The effects of aging on the immune system are widespread and extend from hematopoietic stem cells and lymphoid progenitors in the bone marrow and thymus to mature lymphocytes in secondary lymphoid organs. These changes combine to result in a diminution of immune responsiveness in the elderly. This review aims to provide an overview of age-related changes in lymphocyte development and function and discusses current controversies in the field of aging research.

Age-related changes in lymphocyte development and function

In humans, both aging and GH deficiency are associated with reduced protein synthesis, decreased lean body and bone mass, and increased percent body fat. In healthy individuals, spontaneous and stimulated GH secretion, as well as circulating IGF-I and IGFBP-3 levels, are significantly decreased with advancing age. The extent to which these age-related changes in GH and IGF-I contribute to alterations in body composition and function remains to be elucidated. GH treatment of GH-deficient adults or old men with reduced IGF-I levels with exogenous GH increases plasma IGF-I, nitrogen retention, and lean body mass, decreases percent body fat, and exerts little effect on bone mineral density. Short-term adverse effects of GH therapy have been minimized by using low-dose regimens, but it is still uncertain whether long-term GH supplementation in adult life increases the risk of metabolic abnormalities or malignancy. Administration of GHRH, which has been shown to maintain the pattern of pulsatile GH secretion in old men, may represent another possible physiological approach to therapy. It may be justifiable initially to limit use of GH to certain elderly patients such as those suffering from catabolic illnesses, malnourishment, burns, cachexia, etc. A great deal more research will be necessary to determine whether normalization of GH and IGF-I levels in healthy older persons will lead to improvements in their physical and psychological functional capacity and quality of life.

Human Growth Hormone and Human Aging

It is now becoming apparent that the immune system undergoes age-associated alterations, which accumulate to produce a progressive deterioration in the ability to respond to infections and to develop immunity after vaccination, both of which are associated with a higher mortality rate in the elderly. Immunosenescence, defined as the changes in the immune system associated with age, has been gathering interest in the scientific and health-care sectors alike. The rise in its recognition is both pertinent and timely given the increasing average age and the corresponding failure to increase healthy life expectancy. This review attempts to highlight the age-dependent defects in the innate and adaptive immune systems. While discussing the mechanisms that contribute to immunosenescence, with emphasis on the extrinsic factors, particular attention will be focused on thymic involution. Finally, we illuminate potential therapies that could be employed to help us live a longer, fuller and healthier life.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2567.2007.02555.x

Immunosenescence: emerging challenges for an ageing population

The skin is a known target organ for the proopiomelanocortin (POMC)-derived neuropeptides alpha-melanocyte stimulating hormone (alpha-MSH), beta-endorphin, and ACTH and also a source of these peptides. Skin expression levels of the POMC gene and POMC/corticotropin releasing hormone (CRH) peptides are not static but are determined by such factors as the physiological changes associated with hair cycle (highest in anagen phase), ultraviolet radiation (UVR) exposure, immune cytokine release, or the presence of cutaneous pathology. Among the cytokines, the proinflammatory interleukin-1 produces important upregulation of cutaneous levels of POMC mRNA, POMC peptides, and MSH receptors; UVR also stimulates expression of all the components of the CRH/POMC system including expression of the corresponding receptors. Molecular characterization of the cutaneous POMC gene shows mRNA forms similar to those found in the pituitary, which are expressed together with shorter variants. The receptors for POMC peptides expressed in the skin are functional and include MC1, MC5 and mu-opiate, although most predominant are those of the MC1 class recognizing MSH and ACTH. Receptors for CRH are also present in the skin. Because expression of, for example, the MC1 receptor is stimulated in a similar dose-dependent manner by UVR, cytokines, MSH peptides or melanin precursors, actions of the ligand peptides represent a stochastic (predictable) nonspecific response to environmental/endogenous stresses. The powerful effects of POMC peptides and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis. Hence, cutaneous expression of the CRH/POMC system is highly organized, encoding mediators and receptors similar to the hypothalamic-pituitary-adrenal (HPA) axis. This CRH/POMC skin system appears to generate a function analogous to the HPA axis, that in the skin is expressed as a highly localized response which neutralizes noxious stimuli and attendant immune reactions.

Corticotropin Releasing Hormone and Proopiomelanocortin Involvement in the Cutaneous Response to Stress

IN VERTEBRATES, four major systems of intercellular communication exist: the neural, the endocrine, the neuroendocrine, and the immune system. For many years evidence has accumulated linking the neural, the endocrine, and the neuroendocrine systems, but the immune system was often viewed as essentially autonomous. The enormous recent increase in our knowledge of how the immune system is regulated has led many scientists to postulate that this autonomy may be more apparent than real: that the immune system is subject to endocrine and neural control, and that it exerts, in turn, a reciprocal effect on neuroendocrine systems. In this review we intend to examine the interactions between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis. In the first part of the review we will discuss products and components from the immune system that stimulate or inhibit the HPA axis. These include monokines and lymphokines, i.e. the regulatory secretions of the immune system, and other peptides such as ACT...

The immune-hypothalamic-pituitary-adrenal axis.

Thymic size and T-cell function decrease with age, and it has not yet been possible to totally reverse this thymic atrophy and completely restore T-cell-dependent immune functions. In this study, GH3 pituitary adenoma cells, which secrete growth hormone and prolactin, were implanted subcutaneously into 16- and 22-month-old female Wistar-Furth rats and the rats were sacrificed approximately 2 months later. Only thymic remnants were detected in aged, non-implanted rats, but thymus glands were found in both the 18- and the 24-month-old rats that had been implanted with GH3 cells. Thymus glands from the GH3-implanted 18-month-old rats contained distinct cortical thymocytes and medullary epithelial cells. Depending on the concentration of phytohemagglutinin or concanavalin A, T-cell proliferative responses of splenocytes from these implanted rats were 2- to 5-fold greater than those of 18-month-old controls. At the optimal concentration of mitogen, proliferative responses to either lectin could be restored to those levels observed in splenocytes from 3-month-old Wistar-Furth females. Thymus glands from 24-month-old GH3-implanted rats contained more cortical thymocytes and fewer fat vacuoles than controls, but they were not totally reconstituted. No significant lectin-induced T-cell proliferative responses or IL-2 secretion were detected in 24-month-old control rats, but splenocytes from GH3-implanted rats showed augmented T-cell proliferative responses and increased synthesis of IL-2. Fluorescence-activated cell-sorter analysis of thymocytes revealed that 24-month-old rats implanted with GH3 cells had a higher proportion of lymphocytes with the Thy-1.1 and helper-T-cell phenotypes. These data show that it is possible to regenerate normal thymic tissue in situ and reverse the natural loss in cell-mediated immunity that occurs with aging.

https://www.pnas.org/content/pnas/83/15/5663.full.pdf

GH3 pituitary adenoma cells can reverse thymic aging in rats

Infection of murine splenocytes with Newcastle disease virus results in expression of the proopiomelanocortin gene as determined by dot and northern blot analysis of total cellular and poly(A)+ cytoplasmic RNA. These data provide the first evidence that the precursor protein for adrenocorticotropin and beta-endorphin can be synthesized by lymphoid cells.

https://rupress.org/jem/article-pdf/163/6/1589/1095957/1589.pdf

Newcastle disease virus-infected splenocytes express the proopiomelanocortin gene.

Mild restraint of the domestic pig (Sus scrofa) caused activation of the hypothalamic–pituitary–adrenal axis, atrophy of the thymus gland, and a significant reduction in cell-mediated, delayed-type hypersensitivity reactions. Physiologic concentrations of cortisol suppressed, in vitro, phytohemagglutinin- and concanavalin A-induced proliferation of porcine thymocytes, splenocytes, and peripheral blood mononuclear cells, even though cortisol was only mildly cytolytic. These results extend the concept of an endocrine influence on regulation of cell-mediated immune events to species other than humans and rodents.

Physiologic Concentrations of Cortisol Suppress Cell-Mediated Immune Events in the Domestic Pig

The elderly human population has an increased incidence of respiratory, neoplastic, arthritic and cardiovascular disease.',' I t is generally believed that this increase in disease is related to aberrations that occur in immunoregulation of aged individual^.^ It is well known that thymic size and T-cell function decline with age, but it has not yet been possible to totally reverse this thymic atrophy and completely restore Tdependent immune functions in aged individuals.

Hollie J. Westly

Papers

GH3 pituitary adenoma cells can reverse thymic aging in rats

Newcastle disease virus-infected splenocytes express the proopiomelanocortin gene.

Physiologic Concentrations of Cortisol Suppress Cell-Mediated Immune Events in the Domestic Pig

Hormonal Regulation of the Age‐Associated Decline in Immune Function

The postulated lymphoid-adrenal axis. A molecular approach.