УСПЕХИ ГЕРОНТОЛОГИИ • 2011 • Т. 24 • № 1 © V. I. Goudoshnikov, 2011 УДК 615-053:612.67

Adv. geront. 2011. Vol. 24. № 1. P. 48–53

V. I. Goudoshnikov

THE ROLE OF GLUCOCORTICOIDS IN AGING AND AGE-RELATED PHARMACOTHERAPY Membership of International Society for DOHaD, Santa Maria — RS, Brazil, Rua Matoso Camara, 73, Bairro Dores, CEP 97050–500, Santa Maria — RS, Brazil; e-mail: [email protected]

Recently we have evaluated the role of glucocorticoids (GC) and other stress hormones in the pathogeny of agerelated diseases. In order to perform this evaluation, we considered the DOHaD paradigm discussing long-term effects of adverse perinatal factors. In the present work, a part of the data collected previously was used for analyzing the role of GC in aging, as well as in age-related pharmacotherapy. The data were gathered in various databases, preferably in English, during the last 25–30 years. Although some authors suggest that GC can be considered as hormones of aging, the majority of investigators are quite careful in this respect. Nevertheless, it appears that the role of GC in various stages of ontogeny and transitions between them is well established. Besides, there are a lot of data that confirm a contribution of GC to the phenomena of perinatal programming / imprinting of adult diseases. What for the relationship between GC and aging, some studies confirm its existence, at least partially. Having analyzed the dynamics of morbidity and mortality of age-related diseases, we concluded on the absence of evidence in favor of unique general scheme of aging, where GC could play a role. However, in a rather paradoxal mode it was demonstrated that GC participate, at least indirectly, in the mechanisms of action of various drugs used for the treatment of cardiometabolic disorders (beta-blockers, angiotensin antagonists, some oral hypoglycemic agents) and neuropsychiatric diseases (antidepressants, antipsychotic agents, benzodiazepines and some anticonvulsive medicines), as well as in the effects of toxic agents (for example, drugs of abuse, including caffeine). Using the concept of hormesis, we discuss a reason for frequent utilization of these drugs, and not GC or their antagonists, in age-related pharmacotherapy. The caution is suggested in considering the essential function of GC in aging. Nevertheless, due to existence of theory that connects GC with aging via the mechanisms of allostasis, we are planning to elaborate a more detailed model that might include, besides GC, also some other hormones, cytokines, etc., as well as their interactions. It is stressed that the interactions of GC with other bioregulators should be reevaluated in a chronobiological mode, in order to strengthen the bases of chronopharmacotherapy. One of the principal challenges is the prevention of adverse effects of pharmacotherapy in long term. In this sense, DOHaD paradigm has opened the discussion of possibility for pharmacotoxicologic programming / imprinting, an important question attracting the attention of researchers.

diseases. This evaluation has shown important contribution of GC and CA to etiopathogenic mechanisms of various disorders that compose three groups: cardiometabolic diseases ( hypertension, diabetes mellitus, atherosclerosis and its consequences), neuropsychiatric diseases (depression, schizophrenia, neurodegenerative illness), as well as various cancer types [19]. Besides, our evaluation has allowed to suggest that at least some drugs used for treatment of such diseases could have a contribution of GC and CA in the mechanisms of their action. However, previously we have analyzed the dynamics of morbidity and mortality provoked by these groups of disorders, and this analysis has shown the absence of evidence in favor of unique general scheme of aging [17]. Although the discussion of relationship between stress, disease and aging may be quite complex, there exists an opinion about successful aging, i.e., healthy aging, practically without serious diseases [38]. Some authors suggest that such type of aging is characteristic for 36 % of cases [29]. But it means that at least two thirds of human population have non-healthy aging that involves age-related diseases. Nevertheless, we have decided to evaluate the contribution of GC as principal stress hormones, to aging and ontogeny as a whole, as well as to the mechanisms of action of drugs used for treatment of at least the groups of cardiometabolic and neuropsychiatric disorders. Materials and methods

The data concerning GC and aging were gathered in various databases (Academic Search Premier, Science Direct, etc.) and in the Public Domain of Internet by means of Scholar Google, preferably in English, during the period of the last 25–30 years. Special attention was payed for the area of DOHaD, the abbreviation that means Developmental Origins of Health and Disease. What for the data on phar-

Key words: aging, development, drugs, glucocorticoids, programming

Recently we have evaluated the role of stress hormones (principally, glucocorticoids — GC and catecholamines — CA) in the pathogeny of age-related 48

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macotherapy, our corresponding bibliographic study was rather atypical. Really, the participation of stress hormones in the mechanisms of drug action is not obvious, and it began to appear in the world literature only several years ago. Therefore, information search occurred secondarily, i.e., already in the papers that were retrieved on other reasons (basically, as related to pathogeny of age-related diseases). This search was completed later on by retrieval of data especially on hormesis and chronobiology.

Considering that dehydroepiandrosterone (DHEA) can be a functional antagonist of GC, the diminution of circulating levels of DHEA and its sulphated form (DHEAS) and the corresponding increase in the relation DHEA(S) / cortisol is especially harmful for several organs, including immune system [3]. It is suggested that in the case of DHEA, the aging is propagated from cellular level (attenuation of adrenocortical stem cells) to the level of organ (loss of zona reticularis) and to the whole body level (diminution of DHEA and DHEAS concentrations) [10]. Nevertheless, due to our epidemiologic data already mentioned earlier [17], we propose a caution in considering GC as hormones of principal importance in aging. In our opinion, this is even more valid, if to remember that peer-reviewed journals and Public Domain of Internet contain some publications that simply present GC as hormones of aging [43] and even «death hormones», together with «mortal» function of their receptors [8]. These ideas are discussed already since the studies on the role of GC in premature aging of some animal species, like salmon [13, 33]. Let’s concern now what especially, besides our epidemiologic data, is alarming in relation to these bibliographic data. At first, we can hardly imagine that GC separately are able to regulate the aging process. It is much more probable that GC perform this control together with other hormones and bioregulators, such as insulin, cytokines, etc. [19]. In the second place, modern methods indicate some problems in the theories formulated in the past. In fact, using microarray technique, Landfield et al. [27] arrived at conclusion about great difference in the patterns of gene expression in the hippocampus between aging and exposure to GC. Besides, caloric restriction, one of a few techniques that consistently augment longevity, is accompanied in a paradoxal manner with the increase in circulating levels of GC [40]. Finally, mild stress of short duration is capable to function as anti-aging agent, corrersponding to the phenomenon called hormesis [1, 36]. Obviously, all this does not mean that the theories formulated in the past are completely erroneous. On the contrary, support of scientific community in the last years continues to carry the discussion to the side favourable for important contribution of GC to aging and pathogeny of age-related diseases [19, 38]. On our opinion, in order to resolve this problem, it is necessary to amplify our vision of aging to ontogeny as a whole, including also the period of development and approaching in this way the area of DOHaD.

Results and discussion Circulating levels of glucocorticoids in aging

Despite the decades of studies, this aspect cannot be considered as well understood. In fact, some authors suggest that circulating levels of GC do not change in aging [14], whereas other researchers affirm that in general, the levels of GC in circulation augment in senescence [28]. There exists a third group of investigators that perform more detailed analysis and conclude that principally, due to less efficacious negative feedback of GC, the levels of these hormones in the nadir phase of circadian rhythm are increased (and therefore, the rhythm is flattened), and the response of circulating GC levels to stress is prolonged [12, 45]. The role of glucocorticoids and stress in aging

There are several theories on this theme. According to Sapolsky [41], neurotoxic action in the hippocampus is the principal mechanism, by which GC diminish their own negative feedback in aging. In accord to McEwen and his colleagues [34, 46], the cumulative exposure to GC in excess results in so called allostatic load in the life course, inducing greater risk of age-related pathologies and mortality as a whole. According to Minois [36], in 1970 Hans Selye formulated that aging reflects a sum of all stresses during an individual life. A number of researchers affirm that stress and aging interact in such a way that chronic and intense stress (e.g. in persons taking care of patients with dementia) can provoke premature or accelerated aging, principally via GC [21]. In accord to Hawkley et al. [23], already in 1960 Strehler and Mildvan suggested that the death comes when the magnitude of stress is greater than the capacity of physiologic compensation (resilience). Later on, Parsons [39] proposed that longevity is associated with high resistance to stress. 49

V. I. Goudochnikov

The importance of glucocorticoids in ontogeny

Pharmacotherapy of neuropsychiatric diseases

Since the pioneering works of Liggins [30], GC are considered as principal regulators of fetal growth [26] and parturition [52]. Moreover, together with thyroid hormones, GC exert the function of important regulators of perinatal development and tissue maturation (including that of central nervous system), via the action on cellular differentiation and proliferation [1, 24, 49], as well as the agents of energy resource allocation [55]. Recently the essential role of GC was stressed in the processes of perinatal programming / imprinting of adult disease [26, 44]. Nevertheless, it is not so easy to study the link between development and aging, including the area of DOHaD. In fact, this is possible in humans, principally, in retrospective investigations. On the other hand, in experimental models in vivo using laboratory animals, the shortage of grants and prolonged duration (up to several years) impede the progress of these studies. By the way, we have found only few publications that discuss aging in relation to phenomena of programming / imprinting [42, 51]. Previously we have suggested that GC could participate in this connection [16], but it is still necessary to organize experimental works up to the senescence, at least in mice.

In this case there already exists a literature on the participation of GC in pathogeny of depression, schizophrenia and neurodegenerative diseases (see [19]). Without doubt, major progress has occurred in revelation of the role of GC in mechanisms of action of antidepressants (AD). For example, according to Juruena et al. [25], the function of glucocorticoid receptors (GR) is attenuated in depression, whereas AD prevent this alteration. Partially, this effect of AD can be related to their capacity for augmenting GR translocation from cytoplasm to cellular nucleus, as well as to inhibition of P-glycoprotein that transports GC out of cells. On the other hand, some AD (e.g., tianeptin), anticonvulsive agents (phenytoin) and BZD (alprazolam) can prevent neuronal atrophy in the hippocampus, provoked by GC or stress, what justifies the utilization of these drugs in the treatment of neurodegenerative disorders [4, 35]. Finally, antipsychotic drugs, both conventional and atypical ones, are able to diminish circulating levels of GC in patients with schizophrenia [50]. Pharmacotoxicology of drugs of abuse

Previously, we have identified the important role of GC and CA in the mechanisms of action of practically all drugs of abuse [18]. In this sense, of great interest are the data that confirm the capacity of proteinkinase A activators (such as derivatives of cyclic AMP) to augment GR function [2, 37], what may explain the interaction of GC with phosphodiesterase inhibitors, including caffeine. By the way, this suggests the possibility of interactions of drugs that have a participation of GC in their mechanisms of action with some products containing caffeine.

Pharmacotherapy of cardiometabolic diseases

Since GC participate in pathogeny of hypertension and insulin resistance [19], the data were retrieved on their contribution to the action of drugs used for treatment of metabolic syndrome and its components. In this sense, it is well established that GC potentialize vasoactive responses to CA and angiotensin II [53, 56], what justifies the use of sympatholytic agents (e. g., beta-blockers) and angiotensin II antagonists (inhibitors of angiotensin-converting enzyme and antagonists of AT1 receptors) in the treatment of hypertension. On the other hand, tiazolidinediones («glitazones»), the hypoglycemic agents used to treat diabetes mellitus type 2, are able to inhibit the enzyme 11beta-hydroxysteroid — dehydrogenase type 1 that converts inactive cortisone to cortisol, improving in this mode the sensitivity to insulin [47, 54]. By the way, some benzodiazepines (BZD, e.g., alprazolam) can affect favourably the treatment of diabetes mellitus type 2, since they improve the tolerance to glucose, probably in relation to their capacity for diminution of circulating levels of GC [48].

The question of hormesis

Logically a question emerges: if GC are so important in pathogeny of age-related diseases and in mechanisms of action of drugs used for their treatment, then, why GC or their antagonists are not so much utilized for the same aim? Exactly here the aspect of hormesis enters. This term was proposed for description of a capacity of various bioregulators and toxic substances to create biphasic dose-response curves, i.e. of «U» shape, inverted or not [5]. In fact, both the total absence of GC (via adrenalectomy) and their excess are harmful for the memory, principally, on the level of hippocampus. In the case of GC this capacity is explained by their binding to the two types 50

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between the principal advances of gerontology. In fact, it is suggested that chronic stress provokes premature aging via shortening of telomeres [11]. By the way, GC are able to inhibit telomerase activity in lymphocytes [6]. However, there exist a lot of doubts and questions to be resolved, including the links between stress and GC, telomeres and telomerase, aging and age-related diseases. Besides, we would like to attract the attention of researchers to the possibility of pharmacotoxicologic programming / imprinting [20], when the use of drugs or toxic substances in perinatal period can provoke unfavourable consequences in long term, up to the senescence. We have analyzed this phenomenon principally for GC [15]. However, if various drugs and toxic substances have a participation of GC in their mechanisms of action, then we should reconsider also their use in critical periods of development, such as periconceptional, perinatal and even adolescent one. This is especially important for drugs of abuse, considering the use of alcohol and tobacco during pregnancy and lactation. Fortunately, as referred to perinatal treatment with GC, the doubts are growing more and more about its adequacy (see [19]), especially, in relation to long-term consequences.

of receptors, of mineralocorticoids — MR and GR [31]. Therefore, although inhibitors of GC biosynthesis (methyrapone, aminoglutetimide, ketoconazol) and GC antagonist (mifepristone or RU 486) have found some usage in the treatment, e.g., of depression [4], this progress is quite small yet, perhaps, just because of hormesis. Biorhythms of stress hormones

Another important aspect that should be considered in age-related pharmacotherapy is chronobiologic question. Really, GC demonstrate circadian and ultradian rhythms and participate in the regulation of other biorhythms as synchronizing agents [9, 22]. On our opinion, a therapy with drugs that have a participation of GC in their mechanisms of action, should be adjusted also in accord to the principles of chronopharmacology, especially, if these drugs are used for treatment during years and even decades, as is the case of anti-hypertensives and oral hypoglycemic agents, AD and BZD. Neuroimmunoendocrine interactions

Generally, it is considered that human body contains three regulatory systems: nervous, endocrine and immune. It is important that GC occupy central positions in controlling all these three systems. However, today it is not completely clear, how GC participate in the neuroimmunoendocrine interactions [32]. We expect that the revelation of the role of GC and other stress hormones in the mechanisms of action of drugs used for the treatment of age-related diseases can help to clarify this rather complex aspect, especially, as referred to the interactions of GC with cytokines (interleukins, adipokines, etc.), as well as from the point of view of biorhythmology (see [19]).

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Conclusion

Here we would like to propose again a caution in considering GC as hormones of principal importance in aging. We expect that in near future greater progress may occur in mathematical, theoretical and computational modeling, as referred to the role of GC and stress in aging and in the ontogeny as a whole. In this sense, we would like to note that the first theoretical achievement in relation to telomeres was made by Russian researcher A.M. Olovnikov already in 1971 (see the discussion in [7]). Today, experimental studies of telomeres and telomerase are 51

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УСПЕХИ ГЕРОНТОЛОГИИ • 2011 • Т. 24 • № 1 Успехи геронтол. 2011. Т. 24. № 1. С. 48–53

В. И. Гудошников РОЛЬ ГЛЮКОКОРТИКОИДОВ ПРИ СТАРЕНИИ И В ВОЗРАСТЗАВИСИМОЙ ФАРМАКОТЕРАПИИ Членство Международного общества DOHaD, г. Санта-Мария, штат Риу-Гранди-ду-Сул, Бразилия; e-mail: [email protected] Недавно мы оценили роль глюкокортикоидов (ГК) и других гормонов стресса в патогенезе возрастзависимых заболеваний. Чтобы провести эту оценку, мы имели в виду парадигму DOHaD, которая обсуждает отдаленные последствия влияния неблагоприятных перинатальных факторов. В настоящей работе часть данных, собранных ранее, была использована для анализа роли ГК при старении, а также в возрастзависимой фармакотерапии. Информация былa собранa в ряде банков данных, преимущественно на английском языке, за последние 25–30 лет. Хотя некоторые авторы полагают, что ГК могут считаться гормонами старения, все же большинство исследователей весьма осторожны в этом плане. Тем не менее, похоже на то, что вполне установлена роль ГК на разных стадиях онтогенеза и в переходах между ними. Кроме того, имеется множество данных, подтверждающих вклад ГК в явления перинатального импринтинга/программирования болезней у взрослых. Что касается взаимосвязи ГК и старения, то некоторые работы подтверждают ее существование, по крайней мере отчасти. Анализируя динамику заболеваемости и смертности, вызванных возрастзависимыми расстройствами, мы сделали вывод об отсутствии свидетельств в пользу одной единственной, общей схемы старения, где ГК могли бы играть свою роль. Однако в достаточно парадоксальной манере было показано, что ГК принимают участие, по крайней мере непрямо, в механизмах действия ряда лекарств, используемых для лечения кардиометаболических расстройств (бета-блокаторы, антагонисты ангиотензина, отдельные гипогликемические агенты перорального применения) и нейропсихиатрических заболеваний (антидепрессивные, противопсихозные препараты, бензодиазепиновые агенты и отдельные противосудорожные лекарства), а также в эффектах токсических веществ (например, наркотических и злоупотребляемых соединений, включая кофеин). Используя концепцию гормеза, мы обсуждаем причины использования именно этих лекарств, а не ГК, либо их антагонистов в возрастзависимой фармакотерапии. Нужно с осторожностью относиться к попыткам придания ГК главной роли при старении. Тем не менее, ввиду существования теории, которая связывает ГК со старением через механизмы аллостаза, мы планируем разработать более детальную модель, которая могла бы включать, помимо ГК, некоторые другие гормоны, цитокины и другое, а также их взаимодействия. Подчеркивается, что взаимодействия ГК с другими биорегуляторами должны быть повторно оценены с хронобиологической точки зрения с тем, чтобы укрепить основы хронофармакотерапии. Одной из главных проблем является предупреждение неблагоприятных эффектов фармакотерапии в долгосрочном плане. В этом отношении, парадигма DOHaD открыла дискуссию о возможности фармакотоксикологического импринтинга/программирования, то есть важного вопроса, привлекающего внимание исследователей. Ключевые слова: глюкокортикоиды, импринтинг/программирование, лекарства, развитие, старение

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