Report: Aging and frailty

We hypothesize that the decreased energy available to cells as a result of deficiencies of DNA repair with increasing age may be associated with the development of frailty (5). This may occur through several pathways, at least: decreased lean body mass , muscle function and strength; and decreased oxygen consumption. The hypothesized pathway can be depicted as in the scheme at page 254. REFERENCES 1. Athas W.F., Hedayati M.A., Matanoski G.M., Farmer E.R , Grossman L.: Development and filed-test validation of an assay for DNA repair in circulating human lymphocytes . Can cer Res . 51 : 5786, 1991. 2. Grossman L.: Repair of damaged DNA. In: DulbeccoR (Ed.), Encyclopedia of Human Biology , Vol. 6. Academic Press, Inc., New York , 1991, pp . 547-554. 3 . Friedberg E.C. : DNA Repair. Freem an , New York, 1985. 4 . Setlow RB .: Variations in DNA repair among people. In: Castellani E. (Ed.), Epidemiology and Quantitation of Environmental Risk in Humans from Radiation and other agents. Plenum Press, New York, 1985, pp . 205-212. 5 . Fried L.P., Williamson J ., Kasper J .: The Epidemiology of Frailty: The Scope of the Problem. In: Coe RM. , Perry H.M. III (Eds.), Aging, Musculoskeletal Disorders and Care of the Frail Elderly. Springer Publishing Co. , New York, 1992 (in press).

Relationship between the immune system and frailty: Pathogenesis of immune deficiency in HIV infection and aging J.B. Margolick and R.K. Chopra

Department of Environmental Health Sciences, Johns Hopkins University , School of Public Health, Baltimore, Maryland , U.S.A. There are several reasons for postulating that study of the immune system could provide insight into the mechanisms and definitions of frailty.

First, the immune system has long been known to decline with aging. Aging is associated with an increased incidence of cellular and humoral immune deficiency, as well as many other examples of both cellular and humoral immune dysregulation, such as monoclonal gammopathy, elevations in certain serum immunoglobulins and autoantibodies, and increased risk of reactivating latent infections (1). For this reason, the first surveillance definition of AIDS included the stipulation that age > 60 years excluded the diagnosis of AIDS. Second , because the immune system has the potent ability to kill unwanted organisms and cells, it is apparent that a defect in this function , either too little or too much , could predispose to, or even cause, the tissue damage that presumably underlies the development of frailty in the elderly. Third , the immune system represents an accessible model for analysis of heterogeneous cell populations that might reflect pari passu changes occurring in other, less accessible cell populations in the body as a function of aging. Unfortunately , despite the rapid and profound advances that have occurred in immunology in recent years , the biological mechanism of immunological decline with aging remains un known. In particular, prospective data on immunological change with aging are scarce , and it is not known whether immunological changes with aging bear any relationship to the development of frailty . However, an intriguing line of evidence , based on cross-sectional studies, suggests that aging may be characterized by an accumulation of T lymphocytes in the peripheral blood that respond poorly to conventional T cell stimuli, such as phytohemagglutinin (PHA), in terms of the normal T cell functions of proliferation and lymphokine production (2). Despite their reduced responsiveness to PHA, however, these cells have not lost the capacity to generate these responses, because proliferation and lymphokine production were indistinguishable from those of lymphocytes from young individuals when the stimulus used was phorbol myristate acetate (PMA) in combination with the calcium

Key words : Aging, AIDS. immune system , T lymphocytes. Corresponden ce: Joseph B. Margolick, M.D., Ph .D., Departm ent of Environm ental Health Sciences , The Johns Hopkins School of Hygiene and Public Health , 615 North Wolfe Street, Room 7032, Baltimore, MD 2 1205, U.S.A.

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ionophore A23187. Since PHA stimulates T cells through cell surface receptor molecules, and PMA and calcium ionophore act directly via intracellular signalling pathways (activation of protein kinase C and internalization of extracellular calcium), these results suggest that the T cells of elderly individuals have a reduced ability to transduce signals across the plasma membrane . Interestingly, a similar decrease in the ability of T lymphocytes to respond to PHA was also described in individuals with AIDS. Highly purified lymphocytes of both of the major T cell subsets, i.e. , CD4+ and CD8+ T cells, showed a reduction of approximately 85% in the proportion of cells that could proliferate to form colonies when compared to similarly purified T cells from immunologically normal subjects (3). The proportion of lymphocytes that could respond to the T cell growth factor IL-2 was also reduced (3,4). Further studies using cells purified by cell sorting have indicated that among the CD8 lymphocytes from individuals with AIDS, this decrease in responsiveness to PHA was greater among lymphocytes also expressing HLA-DR molecules on their surface (5). This CD8+HLA-DR+ phenotype is of ambiguous functional meaning , in that HLA-DR is expressed by both activated T cells and developing T cells. In AIDS as in aging, the basis for the reduced proliferative response of T lymphocytes is not known . The reduced proliferative function of T lymphocytes in individuals with AIDS appears to be an intrinsic property of the cells themselves, since it is present in single cells, and our preliminary studies indicate that it cannot be accounted for on the basis of alterations in expression of receptors for growth factors, such as IL-2, or by overproduction of inhibitory cytokines , such as transforming growth factor-B. However, it should be emphasized that these cells may not be inherently abnormal or defective , but may simply represent an increase in cells that are normally present only in very small numbers. However this may be, the similarity between the decrease in lymphocyte responsiveness in AIDS, which is characterized by a profound immune deficiency, and that in aging , which is characterized by a much milder immune deficit, suggests that T lymphocytes with reduced proliferative potential may be produced in response to challenge of the hu-

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man immune system . In AIDS, the challenge would be the loss of CD4 lymphocytes due to the infection with HIV-1, which is tropic for these cells. In aging, the challenge would presumably be related to accumulating damage to circulating lymphocytes or to progenitor cells. The cause of the damage remains to be determined, but changes in DNA or DNA repair, or in scavenging of reactive oxygen species, for example, would be possibilities. Thus, the lymphocytes that respond poorly to PHA may represent the accumulated impairment in the ability of the immune system to produce new , fully mature lymphocytes. Of course, the immune system is wellknown to produce inflammatory substances toxic to other cells and can itself mediate damage to normal tissues. Thus, analysis of immune functioning in elderly or aging populations could shed light on the causation of frailty: 1) the immune system is part of the mechanism of development of frailty; or 2) the immune system itself develops a form of frailty which mirrors or correlates to the overall development of frailty as clinically evident in the patient. For example, it is possible that the accumulation of non-responsive T cells could be a reflection of subtle damage to the immune system , and that it could provide a way of quantitating frailty in a general way. In order to test this hypothesis, it will be necessary to analyze the functional responses of individual lymphocytes to a variety of potential stimuli. Although difficult, this is technically feasible using current immunological methods , such as flow cytometry and gene amplification, that provide detailed information about the properties of single cells.

REFERENCES 1. Finkelstein M.S.: Aging immunocytes and immunity. Clin. Geriatric Med . 1: 899-911 ,1985. 2 . Chopra R.K. : Mechanisms of impaired T cell function in the elderly. Review of Biological Research in Aging 4: 83-104,1990. 3 . Margolick J .B., Volkman D.J ., Lane H.C., Fauci A.S.: Clonal analysis of T lymphocytes in the acquired immunodeficiency syndrome: Evidence for an abnormality affecting individual helper and suppressor T cells. J. Clin . Invest . 76 : 709-715, 1985. 4 . Donnenberg A.D., Margolick J .B., Polk B.F.: Limiting dilution analysis in vivo-activated (IL-2 responsive) pe-

Report: Aging and frailty

ripheral blood lymphocytes in HIV-I-infected subjects. Clin. lmmunol. lmmunopathol. 51 : 91 -98 ,1989. 5. Pantaleo G., Koenig 5. , Baseler M., Lane H.C , Fauci A.S.: Defective clonogenic potential of CD8+ T lymphocytes in patient s with AIDS. J. Immunol. 144: 1696-1704, 1990.

Growth hormone, IGF-I, gonadal steroids, and aging S.M. Harman and M.R. Blackman Gerontology Research Center, NIA, and Departments of Medicine Francis Scott Key Medical Center and Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Recent evidence has suggested that age-related deficits in muscle strength , gait and balance may be more reversible than had previously been suspected (1). It has been well demonstrated that the progressive loss of bone mineral, which leads to osteopenia and an increased risk of fractures in older women , is strongly related to the estrogen deficiency characteristic of the postmenopause , and can be prevented by prophylactic estrogen replacement. In men , there is a downward trend in mean testosterone levels with aging , but no sharp loss of steroid hormone secretion comparable to that seen at menopause. The contribution of androgen deficiency to bone loss in men, and of the decreases in sex steroid levels in both sexes to age-related alterations in tissues other than bone which could lead to frailty, have not been well explored. More recently, it was suggested that decreases in nonsteroid hormones, growth hormone (GH) and its "second messenger" insulin-like growth factor-I (IGF-I), may also contribute to the syndrome of somatic aging. In particular, it was shown that GH treatment mitigates deleterious changes in body composition in both GH-deficient young adults, and in normal elderly persons with low IGF-I levels (2). Thus the model , derived from clinical

experience with estrogens may have wider ap plication than heretofore appreciated. In particular, the role of androgen replacement in older men , and the interactions of both estrogens and androgen treatment with GH replacement therapy remain to be explored. Until recently, the lack of efficacy in humans of animal-derived (e.g., bovine or porcine) GH , and the limited supply of human cadaveric GH , restricted use of exogenous GH to treatment of GH-deficient children. The availability of recombinant human GH (rhGH) led to a renewal of scientific and clinical interest in investigating wider indications for GH administration. Pituitary GH secretion is modulated by two hypothalamic peptides; growth hormone releasing hormone (GHRH), which stimulates, and somatostatin, which inhibits, GH release. Most of the peripheral tissue effects of GH are mediated by IGF-I which is produced in response to GH at various tissue sites. In turn, IGF-I exerts feedback inhibitory effects on GH secretion. Circulating IGF-I is mainly produced in the liver, and its blood level correlates well with 24-hour integrated serum GH values in young adults. However, IGF-I produced within GH-responsive peripheral tissues also acts locally to mediate tissuespecific GH effects. IGF-I exists in blood and tissue both free and complexed to one or more of six known IGF-I binding proteins (lGF-BP's). Evidence suggests that the IGF-BP's modulate the bioavailability and action of IGF-I, but exactly how is as yet unknown . Thus, because of IGF-I's local (paracrine) activity and the role of IGFBP's , serum IGF-I levels do not completely account for, and may not always be an accurate index of IGF-I tissue effects. GH is normally secreted in rhythmic pulses, with highest frequency and amplitude at onset of slow wave sleep; random single blood samples do not adequately reflect 24-hour GH secretory rates. Serial blood sampling showed reduced GH secretion in older persons, and decreased amplitude of spontaneous nocturnal GH pulses (3). Responses of GH to indirect stimuli, such as

Key words : Aging, gonadal steroids, growth hormone, IGF-L Correspondence: S. Mitchell Harman, M.D., Ph.D., Chief of Endocrinology, N.LH. - N.LA , Gerontology Research Center , 4940 Eastern Avenue, Room 2B20, Baltimore , MD 21205, U.S.A.

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Relationship between the immune system and frailty: pathogenesis of immune deficiency in HIV infection and aging.

Report: Aging and frailty We hypothesize that the decreased energy available to cells as a result of deficiencies of DNA repair with increasing age m...
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