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The dynamic of senescent cells accumulation can explain the age-specific incidence of autoimmune diseases
Medical Hypotheses 73 (2009) 667–669
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
The dynamic of senescent cells accumulation can explain the age-specific incidence of autoimmune diseases Teo Manestar-Blazˇic´ *, Maja Volf Polyclinic ‘‘Terme Selce”, 1. Prilaz I.L. Ribara, 51266 Selce, Croatia
a r t i c l e
i n f o
Article history: Received 9 May 2009 Accepted 12 May 2009
s u m m a r y Autoimmune diseases arise when the immune system turns against normal components of the body. Overwhelming evidence indicate that the immune system deteriorates with age. The mechanism that leads to autoimmunity is complex and not fully understood, and in many cases there is no effective therapy. Another process related to aging is the accumulation of senescent cells. These cells are considered to confer deleterious effects, including the promotion of organismal aging and age-related pathologies. We hypothesize that autoimmune diseases are caused by two age related process: (1) different rate of senescent cells accumulation in the immune system and target tissue/organ, (2) heterogeneous accumulation of senescent cells in tissues/organs. Separately or combined, these two processes are at the base of autoimmune diseases. If the hypothesis is correct, the control of the formation, accumulation and elimination of senescent cells can be used to prevent and/or treat autoimmune diseases. The accumulation or removal of senescent cells would modify the microenvironment and therefore the immune reaction. Many other problems caused by immunosenescence can be also partially explained by our hypothesis. Basically, the accumulation of senescent cells is a finely regulated process. Every imbalance in the accumulation of senescent cells between the immune system and the potential target organs can initiate a chronic inflammation or autoimmunity. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Autoimmune diseases arise when the immune system turns against normal components of the body. In order to avoid harmful self-reactivity, there are many tolerance checkpoints exist prevent self-antigens from stimulating the growth of self-reactive B and T lymphocytes [1]. Self-tolerance of the T-cell repertoire is achieved through central and peripheral tolerance. Thymic education constitutes the main process of central tolerance, while after exiting the thymus, mature T cells are subjected to secondary selection by which the majority of self-reactive T cells are deleted or rendered anergic [2]. Ligation of T cell receptor (TCR) alone is insufficient to induce full activation of T lymphocytes, it requires additional ligandreceptor interactions (co-stimulation) on antigen presenting cells (APCs) and T cells [3,4]. These signals play crucial roles in all phases of T cell response (activation, effector, expression phase and memory phase) [4]. Overwhelming evidence indicate that the immune system deteriorates with age [5]. Number of different phenotypes of T and B cells and the expression of many molecules on the immune cells change during aging [5–9]. All these age-associated changes that cause * Corresponding author. Tel.: +385 51 764 076; fax: +385 51 768 310. E-mail address: [email protected] (T. Manestar-Blazˇic´). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.05.010
alterations of the immune response are termed immunosenescence [6]. The primary cause of immunosenescence in cellular immunity is the gradual decline in thymic generation of new naïve T cells, while in vitro evidence indicates that aging causes significant detrimental effects on cells of the innate immune system [5,6]. The connection between ageing and autoimmunity is also evident analyzing the age-specific incidence of many autoimmune diseases. Another process related to aging is the accumulation of senescent cells. These cells are considered to confer deleterious effects, including the promotion of organismal aging and age-related pathologies (atherosclerotic plaques, prostatic hyperplasia and aging skin) (I). These conclusions are based on their presence in the area of chronic tissue damage and their specific gene expression [10,11]. The mechanism that leads to autoimmunity is complex and not fully understood, and in many cases there is no effective therapy [1,8]. After the analysis of our theory new treatment possibilities for autoimmune diseases are also discussed.
Hypothesis We hypothesize that autoimmune diseases are caused by two age related process: (1) different rate of senescent cells
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T. Manestar-Blazˇic´, M. Volf / Medical Hypotheses 73 (2009) 667–669
accumulation in the immune system and target tissue/organ, (2) heterogeneous accumulation of senescent cells in tissues/organs. Separately or combined, these two processes are at the base of autoimmune diseases. For an easier analysis and evaluation, we fragmented the theory into seven smaller hypotheses. 1. During normal aging the dynamic of senescent cells accumulation is similar in all tissues/organs (probably exponential). Different types of cells displaying senescent phenotype accumulate with a similar dynamic. One of the main problems for demonstrating this hypothesis is the determination of the presence of senescent cells in the tissues. There are many senescent cell biomarkers, but not completely reliable [12,13]. Many articles discuss their accumulation in vivo, but there is much less data about their exact proportion in the organism. It has been estimated that in primates the number of senescent fibroblasts increase exponentially [13]. Based on this information and our hypothesis (stable proportion of different types of cells displaying senescent phenotype), the number of senescent cells in tissues/organs increase exponentially during life. 2. The accumulation of senescent cells in the immune system and in the target tissue/organ causes specific alterations in the process of antigen expression and recognition. In different tissues the accumulation of senescent cells causes alteration in the surrounding environment (e.g. promotion of cancer cells formation and prostate hyperplasia) [14,15]. The main problem is to determine how many senescent cells must be present to induce autoimmunity. In vitro analysis of the gene expression of immune cells in the presence of young and senescent cells from target tissue would be useful to understand this process. 3. The distribution of senescent cells in a tissue/organ can be heterogeneous (regions of higher concentration of senescent cells). To prevent autoimmune reactions, homogeneous accumulation of senescent cells must be sustained as long as possible. The probability of the formation of these regions could be analyzed using mathematical or simulation models. 4. Sometimes only parts of the organ or organic system are affected. This is caused by a heterogeneous accumulation of senescent cells in the target tissue/organ. Only part of the tissue/organ could become prematurely senescent. This hypothesis is based mostly on the studies on the presence of senescent cells overlaying atherosclerotic plaques, telomere attrition and hemodynamic stress, and different theories that connect ageing and diseases [10,16,17]. It could be demonstrated analyzing the concentration of senescent cells in different part of the affected organs (e.g. clinically affected on nonaffected articulations in rheumatoid arthritis). Since tissues and organs are composed of different type of cells an additional hypothesis could be considered. 5. An excessive accumulation of only one type of senescent cells can modify the final immune reaction (e.g. fibroblasts, melanocytes). Some cells can be more sensitive to chemical and physical factors and become senescent more easily. Because of that possibility, all types of cells should be considered during the analysis of accumulation of senescent cells. 6. An autoimmune disease could appear when a target organ accumulates more senescent cells than the immune system. Multiple autoimmune diseases could appear when the immune system accumulates more senescent cells than other organs or multiple organs accumulate more senescent cells than the immune system. It has been demonstrated in many articles that donor and recipient age is important for the outcome of kidney transplantation [18–20]. Also, an important independent risk factor in renal transplantation is the donor-recipient age differ-
ence [21]. More detailed analysis on the effect of age difference on the outcome of organs transplantation could lead to new information on autoimmune diseases. 7. The curve of age-specific incidence of autoimmune diseases is the result of the combined probability of two processes: (1) probability of the formation of a focus of senescent cells in tissues/organs and (2) the probability of a non-balanced accumulation of senescent cells between the immune system and the target tissue/organ. To demonstrate the last hypothesis, detailed epidemiological data should be collected and compared with mathematical and simulation models. When the age-specific incidence of the autoimmune disease do not increases with age (peak incidence is in childhood or young adulthood), other factors should be taken into consideration (e.g. inherited genetic mutations, exposure to toxic agents).
Possible treatments for autoimmune diseases If the hypothesis is correct, the control of the formation, accumulation and elimination of senescent cells can be used to prevent and/or treat autoimmune diseases. Current treatment modalities of autoimmune diseases include different therapies: corticosteroids, biologicals (e.g. etanercept, efalizumab), plasmapheresis, etc. These treatments have only a temporary effect with many adverse effects. The accumulation or removal of senescent cells would modify the microenvironment and therefore the immune reaction. A similar method of microenvironment control for cancer therapy has already been analyzed [22,23]. The formation of senescent cells can be induced by different drugs and radiations [17]. This could be used to induce senescence in target organs and/or immune system. The removal of senescent cells is technically more difficult to achieve, manly because there is no specific marker to use as target. There are many other problems caused by immunosenescence that can be also partially explained by our hypothesis [6]. Every imbalance in the accumulation of senescent cells between the immune system and the potential target organs could initiate a chronic inflammation. Basically, the accumulation of senescent cells is a finely regulated process. When this process is compromised it manifests as an inflammation or an autoimmune disease. In conclusion, the dynamic of accumulation of senescent cells could be important not only for understanding autoimmune diseases but for many other age-related pathologies (e.g. non-specific inflammations, deterioration of parts of organs, immune response to infections and cancer cells). Therefore, therapies directed to control the accumulation of senescent cells could be used to treat patients with autoimmune diseases and other age-related pathologies. References [1] Goodnow CC. Multistep pathogenesis of autoimmune disease. Cell 2007;130(1):25–35. [2] Pan PY, Ozao J, Zhou Z, Chen SH. Advancements in immune tolerance. Adv Drug Deliv Rev 2008;60(2):91–105. [3] Goronzy J, Weyand CM. T-cell co-stimulatory pathways in autoimmunity. Arthritis Res Ther 2008;10(Suppl. 1):S3. [4] Song J, Lei FT, Xiong X, Haque R. Intracellular signals of T cell costimulation. Cell Mol Immunol 2008;5(4):239–47. [5] Gomez C, Boehmer EC, Kovacs EJ. The aging innate immune system. Curr Opin Immunol 2005;17(5):457–62. [6] Hakim FT, Gress RE. Immunosenescence: deficits in adaptive immunity in the eldery. Tissue Antigens 2007;70(3):179–89. [7] Goronzy JJ, Lee WW, Weyand CM. Aging and T-cell diversity. Exp Gerontol 2007;42(5):400–6. [8] Goronzy J, Weyand CM. Ageing, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity–catalysts of autoimmunity and chronic inflammation. Arthtitis Res Ther 2003;5:225–34. [9] Gregg R, Smith CM, Clark FJ, et al. The number of human peripheral blood CD4+ CD25high regulatory T-cells increases with age. Clin Exp Immunol 2005;140(3):540–6.
T. Manestar-Blazˇic´, M. Volf / Medical Hypotheses 73 (2009) 667–669 [10] Jeyapalan JC, Sedivy JM. Cellular senescence and organismal aging. Mech Ageing Dev 2008;129(7–8):467–74. [11] Borlon C, Weemaels G, Godard P, et al. Expression profiling of senescentassociated genes in human dermis from young and old donors. Proof-ofconcept study. Biogerontology 2008;9:197–208. [12] Yang NC, Hu ML. The limitations and validities of senescence associated-betagalactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol 2005;40(10):813–9. [13] Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science 2006;311(5765):1257. [14] Castro P, Giri D, Lamb D, Ittmann M. Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate 2003;55(1):30–8. [15] Parrinello S, Coppe JP, Krtolica A, Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 2005;118:485–96. [16] Mikhelson MV. Replicative mosaicism might explain the seeming contradictions in the telomere theory of aging. Mech Ageing Dev 2001;122(13):1361–5.
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[17] Toussaint O, Remacle J, Dierick JF, et al. From the Hayflick mosaic to the mosaics of ageing. Roles of stress-induced premature senescence in human ageing. Int J Biochem Cell Biol 2002;34(11):1415–29. [18] Schratzberger G, Mayer G. Age and renal transplantation: an interim analysis. Nephrol Dial Transplant 2003;18(3):471–6. [19] Basar H, Soran A, Shapiro R, et al. Renal transplantation in recipients over the age of 60: the impact of donor age. Transplantation 1999;67(8):1191–3. [20] Kwon OJ, Lee HG, Kwak JY. The impact of donor and recipient age on the outcome of kidney transplantation. Transplant Proc 2004;36(7):2043–5. [21] Donnelly P, Veitch P, Bell P, Henderson R, Oman P, Proud G. Donor-recipient age difference – an independent risk factor in cyclosporine-treated renal transplant recipients. Transplant Int 1991;4(2):88–91. [22] Di X, Bright AT, Bellott R, et al. A chemotherapy associated senescence bystander effect in breast cancer cells. Cancer Biol Ther 2008;7(6):864–72. [23] Ewald J, Desotelle J, Almassi N, Jarrard D. Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo. Br J Cancer 2008;98(7):1244–9.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
The dynamic of senescent cells accumulation can explain the age-specific incidence of autoimmune diseases Teo Manestar-Blazˇic´ *, Maja Volf Polyclinic ‘‘Terme Selce”, 1. Prilaz I.L. Ribara, 51266 Selce, Croatia
a r t i c l e
i n f o
Article history: Received 9 May 2009 Accepted 12 May 2009
s u m m a r y Autoimmune diseases arise when the immune system turns against normal components of the body. Overwhelming evidence indicate that the immune system deteriorates with age. The mechanism that leads to autoimmunity is complex and not fully understood, and in many cases there is no effective therapy. Another process related to aging is the accumulation of senescent cells. These cells are considered to confer deleterious effects, including the promotion of organismal aging and age-related pathologies. We hypothesize that autoimmune diseases are caused by two age related process: (1) different rate of senescent cells accumulation in the immune system and target tissue/organ, (2) heterogeneous accumulation of senescent cells in tissues/organs. Separately or combined, these two processes are at the base of autoimmune diseases. If the hypothesis is correct, the control of the formation, accumulation and elimination of senescent cells can be used to prevent and/or treat autoimmune diseases. The accumulation or removal of senescent cells would modify the microenvironment and therefore the immune reaction. Many other problems caused by immunosenescence can be also partially explained by our hypothesis. Basically, the accumulation of senescent cells is a finely regulated process. Every imbalance in the accumulation of senescent cells between the immune system and the potential target organs can initiate a chronic inflammation or autoimmunity. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Autoimmune diseases arise when the immune system turns against normal components of the body. In order to avoid harmful self-reactivity, there are many tolerance checkpoints exist prevent self-antigens from stimulating the growth of self-reactive B and T lymphocytes [1]. Self-tolerance of the T-cell repertoire is achieved through central and peripheral tolerance. Thymic education constitutes the main process of central tolerance, while after exiting the thymus, mature T cells are subjected to secondary selection by which the majority of self-reactive T cells are deleted or rendered anergic [2]. Ligation of T cell receptor (TCR) alone is insufficient to induce full activation of T lymphocytes, it requires additional ligandreceptor interactions (co-stimulation) on antigen presenting cells (APCs) and T cells [3,4]. These signals play crucial roles in all phases of T cell response (activation, effector, expression phase and memory phase) [4]. Overwhelming evidence indicate that the immune system deteriorates with age [5]. Number of different phenotypes of T and B cells and the expression of many molecules on the immune cells change during aging [5–9]. All these age-associated changes that cause * Corresponding author. Tel.: +385 51 764 076; fax: +385 51 768 310. E-mail address: [email protected] (T. Manestar-Blazˇic´). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.05.010
alterations of the immune response are termed immunosenescence [6]. The primary cause of immunosenescence in cellular immunity is the gradual decline in thymic generation of new naïve T cells, while in vitro evidence indicates that aging causes significant detrimental effects on cells of the innate immune system [5,6]. The connection between ageing and autoimmunity is also evident analyzing the age-specific incidence of many autoimmune diseases. Another process related to aging is the accumulation of senescent cells. These cells are considered to confer deleterious effects, including the promotion of organismal aging and age-related pathologies (atherosclerotic plaques, prostatic hyperplasia and aging skin) (I). These conclusions are based on their presence in the area of chronic tissue damage and their specific gene expression [10,11]. The mechanism that leads to autoimmunity is complex and not fully understood, and in many cases there is no effective therapy [1,8]. After the analysis of our theory new treatment possibilities for autoimmune diseases are also discussed.
Hypothesis We hypothesize that autoimmune diseases are caused by two age related process: (1) different rate of senescent cells
668
T. Manestar-Blazˇic´, M. Volf / Medical Hypotheses 73 (2009) 667–669
accumulation in the immune system and target tissue/organ, (2) heterogeneous accumulation of senescent cells in tissues/organs. Separately or combined, these two processes are at the base of autoimmune diseases. For an easier analysis and evaluation, we fragmented the theory into seven smaller hypotheses. 1. During normal aging the dynamic of senescent cells accumulation is similar in all tissues/organs (probably exponential). Different types of cells displaying senescent phenotype accumulate with a similar dynamic. One of the main problems for demonstrating this hypothesis is the determination of the presence of senescent cells in the tissues. There are many senescent cell biomarkers, but not completely reliable [12,13]. Many articles discuss their accumulation in vivo, but there is much less data about their exact proportion in the organism. It has been estimated that in primates the number of senescent fibroblasts increase exponentially [13]. Based on this information and our hypothesis (stable proportion of different types of cells displaying senescent phenotype), the number of senescent cells in tissues/organs increase exponentially during life. 2. The accumulation of senescent cells in the immune system and in the target tissue/organ causes specific alterations in the process of antigen expression and recognition. In different tissues the accumulation of senescent cells causes alteration in the surrounding environment (e.g. promotion of cancer cells formation and prostate hyperplasia) [14,15]. The main problem is to determine how many senescent cells must be present to induce autoimmunity. In vitro analysis of the gene expression of immune cells in the presence of young and senescent cells from target tissue would be useful to understand this process. 3. The distribution of senescent cells in a tissue/organ can be heterogeneous (regions of higher concentration of senescent cells). To prevent autoimmune reactions, homogeneous accumulation of senescent cells must be sustained as long as possible. The probability of the formation of these regions could be analyzed using mathematical or simulation models. 4. Sometimes only parts of the organ or organic system are affected. This is caused by a heterogeneous accumulation of senescent cells in the target tissue/organ. Only part of the tissue/organ could become prematurely senescent. This hypothesis is based mostly on the studies on the presence of senescent cells overlaying atherosclerotic plaques, telomere attrition and hemodynamic stress, and different theories that connect ageing and diseases [10,16,17]. It could be demonstrated analyzing the concentration of senescent cells in different part of the affected organs (e.g. clinically affected on nonaffected articulations in rheumatoid arthritis). Since tissues and organs are composed of different type of cells an additional hypothesis could be considered. 5. An excessive accumulation of only one type of senescent cells can modify the final immune reaction (e.g. fibroblasts, melanocytes). Some cells can be more sensitive to chemical and physical factors and become senescent more easily. Because of that possibility, all types of cells should be considered during the analysis of accumulation of senescent cells. 6. An autoimmune disease could appear when a target organ accumulates more senescent cells than the immune system. Multiple autoimmune diseases could appear when the immune system accumulates more senescent cells than other organs or multiple organs accumulate more senescent cells than the immune system. It has been demonstrated in many articles that donor and recipient age is important for the outcome of kidney transplantation [18–20]. Also, an important independent risk factor in renal transplantation is the donor-recipient age differ-
ence [21]. More detailed analysis on the effect of age difference on the outcome of organs transplantation could lead to new information on autoimmune diseases. 7. The curve of age-specific incidence of autoimmune diseases is the result of the combined probability of two processes: (1) probability of the formation of a focus of senescent cells in tissues/organs and (2) the probability of a non-balanced accumulation of senescent cells between the immune system and the target tissue/organ. To demonstrate the last hypothesis, detailed epidemiological data should be collected and compared with mathematical and simulation models. When the age-specific incidence of the autoimmune disease do not increases with age (peak incidence is in childhood or young adulthood), other factors should be taken into consideration (e.g. inherited genetic mutations, exposure to toxic agents).
Possible treatments for autoimmune diseases If the hypothesis is correct, the control of the formation, accumulation and elimination of senescent cells can be used to prevent and/or treat autoimmune diseases. Current treatment modalities of autoimmune diseases include different therapies: corticosteroids, biologicals (e.g. etanercept, efalizumab), plasmapheresis, etc. These treatments have only a temporary effect with many adverse effects. The accumulation or removal of senescent cells would modify the microenvironment and therefore the immune reaction. A similar method of microenvironment control for cancer therapy has already been analyzed [22,23]. The formation of senescent cells can be induced by different drugs and radiations [17]. This could be used to induce senescence in target organs and/or immune system. The removal of senescent cells is technically more difficult to achieve, manly because there is no specific marker to use as target. There are many other problems caused by immunosenescence that can be also partially explained by our hypothesis [6]. Every imbalance in the accumulation of senescent cells between the immune system and the potential target organs could initiate a chronic inflammation. Basically, the accumulation of senescent cells is a finely regulated process. When this process is compromised it manifests as an inflammation or an autoimmune disease. In conclusion, the dynamic of accumulation of senescent cells could be important not only for understanding autoimmune diseases but for many other age-related pathologies (e.g. non-specific inflammations, deterioration of parts of organs, immune response to infections and cancer cells). Therefore, therapies directed to control the accumulation of senescent cells could be used to treat patients with autoimmune diseases and other age-related pathologies. References [1] Goodnow CC. Multistep pathogenesis of autoimmune disease. Cell 2007;130(1):25–35. [2] Pan PY, Ozao J, Zhou Z, Chen SH. Advancements in immune tolerance. Adv Drug Deliv Rev 2008;60(2):91–105. [3] Goronzy J, Weyand CM. T-cell co-stimulatory pathways in autoimmunity. Arthritis Res Ther 2008;10(Suppl. 1):S3. [4] Song J, Lei FT, Xiong X, Haque R. Intracellular signals of T cell costimulation. Cell Mol Immunol 2008;5(4):239–47. [5] Gomez C, Boehmer EC, Kovacs EJ. The aging innate immune system. Curr Opin Immunol 2005;17(5):457–62. [6] Hakim FT, Gress RE. Immunosenescence: deficits in adaptive immunity in the eldery. Tissue Antigens 2007;70(3):179–89. [7] Goronzy JJ, Lee WW, Weyand CM. Aging and T-cell diversity. Exp Gerontol 2007;42(5):400–6. [8] Goronzy J, Weyand CM. Ageing, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity–catalysts of autoimmunity and chronic inflammation. Arthtitis Res Ther 2003;5:225–34. [9] Gregg R, Smith CM, Clark FJ, et al. The number of human peripheral blood CD4+ CD25high regulatory T-cells increases with age. Clin Exp Immunol 2005;140(3):540–6.
T. Manestar-Blazˇic´, M. Volf / Medical Hypotheses 73 (2009) 667–669 [10] Jeyapalan JC, Sedivy JM. Cellular senescence and organismal aging. Mech Ageing Dev 2008;129(7–8):467–74. [11] Borlon C, Weemaels G, Godard P, et al. Expression profiling of senescentassociated genes in human dermis from young and old donors. Proof-ofconcept study. Biogerontology 2008;9:197–208. [12] Yang NC, Hu ML. The limitations and validities of senescence associated-betagalactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol 2005;40(10):813–9. [13] Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science 2006;311(5765):1257. [14] Castro P, Giri D, Lamb D, Ittmann M. Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate 2003;55(1):30–8. [15] Parrinello S, Coppe JP, Krtolica A, Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 2005;118:485–96. [16] Mikhelson MV. Replicative mosaicism might explain the seeming contradictions in the telomere theory of aging. Mech Ageing Dev 2001;122(13):1361–5.
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[17] Toussaint O, Remacle J, Dierick JF, et al. From the Hayflick mosaic to the mosaics of ageing. Roles of stress-induced premature senescence in human ageing. Int J Biochem Cell Biol 2002;34(11):1415–29. [18] Schratzberger G, Mayer G. Age and renal transplantation: an interim analysis. Nephrol Dial Transplant 2003;18(3):471–6. [19] Basar H, Soran A, Shapiro R, et al. Renal transplantation in recipients over the age of 60: the impact of donor age. Transplantation 1999;67(8):1191–3. [20] Kwon OJ, Lee HG, Kwak JY. The impact of donor and recipient age on the outcome of kidney transplantation. Transplant Proc 2004;36(7):2043–5. [21] Donnelly P, Veitch P, Bell P, Henderson R, Oman P, Proud G. Donor-recipient age difference – an independent risk factor in cyclosporine-treated renal transplant recipients. Transplant Int 1991;4(2):88–91. [22] Di X, Bright AT, Bellott R, et al. A chemotherapy associated senescence bystander effect in breast cancer cells. Cancer Biol Ther 2008;7(6):864–72. [23] Ewald J, Desotelle J, Almassi N, Jarrard D. Drug-induced senescence bystander proliferation in prostate cancer cells in vitro and in vivo. Br J Cancer 2008;98(7):1244–9.