Debate Gerontology 1991;37:208-213
© 1991 S. Kargcr AG, Basel 0304-324X/91/0374-0208$2.75/0
The Immune-Neuroendocrine Homeostatic Network and Aging Rodolfo G. Goya Center of Endocrine Studies, Faculty of Medicine, National University of La Plata, Argentina
Key Words. Homeostatic network • Thymus • Neuroendocrine system
The progressive imbalances of immune and neuroendocrine function that typically develop with age in animals and humans have been long regarded as key causal factors of systemic aging. This perception led to the independent development of immunologic [1,2] and neuroendocrine [3, 4] theories of organismal aging. The underlying assump tion of these models was that both the im mune and the neuroendocrine systems func tion as essentially independent entities, a concept widely accepted at the time these theories appeared. In recent years, however,
a growing body of evidence has accumulated suggesting that these two systems function coordinately as a bidirectional network [5, 6], The purpose of the present paper is to propose a unified view of immune and neu roendocrine aging. In doing so, the first part will be devoted to introducing the idea of an immune-neuroendocrine homeostatic net work in higher animals. Next, the concepts of homeorrhesis, developmental program and their relation to systemic aging will be discussed. Finally, the experimental evi
Downloaded by: UCL 144.82.238.225 - 1/12/2018 10:44:49 AM
Abstract. A unified model of immune and neuroendocrine aging is proposed. In doing so, the idea of an immune-neuroendocrine homeostatic network in higher animals is introduced. Next the concepts of homeorrhesis (moving homeostasis), developmental program and their relation to systemic aging are discussed. Finally, the experimental evidence supporting the view that immune and neuroendocrine aging are interdependent processes is briefly reviewed. This evidence makes it clear that organismal aging can no longer be described in terms of purely neuroendocrine or immunologic models. It is hoped that the idea of an immune-neuroendocrine homeostatic network will provide a conceptual frame of reference where the growing body of experimental data regarding immune-neuroendocrine interac tions during aging can be naturally accommodated.
dence supporting the view that immune and neuroendocrine senescence are interdepen dent processes will be briefly reviewed. It should be pointed out that although the present model has its own idenity, which is based on the experience of the author in the study of neuroimmunomodulation during aging, it has been enriched by the work and ideas of other researchers in the field.
Homeostasis in Higher Animals
Unicellular organisms and simple meta zoans display only one level of homeostasis: the intracellular. In these systems, the cellu lar response to environmental challenges is coordinated at the level of DNA. Each cell functions with a great degree of autonomy in an unregulated environment. Higher organ isms on the other hand possess three levels of homeostasis: (a) intracellular homeostasis, which again is under the genomic control of each cell; (b) cell-to-cell communication, which constitutes a homeostatic mechanism at tissue level and represents an intermediate stage between intracellular and systemic ho meostasis, and (c) homeostasis of the extra cellular milieu, controlled by groups of spe cialized cells. In higher animals, most of these specialized cells belong to the neuroen docrine and immune systems. The neuroen docrine system monitors and controls the physical and chemical characteristics of the internal milieu. On its part the immune sys tem perceives, through antigenic recogni tion, an internal image of the macromolecular and cellular constituents of the body and reacts to particular distortions of the image. It can be said, therefore, that the immune system maintains the ‘biological’ homeosta sis of the organism. An increasing amount of
209
experimental data suggests the existence of a complex immune-neuroendocrine network involving different cell types and structures which are capable of emitting and receiving bidirectional signals [5, 6]. Under this new perspective, the immune system appears not as a separate entity but as an integral part of the homeostatic network.
Ilomeorrhesis, Developmental Program and Aging
The term homeorrhesis, or moving ho meostasis, was first used by Waddington [7] in 1957. It refers to the fact that the set point of homeostasis changes during the different phases of life, as do other physiological pa rameters. What we usually call normal phys iology is that of the young, optimally func tioning adult, human or animal. From a de velopmental point of view, however, there is a sequence of normal physiologies, begin ning in the egg and ending in the senescent individual. The homeostasis that gives us our frame of reference to define ‘normal’ function is in fact homeostasis about a developmentally changing point. Up to sexual maturation, all develop mental changes must be genetically program med. There are two possibilities after sexual maturity has been reached: (1) both the re productive period and the aging process are programmed; (2) the developmental pro gram runs out shortly after sexual matura tion takes place. In this case, the length of the reproductive period would be determined by the degree of perfection of the homeostatic network of the adult organism. Senescence would appear when this network begins to run over tolerance. Both of the above possi bilities remain viable so far and the elucida
Downloaded by: UCL 144.82.238.225 - 1/12/2018 10:44:49 AM
Homeostatic Network and Aging
tion of the correct one represents one of the major challenges of basic gerontology.
The Immune-Neuroendocrine Network from Development to Aging
It now seems clear that the thymus gland and the neuroendocrine system influence the maturation of each other during early ontog eny and perinatal life in mammals. In many species, neonatal thymectomy produces clear changes in pituitary morphology as well as in other peripheral endocrine glands [8], Neonatal thymectomy in female mice results in permanent derangements of reproductive function and alterations in plasma levels of pituitary hormones [9, 10]. There are also the established findings that in species in which neonatal thymectomy does not pro duce any evident impairment of the immune capacity [11], neuroendocrine functions are already highly developed at birth [12]. In adult animals, clear changes in the electric activity of the hypothalamus have been shown to occur during the immune response [13, 14], The immunologic activity also affects hormone levels. Thus, during the course of the immune response in vivo the serum levels of corticosterone increase [15, 16] whereas circulating thyroxine (T4) and triiodothyronine (T3) decline [16, 17], These hormonal changes seem to play a role in the modulation of the immune response. Thus, adrenalectomy in rats abolishes the phenom enon of sequential antigenic competition [ 15] which is defined as the blockade of an immune response against one antigen by the administration of a second, unrelated anti gen, a few days before the first one. It is believed that the corticosterone surge during the immune response contributes to prevent
Goya
an exaggerated or nonspecific production of antibodies. Interestingly, by 12 months of age, mice lose the ability to increase their cir culating levels of corticosterone during the immune response, an occurrence that is ac companied by a parallel loss of their ability to show sequential antigenic competition [18]. It seems therefore possible that aging may bring about a progressive disruption in immune-endocrine integration which in turn could play a significant role in age-associated immunopathologies, particularly autoimmu nity. Although much attention has been de voted to the role of the thymus as a pace maker of immunologic aging, very little work has been done on the endocrine conse quences (and nonimmune consequences, in general) of thymus decline during aging. Par ticularly significant in this area is the work of Fabris et al. [19]. These authors reported that injection of mature lymph node lym phocytes from normal littermates into SnellBagg dwarf mice or reconstitution of their lymphoid system with growth hormone (GH) and T4 markedly prolonged the mean life span of these short-lived animals (mean life span is 5 months). Not only were the immune deficiencies corrected but also other nonimmune aging characteristics like gray ing and loss of hair, cutaneous and subcuta neous atrophy, bilateral cataracts and re duced cellular turnover, were prevented in 7-month-old animals. In other studies the same group has shown that grafting of neo natal thymus into old mice was able to cor rect their abnormal serum levels of T3 and insulin, as well as the decreased response of their submandibular glands to isoproterenol [20], Neonatal thymus grafting into old mice has also been reported to reverse the agerelated decrease of Pi-adrenoceptor density
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Homeostatic Network and Aging
Thymic Hormones and Aging
The endocrine thymus produces a num ber of immunoregulatory substances, some of which are also active on nervous and endocrine circuits [30], Of particular interest as neuroendocrine modulators are thymosin fraction five (TF5) and homeostatic thymus hormone (HTH), two well-characterized thymic preparations which can prevent the
immune and endocrine consequences of neonatal thymectomy when administered shortly after thymus removal [31]. It has been recently reported that TF5 and HTH have thyrotropin (TSH)-inhibiting activity in young but not in old rats [32-34], Further more, intravenous administration of HTH was also able to reduce plasma GH and increase corticosterone levels in both young and old rats, although these responses were much weaker in the old animals [34, 35]. These results suggest that aging brings about a progressive desensitization of the neuroen docrine system to thymic signals. Reciprocally, the endocrine activity of the thymus seems to be strongly affected by the age-associated decrements in neuroendo crine function. Thus, in rodents there is a significant correlation between the age-dependent decline in circulating levels of T4 and those of ‘facteur thymique serique’ (FTS) and thymosin ai (Taj), two immuno regulatory thymic peptides [36, 37], Further more, treatment of old mice with T4 [36] or hypothalamic extracts from young mice [38] results in reappearance of detectable levels of circulating FTS. In aged dogs, treatment with bovine GH partially restores their de pressed circulating levels of thymulin, the zinc-conjugated form of FTS [39].
Concluding Remarks
The experimental evidence reviewed here clearly shows that organismal aging can no longer be described in terms of purely neu roendocrine or immunologic models. The idea of an immune-neuroendocrine homeo static network provides a conceptual frame of reference where the growing body of ex perimental data regarding immune-neuroen
Downloaded by: UCL 144.82.238.225 - 1/12/2018 10:44:49 AM
in brain cortex [21] and to correct the ageassociated increase in hepatocyte mean nu clear volume [22]. Other workers have re ported that the accelerated aging and tumorigenesis of the ovaries that occur in neonatally thymectomized mice can be overcome by the transplant of an intact thymus or injection of T cells [23, 24], The neuroendocrine system has a power ful influence on immune function [25]. Fur thermore, there is compelling evidence that thymus involution, which begins shortly af ter puberty, is triggered by the neuroendo crine system. Thus, adrenal and gonadal ste roids have a marked inhibitory effect on the thymus while adrenalectomy or castration are followed by hypertrophy of the thymus in adult animals [26]. Interestingly, castra tion in old male rats and mice is followed by a spectacular recovery of thymic mass and morphology, indicating that even the low levels of circulating testosterone in the old animals are exerting a significant inhibitory action on the thymus [27, 28]. Grafting of GH3 pituitary tumour cells, which secrete GH and some prolactin, has been shown to be another effective intervention to restore thymus structure as well as T-cell prolifera tion and interleukin-2 synthesis in old rats [29],
211
Goya
docrine interactions during aging can be nat urally accomodated. It is hoped that the pro posed model may prove to be a useful work ing hypothesis for both immunologists and neuroendocrinologists interested in the problem of aging. Acknowledgements The author is indebted to Dr. Joseph Meites for helpful discussions of the ideas presented here and to Yolanda E. Sosa for typing of the manuscript. Part of the work by the author discussed here was supported by grants from the Argentine Research Council (CON1CET) and the Sandoz Foundation for Geron tological Research.
References 1 Walford RL: Immunologic theory of aging: cur rent status. Fed Proc 1974;33:2020-2027. 2 Macfarlane Burnet: Immunological Surveillance. Sydney. Pergamon Press, 1970. 3 Everitt AV: The neuroendocrine system and aging. Gerontology 1980;26:108-119. 4 Finch CE: The regulation of physiological changes during mammalian aging. Q Rev Biol 1976;51: 49-83. 5 Roszman TL, Brooks H: Signaling pathways of the ncuroendocrine-immune network. Prog Allergy. Basel. Karger, 1988, vol 43. pp 140-159. 6 Jankovic BD: Neuroimmunomodulation: facts and dilemmas. Immunol Lett 1989;21:101-118. 7 Waddington CH: The Strategy of the Genes. Lon don, Allen & Unwin. 1957. 8 Comsa J, Hook RR Jr: Thymectomy; in Luckey TD (ed): Thymic Hormones. Baltimore, Univer sity Park Press, 1973. pp 1-18. 9 Michael SD. Taguchi O, Nishizuka Y: Effect of neonatal thymectomy on ovarian development and plasma LH, FSH, GH and Prl in the mouse. Biol Reprod 1980;22:343-350. 10 Michael SD, Taguchi O, Nishizuka Y: Changes in hypophyseal hormones associated with acceler ated aging and tumorigenesis of the ovaries in neonatally thymectomized mice. Endocrinology 1981;181:2375-2380.
11 Solomon JB: Ontogeny of defined immunity in mammals; in Neuberger A, Tatum EL (eds): Foe tal and Neonatal Immunology. Frontiers of Biolo gy. New York, American Elsevier Publishing Co. 1971, vol 20, pp 234-306. 12 Jost A: The extent of foetal and endocrine auton omy; in Wolstenholme GEW, O’Connor M (eds): Foetal Autonomy. Ciba Foundation Symposium. London. Churchill, 1969, pp 79-94. 13 Bcsedovsky HO, Sorkin E: Network of immuneneuroendocrine interactions. Clin Exp Immunol 1977;27:1-12. 14 Saphier D, Abramsky O, Mor G, et al: A neuro physiological correlate of an immune response; in Jankovic BD, Markovic BM, Spector NH (eds): Neuroimmune Interactions. Proceedings of the Second International Workshop on Ncuroimmunomodulation. Ann NY Acad Sci 1987:496:354— 359. 15 Besedovsky HO, Del Rey AE, Sorkin E: Antigenic competition between horse and sheep red blood cells as a hormone-dependent phenomenon. Clin Exp Immunol 1979;37:106-113. 16 Bcsedovsky HO. Sorkin E, Keller M. et al: Changes in blood hormone levels during the im mune response. Proc Soc Exp Biol Med 1975; 150: 466-470. 17 Keast D, Ayre DJ: Antibody regulation in birds by thyroid hormones. Dev Comp Immunol 1980:4: 323-330. 18 Tokuda S, Trujillo LC, Nofchisscy RA: Hormonal regulation of the immune function; in Cooper EL (ed): Stress, Immunity and Aging. New York, Dckker, 1984. pp 141-155. 19 Fabris N, Pierpaoli W, Sorkin E: Lymphocytes, hormones and aging. Nature 1972;240:557-559. 20 Piantanelli L, Basso A, Muzzioli M, et al: Thy mus-dependent reversibility of physiological and isoproterenol evoked age-related parameters in athymic (nude) and old normal mice. Mech Age ing Dev 1978;7:171-182. 21 Viticchi C, Gentile S, Piantanelli L: Ageing and thymus-induced differential regulation of pr and p2-adrenoceptors of mouse brain cortex. Arch Ge rontol Geriatr 1989;8:13-20. 22 Pieri C, Giuli C, Del Moro M, et al: Electron microscopic morphometric analysis of mouse liv er. II. Effect of ageing and thymus transplantation in old animals. Mech Ageing Dev 1980; 13:275— 283.
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33 Goya RG, Sosa YE, Quigley KL, et al: Differential activity of thymosin peptides (TF5) on plasma thyrotropin in female rats of different ages. Neu roendocrinology 1988:47:379-383. 34 Goya RG. Quigley KL, Takahashi S, et al: Differ ential effect of homeostatic thymus hormone on plasma thyrotropin and somatotropin in young and old rats. Mech Ageing Dev 1989:49:119128. 35 Goya RG, Sosa YE, Quigley KL, et al: Homeo static thymus hormone stimulates corticosterone secretion in a dose-and age-dependent manner in rats. Neuroendocrinology 1990;51:59-63. 36 Fabris N, Mocchegiani E: Endocrine control of thymic serum factor production in young-adult and old mice. Cell Immunol 1985:91:325-335. 37 Goya RG, Naylor PH, Goldstein AL, et al: Changes in circulating levels of neuroendocrine and thymic hormones during aging in rats: a cor relation study. Exp Gerontol 1990;25:149-157. 38 Folch H, Eller G, Mena M, et al: Neuroendocrine regulation of thymus hormones: hypothalamic de pendence of facteur thymique serique level. Cell Immunol 1986;102:211-216. 39 Goff BL, Roth JA, Arp LH. et al: Growth hor mone treatment stimulates thymulin production in aged dogs. Clin Exp Immunol 1987,68:580587.
Received: August 2, 1990 Accepted: October 24, 1990 Dr. Rodolfo G. Goya Centro de Estudios Endocrinos Facultad de Ciencias Medicas, UNLP Casilla de correo 455 1900 La Plata (Argentina)
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23 Sakakura T, Nishizuka Y: Thymic control mecha nism in ovarian dysgenesis in thymectomized mice by replacement with thymic and other lym phoid tissues. Endocrinology 1972;90:431-437. 24 Sakaguchi S, Takahashi T, Nishizuka Y: Study on cellular events in post-thymectomy autoimmunity oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oo phoritis. Exp Med 1982;156:1577-1586. 25 Comsa J, Leonhardt H, Wekerle H: Hormonal coordination of the immune response. Rev Phys iol Biochem Pharmacol 1982:92:115-191. 26 Comsa J: Hormonal interactions of the thymus; in Luckey TD (ed): Thymic Hormones. Baltimore, University Park Press. 1973. pp 59-96. 27 Greenstein BD, Fitzpatrick FTA, Adcock IM, et al: Reappearance of the thymus in old rats after orchidectomy: inhibition of regeneration by tes tosterone. J Endocrinol 1986;110:417-422. 28 Utsuyama M, Hirokawa K: Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy. Mech Ageing Dev 1989;47:175-185. 29 Kelley KW. Brief S. Westly HJ, et al: GH, pitu itary adenoma cells can reverse thymic aging in rats. Proc Natl Acad Sci USA 1986:83:5663— 5667. 30 Hall NR, McGillis JP, Spangelo BL, et al: Evi dence that thymosins and other biological re sponse modifiers can function as neuroactive neu rotransmitters. J Immunol 1985; 135:806s—8 11s. 31 Deschaux P, Binimbi Massengo, Fontanges R: Endocrine interaction of the thymus with the hy pophysis, adrenals and testes: effects for two thymic extracts. Thymus 1979:1:95-108. 32 Goya RG, Takahashi S, Quigley KL, et al: Im mune-neuroendocrine interactions during aging: age-dependent thyrotropin-inhibiting activity of thymosin peptides. Mech Ageing Dev 1987;41: 219-227.
© 1991 S. Kargcr AG, Basel 0304-324X/91/0374-0208$2.75/0
The Immune-Neuroendocrine Homeostatic Network and Aging Rodolfo G. Goya Center of Endocrine Studies, Faculty of Medicine, National University of La Plata, Argentina
Key Words. Homeostatic network • Thymus • Neuroendocrine system
The progressive imbalances of immune and neuroendocrine function that typically develop with age in animals and humans have been long regarded as key causal factors of systemic aging. This perception led to the independent development of immunologic [1,2] and neuroendocrine [3, 4] theories of organismal aging. The underlying assump tion of these models was that both the im mune and the neuroendocrine systems func tion as essentially independent entities, a concept widely accepted at the time these theories appeared. In recent years, however,
a growing body of evidence has accumulated suggesting that these two systems function coordinately as a bidirectional network [5, 6], The purpose of the present paper is to propose a unified view of immune and neu roendocrine aging. In doing so, the first part will be devoted to introducing the idea of an immune-neuroendocrine homeostatic net work in higher animals. Next, the concepts of homeorrhesis, developmental program and their relation to systemic aging will be discussed. Finally, the experimental evi
Downloaded by: UCL 144.82.238.225 - 1/12/2018 10:44:49 AM
Abstract. A unified model of immune and neuroendocrine aging is proposed. In doing so, the idea of an immune-neuroendocrine homeostatic network in higher animals is introduced. Next the concepts of homeorrhesis (moving homeostasis), developmental program and their relation to systemic aging are discussed. Finally, the experimental evidence supporting the view that immune and neuroendocrine aging are interdependent processes is briefly reviewed. This evidence makes it clear that organismal aging can no longer be described in terms of purely neuroendocrine or immunologic models. It is hoped that the idea of an immune-neuroendocrine homeostatic network will provide a conceptual frame of reference where the growing body of experimental data regarding immune-neuroendocrine interac tions during aging can be naturally accommodated.
dence supporting the view that immune and neuroendocrine senescence are interdepen dent processes will be briefly reviewed. It should be pointed out that although the present model has its own idenity, which is based on the experience of the author in the study of neuroimmunomodulation during aging, it has been enriched by the work and ideas of other researchers in the field.
Homeostasis in Higher Animals
Unicellular organisms and simple meta zoans display only one level of homeostasis: the intracellular. In these systems, the cellu lar response to environmental challenges is coordinated at the level of DNA. Each cell functions with a great degree of autonomy in an unregulated environment. Higher organ isms on the other hand possess three levels of homeostasis: (a) intracellular homeostasis, which again is under the genomic control of each cell; (b) cell-to-cell communication, which constitutes a homeostatic mechanism at tissue level and represents an intermediate stage between intracellular and systemic ho meostasis, and (c) homeostasis of the extra cellular milieu, controlled by groups of spe cialized cells. In higher animals, most of these specialized cells belong to the neuroen docrine and immune systems. The neuroen docrine system monitors and controls the physical and chemical characteristics of the internal milieu. On its part the immune sys tem perceives, through antigenic recogni tion, an internal image of the macromolecular and cellular constituents of the body and reacts to particular distortions of the image. It can be said, therefore, that the immune system maintains the ‘biological’ homeosta sis of the organism. An increasing amount of
209
experimental data suggests the existence of a complex immune-neuroendocrine network involving different cell types and structures which are capable of emitting and receiving bidirectional signals [5, 6]. Under this new perspective, the immune system appears not as a separate entity but as an integral part of the homeostatic network.
Ilomeorrhesis, Developmental Program and Aging
The term homeorrhesis, or moving ho meostasis, was first used by Waddington [7] in 1957. It refers to the fact that the set point of homeostasis changes during the different phases of life, as do other physiological pa rameters. What we usually call normal phys iology is that of the young, optimally func tioning adult, human or animal. From a de velopmental point of view, however, there is a sequence of normal physiologies, begin ning in the egg and ending in the senescent individual. The homeostasis that gives us our frame of reference to define ‘normal’ function is in fact homeostasis about a developmentally changing point. Up to sexual maturation, all develop mental changes must be genetically program med. There are two possibilities after sexual maturity has been reached: (1) both the re productive period and the aging process are programmed; (2) the developmental pro gram runs out shortly after sexual matura tion takes place. In this case, the length of the reproductive period would be determined by the degree of perfection of the homeostatic network of the adult organism. Senescence would appear when this network begins to run over tolerance. Both of the above possi bilities remain viable so far and the elucida
Downloaded by: UCL 144.82.238.225 - 1/12/2018 10:44:49 AM
Homeostatic Network and Aging
tion of the correct one represents one of the major challenges of basic gerontology.
The Immune-Neuroendocrine Network from Development to Aging
It now seems clear that the thymus gland and the neuroendocrine system influence the maturation of each other during early ontog eny and perinatal life in mammals. In many species, neonatal thymectomy produces clear changes in pituitary morphology as well as in other peripheral endocrine glands [8], Neonatal thymectomy in female mice results in permanent derangements of reproductive function and alterations in plasma levels of pituitary hormones [9, 10]. There are also the established findings that in species in which neonatal thymectomy does not pro duce any evident impairment of the immune capacity [11], neuroendocrine functions are already highly developed at birth [12]. In adult animals, clear changes in the electric activity of the hypothalamus have been shown to occur during the immune response [13, 14], The immunologic activity also affects hormone levels. Thus, during the course of the immune response in vivo the serum levels of corticosterone increase [15, 16] whereas circulating thyroxine (T4) and triiodothyronine (T3) decline [16, 17], These hormonal changes seem to play a role in the modulation of the immune response. Thus, adrenalectomy in rats abolishes the phenom enon of sequential antigenic competition [ 15] which is defined as the blockade of an immune response against one antigen by the administration of a second, unrelated anti gen, a few days before the first one. It is believed that the corticosterone surge during the immune response contributes to prevent
Goya
an exaggerated or nonspecific production of antibodies. Interestingly, by 12 months of age, mice lose the ability to increase their cir culating levels of corticosterone during the immune response, an occurrence that is ac companied by a parallel loss of their ability to show sequential antigenic competition [18]. It seems therefore possible that aging may bring about a progressive disruption in immune-endocrine integration which in turn could play a significant role in age-associated immunopathologies, particularly autoimmu nity. Although much attention has been de voted to the role of the thymus as a pace maker of immunologic aging, very little work has been done on the endocrine conse quences (and nonimmune consequences, in general) of thymus decline during aging. Par ticularly significant in this area is the work of Fabris et al. [19]. These authors reported that injection of mature lymph node lym phocytes from normal littermates into SnellBagg dwarf mice or reconstitution of their lymphoid system with growth hormone (GH) and T4 markedly prolonged the mean life span of these short-lived animals (mean life span is 5 months). Not only were the immune deficiencies corrected but also other nonimmune aging characteristics like gray ing and loss of hair, cutaneous and subcuta neous atrophy, bilateral cataracts and re duced cellular turnover, were prevented in 7-month-old animals. In other studies the same group has shown that grafting of neo natal thymus into old mice was able to cor rect their abnormal serum levels of T3 and insulin, as well as the decreased response of their submandibular glands to isoproterenol [20], Neonatal thymus grafting into old mice has also been reported to reverse the agerelated decrease of Pi-adrenoceptor density
Downloaded by: UCL 144.82.238.225 - 1/12/2018 10:44:49 AM
210
Homeostatic Network and Aging
Thymic Hormones and Aging
The endocrine thymus produces a num ber of immunoregulatory substances, some of which are also active on nervous and endocrine circuits [30], Of particular interest as neuroendocrine modulators are thymosin fraction five (TF5) and homeostatic thymus hormone (HTH), two well-characterized thymic preparations which can prevent the
immune and endocrine consequences of neonatal thymectomy when administered shortly after thymus removal [31]. It has been recently reported that TF5 and HTH have thyrotropin (TSH)-inhibiting activity in young but not in old rats [32-34], Further more, intravenous administration of HTH was also able to reduce plasma GH and increase corticosterone levels in both young and old rats, although these responses were much weaker in the old animals [34, 35]. These results suggest that aging brings about a progressive desensitization of the neuroen docrine system to thymic signals. Reciprocally, the endocrine activity of the thymus seems to be strongly affected by the age-associated decrements in neuroendo crine function. Thus, in rodents there is a significant correlation between the age-dependent decline in circulating levels of T4 and those of ‘facteur thymique serique’ (FTS) and thymosin ai (Taj), two immuno regulatory thymic peptides [36, 37], Further more, treatment of old mice with T4 [36] or hypothalamic extracts from young mice [38] results in reappearance of detectable levels of circulating FTS. In aged dogs, treatment with bovine GH partially restores their de pressed circulating levels of thymulin, the zinc-conjugated form of FTS [39].
Concluding Remarks
The experimental evidence reviewed here clearly shows that organismal aging can no longer be described in terms of purely neu roendocrine or immunologic models. The idea of an immune-neuroendocrine homeo static network provides a conceptual frame of reference where the growing body of ex perimental data regarding immune-neuroen
Downloaded by: UCL 144.82.238.225 - 1/12/2018 10:44:49 AM
in brain cortex [21] and to correct the ageassociated increase in hepatocyte mean nu clear volume [22]. Other workers have re ported that the accelerated aging and tumorigenesis of the ovaries that occur in neonatally thymectomized mice can be overcome by the transplant of an intact thymus or injection of T cells [23, 24], The neuroendocrine system has a power ful influence on immune function [25]. Fur thermore, there is compelling evidence that thymus involution, which begins shortly af ter puberty, is triggered by the neuroendo crine system. Thus, adrenal and gonadal ste roids have a marked inhibitory effect on the thymus while adrenalectomy or castration are followed by hypertrophy of the thymus in adult animals [26]. Interestingly, castra tion in old male rats and mice is followed by a spectacular recovery of thymic mass and morphology, indicating that even the low levels of circulating testosterone in the old animals are exerting a significant inhibitory action on the thymus [27, 28]. Grafting of GH3 pituitary tumour cells, which secrete GH and some prolactin, has been shown to be another effective intervention to restore thymus structure as well as T-cell prolifera tion and interleukin-2 synthesis in old rats [29],
211
Goya
docrine interactions during aging can be nat urally accomodated. It is hoped that the pro posed model may prove to be a useful work ing hypothesis for both immunologists and neuroendocrinologists interested in the problem of aging. Acknowledgements The author is indebted to Dr. Joseph Meites for helpful discussions of the ideas presented here and to Yolanda E. Sosa for typing of the manuscript. Part of the work by the author discussed here was supported by grants from the Argentine Research Council (CON1CET) and the Sandoz Foundation for Geron tological Research.
References 1 Walford RL: Immunologic theory of aging: cur rent status. Fed Proc 1974;33:2020-2027. 2 Macfarlane Burnet: Immunological Surveillance. Sydney. Pergamon Press, 1970. 3 Everitt AV: The neuroendocrine system and aging. Gerontology 1980;26:108-119. 4 Finch CE: The regulation of physiological changes during mammalian aging. Q Rev Biol 1976;51: 49-83. 5 Roszman TL, Brooks H: Signaling pathways of the ncuroendocrine-immune network. Prog Allergy. Basel. Karger, 1988, vol 43. pp 140-159. 6 Jankovic BD: Neuroimmunomodulation: facts and dilemmas. Immunol Lett 1989;21:101-118. 7 Waddington CH: The Strategy of the Genes. Lon don, Allen & Unwin. 1957. 8 Comsa J, Hook RR Jr: Thymectomy; in Luckey TD (ed): Thymic Hormones. Baltimore, Univer sity Park Press, 1973. pp 1-18. 9 Michael SD. Taguchi O, Nishizuka Y: Effect of neonatal thymectomy on ovarian development and plasma LH, FSH, GH and Prl in the mouse. Biol Reprod 1980;22:343-350. 10 Michael SD, Taguchi O, Nishizuka Y: Changes in hypophyseal hormones associated with acceler ated aging and tumorigenesis of the ovaries in neonatally thymectomized mice. Endocrinology 1981;181:2375-2380.
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Received: August 2, 1990 Accepted: October 24, 1990 Dr. Rodolfo G. Goya Centro de Estudios Endocrinos Facultad de Ciencias Medicas, UNLP Casilla de correo 455 1900 La Plata (Argentina)
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