REVIEW URRENT C OPINION
Cellular senescence and the senescent secretory phenotype in age-related chronic diseases Yi Zhu, Jacqueline L. Armstrong, Tamara Tchkonia, and James L. Kirkland
Purpose of review Possible mechanisms in cellular senescence and the senescence-associated secretory phenotype (SASP) that drive and promote chronic inflammation in multiple age-related chronic diseases are considered. Recent findings A series of studies about the SASP indicate that senescent cells may be involved in the development of chronic inflammatory diseases associated with aging. Summary Aging is a complex biological process accompanied by a state of chronic, low-grade, ‘sterile’ inflammation, which is a major contributor to the development of many age-related chronic disorders including atherosclerosis, osteoarthritis, Alzheimer’s disease, type 2 diabetes, cancers, and others. It appears that cellular senescence plays a role in causing inflammation through the SASP. A better understanding of the contribution of senescent cells to the pathologies of chronic inflammatory disorders could have potentially profound diagnostic and therapeutic implications. Keywords inflammation, senescence, senescence-associated secretory phenotype
INTRODUCTION
CELLULAR SENESCENCE
Aging and inflammation are antecedents of many of the age-related chronic diseases that account for the bulk of mortality, morbidity, and health costs in developed and developing societies. Aging is frequently associated with low-grade, ‘sterile’ (i.e., not associated with infection) inflammation in multiple tissues. Potential clinical consequences of this chronic inflammation are predispositions to atherosclerosis, diabetes, Alzheimer’s disease, cancers, osteoarthritis, and many other chronic disorders. Inflammation may be a mechanism through which fundamental aging processes contribute to the pathophysiology of the multiple chronic diseases prevalent in the elderly, frequently in combination. Although it is not clear what causes age-associated chronic inflammation, cellular senescence, and the senescence-associated secretory phenotype (SASP), which entails release of inflammatory cytokines, chemokines, and extracellular matrix (ECM) proteases, appears to play an important role in its initiation and progression. We will consider links between cellular senescence and agerelated chronic disease.
Cellular senescence was originally described as permanent growth arrest of normally proliferating cells following repeated divisions in cell culture – ‘replicative senescence’ [1]. Two pathways, p53/p21 and p16 INK4a/retinoblastoma (Rb), can orchestrate the development of senescence in response to external or intracellular cues [2]. Senescence can be induced by telomere shortening or dysfunction, DNA damage and mutations, and many different cellular damage-associated stimuli, including protein aggregation, increased levels of reactive oxygen species (ROS), other metabolic signals, and inflammatory insults (Fig. 1) [3–5,6 ]. Together with the increased duration and extent of exposure to these insults that
www.co-clinicalnutrition.com
&&
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA Correspondence to James L. Kirkland, Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street, S.W, Rochester, Minnesota 55905, USA. Tel: +1 507 266 9151; fax: +1 507 293 3853; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:324–328 DOI:10.1097/MCO.0000000000000065 Volume 17 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Senescence and age-related chronic disease Zhu et al.
KEY POINTS Cellular senescence is a major contributor to aging and age-related chronic inflammatory disorders. Cellular senescence parallels the development of dysfunction in different tissues and possibly has a central role in the cause and progression of common age-related, chronic inflammatory diseases. SASP factors and associated feedback signaling networks reinforce senescence, causing spread of cell dysfunction and tissue damage.
occurs in the course of chronological aging, reduced clearance of senescent cells by the immune system with aging may contribute to senescent cell accumulation [7 ]. Once cells become senescent, chromatin extensively reorganizes and widespread changes in gene expression occur. These changes can cause &&
Oncogene mutations Oxidative stress(ROS)/metabolites
Telomere shortening or dysfunction
Chromatin destruction
DNA damage Senescence
NF-κB signaling; TGF-β signaling; IL-1 /inflammasomal signaling
SASP
Proinflammatory cytokines Chemokines Proteases and others
Chronic inflammation and tissue dysfunction
senescent cells to secrete the wide array of proinflammatory cytokines, chemokines, proteases, growth factors, and other peptides and proteins that constitute the SASP [8,9]. The SASP has potent autocrine and paracrine signaling effects, through which senescent cells appear to contribute to multiple agerelated chronic diseases.
THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE The SASP appears to be regulated through transcriptional cascades, autocrine feedback loops, and a persistent DNA damage response, which involve the tumor suppressor, p53 [10]. SASP components form complex signaling networks that operate dependently or independently to promote inflammation (Fig. 1). Nuclear factor (NF)-kB and p38MAPK are involved in regulating the inflammatory elements of the SASP [10–12]. More recently, the inflammasome, a component of the innate immune system, has been implicated as a regulator of the SASP. Interleukin(IL)-1, whose expression is initiated and amplified during activation of inflammasomal pathways through paracrine mechanisms, is an upstream regulator of NF-kB signaling. It may be responsible for IL-6/IL-8 production through the SASP [6 ]. Additionally, IL-1 and transforming growth factor-b act together to mediate senescence and constitute components of a positive feedback loop that maintains the SASP [6 ,13]. &&
&&
ATHEROSCLEROSIS AND HYPERTENSION Aging is the main risk factor for many cardiovascular diseases [14]. A central feature of atherosclerosis is vascular endothelial cell and smooth muscle cell dysfunction. Senescent vascular smooth muscle cells and endothelial cells accumulate with aging in arteries and atherosclerotic plaques [15 ]. Endothelial cells within atherosclerotic plaques display features of cellular senescence and telomere shortening. These cells are associated with increased risk for atherosclerosis and hypertension [16 ,17]. Activated angiotensin II signaling, which is linked to age-related cardiovascular diseases, including atherosclerosis, is associated with premature senescence in vascular smooth muscle and endothelial cells. This in turn is related to telomere shortening and DNA damage activation through a p21-dependent pathway [18,19]. There is evidence suggesting possible causal connections between cellular senescence and atherosclerosis [20 ,21]. Peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a) deletion in mice leads to cellular senescence because of ROS &
Chronic inflammatory diseases
FIGURE 1. Relations among inducers of senescence, the senescence-associated secretory phenotype (SASP), and genesis of age-related chronic inflammatory diseases. Multiple cues can induce cellular senescence, often in combination. Cellular senescence is frequently driven by transcriptional cascades involving p16/retinoblastoma protein or p53/p21, leading over days or weeks to loss of replicative potential, changes in expression of several thousand genes, and increased heterochromatin formation. Pathways involving IL-1, IL-6, and C/EBPb or NF-kB, TGF-b, and ROS can lead to the SASP. Inflammatory mediators and metabolites released as part of the SASP might lead to further spread of senescence and increase predisposition to multiple age-related chronic diseases.
1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
&
www.co-clinicalnutrition.com
325
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Genes and cell metabolism
accumulation. This induces endothelial cell dysfunction and inflammation that may cause vascular dysfunction in mice. LMNA p.R482 mutations induce oxidative stress and DNA damage, leading to accumulation of senescent endothelial cells that have a directly atherogenic effect in normal endothelial cells, contributing to spread of atherosclerosis. The SASP factors, IL-6, IL-8, intercellular adhesion molecule 1 (ICAM-1), metalloproteases (MMPs), monocyte attractants, plasminogen activator inhibitor 1 (PAI-1), and vascular endothelial growth factor, can contribute to degenerative and proliferative age-related vascular dysfunction and atherosclerosis through promoting chronic inflammation. These factors induce cellular proliferation, migration, invasion, tissue remodeling, inflammation, and oxidative stress. For example, MMP-2, which is involved in ECM remodeling, induces conversion of inactive proendothelin-1 into the active form, endothelin-1, which causes vasoconstriction and enhances inflammation [22]. Senescent vascular endothelial cells have also been shown to produce IL-1b through an NF-kB-dependent pathway, which potently induces vascular inflammation, contributing to cardiovascular dysfunction [23 ]. &
DIABETES Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases associated with aging. T2DM linked to aging is associated with impaired insulin secretion and peripheral insulin resistance. Cellular senescence is related to T2DM, with accumulation of senescent preadipocytes and endothelial cells in adipose tissue of diabetic, obese individuals [7 ,24]. Telomere length is inversely correlated with triglycerides and cholesterol in South Asian males with T2DM [25]. Furthermore, p14 (Arf) and p21 (Cip), which are related to cellular senescence, are highly expressed in white adipose tissue from patients with T2DM [26]. Although there is no definitive published evidence that we are aware of proving that senescence causes diabetes, chronic high glucose has been shown to accelerate cell replication and premature replicative senescence in vitro [27–29]. High glucose can also impair mitochondrial function by overproduction of ROS, potentially leading to acceleration of cellular senescence. Mounting evidence indicates that the dipeptide, carnosine, which delays cellular senescence, improves glucose homeostasis in diabetic patients, further suggesting that cellular dysfunction caused by senescence may contribute to the pathogenesis of diabetes [30 ]. SASP proinflammatory cytokines, chemokines, and ECM proteases have potent autocrine and &&
&
326
www.co-clinicalnutrition.com
paracrine signaling activities that may contribute to insulin resistance. Monocyte chemoattractant protein-1 (MCP-1) has been shown to be involved in adipose tissue macrophage accumulation, as well as inflammation and metabolic dysfunction in dietinduced obesity [31]. Also, MCP-1 levels are positively related to insulin resistance [32]. IL-6, another major proinflammatory SASP factor, also plays a role in the pathophysiology of insulin resistance. IL-6 impairs hepatic and adipocyte insulin signaling in vitro through inhibiting insulin receptor substrate-1 (IRS-1) and acts both centrally and peripherally to induce energy expenditure and impair insulin signaling [33 ]. Notably, chronic treatment of 3T3-L1 or human adipocytes with IL-1b, a SASP factor, induced insulin resistance by down-regulating IRS-1 and deactivating IRS-1 tyrosine phosphorylation [34]. &
OSTEOARTHRITIS Osteoarthritis is a chronic degenerative disease characterized by degeneration or destruction of articular cartilage, with other joint tissues likely also to be playing a role in this disease [35]. Cartilage cells have a key role in disease progression, as they are mainly responsible for the anabolic-catabolic balance required for tissue integrity. Dysfunction of cartilage cells is associated with accumulation of senescent articular chondrocytes [36]. They secrete a number of cartilage-degrading proteinases and proinflammatory cytokines, such as IL-1b, IL-6, MCP-1, MMP-3, and MMP-13, which can promote the catabolic processes leading to degeneration of cartilage and subchondral bone [37,38]. A recent study indicated that accelerated chondrocyte senescence resulting from 1,25(OH)2 vitamin D deficiency in cartilage and bone contributes to development and progression of osteoarthritis [39]. This study also found that proinflammatory proteins and proteases, including SASP factors, such as IL-1a, IL-1b, IL-6, ADAM5 (a disintegrin and metalloproteinase with thrombospondin motifs 5), MMP-3, and MMP-13, were highly expressed in vitamin D 1a-hydroxylase / mice compared with their wild-type littermates. These factors may affect surrounding cells to alter their microenvironment by activating various cell surface receptors and related signal transduction pathways, contributing to the pathogenesis of osteoarthritis.
ALZHEIMER’S DISEASE Alzheimer’s disease is a chronic degenerative disorder of the brain, associated with progressive cognitive impairment. The disease is characterized by brain atrophy, extracellular deposition of beta Volume 17 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Senescence and age-related chronic disease Zhu et al.
amyloid peptide, loss of neurons and synapses, and inflammation [40]. Inflammation has been proposed as a key effector in pathogenesis of Alzheimer’s disease [41 ]. Astrocytes are the most abundant non-neuronal cells in the central nervous system (CNS), constituting about 20–50% of the human brain volume – much more than microglia [42]. The function of astrocytes is critical for the support of neuronal homeostasis. Chronic loss of the ability of astrocytes to maintain homeostasis throughout the CNS appears to be a major effector of Alzheimer’s disease pathogenesis [43]. In response to oxidative stress and telomere shortening, these cells develop a senescent phenotype, with high expression of p16, p21, p53, and senescence-associated heterochromatic foci [44]. Recently, studies have indicated appearance of senescent astrocytes in brain tissue from elderly subjects as well as patients with Alzheimer’s disease. Increased production of proinflammatory factors and proteases secreted by senescent astrocytes, such as IL-6, IL-8, ICAM-1, and MMP-1, are thought to be mediators of the chronic inflammation associated with Alzheimer’s disease [45]. Microglia constitute around 20% of the total glial cells in the brain and 10% of the cells in the CNS [46]. They function like macrophages in the CNS. Activated microglial cells have phagocytic ability and can migrate to damaged cells and clear debris. Like astrocytes, microglia can generate inflammatory molecules, such as cytokines, chemokines, and ROS and nitrogen species [47]. Depletion of microglial cells in animal models increases amyloid-b levels, suggesting microglial cells could be involved in clearing amyloid-b by phagocytosis [46,48]. Chronic microglial activation has been implicated in the neuronal death associated with Alzheimer’s disease [49]. Strong evidence indicates that with advanced age, functional abnormalities occur in microglia that impair their ability to respond efficiently [50]. As telomere shortening was found in rat microglia both in culture and in vivo with advancing age, cellular senescence might be involved. The accompanying SASP could contribute to impaired function of microglia [51,52 ]. &
&
CONCLUSION Based on current understanding of the mechanisms underlying several age-related chronic diseases, it appears that cellular senescence could be associated with their genesis and progression. Additional evidence is needed to prove this. Furthermore, distinct phenotypes of cellular senescence and differences in the SASP across cell types and tissues could make specific contributions to particular age-related
inflammatory diseases. A better understanding of the signaling and regulatory cascades in senescent cells that cause the SASP would contribute to developing mechanism-based approaches for preventing adverse paracrine effects of senescent cells. A great deal of work is needed to identify the range of potential SASP components, including active amines, nucleotides, lipids, other metabolites, and exosomes, in addition to the full range of peptides and proteins. Identification of these factors may lead to the development of diagnostic tests based on their presence in blood or other body fluids, and may suggest therapeutic opportunities. Targeting senescent cells using senolytic agents might be the best strategy for reducing chronic low-grade inflammation due to the SASP as well as for treating multiple age-related chronic inflammatory diseases as a group, instead of one at a time [7 ,53 ]. &&
&&
Acknowledgements The authors wish to acknowledge NIH grants AG013925 (to J.L.K.), AG041122 (J.L.K.), and AG31736, Project 4 (J.L.K.). Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37:614–636. 2. Larsson LG. Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence. Semin Cancer Biol 2011; 21:367–376. 3. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8:729–740. 4. Strowig T, Henao-Mejia J, Elinav E, et al. Inflammasomes in health and disease. Nature 2012; 481:278–286. 5. Hoare M, Narita M. Transmitting senescence to the cell neighbourhood. Nat Cell Biol 2013; 15:887–889. 6. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program && orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 2013; 15:978–990. This study demonstrates that the SASP can cause paracrine senescence both in vitro and in vivo through inflammasomal signaling. 7. Tchkonia T, Zhu Y, van Deursen J, et al. Cellular senescence and the && senescent secretory phenotype: therapeutic opportunities. J Clin Invest 2013; 123:966–972. This paper provides a review of therapeutic interventions for senescence 8. Coppe JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008; 6:2853–2868. 9. Kuilman T, Michaloglou C, Vredeveld LC, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008; 133:1019–1031. 10. Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage responseindependent regulator of the senescence-associated secretory phenotype. EMBO J 2011; 30:1536–1548. 11. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal 2012; 24:835–845. 12. Salminen A, Kaarniranta K. Control of p53 and NF-kappaB signaling by WIP1 and MIF: role in cellular senescence and organismal aging. Cell Signal 2011; 23:747–752.
1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-clinicalnutrition.com
327
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Genes and cell metabolism 13. Hubackova S, Krejcikova K, Bartek J, et al. IL1- and TGFbeta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ’bystander senescence’. Aging (Albany NY) 2012; 4:932–951. 14. Wang M, Lakatta EG. The salted artery and angiotensin II signaling: a deadly duo in arterial disease. J Hypertens 2009; 27:19–21. 15. Sikora E, Bielak-Zmijewska A, Mosieniak G. Cellular senescence in ageing, & age-related disease and longevity. Curr Vasc Pharmacol 2013. [Epub ahead of print] This article provides a review of senescence in aging and its contibution to aging and age-related diseases. 16. Fyhrquist F, Saijonmaa O, Strandberg T. The roles of senescence and telomere && shortening in cardiovascular disease. Nat Rev Cardiol 2013; 10:274–283. This article dicusses the relationship between telomere shortening, senescence, and cardiovascular disease. 17. Sanders JL, Newman AB. Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol Rev 2013. [Epub ahead of print] 18. Kunieda T, Minamino T, Nishi J, et al. Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation 2006; 114:953–960. 19. Herbert KE, Mistry Y, Hastings R, et al. Angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells via telomere-dependent and independent pathways. Circ Res 2008; 102:201–208. 20. Kroller-Schon S, Jansen T, Schuler A, et al. Peroxisome proliferator-activated & receptor gamma, coactivator 1alpha deletion induces angiotensin II-associated vascular dysfunction by increasing mitochondrial oxidative stress and vascular inflammation. Arterioscler Thromb Vasc Biol 2013; 33:1928–1935. This study demonstrates that PGC-1a deletion induces senescnce, which may cause vascular dysfunction. 21. Bidault G, Garcia M, Vantyghem MC, et al. Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction. Arterioscler Thromb Vasc Biol 2013; 33:2162–2171. 22. Wang M, Zhang J, Telljohann R, et al. Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure. Hypertension 2012; 60:459–466. 23. Suzuki E, Takahashi M, Oba S, et al. Oncogene- and oxidative stress-induced & cellular senescence shows distinct expression patterns of proinflammatory cytokines in vascular endothelial cells. ScientificWorldJournal 2013; 2013:754735. This study demonstrates that both oncogene and oxidative stress-induced cellular senescence produce a distinct proinflammatory cytokine profile in vascular endothelial cells. 24. Tchkonia T, Morbeck DE, Von Zglinicki T, et al. Fat tissue, aging, and cellular senescence. Aging Cell 2010; 9:667–684. 25. Harte AL, da Silva NF, Miller MA, et al. Telomere length attrition, a marker of biological senescence, is inversely correlated with triglycerides and cholesterol in South Asian males with type 2 diabetes mellitus. Exp Diabetes Res 2012; 2012:895185. 26. Markowski DN, Thies HW, Gottlieb A, et al. HMGA2 expression in white adipose tissue linking cellular senescence with diabetes. Genes Nutr 2013; 8:449–456. 27. Mortuza R, Chen S, Feng B, et al. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PLoS One 2013; 8:e54514. 28. Larsen SA, Kassem M, Rattan SI. Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells. Chem Cent J 2012; 6:18. 29. Cao D, Zhang M, Jiang C, et al. Protection of Tanshinone IIA to human peritoneal mesothelial cells (HPMC) through delaying cellular senescence induced by high glucose. Ren Fail 2012; 34:88–94. 30. Hipkiss AR, Cartwright SP, Bromley C, et al. Carnosine: can understanding its & actions on energy metabolism and protein homeostasis inform its therapeutic potential? Chem Cent J 2013; 7:38. This study indicates that the prevention of senescence could be a posiible treatment for age-related chronic diseases.
328
www.co-clinicalnutrition.com
31. Enos RT, Davis JM, Velazquez KT, et al. Influence of dietary saturated fat content on adiposity, macrophage behavior, inflammation, and metabolism: composition matters. J Lipid Res 2013; 54:152–163. 32. Daniele G, Guardado Mendoza R, Winnier D, et al. The inflammatory status score including IL-6, TNF-alpha, osteopontin, fractalkine, MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus. Acta Diabetol 2014; 51:123–131. 33. Sarvas JL, Khaper N, Lees SJ. The IL-6 paradox: context dependent interplay & of SOCS3 and AMPK. J Diabetes Metab 2013; Suppl. 13:S13–003. This article provides a review on the role of IL-6 in type 2 diabetes. 34. Handa M, Vanegas S, Maddux BA, et al. XOMA 052, an anti-IL-1beta monoclonal antibody, prevents IL-1beta-mediated insulin resistance in 3T3L1 adipocytes. Obesity (Silver Spring) 2013; 21:306–309. 35. Krasnokutsky S, Attur M, Palmer G, et al. Current concepts in the pathogenesis of osteoarthritis. Osteoarthritis Cartilage 2008; 16 (Suppl 3):S1–S3. 36. Rose J, Soder S, Skhirtladze C, et al. DNA damage, discoordinated gene expression and cellular senescence in osteoarthritic chondrocytes. Osteoarthritis Cartilage 2012; 20:1020–1028. 37. Philipot D, Guerit D, Platano D, et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodelling in osteoarthritis. Arthritis Res Ther 2014; 16:R58. 38. So MW, Lee EJ, Lee HS, et al. Protective effects of ginsenoside Rg3 on human osteoarthritic chondrocytes. Mod Rheumatol 2013; 23:104–111. 39. Shen M, Luo Y, Niu Y, et al. 1,25(OH)2D deficiency induces temporomandibular joint osteoarthritis via secretion of senescence-associated inflammatory cytokines. Bone 2013; 55:400–409. 40. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 2012; 148:1204–1222. 41. Olivieri F, Rippo MR, Procopio AD, et al. Circulating inflamma-miRs in aging & and age-related diseases. Front Genet 2013; 4:121. This article provides a review of how inflammation through circulating microRNAs might play a role in major age-related diseases, such as cardiovascular disease, T2DM, Alzheimer’s disease, rheumatoid arthritis, and cancers. 42. Shimada IS, LeComte MD, Granger JC, et al. Self-renewal and differentiation of reactive astrocyte-derived neural stem/progenitor cells isolated from the cortical peri-infarct area after stroke. J Neurosci 2012; 32:7926–7940. 43. Verkhratsky A, Sofroniew MV, Messing A, et al. Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 2012; 131–149. 44. Hewitt G, Jurk D, Marques FD, et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 2012; 3:708. 45. Bhat R, Crowe EP, Bitto A, et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 2012; 7:e45069. 46. Varnum MM, Ikezu T. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp (Warsz) 2012; 60:251–266. 47. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012; 2012:756357. 48. Broussard GJ, Mytar J, Li RC, et al. The role of inflammatory processes in Alzheimer’s disease. Inflammopharmacology 2012; 20:109–126. 49. Sugama S, Takenouchi T, Cho BP, et al. Possible roles of microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models. Inflamm Allergy Drug Targets 2009; 8:277–284. 50. Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 2013; 39:19–34. 51. Yu HM, Zhao YM, Luo XG, et al. Repeated lipopolysaccharide stimulation induces cellular senescence in BV2 cells. Neuroimmunomodulation 2012; 19:131–136. 52. Chinta SJ, Lieu CA, Demaria M, et al. Environmental stress, ageing and glial & cell senescence: a novel mechanistic link to Parkinson’s disease? J Intern Med 2013; 273:429–436. This article is a review of glial cell senescence in the aging brain and its relation to neurodegeneration. 53. Kirkland JL. Translating advances from the basic biology of aging into clinical && application. Exp Gerontol 2013; 48:1–5. This article is a review of options for developing interventions that target aging.
Volume 17 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cellular senescence and the senescent secretory phenotype in age-related chronic diseases Yi Zhu, Jacqueline L. Armstrong, Tamara Tchkonia, and James L. Kirkland
Purpose of review Possible mechanisms in cellular senescence and the senescence-associated secretory phenotype (SASP) that drive and promote chronic inflammation in multiple age-related chronic diseases are considered. Recent findings A series of studies about the SASP indicate that senescent cells may be involved in the development of chronic inflammatory diseases associated with aging. Summary Aging is a complex biological process accompanied by a state of chronic, low-grade, ‘sterile’ inflammation, which is a major contributor to the development of many age-related chronic disorders including atherosclerosis, osteoarthritis, Alzheimer’s disease, type 2 diabetes, cancers, and others. It appears that cellular senescence plays a role in causing inflammation through the SASP. A better understanding of the contribution of senescent cells to the pathologies of chronic inflammatory disorders could have potentially profound diagnostic and therapeutic implications. Keywords inflammation, senescence, senescence-associated secretory phenotype
INTRODUCTION
CELLULAR SENESCENCE
Aging and inflammation are antecedents of many of the age-related chronic diseases that account for the bulk of mortality, morbidity, and health costs in developed and developing societies. Aging is frequently associated with low-grade, ‘sterile’ (i.e., not associated with infection) inflammation in multiple tissues. Potential clinical consequences of this chronic inflammation are predispositions to atherosclerosis, diabetes, Alzheimer’s disease, cancers, osteoarthritis, and many other chronic disorders. Inflammation may be a mechanism through which fundamental aging processes contribute to the pathophysiology of the multiple chronic diseases prevalent in the elderly, frequently in combination. Although it is not clear what causes age-associated chronic inflammation, cellular senescence, and the senescence-associated secretory phenotype (SASP), which entails release of inflammatory cytokines, chemokines, and extracellular matrix (ECM) proteases, appears to play an important role in its initiation and progression. We will consider links between cellular senescence and agerelated chronic disease.
Cellular senescence was originally described as permanent growth arrest of normally proliferating cells following repeated divisions in cell culture – ‘replicative senescence’ [1]. Two pathways, p53/p21 and p16 INK4a/retinoblastoma (Rb), can orchestrate the development of senescence in response to external or intracellular cues [2]. Senescence can be induced by telomere shortening or dysfunction, DNA damage and mutations, and many different cellular damage-associated stimuli, including protein aggregation, increased levels of reactive oxygen species (ROS), other metabolic signals, and inflammatory insults (Fig. 1) [3–5,6 ]. Together with the increased duration and extent of exposure to these insults that
www.co-clinicalnutrition.com
&&
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA Correspondence to James L. Kirkland, Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street, S.W, Rochester, Minnesota 55905, USA. Tel: +1 507 266 9151; fax: +1 507 293 3853; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:324–328 DOI:10.1097/MCO.0000000000000065 Volume 17 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Senescence and age-related chronic disease Zhu et al.
KEY POINTS Cellular senescence is a major contributor to aging and age-related chronic inflammatory disorders. Cellular senescence parallels the development of dysfunction in different tissues and possibly has a central role in the cause and progression of common age-related, chronic inflammatory diseases. SASP factors and associated feedback signaling networks reinforce senescence, causing spread of cell dysfunction and tissue damage.
occurs in the course of chronological aging, reduced clearance of senescent cells by the immune system with aging may contribute to senescent cell accumulation [7 ]. Once cells become senescent, chromatin extensively reorganizes and widespread changes in gene expression occur. These changes can cause &&
Oncogene mutations Oxidative stress(ROS)/metabolites
Telomere shortening or dysfunction
Chromatin destruction
DNA damage Senescence
NF-κB signaling; TGF-β signaling; IL-1 /inflammasomal signaling
SASP
Proinflammatory cytokines Chemokines Proteases and others
Chronic inflammation and tissue dysfunction
senescent cells to secrete the wide array of proinflammatory cytokines, chemokines, proteases, growth factors, and other peptides and proteins that constitute the SASP [8,9]. The SASP has potent autocrine and paracrine signaling effects, through which senescent cells appear to contribute to multiple agerelated chronic diseases.
THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE The SASP appears to be regulated through transcriptional cascades, autocrine feedback loops, and a persistent DNA damage response, which involve the tumor suppressor, p53 [10]. SASP components form complex signaling networks that operate dependently or independently to promote inflammation (Fig. 1). Nuclear factor (NF)-kB and p38MAPK are involved in regulating the inflammatory elements of the SASP [10–12]. More recently, the inflammasome, a component of the innate immune system, has been implicated as a regulator of the SASP. Interleukin(IL)-1, whose expression is initiated and amplified during activation of inflammasomal pathways through paracrine mechanisms, is an upstream regulator of NF-kB signaling. It may be responsible for IL-6/IL-8 production through the SASP [6 ]. Additionally, IL-1 and transforming growth factor-b act together to mediate senescence and constitute components of a positive feedback loop that maintains the SASP [6 ,13]. &&
&&
ATHEROSCLEROSIS AND HYPERTENSION Aging is the main risk factor for many cardiovascular diseases [14]. A central feature of atherosclerosis is vascular endothelial cell and smooth muscle cell dysfunction. Senescent vascular smooth muscle cells and endothelial cells accumulate with aging in arteries and atherosclerotic plaques [15 ]. Endothelial cells within atherosclerotic plaques display features of cellular senescence and telomere shortening. These cells are associated with increased risk for atherosclerosis and hypertension [16 ,17]. Activated angiotensin II signaling, which is linked to age-related cardiovascular diseases, including atherosclerosis, is associated with premature senescence in vascular smooth muscle and endothelial cells. This in turn is related to telomere shortening and DNA damage activation through a p21-dependent pathway [18,19]. There is evidence suggesting possible causal connections between cellular senescence and atherosclerosis [20 ,21]. Peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a) deletion in mice leads to cellular senescence because of ROS &
Chronic inflammatory diseases
FIGURE 1. Relations among inducers of senescence, the senescence-associated secretory phenotype (SASP), and genesis of age-related chronic inflammatory diseases. Multiple cues can induce cellular senescence, often in combination. Cellular senescence is frequently driven by transcriptional cascades involving p16/retinoblastoma protein or p53/p21, leading over days or weeks to loss of replicative potential, changes in expression of several thousand genes, and increased heterochromatin formation. Pathways involving IL-1, IL-6, and C/EBPb or NF-kB, TGF-b, and ROS can lead to the SASP. Inflammatory mediators and metabolites released as part of the SASP might lead to further spread of senescence and increase predisposition to multiple age-related chronic diseases.
1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
&
www.co-clinicalnutrition.com
325
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Genes and cell metabolism
accumulation. This induces endothelial cell dysfunction and inflammation that may cause vascular dysfunction in mice. LMNA p.R482 mutations induce oxidative stress and DNA damage, leading to accumulation of senescent endothelial cells that have a directly atherogenic effect in normal endothelial cells, contributing to spread of atherosclerosis. The SASP factors, IL-6, IL-8, intercellular adhesion molecule 1 (ICAM-1), metalloproteases (MMPs), monocyte attractants, plasminogen activator inhibitor 1 (PAI-1), and vascular endothelial growth factor, can contribute to degenerative and proliferative age-related vascular dysfunction and atherosclerosis through promoting chronic inflammation. These factors induce cellular proliferation, migration, invasion, tissue remodeling, inflammation, and oxidative stress. For example, MMP-2, which is involved in ECM remodeling, induces conversion of inactive proendothelin-1 into the active form, endothelin-1, which causes vasoconstriction and enhances inflammation [22]. Senescent vascular endothelial cells have also been shown to produce IL-1b through an NF-kB-dependent pathway, which potently induces vascular inflammation, contributing to cardiovascular dysfunction [23 ]. &
DIABETES Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases associated with aging. T2DM linked to aging is associated with impaired insulin secretion and peripheral insulin resistance. Cellular senescence is related to T2DM, with accumulation of senescent preadipocytes and endothelial cells in adipose tissue of diabetic, obese individuals [7 ,24]. Telomere length is inversely correlated with triglycerides and cholesterol in South Asian males with T2DM [25]. Furthermore, p14 (Arf) and p21 (Cip), which are related to cellular senescence, are highly expressed in white adipose tissue from patients with T2DM [26]. Although there is no definitive published evidence that we are aware of proving that senescence causes diabetes, chronic high glucose has been shown to accelerate cell replication and premature replicative senescence in vitro [27–29]. High glucose can also impair mitochondrial function by overproduction of ROS, potentially leading to acceleration of cellular senescence. Mounting evidence indicates that the dipeptide, carnosine, which delays cellular senescence, improves glucose homeostasis in diabetic patients, further suggesting that cellular dysfunction caused by senescence may contribute to the pathogenesis of diabetes [30 ]. SASP proinflammatory cytokines, chemokines, and ECM proteases have potent autocrine and &&
&
326
www.co-clinicalnutrition.com
paracrine signaling activities that may contribute to insulin resistance. Monocyte chemoattractant protein-1 (MCP-1) has been shown to be involved in adipose tissue macrophage accumulation, as well as inflammation and metabolic dysfunction in dietinduced obesity [31]. Also, MCP-1 levels are positively related to insulin resistance [32]. IL-6, another major proinflammatory SASP factor, also plays a role in the pathophysiology of insulin resistance. IL-6 impairs hepatic and adipocyte insulin signaling in vitro through inhibiting insulin receptor substrate-1 (IRS-1) and acts both centrally and peripherally to induce energy expenditure and impair insulin signaling [33 ]. Notably, chronic treatment of 3T3-L1 or human adipocytes with IL-1b, a SASP factor, induced insulin resistance by down-regulating IRS-1 and deactivating IRS-1 tyrosine phosphorylation [34]. &
OSTEOARTHRITIS Osteoarthritis is a chronic degenerative disease characterized by degeneration or destruction of articular cartilage, with other joint tissues likely also to be playing a role in this disease [35]. Cartilage cells have a key role in disease progression, as they are mainly responsible for the anabolic-catabolic balance required for tissue integrity. Dysfunction of cartilage cells is associated with accumulation of senescent articular chondrocytes [36]. They secrete a number of cartilage-degrading proteinases and proinflammatory cytokines, such as IL-1b, IL-6, MCP-1, MMP-3, and MMP-13, which can promote the catabolic processes leading to degeneration of cartilage and subchondral bone [37,38]. A recent study indicated that accelerated chondrocyte senescence resulting from 1,25(OH)2 vitamin D deficiency in cartilage and bone contributes to development and progression of osteoarthritis [39]. This study also found that proinflammatory proteins and proteases, including SASP factors, such as IL-1a, IL-1b, IL-6, ADAM5 (a disintegrin and metalloproteinase with thrombospondin motifs 5), MMP-3, and MMP-13, were highly expressed in vitamin D 1a-hydroxylase / mice compared with their wild-type littermates. These factors may affect surrounding cells to alter their microenvironment by activating various cell surface receptors and related signal transduction pathways, contributing to the pathogenesis of osteoarthritis.
ALZHEIMER’S DISEASE Alzheimer’s disease is a chronic degenerative disorder of the brain, associated with progressive cognitive impairment. The disease is characterized by brain atrophy, extracellular deposition of beta Volume 17 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Senescence and age-related chronic disease Zhu et al.
amyloid peptide, loss of neurons and synapses, and inflammation [40]. Inflammation has been proposed as a key effector in pathogenesis of Alzheimer’s disease [41 ]. Astrocytes are the most abundant non-neuronal cells in the central nervous system (CNS), constituting about 20–50% of the human brain volume – much more than microglia [42]. The function of astrocytes is critical for the support of neuronal homeostasis. Chronic loss of the ability of astrocytes to maintain homeostasis throughout the CNS appears to be a major effector of Alzheimer’s disease pathogenesis [43]. In response to oxidative stress and telomere shortening, these cells develop a senescent phenotype, with high expression of p16, p21, p53, and senescence-associated heterochromatic foci [44]. Recently, studies have indicated appearance of senescent astrocytes in brain tissue from elderly subjects as well as patients with Alzheimer’s disease. Increased production of proinflammatory factors and proteases secreted by senescent astrocytes, such as IL-6, IL-8, ICAM-1, and MMP-1, are thought to be mediators of the chronic inflammation associated with Alzheimer’s disease [45]. Microglia constitute around 20% of the total glial cells in the brain and 10% of the cells in the CNS [46]. They function like macrophages in the CNS. Activated microglial cells have phagocytic ability and can migrate to damaged cells and clear debris. Like astrocytes, microglia can generate inflammatory molecules, such as cytokines, chemokines, and ROS and nitrogen species [47]. Depletion of microglial cells in animal models increases amyloid-b levels, suggesting microglial cells could be involved in clearing amyloid-b by phagocytosis [46,48]. Chronic microglial activation has been implicated in the neuronal death associated with Alzheimer’s disease [49]. Strong evidence indicates that with advanced age, functional abnormalities occur in microglia that impair their ability to respond efficiently [50]. As telomere shortening was found in rat microglia both in culture and in vivo with advancing age, cellular senescence might be involved. The accompanying SASP could contribute to impaired function of microglia [51,52 ]. &
&
CONCLUSION Based on current understanding of the mechanisms underlying several age-related chronic diseases, it appears that cellular senescence could be associated with their genesis and progression. Additional evidence is needed to prove this. Furthermore, distinct phenotypes of cellular senescence and differences in the SASP across cell types and tissues could make specific contributions to particular age-related
inflammatory diseases. A better understanding of the signaling and regulatory cascades in senescent cells that cause the SASP would contribute to developing mechanism-based approaches for preventing adverse paracrine effects of senescent cells. A great deal of work is needed to identify the range of potential SASP components, including active amines, nucleotides, lipids, other metabolites, and exosomes, in addition to the full range of peptides and proteins. Identification of these factors may lead to the development of diagnostic tests based on their presence in blood or other body fluids, and may suggest therapeutic opportunities. Targeting senescent cells using senolytic agents might be the best strategy for reducing chronic low-grade inflammation due to the SASP as well as for treating multiple age-related chronic inflammatory diseases as a group, instead of one at a time [7 ,53 ]. &&
&&
Acknowledgements The authors wish to acknowledge NIH grants AG013925 (to J.L.K.), AG041122 (J.L.K.), and AG31736, Project 4 (J.L.K.). Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37:614–636. 2. Larsson LG. Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence. Semin Cancer Biol 2011; 21:367–376. 3. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8:729–740. 4. Strowig T, Henao-Mejia J, Elinav E, et al. Inflammasomes in health and disease. Nature 2012; 481:278–286. 5. Hoare M, Narita M. Transmitting senescence to the cell neighbourhood. Nat Cell Biol 2013; 15:887–889. 6. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program && orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 2013; 15:978–990. This study demonstrates that the SASP can cause paracrine senescence both in vitro and in vivo through inflammasomal signaling. 7. Tchkonia T, Zhu Y, van Deursen J, et al. Cellular senescence and the && senescent secretory phenotype: therapeutic opportunities. J Clin Invest 2013; 123:966–972. This paper provides a review of therapeutic interventions for senescence 8. Coppe JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008; 6:2853–2868. 9. Kuilman T, Michaloglou C, Vredeveld LC, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008; 133:1019–1031. 10. Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage responseindependent regulator of the senescence-associated secretory phenotype. EMBO J 2011; 30:1536–1548. 11. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal 2012; 24:835–845. 12. Salminen A, Kaarniranta K. Control of p53 and NF-kappaB signaling by WIP1 and MIF: role in cellular senescence and organismal aging. Cell Signal 2011; 23:747–752.
1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-clinicalnutrition.com
327
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Genes and cell metabolism 13. Hubackova S, Krejcikova K, Bartek J, et al. IL1- and TGFbeta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ’bystander senescence’. Aging (Albany NY) 2012; 4:932–951. 14. Wang M, Lakatta EG. The salted artery and angiotensin II signaling: a deadly duo in arterial disease. J Hypertens 2009; 27:19–21. 15. Sikora E, Bielak-Zmijewska A, Mosieniak G. Cellular senescence in ageing, & age-related disease and longevity. Curr Vasc Pharmacol 2013. [Epub ahead of print] This article provides a review of senescence in aging and its contibution to aging and age-related diseases. 16. Fyhrquist F, Saijonmaa O, Strandberg T. The roles of senescence and telomere && shortening in cardiovascular disease. Nat Rev Cardiol 2013; 10:274–283. This article dicusses the relationship between telomere shortening, senescence, and cardiovascular disease. 17. Sanders JL, Newman AB. Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol Rev 2013. [Epub ahead of print] 18. Kunieda T, Minamino T, Nishi J, et al. Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation 2006; 114:953–960. 19. Herbert KE, Mistry Y, Hastings R, et al. Angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells via telomere-dependent and independent pathways. Circ Res 2008; 102:201–208. 20. Kroller-Schon S, Jansen T, Schuler A, et al. Peroxisome proliferator-activated & receptor gamma, coactivator 1alpha deletion induces angiotensin II-associated vascular dysfunction by increasing mitochondrial oxidative stress and vascular inflammation. Arterioscler Thromb Vasc Biol 2013; 33:1928–1935. This study demonstrates that PGC-1a deletion induces senescnce, which may cause vascular dysfunction. 21. Bidault G, Garcia M, Vantyghem MC, et al. Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction. Arterioscler Thromb Vasc Biol 2013; 33:2162–2171. 22. Wang M, Zhang J, Telljohann R, et al. Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure. Hypertension 2012; 60:459–466. 23. Suzuki E, Takahashi M, Oba S, et al. Oncogene- and oxidative stress-induced & cellular senescence shows distinct expression patterns of proinflammatory cytokines in vascular endothelial cells. ScientificWorldJournal 2013; 2013:754735. This study demonstrates that both oncogene and oxidative stress-induced cellular senescence produce a distinct proinflammatory cytokine profile in vascular endothelial cells. 24. Tchkonia T, Morbeck DE, Von Zglinicki T, et al. Fat tissue, aging, and cellular senescence. Aging Cell 2010; 9:667–684. 25. Harte AL, da Silva NF, Miller MA, et al. Telomere length attrition, a marker of biological senescence, is inversely correlated with triglycerides and cholesterol in South Asian males with type 2 diabetes mellitus. Exp Diabetes Res 2012; 2012:895185. 26. Markowski DN, Thies HW, Gottlieb A, et al. HMGA2 expression in white adipose tissue linking cellular senescence with diabetes. Genes Nutr 2013; 8:449–456. 27. Mortuza R, Chen S, Feng B, et al. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PLoS One 2013; 8:e54514. 28. Larsen SA, Kassem M, Rattan SI. Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells. Chem Cent J 2012; 6:18. 29. Cao D, Zhang M, Jiang C, et al. Protection of Tanshinone IIA to human peritoneal mesothelial cells (HPMC) through delaying cellular senescence induced by high glucose. Ren Fail 2012; 34:88–94. 30. Hipkiss AR, Cartwright SP, Bromley C, et al. Carnosine: can understanding its & actions on energy metabolism and protein homeostasis inform its therapeutic potential? Chem Cent J 2013; 7:38. This study indicates that the prevention of senescence could be a posiible treatment for age-related chronic diseases.
328
www.co-clinicalnutrition.com
31. Enos RT, Davis JM, Velazquez KT, et al. Influence of dietary saturated fat content on adiposity, macrophage behavior, inflammation, and metabolism: composition matters. J Lipid Res 2013; 54:152–163. 32. Daniele G, Guardado Mendoza R, Winnier D, et al. The inflammatory status score including IL-6, TNF-alpha, osteopontin, fractalkine, MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus. Acta Diabetol 2014; 51:123–131. 33. Sarvas JL, Khaper N, Lees SJ. The IL-6 paradox: context dependent interplay & of SOCS3 and AMPK. J Diabetes Metab 2013; Suppl. 13:S13–003. This article provides a review on the role of IL-6 in type 2 diabetes. 34. Handa M, Vanegas S, Maddux BA, et al. XOMA 052, an anti-IL-1beta monoclonal antibody, prevents IL-1beta-mediated insulin resistance in 3T3L1 adipocytes. Obesity (Silver Spring) 2013; 21:306–309. 35. Krasnokutsky S, Attur M, Palmer G, et al. Current concepts in the pathogenesis of osteoarthritis. Osteoarthritis Cartilage 2008; 16 (Suppl 3):S1–S3. 36. Rose J, Soder S, Skhirtladze C, et al. DNA damage, discoordinated gene expression and cellular senescence in osteoarthritic chondrocytes. Osteoarthritis Cartilage 2012; 20:1020–1028. 37. Philipot D, Guerit D, Platano D, et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodelling in osteoarthritis. Arthritis Res Ther 2014; 16:R58. 38. So MW, Lee EJ, Lee HS, et al. Protective effects of ginsenoside Rg3 on human osteoarthritic chondrocytes. Mod Rheumatol 2013; 23:104–111. 39. Shen M, Luo Y, Niu Y, et al. 1,25(OH)2D deficiency induces temporomandibular joint osteoarthritis via secretion of senescence-associated inflammatory cytokines. Bone 2013; 55:400–409. 40. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 2012; 148:1204–1222. 41. Olivieri F, Rippo MR, Procopio AD, et al. Circulating inflamma-miRs in aging & and age-related diseases. Front Genet 2013; 4:121. This article provides a review of how inflammation through circulating microRNAs might play a role in major age-related diseases, such as cardiovascular disease, T2DM, Alzheimer’s disease, rheumatoid arthritis, and cancers. 42. Shimada IS, LeComte MD, Granger JC, et al. Self-renewal and differentiation of reactive astrocyte-derived neural stem/progenitor cells isolated from the cortical peri-infarct area after stroke. J Neurosci 2012; 32:7926–7940. 43. Verkhratsky A, Sofroniew MV, Messing A, et al. Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro 2012; 131–149. 44. Hewitt G, Jurk D, Marques FD, et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 2012; 3:708. 45. Bhat R, Crowe EP, Bitto A, et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 2012; 7:e45069. 46. Varnum MM, Ikezu T. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp (Warsz) 2012; 60:251–266. 47. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012; 2012:756357. 48. Broussard GJ, Mytar J, Li RC, et al. The role of inflammatory processes in Alzheimer’s disease. Inflammopharmacology 2012; 20:109–126. 49. Sugama S, Takenouchi T, Cho BP, et al. Possible roles of microglial cells for neurotoxicity in clinical neurodegenerative diseases and experimental animal models. Inflamm Allergy Drug Targets 2009; 8:277–284. 50. Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 2013; 39:19–34. 51. Yu HM, Zhao YM, Luo XG, et al. Repeated lipopolysaccharide stimulation induces cellular senescence in BV2 cells. Neuroimmunomodulation 2012; 19:131–136. 52. Chinta SJ, Lieu CA, Demaria M, et al. Environmental stress, ageing and glial & cell senescence: a novel mechanistic link to Parkinson’s disease? J Intern Med 2013; 273:429–436. This article is a review of glial cell senescence in the aging brain and its relation to neurodegeneration. 53. Kirkland JL. Translating advances from the basic biology of aging into clinical && application. Exp Gerontol 2013; 48:1–5. This article is a review of options for developing interventions that target aging.
Volume 17 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
