in tissues or culture media and thereby produce biological effects.
- Metabolic memory
-
The durable effect of prior hyperglycaemia on the initiation and progression of diabetic complications.
- Tenocytes
-
Elongated fibroblasts and fibrocytes that reside between collagen fibres.
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Huang, W., Hickson, L.J., Eirin, A. et al. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol 18, 611–627 (2022). https://doi.org/10.1038/s41581-022-00601-z
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DOI: https://doi.org/10.1038/s41581-022-00601-z
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