Next Article in Journal
Using a Quantitative High-Throughput Screening Platform to Identify Molecular Targets and Compounds as Repurposing Candidates for Endometriosis
Next Article in Special Issue
The History and Science of the Major Birch Pollen Allergen Bet v 1
Previous Article in Journal
Assessing B-Z DNA Transitions in Solutions via Infrared Spectroscopy
Previous Article in Special Issue
The Janus-Faced Role of Lipid Droplets in Aging: Insights from the Cellular Perspective
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomolecules
Volume 13
Issue 6
10.3390/biom13060966
biomolecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Opinion

Senopathies—Diseases Associated with Cellular Senescence

by
Oleh Lushchak
1,2,3,
Markus Schosserer
4,5 and
Johannes Grillari
1,5,6,*
1
Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria
2
Department of Biochemistry and Biotechnology, Precarpathian National University, 76000 Ivano-Frankivsk, Ukraine
3
Research and Development University, 76018 Ivano-Frankivsk, Ukraine
4
Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria
5
Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
6
Institute of Molecular Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, 1190 Vienna, Austria
*
Author to whom correspondence should be addressed.
Biomolecules 2023, 13(6), 966; https://doi.org/10.3390/biom13060966
Submission received: 8 May 2023 / Revised: 5 June 2023 / Accepted: 6 June 2023 / Published: 8 June 2023
(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)
Review Reports Versions Notes

Abstract

:
Cellular senescence describes a stable cell cycle arrest state with a characteristic phenotype. Senescent cells accumulate in the human body during normal aging, limiting the lifespan and promoting aging-related, but also several non-related, pathologies. We propose to refer to all diseases whose pathogenesis or progression is associated with cellular senescence as “senopathies”. Targeting senescent cells with senolytics or senomorphics is likely to mitigate these pathologies. Examples of senopathies include cardiovascular, metabolic, musculoskeletal, liver, kidney, and lung diseases and neurodegeneration. For all these pathologies, animal studies provide clear mechanistic evidence for a connection between senescent cell accumulation and disease progression. The major persisting challenge in developing novel senotherapies is the heterogeneity of senescence phenotypes, causing a lack of universal biomarkers and difficulties in discriminating senescent from non-senescent cells.

1. Introduction

Cellular senescence is a state of stable cell cycle arrest. It is, in vivo, most commonly induced in response to various physiological and pathological conditions through DNA damage signaling [1,2,3,4] or the expression of oncogenes [5,6]. Leonard Hayflick discovered cellular senescence in 1965 as a phenomenon when human fetal fibroblasts stopped dividing but maintained viability and metabolic activity after prolonged cultivation [7]. In these early days, the permanent cell cycle arrest and characteristic morphological changes associated with senescence were considered mere artifacts of in vitro cultivation of primary cells [8,9]. Several decades later, the progressive shortening of telomeres was shown to be associated with the proliferation limit of cells in culture, known now as replicative senescence [10]. After that, an increasing body of evidence emerged, demonstrating that senescent cells (SCs) also accumulate in vivo, preferentially in aged individuals, and specifically at sites of aging-related pathologies [11,12,13]. Ultimately, elegant experiments in mice showed that the accumulation of SCs during aging limits the healthy murine lifespan [14,15]. These discoveries initiated ongoing endeavors to identify novel “senotherapies”, which comprise pharmacological compounds to eliminate SCs specifically (“senolytics”) or to mitigate or modify their senescence-associated secretory phenotype (SASP) (“senomorphics”) [16,17,18,19,20,21].
The SASP is considered the main trigger of tissue damage caused by SCs and is composed of pro-inflammatory cytokines, chemokines, and matrix-remodeling factors [22]. In addition, extracellular vesicles, miRNAs [23,24,25,26], and pro-inflammatory lipids [27] have been identified as SASP members. Recent evidence suggests that SCs attract innate immune cells by their SASP and activate dendritic and CD8 T-cells by increased MHC class I expression and self-antigen presentation [28]. However, SCs are also highly efficient in resisting immune clearance, partially explaining the increased SC burden in aged individuals. Cellular senescence is also associated with increased cell plasticity and a concomitant loss of cell identity. Senescent cells promote the de-differentiation of non-senescent neighboring cells, causing further tissue damage [29]. This relatively new concept is supported by a study demonstrating that Alzheimer’s disease (AD) patients induced neurons simultaneously expressed markers of de-differentiation and cellular senescence [30]. On the contrary, SCs play essential roles in embryogenesis, wound healing, and tissue regeneration [31,32]. Thus, while the transient presence of SCs is beneficial for maintaining tissue homeostasis and preventing tumorigenesis early in life, the accumulation of these cells drives age-related disease and promotes chronic inflammation [31].
Similarly, the contribution of cellular senescence to a wide range of pathological conditions is highly complex, combining beneficial and detrimental effects [1,33]. Many, but not all, of these are associated with aging, such as cardiovascular pathologies [12,34], neurodegeneration [35], and ocular diseases [36]. However, it is often unclear if the accumulation of SCs is a cause or consequence of the respective pathological condition [37]. Cystic fibrosis [38] and acute infections, such as SARS-CoV-2 [39], are not considered age-related pathologies but are both characterized and worsened by SC presence and accumulation.
We propose to refer to all diseases whose pathogenesis or progression is associated with cellular senescence as “senopathies” and aim to provide examples and mechanistic explanations in this opinion paper. While, on the one hand, precision medicine identifies more and more subtypes of disease entities, senescence might, on the other hand, be a common denominator and therapeutic (co-) target for a variety of very different disease entities. Here, we do not cover the connection between cellular senescence, cancer, and senolytic cancer therapy. This topic has already been extensively reviewed elsewhere [40,41,42] and is recently extended by the idea of a one-two-punch strategy against cancer [43].

2. Biomarkers of Cellular Senescence

In 1995, Dimri and colleagues demonstrated that cellular senescence occurs in cultures of human cells and aging skin by developing a first biomarker, such as the activity of β-galactosidase at pH 6.0, referred to as SA-β-Gal [11]. Increased SA-β-Gal due to elevated lysosomal content with altered activity is widely adopted as a biomarker both in vitro and in vivo. Later studies showed that SCs are distinct from quiescent and differentiated cells with specific morphological and metabolic signatures, reorganized chromatin, altered gene expression, and expression of the SASP. Before highlighting biomarkers of SCs based on these characteristic features, it is essential to emphasize that not all senescent cells display the full panel of all senescence biomarkers. Moreover, some senescence markers are also present in apoptotic and quiescent cells. Thus, only complex phenotyping using several biomarkers might lead to correct conclusions.
In general, SCs are characterized by a stable cell cycle arrest primarily due to DNA damage signaling in response to the shortening of telomeres, exposure to growth factors and inflammatory cytokines, high levels of reactive oxygen species (ROS), and mitochondrial dysfunction. These cells are typically larger, displaying a flattened shape and extensive vacuolization. Disrupted integrity of the nuclear envelope is observed due to a loss of Lamin B1 protein, whose decreased expression is currently one of the most useful senescence biomarkers [44]. Senescent cells accumulate many dysfunctional mitochondria producing increased levels of ROS, further causing DNA damage [45].
Chromatin reorganization in SCs provokes the formation of senescence-associated heterochromatin foci (SAHFs) to induce the silencing of genes that promote proliferation, including E2F target genes. SAHFs are characterized by extensive DAPI staining and immunoreactivity to macroH2A, heterochromatin protein 1 (HP1), and lysine 9 di-or-tri-methylated histone H3 (H3K9me2/3) [46].
Moreover, SCs display a persistent DNA damage response (DDR) and contain nuclear foci called “DNA segments with chromatin alterations reinforcing senescence” (DNA-SCARS). DNA-SCARS in uncapped telomeres are called “telomere dysfunction-induced foci” (TIF). Another indicator of the DDR is the phosphorylated form of H2A.X or γ-H2A.X, a variant of a histone required for checkpoint-mediated cell cycle arrest and DNA repair of double-stranded DNA breaks. Regulatory protein p53, as a mediator of the DDR, promotes the activation of p21WAF1/CIP1 (CDKN1A) and p16INK4A (CDKN2A) to inhibit the activity of cyclin-dependent kinase [3]. Both protein and mRNA levels for p53, p16INK4A, and p21WAF1/CIP1, are extensively used to detect cellular senescence in vitro and in vivo [3,37,47].
Senescent cells maintain their metabolic activity and secrete inflammatory cytokines (IL-6, IL-8, TNF-⍺), growth factors such as TGFβ, chemokines, specific micro-RNAs, and matrix metalloproteinases, collectively known as the SASP [47]. The SASP modulates the surrounding environment, exerting its pathophysiological effects [47,48]. Given the nature of the SASP, senescence signaling is often linked to inflammation. Remarkably, some SASP factors, such as colony-stimulating factor 1 (CSF1), CCL2, and IL-8, recruit the immune system to promote the self-clearance of SCs [4]. This process seems critical to control the levels of SCs in a given setting and prevent chronic inflammatory responses.
Manifestation of each senescence hallmark is context-dependent and varies according to the trigger, cell or tissue type, and time from induction of the senescence program [49]. Changes at the levels of transcripts or proteins in response to multiple senescence inducers in different cell types demonstrate variability within specific pathological contexts and the requirement for a multi-marker system to identify SCs with precise accuracy [50]. A three-step multi-marker workflow was suggested to include (1) SA-β-gal or lipofuscin accumulation; (2) co-staining with markers frequently present (p16INK4A, p21WAF1/CIP1) or absent (proliferation markers, Lamin B1); and (3) identification of factors predicted to be altered in specific senescence contexts (SASP, DNA damage, and PI3K/FOXO/mTOR) [3]. Similarly, recent endeavors led to the development of the SenMayo marker panel, which identifies SCs based on their mRNA expression signatures across different tissues with high accuracy [51].

3. Selected Examples of Senopathies and Their Treatment with Senotherapies

Aging and related functional declines are strong drivers for many diseases and can be treated pharmacologically [52,53,54,55]. Aging-related senopathies are characterized by the accumulation of SCs over time, causing tissue and organ dysfunctions and the development of pathophysiological changes [56,57]. Targeting SCs with senolytics; however, may improve the functionality of various organ systems and prevent disease progression [18,20,58,59,60]. Similar mechanistic relationships are more difficult to establish for senomorphics because these compounds target the SASP, not SCs as such. Since most SASP components are commonly present in inflammatory diseases, it is difficult to determine if a therapeutically effective compound’s mode of action is via its senomorphic or more general anti-inflammatory properties. Thus, readouts, such as the most common SASP factors IL-6 or IL-8, are insufficient to establish a clear mechanistic connection between SCs and a specific disease. Several compounds with senomorphic activity in vitro, such as rapamycin, metformin, aspirin, statins and NF-κB-, p38MAPK-, JAK/STAT-, and ATM-inhibitors, are effective in potential senopathies [61].
Several studies connecting SC accumulation to disease progression used the p16-3MR [32] or the INK-ATTAC [14] mouse model. Both models contain a transgene that permits the visualization and inducible elimination of p16INK4A-expressing cells.

3.1. Cardiovascular Diseases

Improved cardiovascular function, increased regeneration, and prevention of hypertrophy and fibrosis were shown under the treatment of old animals with navitoclax or a combination of dasatinib and quercetin (D+Q) [16,62]. These drugs significantly decreased the SC burden, shown by reduced SA-β-gal staining, telomere-associated DNA damage foci (TAF), and p16INK4A mRNA. Navitoclax effectively eliminated SCs from advanced atherosclerotic lesions in LDL receptor knockout mice exposed to a high-fat diet. Thereby, navitoclax prevented elastic fiber degradation and fibrous cap thinning through increased metalloprotease production [63].

3.2. Metabolic Disorders

Ruxolitinib treatment enhanced adipogenesis, reduced fat tissue loss and lipotoxicity, and improved insulin sensitivity of old animals by reducing the amounts of SA-β-gal positive cells and transcription of IL-6, p21WAF1/CIP1, and p16INK4A [64]. Even more so, diabetes was prevented in the NOD mouse model of type 1 diabetes, pointing toward diabetes as a potential senopathy [65]. Alleviated anxiety-related behavior and decreased inflammation in db/db diabetes-prone animals fed a high-fat diet were observed after treatment with D+Q [66]. A subset of insulin-producing pancreatic β-cells acquires a SASP during the natural history of T1D in humans. Senescent β-cells upregulated the pro-survival mediator Bcl-2 in non-obese diabetic mice. Thompson and colleagues used ABT-737 and ABT-199, inhibitors of Bcl-2, to eliminate senescent β-cells sufficiently to prevent diabetes [65]. Metformin is an approved drug for type 2 diabetes in humans, but also positively affects other age-related disorders [67] and extends the healthy lifespan of male mice [68]. Although several senescence markers in different cell types are down-regulated upon exposure to this drug [69,70], the precise mechanisms of metformin action remain elusive [61].

3.3. Musculoskeletal Diseases

Significant reduction in SCs and SASP factors in old mice by treatment with Ruxolitinib or D+Q prevented loss of bone mass and increased their strength, effectively preventing osteoporosis and frailty [71]. Moreover, UBX0101 inhibited erosion of articular cartilage by targeting transcription of SASP-associated genes [72] and thus points towards osteoarthritis as senopathy as well. Aspirin, for which senomorphic properties were described [73], is also effective in arthritis and osteoporosis [74]. The novel small molecule NF-κB-inhibitor SR12343 reduced senescence markers and improved muscle pathologies in the Zmpste24−/− progeroid mouse model [75].

3.4. Liver and Kidney Diseases

Age-related liver steatosis and fibrosis were effectively treated with A-1331852 or D+Q by elimination of SCs with decreased production of the SASP, both in INK-ATTAC and in the Mdr2−/− mouse model of primary sclerosing cholangitis [76,77]. Moreover, treatment with FOXO4-DRI improved kidney function by affecting amounts of Lamin B1 positive cells and expression of IL-6 [21].

3.5. Neurodegeneration

Senopathies have detrimental effects on the nervous system by affecting both its structure and function. One prominent example of a neurodegenerative condition likely promoted by the accumulation of SCs and characterized by the expression of tau is AD. Studies in SAMP8 mice developing pathophysiological alterations similar to human AD and in the tauNFT-Mapt0/0 model acquiring tau-related pathologies at a faster rate show that treatments with fisetin or D+Q decreased inflammation and stress with restored synaptic function, cognitive deficits, and cerebral blood flow [78,79]. Moreover, navitoclax prevented cognitive function decline, gliosis, and hyper-phosphorylation of tau in INK-ATTAC PS19 mice, which express high levels of human tau, specifically in neurons [80].

3.6. Lung Diseases

An accumulation of senescent cells induces fibrotic pulmonary disease, especially in idiopathic pulmonary fibrosis [81]. D+Q improved lung function in bleomycin-treated mice by affecting the mRNA levels of Mcpl, 11-6, and Mmpl2 [81]. Moreover, signatures of pulmonary fibrosis induced by irradiation were successfully treated with navitoclax [82]. In this model, the elimination of SCs and decreased inflammation were shown by reduced amounts of SA-β-gal positive cells and mRNA levels of p16INK4A, Bcl-2, IL-la, and IL-1β. It would be interesting if also chronic obstructive pulmonary disease (COPD), in which senescent cells are known to accumulate, were alleviated by senolytic treatment [83].
In Table 1, we summarize the effects of senolytic treatment on cardiovascular diseases, detrimental changes in bones, cartilage, liver, kidney, brain, and fat tissues, as well as treatment of atherosclerosis, neurodegeneration, fibrotic pulmonary disease, and diabetes, clearly qualifying these diseases as senopathies.

4. Conclusions

While we are moving towards precision medicine with more disease entities identified by molecular patterning than before by clinical phenotypic classification alone [84], one common denominator of several very different and heterogeneous conditions emerges: cellular senescence is present and accumulates in a plethora of mainly, but not exclusively, age-associated diseases and can be targeted by senotherapies as a single treatment strategy. Therefore, we postulate the term “senopathy” to define such diseases and conditions. One caveat, however, is the so far not well-described and understood heterogeneity of senescence depending on different senescence triggers and specific cell types. At this point, developing single senolytic or senomorphic drugs that specifically target all senescent cells in an organism is not well-conceivable.

Author Contributions

O.L.: Conceptualization, Investigation, Writing—original draft, Writing—review and editing. M.S.: Conceptualization, Writing—original draft, Writing—review and editing. J.G.: Conceptualization, Writing—original draft, Writing—review and editing, Supervision, Project administration, Funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

We kindly acknowledge support by the Austrian Science Fund (FWF) and ‘Herzfelder’sche Familienstiftung: P35268-B and FG 2400-B. OL is supported by a FEBS Ukrainian Short-Term Fellowship. This research was conducted while MS was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. The APC was funded by Open Access Funding by the Austrian Science Fund (FWF): P35268-B.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

J.G. is co-founder and shareholder of Rockfish Bio AG. O.L. and M.S. declare no conflict of interest.

References

  1. Borghesan, M.; Hoogaars, W.M.H.; Varela-Eirin, M.; Talma, N.; Demaria, M. A Senescence-Centric View of Aging: Implications for Longevity and Disease. Trends Cell Biol. 2020, 30, 777–791. [Google Scholar] [CrossRef] [PubMed]
  2. Van Deursen, J.M. The Role of Senescent Cells in Ageing. Nature 2014, 509, 439–446. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Gorgoulis, V.; Adams, P.D.; Alimonti, A.; Bennett, D.C.; Bischof, O.; Bishop, C.; Campisi, J.; Collado, M.; Evangelou, K.; Ferbeyre, G.; et al. Cellular Senescence: Defining a Path Forward. Cell 2019, 179, 813–827. [Google Scholar] [CrossRef]
  4. Muñoz-Espín, D.; Serrano, M. Cellular Senescence: From Physiology to Pathology. Nat. Rev. Mol. Cell Biol. 2014, 15, 482–496. [Google Scholar] [CrossRef]
  5. Baker, D.J.; Alimirah, F.; van Deursen, J.M.; Campisi, J.; Hildesheim, J. Oncogenic Senescence: A Multi-Functional Perspective. Oncotarget 2017, 8, 27661–27672. [Google Scholar] [CrossRef] [Green Version]
  6. Toussaint, O.; Royer, V.; Salmon, M.; Remacle, J. Stress-Induced Premature Senescence and Tissue Ageing. Biochem. Pharmacol. 2002, 64, 1007–1009. [Google Scholar] [CrossRef]
  7. Hayflick, L. The Limited in Vitro Lifetime of Human Diploid Cell Strains. Exp. Cell Res. 1965, 37, 614–636. [Google Scholar] [CrossRef]
  8. Hayflick, L.; Moorhead, P.S. The Serial Cultivation of Human Diploid Cell Strains. Exp. Cell Res. 1961, 25, 585–621. [Google Scholar] [CrossRef] [PubMed]
  9. Shay, J.W.; Wright, W.E. Hayflick, His Limit, and Cellular Ageing. Nat. Rev. Mol. Cell Biol. 2000, 1, 72–76. [Google Scholar] [CrossRef]
  10. Harley, C.B.; Futcher, A.B.; Greider, C.W. Telomeres Shorten during Ageing of Human Fibroblasts. Nature 1990, 345, 458–460. [Google Scholar] [CrossRef]
  11. Dimri, G.P.; Lee, X.; Basile, G.; Acosta, M.; Scott, G.; Roskelley, C.; Medrano, E.E.; Linskens, M.; Rubelj, I.; Pereira-Smith, O. A Biomarker That Identifies Senescent Human Cells in Culture and in Aging Skin In Vivo. Proc. Natl. Acad. Sci. USA 1995, 92, 9363–9367. [Google Scholar] [CrossRef] [Green Version]
  12. Erusalimsky, J.D.; Kurz, D.J. Cellular Senescence In Vivo: Its Relevance in Ageing and Cardiovascular Disease. Exp. Gerontol. 2005, 40, 634–642. [Google Scholar] [CrossRef]
  13. Herbig, U.; Ferreira, M.; Condel, L.; Carey, D.; Sedivy, J.M. Cellular Senescence in Aging Primates. Science 2006, 311, 1257. [Google Scholar] [CrossRef] [Green Version]
  14. Baker, D.J.; Wijshake, T.; Tchkonia, T.; LeBrasseur, N.K.; Childs, B.G.; van de Sluis, B.; Kirkland, J.L.; van Deursen, J.M. Clearance of P16Ink4a-Positive Senescent Cells Delays Ageing-Associated Disorders. Nature 2011, 479, 232–236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Baker, D.J.; Childs, B.G.; Durik, M.; Wijers, M.E.; Sieben, C.J.; Zhong, J.; Saltness, R.A.; Jeganathan, K.B.; Verzosa, G.C.; Pezeshki, A.; et al. Naturally Occuring P16INK4a-Positive Cells Shorten Healthy Lifespan. Nature 2016, 530, 184–189. [Google Scholar] [CrossRef] [Green Version]
  16. Zhu, Y.; Tchkonia, T.; Pirtskhalava, T.; Gower, A.C.; Ding, H.; Giorgadze, N.; Palmer, A.K.; Ikeno, Y.; Hubbard, G.B.; Hara, S.P.O.; et al. The ‘Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Aging Cell 2015, 14, 644–658. [Google Scholar] [CrossRef]
  17. Xu, M.; Pirtskhalava, T.; Farr, J.N.; Weigand, B.M.; Palmer, A.K.; Weivoda, M.M.; Inman, C.L.; Ogrodnik, M.B.; Hachfeld, C.M.; Fraser, D.G.; et al. Senolytics Improve Physical Function and Increase Lifespan in Old Age. Nat. Med. 2018, 24, 1246–1256. [Google Scholar] [CrossRef] [PubMed]
  18. Robbins, P.D.; Jurk, D.; Khosla, S.; Kirkland, J.L.; LeBrasseur, N.K.; Miller, J.D.; Passos, J.F.; Pignolo, R.J.; Tchkonia, T.; Niedernhofer, L.J. Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span. Annu. Rev. Pharmacol. Toxicol. 2021, 61, 779–803. [Google Scholar] [CrossRef]
  19. Tchkonia, T.; Zhu, Y.; van Deursen, J.; Campisi, J.; Kirkland, J.L. Cellular Senescence and the Senescent Secretory Phenotype: Therapeutic Opportunities. J. Clin. Investig. 2013, 123, 966–972. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Birch, J.; Gil, J. Senescence and the SASP: Many Therapeutic Avenues. Genes Dev. 2020, 34, 1565–1576. [Google Scholar] [CrossRef]
  21. Baar, M.P.; Brandt, R.M.C.; Putavet, D.A.; Klein, J.D.D.; Derks, K.W.J.; Bourgeois, B.R.M.; Stryeck, S.; Rijksen, Y.; van Willigenburg, H.; Feijtel, D.A.; et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 2017, 169, 132–147.e16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Coppé, J.-P.; Patil, C.K.; Rodier, F.; Sun, Y.; Muñoz, D.P.; Goldstein, J.; Nelson, P.S.; Desprez, P.-Y.; Campisi, J. Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the P53 Tumor Suppressor. PLoS Biol. 2008, 6, 2853–2868. [Google Scholar] [CrossRef]
  23. Weilner, S.; Schraml, E.; Redl, H.; Grillari-Voglauer, R.; Grillari, J. Secretion of Microvesicular MiRNAs in Cellular and Organismal Aging. Exp. Gerontol. 2013, 48, 626–633. [Google Scholar] [CrossRef] [Green Version]
  24. Terlecki-Zaniewicz, L.; Lämmermann, I.; Latreille, J.; Bobbili, M.R.; Pils, V.; Schosserer, M.; Weinmüllner, R.; Dellago, H.; Skalicky, S.; Pum, D.; et al. Small Extracellular Vesicles and Their MiRNA Cargo Are Anti-Apoptotic Members of the Senescence-Associated Secretory Phenotype. Aging 2018, 10, 1103–1132. [Google Scholar] [CrossRef] [PubMed]
  25. Fafián-Labora, J.A.; O’Loghlen, A. NF-ΚB/IKK Activation by Small Extracellular Vesicles within the SASP. Aging Cell 2021, 20, e13426. [Google Scholar] [CrossRef]
  26. Tanaka, Y.; Takahashi, A. Senescence-Associated Extracellular Vesicle Release Plays a Role in Senescence-Associated Secretory Phenotype (SASP) in Age-Associated Diseases. J. Biochem. 2021, 169, 147–153. [Google Scholar] [CrossRef]
  27. Lopes-Paciencia, S.; Saint-Germain, E.; Rowell, M.-C.; Ruiz, A.F.; Kalegari, P.; Ferbeyre, G. The Senescence-Associated Secretory Phenotype and Its Regulation. Cytokine 2019, 117, 15–22. [Google Scholar] [CrossRef]
  28. Marin, I.; Boix, O.; Garcia-Garijo, A.; Sirois, I.; Caballe, A.; Zarzuela, E.; Ruano, I.; Stephan-Otto Attolini, C.; Prats, N.; Lopez-Dominguez, J.A.; et al. Cellular Senescence Is Immunogenic and Promotes Anti-Tumor Immunity. Cancer Discov. 2022, 13, 410–431. [Google Scholar] [CrossRef] [PubMed]
  29. Ring, N.A.R.; Valdivieso, K.; Grillari, J.; Redl, H.; Ogrodnik, M. The Role of Senescence in Cellular Plasticity: Lessons from Regeneration and Development and Implications for Age-Related Diseases. Dev. Cell 2022, 57, 1083–1101. [Google Scholar] [CrossRef]
  30. Mertens, J.; Herdy, J.R.; Traxler, L.; Schafer, S.T.; Schlachetzki, J.C.M.; Böhnke, L.; Reid, D.A.; Lee, H.; Zangwill, D.; Fernandes, D.P.; et al. Age-Dependent Instability of Mature Neuronal Fate in Induced Neurons from Alzheimer’s Patients. Cell Stem Cell 2021, 28, 1533–1548.e6. [Google Scholar] [CrossRef]
  31. Schosserer, M. The Role and Biology of Senescent Cells in Ageing-Related Tissue Damage and Repair. Mech. Ageing Dev. 2022, 202, 111629. [Google Scholar] [CrossRef] [PubMed]
  32. Demaria, M.; Ohtani, N.; Youssef, S.A.; Rodier, F.; Toussaint, W.; Mitchell, J.R.; Laberge, R.M.; Vijg, J.; VanSteeg, H.; Dollé, M.E.T.; et al. An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA. Dev. Cell 2014, 31, 722–733. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. He, S.; Sharpless, N.E. Senescence in Health and Disease. Cell 2017, 169, 1000–1011. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Mehdizadeh, M.; Aguilar, M.; Thorin, E.; Ferbeyre, G.; Nattel, S. The Role of Cellular Senescence in Cardiac Disease: Basic Biology and Clinical Relevance. Nat. Rev. Cardiol. 2022, 19, 250–264. [Google Scholar] [CrossRef]
  35. Kritsilis, M.; Rizou, V.S.; Koutsoudaki, P.N.; Evangelou, K.; Gorgoulis, V.G.; Papadopoulos, D. Ageing, Cellular Senescence and Neurodegenerative Disease. Int. J. Mol. Sci. 2018, 19, 2937. [Google Scholar] [CrossRef] [Green Version]
  36. Sreekumar, P.G.; Hinton, D.R.; Kannan, R. The Emerging Role of Senescence in Ocular Disease. Oxidative Med. Cell. Longev. 2020, 2020, e2583601. [Google Scholar] [CrossRef] [Green Version]
  37. Childs, B.G.; Durik, M.; Baker, D.J.; van Deursen, J.M. Cellular Senescence in Aging and Age-Related Disease: From Mechanisms to Therapy. Nat. Med. 2015, 21, 1424–1435. [Google Scholar] [CrossRef] [Green Version]
  38. Fischer, B.M.; Wong, J.K.; Degan, S.; Kummarapurugu, A.B.; Zheng, S.; Haridass, P.; Voynow, J.A. Increased Expression of Senescence Markers in Cystic Fibrosis Airways. Am. J. Physiol. Lung Cell Mol. Physiol. 2013, 304, L394–L400. [Google Scholar] [CrossRef] [Green Version]
  39. Schmitt, C.A.; Tchkonia, T.; Niedernhofer, L.J.; Robbins, P.D.; Kirkland, J.L.; Lee, S. COVID-19 and Cellular Senescence. Nat. Rev. Immunol. 2022, 23, 251–263. [Google Scholar] [CrossRef]
  40. Schosserer, M.; Grillari, J.; Breitenbach, M. The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy. Front. Oncol. 2017, 7, 278. [Google Scholar] [CrossRef] [Green Version]
  41. Campisi, J.; Andersen, J.K.; Kapahi, P.; Melov, S. Cellular Senescence: A Link between Cancer and Age-Related Degenerative Disease? Semin. Cancer Biol. 2011, 21, 354–359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Loaiza, N.; Demaria, M. Cellular Senescence and Tumor Promotion: Is Aging the Key? Biochim. Biophys. Acta Rev. Cancer 2016, 1865, 155–167. [Google Scholar] [CrossRef] [PubMed]
  43. Wang, L.; Lankhorst, L.; Bernards, R. Exploiting Senescence for the Treatment of Cancer. Nat. Rev. Cancer 2022, 22, 340–355. [Google Scholar] [CrossRef] [PubMed]
  44. Matias, I.; Diniz, L.P.; Damico, I.V.; Araujo, A.P.B.; Neves, L.D.S.; Vargas, G.; Leite, R.E.P.; Suemoto, C.K.; Nitrini, R.; Jacob-Filho, W.; et al. Loss of Lamin-B1 and Defective Nuclear Morphology Are Hallmarks of Astrocyte Senescence In Vitro and in the Aging Human Hippocampus. Aging Cell 2022, 21, e13521. [Google Scholar] [CrossRef] [PubMed]
  45. Giorgi, C.; Marchi, S.; Simoes, I.C.M.; Ren, Z.; Morciano, G.; Perrone, M.; Patalas-Krawczyk, P.; Borchard, S.; Jędrak, P.; Pierzynowska, K.; et al. Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases. In International Review of Cell and Molecular Biology; Elsevier: Amsterdam, The Netherlands, 2018; Volume 340, pp. 209–344. ISBN 978-0-12-815736-7. [Google Scholar]
  46. Aird, K.M.; Zhang, R. Detection of Senescence-Associated Heterochromatin Foci (SAHF). In Cell Senescence; Galluzzi, L., Vitale, I., Kepp, O., Kroemer, G., Eds.; Methods in Molecular Biology Series; Humana Press: Totowa, NJ, USA, 2013; Volume 965, pp. 185–196. ISBN 978-1-62703-238-4. [Google Scholar]
  47. Coppé, J.-P.; Desprez, P.-Y.; Krtolica, A.; Campisi, J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu. Rev. Pathol. 2010, 5, 99–118. [Google Scholar] [CrossRef] [Green Version]
  48. Hearps, A.C.; Martin, G.E.; Angelovich, T.A.; Cheng, W.-J.; Maisa, A.; Landay, A.L.; Jaworowski, A.; Crowe, S.M. Aging Is Associated with Chronic Innate Immune Activation and Dysregulation of Monocyte Phenotype and Function. Aging Cell 2012, 11, 867–875. [Google Scholar] [CrossRef]
  49. Calcinotto, A.; Kohli, J.; Zagato, E.; Pellegrini, L.; Demaria, M.; Alimonti, A. Cellular Senescence: Aging, Cancer, and Injury. Physiol. Rev. 2019, 99, 1047–1078. [Google Scholar] [CrossRef]
  50. Basisty, N.; Kale, A.; Jeon, O.H.; Kuehnemann, C.; Payne, T.; Rao, C.; Holtz, A.; Shah, S.; Sharma, V.; Ferrucci, L.; et al. A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development. PLoS Biol. 2020, 18, e3000599. [Google Scholar] [CrossRef] [Green Version]
  51. Saul, D.; Kosinsky, R.L.; Atkinson, E.J.; Doolittle, M.L.; Zhang, X.; LeBrasseur, N.K.; Pignolo, R.J.; Robbins, P.D.; Niedernhofer, L.J.; Ikeno, Y.; et al. A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways across Tissues. Nat. Commun. 2022, 13, 4827. [Google Scholar] [CrossRef]
  52. Piskovatska, V.; Strilbytska, O.; Koliada, A.; Vaiserman, A.; Lushchak, O. Health Benefits of Anti-Aging Drugs. Subcell. Biochem. 2019, 91, 339–392. [Google Scholar] [CrossRef]
  53. Lushchak, O.; Strilbytska, O.; Koliada, A.; Zayachkivska, A.; Burdyliuk, N.; Yurkevych, I.; Storey, K.B.; Vaiserman, A. Nanodelivery of Phytobioactive Compounds for Treating Aging-Associated Disorders. Geroscience 2020, 42, 117–139. [Google Scholar] [CrossRef]
  54. Vaiserman, A.; Koliada, A.; Lushchak, O. Neuroinflammation in Pathogenesis of Alzheimer’s Disease: Phytochemicals as Potential Therapeutics. Mech. Ageing Dev. 2020, 189, 111259. [Google Scholar] [CrossRef]
  55. Vaiserman, A.; Koliada, A.; Lushchak, O.; Castillo, M.J. Repurposing Drugs to Fight Aging: The Difficult Path from Bench to Bedside. Med. Res. Rev. 2021, 41, 1676–1700. [Google Scholar] [CrossRef] [PubMed]
  56. Khosla, S.; Farr, J.N.; Tchkonia, T.; Kirkland, J.L. The Role of Cellular Senescence in Ageing and Endocrine Disease. Nat. Rev. Endocrinol. 2020, 16, 263–275. [Google Scholar] [CrossRef] [PubMed]
  57. Doolittle, M.L.; Monroe, D.G.; Farr, J.N.; Khosla, S. The Role of Senolytics in Osteoporosis and Other Skeletal Pathologies. Mech. Ageing Dev. 2021, 199, 111565. [Google Scholar] [CrossRef]
  58. Sikora, E.; Bielak-Zmijewska, A.; Mosieniak, G. Targeting Normal and Cancer Senescent Cells as a Strategy of Senotherapy. Ageing Res. Rev. 2019, 55, 100941. [Google Scholar] [CrossRef] [PubMed]
  59. Al-Naggar, I.M.A.; Kuchel, G.A.; Xu, M. Senolytics: Targeting Senescent Cells for Age-Associated Diseases. Curr. Mol. Biol. Rep. 2020, 6, 161–172. [Google Scholar] [CrossRef]
  60. Owens, W.A.; Walaszczyk, A.; Spyridopoulos, I.; Dookun, E.; Richardson, G.D. Senescence and Senolytics in Cardiovascular Disease: Promise and Potential Pitfalls. Mech. Ageing Dev. 2021, 198, 111540. [Google Scholar] [CrossRef]
  61. Zhang, L.; Pitcher, L.E.; Prahalad, V.; Niedernhofer, L.J.; Robbins, P.D. Targeting Cellular Senescence with Senotherapeutics: Senolytics and Senomorphics. FEBS J. 2023, 290, 1362–1383. [Google Scholar] [CrossRef]
  62. Anderson, R.; Lagnado, A.; Maggiorani, D.; Walaszczyk, A.; Dookun, E.; Chapman, J.; Birch, J.; Salmonowicz, H.; Ogrodnik, M.; Jurk, D.; et al. Length-Independent Telomere Damage Drives Post-Mitotic Cardiomyocyte Senescence. EMBO J. 2019, 38, e100492. [Google Scholar] [CrossRef]
  63. Childs, B.G.; Baker, D.J.; Wijshake, T.; Conover, C.A.; Campisi, J.; van Deursen, J.M. Senescent Intimal Foam Cells Are Deleterious at All Stages of Atherosclerosis. Science 2016, 354, 472–477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Xu, M.; Palmer, A.K.; Ding, H.; Weivoda, M.M.; Pirtskhalava, T.; White, T.A.; Sepe, A.; Johnson, K.O.; Stout, M.B.; Giorgadze, N.; et al. Targeting Senescent Cells Enhances Adipogenesis and Metabolic Function in Old Age. eLife 2015, 4, e12997. [Google Scholar] [CrossRef]
  65. Thompson, P.J.; Shah, A.; Ntranos, V.; Van Gool, F.; Atkinson, M.; Bhushan, A. Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes. Cell Metab. 2019, 29, 1045–1060.e10. [Google Scholar] [CrossRef] [PubMed]
  66. Ogrodnik, M.; Zhu, Y.; Langhi, L.G.P.; Tchkonia, T.; Krüger, P.; Fielder, E.; Victorelli, S.; Ruswhandi, R.A.; Giorgadze, N.; Pirtskhalava, T.; et al. Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis. Cell Metab. 2019, 29, 1061–1077.e8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Foretz, M.; Guigas, B.; Bertrand, L.; Pollak, M.; Viollet, B. Metformin: From Mechanisms of Action to Therapies. Cell Metab. 2014, 20, 953–966. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Martin-Montalvo, A.; Mercken, E.M.; Mitchell, S.J.; Palacios, H.H.; Mote, P.L.; Scheibye-Knudsen, M.; Gomes, A.P.; Ward, T.M.; Minor, R.K.; Blouin, M.-J.; et al. Metformin Improves Healthspan and Lifespan in Mice. Nat. Commun. 2013, 4, 2192. [Google Scholar] [CrossRef] [Green Version]
  69. Moiseeva, O.; Deschênes-Simard, X.; St-Germain, E.; Igelmann, S.; Huot, G.; Cadar, A.E.; Bourdeau, V.; Pollak, M.N.; Ferbeyre, G. Metformin Inhibits the Senescence-Associated Secretory Phenotype by Interfering with IKK/NF-ΚB Activation. Aging Cell 2013, 12, 489–498. [Google Scholar] [CrossRef]
  70. Zhang, C.; Chen, M.; Zhou, N.; Qi, Y. Metformin Prevents H2O2-Induced Senescence in Human Lens Epithelial B3 Cells. Med. Sci. Monit. Basic Res. 2020, 26, e923391. [Google Scholar] [CrossRef]
  71. Farr, J.N.; Xu, M.; Weivoda, M.M.; Monroe, D.G.; Fraser, D.G.; Onken, J.L.; Negley, B.A.; Sfeir, J.G.; Ogrodnik, M.B.; Hachfeld, C.M.; et al. Targeting Cellular Senescence Prevents Age-Related Bone Loss in Mice. Nat. Med. 2017, 23, 1072–1079. [Google Scholar] [CrossRef] [Green Version]
  72. Jeon, O.H.; Kim, C.; Laberge, R.-M.; Demaria, M.; Rathod, S.; Vasserot, A.P.; Chung, J.W.; Kim, D.H.; Poon, Y.; David, N.; et al. Local Clearance of Senescent Cells Attenuates the Development of Post-Traumatic Osteoarthritis and Creates a pro-Regenerative Environment. Nat. Med. 2017, 23, 775–781. [Google Scholar] [CrossRef] [Green Version]
  73. Feng, M.; Kim, J.; Field, K.; Reid, C.; Chatzistamou, I.; Shim, M. Aspirin Ameliorates the Long-Term Adverse Effects of Doxorubicin through Suppression of Cellular Senescence. FASEB Bioadv. 2019, 1, 579–590. [Google Scholar] [CrossRef] [PubMed]
  74. Hybiak, J.; Broniarek, I.; Kiryczyński, G.; Los, L.D.; Rosik, J.; Machaj, F.; Sławiński, H.; Jankowska, K.; Urasińska, E. Aspirin and Its Pleiotropic Application. Eur. J. Pharmacol 2020, 866, 172762. [Google Scholar] [CrossRef] [PubMed]
  75. Zhang, L.; Zhao, J.; Mu, X.; McGowan, S.J.; Angelini, L.; O’Kelly, R.D.; Yousefzadeh, M.J.; Sakamoto, A.; Aversa, Z.; LeBrasseur, N.K.; et al. Novel Small Molecule Inhibition of IKK/NF-ΚB Activation Reduces Markers of Senescence and Improves Healthspan in Mouse Models of Aging. Aging Cell 2021, 20, e13486. [Google Scholar] [CrossRef] [PubMed]
  76. Ogrodnik, M.; Miwa, S.; Tchkonia, T.; Tiniakos, D.; Wilson, C.L.; Lahat, A.; Day, C.P.; Burt, A.; Palmer, A.; Anstee, Q.M.; et al. Cellular Senescence Drives Age-Dependent Hepatic Steatosis. Nat. Commun. 2017, 8, 15691. [Google Scholar] [CrossRef] [Green Version]
  77. Moncsek, A.; Al-Suraih, M.S.; Trussoni, C.E.; O’Hara, S.P.; Splinter, P.L.; Zuber, C.; Patsenker, E.; Valli, P.V.; Fingas, C.D.; Weber, A.; et al. Targeting Senescent Cholangiocytes and Activated Fibroblasts with B-Cell Lymphoma-Extra Large Inhibitors Ameliorates Fibrosis in Multidrug Resistance 2 Gene Knockout (Mdr2−/−) Mice. Hepatology 2018, 67, 247–259. [Google Scholar] [CrossRef] [Green Version]
  78. Currais, A.; Farrokhi, C.; Dargusch, R.; Armando, A.; Quehenberger, O.; Schubert, D.; Maher, P. Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse. J. Gerontol. Ser. A 2018, 73, 299–307. [Google Scholar] [CrossRef] [Green Version]
  79. Musi, N.; Valentine, J.M.; Sickora, K.R.; Baeuerle, E.; Thompson, C.S.; Shen, Q.; Orr, M.E. Tau Protein Aggregation Is Associated with Cellular Senescence in the Brain. Aging Cell 2018, 17, e12840. [Google Scholar] [CrossRef]
  80. Bussian, T.J.; Aziz, A.; Meyer, C.F.; Swenson, B.L.; van Deursen, J.M.; Baker, D.J. Clearance of Senescent Glial Cells Prevents Tau-Dependent Pathology and Cognitive Decline. Nature 2018, 562, 578–582. [Google Scholar] [CrossRef]
  81. Schafer, M.J.; White, T.A.; Iijima, K.; Haak, A.J.; Ligresti, G.; Atkinson, E.J.; Oberg, A.L.; Birch, J.; Salmonowicz, H.; Zhu, Y.; et al. Cellular Senescence Mediates Fibrotic Pulmonary Disease. Nat. Commun. 2017, 8, 14532. [Google Scholar] [CrossRef] [Green Version]
  82. Pan, J.; Li, D.; Xu, Y.; Zhang, J.; Wang, Y.; Chen, M.; Lin, S.; Huang, L.; Chung, E.J.; Citrin, D.E.; et al. Inhibition of Bcl-2/Xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice. Int. J. Radiat. Oncol. Biol. Phys. 2017, 99, 353–361. [Google Scholar] [CrossRef]
  83. Majewska, J.; Krizhanovsky, V. Breathe It in—Spotlight on Senescence and Regeneration in the Lung. Mech. Ageing Dev. 2021, 199, 111550. [Google Scholar] [CrossRef] [PubMed]
  84. Hopp, W.J.; Li, J.; Wang, G. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease; National Academies Press: Washington, DC, USA, 2011; Volume 27, ISBN 978-0-309-22222-8. [Google Scholar]
Table
Table 1. Examples of medical conditions with evidence for an implication of senescent cells. Italic font indicates mRNA. “Age” reflects the age at analysis. * Initial age of mice before the start of the treatment is not specified; mo: month; WT: wildtype; p16-3MR: p16INK4A trimodality reporter; HFD: high-fat diet; INK-ATTAC: p16INK4A-induced apoptosis through targeted activation of caspase; SAMP8: Senescence Accelerated Mouse-Prone 8; PS19: Tau P301S (PS19Tg); NOD: Non-Obese Diabetic Mouse; db/db: BKS.Cg-Dock7m+/+LeprdbJ; D+Q: Dasatinib and Quercetin; SASP: senescence-associated secretory phenotype; TAF: telomere-associated DNA damage repair foci; AECII: alveolar epithelial type II cell; SA-β-gal: senescence-associated β-galactosidase activity.
Table 1. Examples of medical conditions with evidence for an implication of senescent cells. Italic font indicates mRNA. “Age” reflects the age at analysis. * Initial age of mice before the start of the treatment is not specified; mo: month; WT: wildtype; p16-3MR: p16INK4A trimodality reporter; HFD: high-fat diet; INK-ATTAC: p16INK4A-induced apoptosis through targeted activation of caspase; SAMP8: Senescence Accelerated Mouse-Prone 8; PS19: Tau P301S (PS19Tg); NOD: Non-Obese Diabetic Mouse; db/db: BKS.Cg-Dock7m+/+LeprdbJ; D+Q: Dasatinib and Quercetin; SASP: senescence-associated secretory phenotype; TAF: telomere-associated DNA damage repair foci; AECII: alveolar epithelial type II cell; SA-β-gal: senescence-associated β-galactosidase activity.
Organ/System/
Diseases		Age/GenotypeSenolytic TreatmentEvidence for Targeting SCsEffectsReference
Cardiovascular system24-mo-old
WT		D+QSA-β-gal, p16INK4AImproved cardiovascular function[16]: Zhu et al., 2015
23-mo-old
WT		navitoclaxTAF, p16INK4AReduced hypertrophy and fibrosis, increased regeneration[62]: Anderson et al., 2019
8-mo-old
p16-3MR; Ldlr−/−
HFD		navitoclaxSA-β-gal, p16INK4A, pl9ARF, p21WAF1/CIP1, IL-1a, Mmp3, Mmpl3Reduced plaque number and size, smaller fatty streaks, and protection from plaques rupture[63]: Childs et al., 2016
Fat tissue24-mo-old
WT		ruxolitinibSA-β-gal, IL-6, p21WAF1/CIP1, p16INK4AEnhanced adipogenesis, reduced loss of fat tissue, reduced lipotoxicity, and enhanced insulin sensitivity[64]: Xu et al., 2015
min. 4-mo-old *
INK-ATTAC
HFD		D+QSA-β-gal, p16INK4A, TAF, SASP factors in plasmaAlleviated anxiety-related behavior and decreased inflammation[66]: Ogrodnik et al., 2019
Bones and cartilages20-mo-old
WT		D+Qp16INK4A, bone fluorescence, distention of satellites osteocytesHigher bone mass and strength, better bone microarchitecture, reduced osteoporosis, and frailty[71]: Farr et al., 2017
22-mo-old
WT		ruxolitinib
19-mo-old
p16-3MR		UBX0101p16INK4A, p21WAF1/CIP1, 11-6, Mmpl3Inhibited articular cartilage erosion[72]: Jeon et al., 2017
5-mo-old
Zmpste24−/−		SR12343SA-β-gal, p16INK4A, p21WAF1/CIP1, IL-6Inhibited fibrosis formation (trichrome staining), improved myogenesis[75]: Zhang et al., 2021
Liver and kidney4-mo-old
Mdr−/−		A-1331852p16INK4A-positive cholangiocytes and SASP levelsReduction in liver fibrosis and amounts of growth factors and cytokines[77]: Moncsek et al., 2018
24-mo-old
INK-ATTAC		D+QKaryomegalic and TAF-positive hepatocytesReduced hepatic steatosis[76]: Ogrodnik et al., 2017
24-28-mo-old
p16-3MR		FOXO4-DRILamin B1-positive cells, IL-6Improved kidney function[21]: Baar et al., 2017
Brain and neurodegeneration10-mo-old
SAMP8		fisetin Reduced cognitive deficits, restored synaptic function, stress, and inflammation[78]: Currais et al., 2018
23-mo-old
tauNFT-Mapt0/0		D+Qp16INK4A, p21WAF1/CIP, Cxcl1, IL-1aNeuroprotective effects, improved brain structure, and cerebral blood flow[79]: Musi et al., 2018
6-8-mo-old
INK-ATTAC; PS19		navitoclaxX-Gal crystalsPrevented gliosis and hyper-phosphorylation of tau, preserved cognitive function[80]: Bussian et al., 2018
Fibrotic pulmonary disease4-9-mo-old
INK-ATTAC
bleomycin-treated		D+Qp16INK4A, Mcpl,
11-6, Mmpl2		Improvement of lung function measured by plethysmography, increased body weight, and improved exercise capacity[81]: Schafer et al., 2017
8-9-mo-old
WT
irradiated		navitoclaxSA-β-gal positive AECIIs, p16INK4A, Bcl-2, IL-1a, IL-1bReversed pulmonary fibrosis[82]: Pan et al., 2017
Diabetes9-mo-old
NOD		ABT-737
ABT-199		SA-β-gal, p16INK4A, p21WAF1/CIP, Igfbp3, IL-6Prevention of type-1 diabetes by inhibition of b-cell destruction[65]: Thompson et al., 2019
min. 2-mo-old *
db/db mice		D+QSA-β-gal, p16INK4A, TAFAlleviated anxiety-related behavior[66]: Ogrodnik et al., 2019
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Lushchak, O.; Schosserer, M.; Grillari, J. Senopathies—Diseases Associated with Cellular Senescence. Biomolecules 2023, 13, 966. https://doi.org/10.3390/biom13060966

AMA Style

Lushchak O, Schosserer M, Grillari J. Senopathies—Diseases Associated with Cellular Senescence. Biomolecules. 2023; 13(6):966. https://doi.org/10.3390/biom13060966

Chicago/Turabian Style

Lushchak, Oleh, Markus Schosserer, and Johannes Grillari. 2023. "Senopathies—Diseases Associated with Cellular Senescence" Biomolecules 13, no. 6: 966. https://doi.org/10.3390/biom13060966

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop