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Potential mechanisms of the age-related changes in the blood-brain barrier
Neurobiologyof Aging,Vol. 15, No. 6, p. 769, 1994 Copyright© 1994ElsevierScienceLtd Printedin the USA.All rightsreserved 0197-4580/94$6.00 + .00
Pergamon 0197-4580(94)00081-6
AUTHOR'S RESPONSE TO COMMENTARIES
Potential Mechanisms of the Age-Related Changes in the Blood-Brain Barrier ARSHAG D. MOORADIAN
St. Louis V.A. Medical Center and the Division of Endocrinology, Department of Internal Medicine, St. Louis University Health Sciences Center, St. Louis, MO 63104 THE LITERATURE ON the age-related changes in the bloodbrain barrier (BBB) is still in its infancy. Several questions still remain unanswered. The potential interdependence of aging brain and aging BBB emphasized by Rapoport (7) is an intriguing concept that requires additional experimental data. It is likely that with the refinement in techniques of estimating transport kinetics and with the recent advances in molecular biology techniques there will be significant strides made in our understanding of the role of the BBB in aging central nervous system (CNS). Some of the experiments that are likely to yield useful information as to the molecular basis of the age-related changes in BBB transport are described by Friden. (2) However, heterogeneity of microvessel preparations as pointed out by Kalaria (3) has to be borne in mind. Whereas this problem can be attenuated by careful preparation of the microvessels with use of glass beads, and monitoring of other markers of cerebral microvessels in various age groups, the problem of heterogeneity in the aging population is more difficult to circumvent. This is even more of a limitation in human studies. In addition, the age-related differences are often difficult to distinguish from those that are secondary to diseases commonly occurring in aging. The availability of reliable and quantifiable biomarkers of aging would at
least hypothetically help eliminate the problem of heterogeneity in the aging groups (5,6). However, as Klein and Hackler (4) indicate some diseases of the CNS may augment the age-related changes in the BBB and thereby help unmask some of the subtle changes that would have gone unnoticed in healthy elderly subjects. Tuomanen suggests that the age-related changes in the BBB plays a role in the susceptibility of the brain to bacterial infections (8). Although not emphasized in Table 1 provided by Tuomanen, it is noteworthy that in the elderly, the bacterial etiology of meningitis closely resembles that of neonates (9). Thus, it appears that following a maturational decline in susceptibility to meningitis the susceptibility of the brain to pathogens especially those commonly found in neonatal infections increases with further senescence. This is in agreement with the hypothesis suggested by Tuomanen (8). Most of the current studies on age-related changes in the BBB are limited to the animal model. As pointed out by Kalaria (3), Klein and Hackler (4), Rapaport (7) and Bradbury (1) studies in animal models can not necessarily be extrapolated to human subjects. Nevertheless, considering the current technical limitations of the studies in humans, the observations in animal models provide invaluable insights into the various facets of aging BBB.
REFERENCES 1. Bradbury,M. W. R. Potentialmechanismsof the age-relatedchanges in the blood-brain barrier. NeurobiolAging 15:767; 1994. 2. Friden, P. M. Commentaryon potentialmechanismsof the age-related changes in the bltxxi-brainbarrier. NeurobiolAging 15:761-762; 1994. 3. Kalaria, R. N. The brain microvasculaturein aging. NeurobiolAging 15:765-766; 1994. 4. Kieine, T. O.; Hackler, R. Age-related changes in the blood-brain barrier of humans. NeurobiolAging 15:763-764; 1994. 5. Mooradian, A. D. Biomarkers of aging: Do we know what to look for. J. Gerontol. Biol. Sci. 45:B183-186; 1990.
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6. Mooradian, A. D. The biological and functional definition of older patient. The role of biomarkers of aging. Oncology 6 (Suppl. 2): 39--44; 1992. 7. Rapoport, S. I. Aging and the blood-brain barrier: Commentary. Neurobiol Aging 15:759--760;1994. 8. Tuomanen, E. Susceptibilityto infection and age-related changes in the blood-brain barrier. NeurobiolAging 15:757-758; 1994. 9. YoshikawaT. T.; Norman, D. C. Aging and clinical practice: Infectious diseases diagnosisand treatment. New York: Igaku-ShoinMedical Publishers, Inc; 1987: 90-107.
Pergamon 0197-4580(94)00081-6
AUTHOR'S RESPONSE TO COMMENTARIES
Potential Mechanisms of the Age-Related Changes in the Blood-Brain Barrier ARSHAG D. MOORADIAN
St. Louis V.A. Medical Center and the Division of Endocrinology, Department of Internal Medicine, St. Louis University Health Sciences Center, St. Louis, MO 63104 THE LITERATURE ON the age-related changes in the bloodbrain barrier (BBB) is still in its infancy. Several questions still remain unanswered. The potential interdependence of aging brain and aging BBB emphasized by Rapoport (7) is an intriguing concept that requires additional experimental data. It is likely that with the refinement in techniques of estimating transport kinetics and with the recent advances in molecular biology techniques there will be significant strides made in our understanding of the role of the BBB in aging central nervous system (CNS). Some of the experiments that are likely to yield useful information as to the molecular basis of the age-related changes in BBB transport are described by Friden. (2) However, heterogeneity of microvessel preparations as pointed out by Kalaria (3) has to be borne in mind. Whereas this problem can be attenuated by careful preparation of the microvessels with use of glass beads, and monitoring of other markers of cerebral microvessels in various age groups, the problem of heterogeneity in the aging population is more difficult to circumvent. This is even more of a limitation in human studies. In addition, the age-related differences are often difficult to distinguish from those that are secondary to diseases commonly occurring in aging. The availability of reliable and quantifiable biomarkers of aging would at
least hypothetically help eliminate the problem of heterogeneity in the aging groups (5,6). However, as Klein and Hackler (4) indicate some diseases of the CNS may augment the age-related changes in the BBB and thereby help unmask some of the subtle changes that would have gone unnoticed in healthy elderly subjects. Tuomanen suggests that the age-related changes in the BBB plays a role in the susceptibility of the brain to bacterial infections (8). Although not emphasized in Table 1 provided by Tuomanen, it is noteworthy that in the elderly, the bacterial etiology of meningitis closely resembles that of neonates (9). Thus, it appears that following a maturational decline in susceptibility to meningitis the susceptibility of the brain to pathogens especially those commonly found in neonatal infections increases with further senescence. This is in agreement with the hypothesis suggested by Tuomanen (8). Most of the current studies on age-related changes in the BBB are limited to the animal model. As pointed out by Kalaria (3), Klein and Hackler (4), Rapaport (7) and Bradbury (1) studies in animal models can not necessarily be extrapolated to human subjects. Nevertheless, considering the current technical limitations of the studies in humans, the observations in animal models provide invaluable insights into the various facets of aging BBB.
REFERENCES 1. Bradbury,M. W. R. Potentialmechanismsof the age-relatedchanges in the blood-brain barrier. NeurobiolAging 15:767; 1994. 2. Friden, P. M. Commentaryon potentialmechanismsof the age-related changes in the bltxxi-brainbarrier. NeurobiolAging 15:761-762; 1994. 3. Kalaria, R. N. The brain microvasculaturein aging. NeurobiolAging 15:765-766; 1994. 4. Kieine, T. O.; Hackler, R. Age-related changes in the blood-brain barrier of humans. NeurobiolAging 15:763-764; 1994. 5. Mooradian, A. D. Biomarkers of aging: Do we know what to look for. J. Gerontol. Biol. Sci. 45:B183-186; 1990.
769
6. Mooradian, A. D. The biological and functional definition of older patient. The role of biomarkers of aging. Oncology 6 (Suppl. 2): 39--44; 1992. 7. Rapoport, S. I. Aging and the blood-brain barrier: Commentary. Neurobiol Aging 15:759--760;1994. 8. Tuomanen, E. Susceptibilityto infection and age-related changes in the blood-brain barrier. NeurobiolAging 15:757-758; 1994. 9. YoshikawaT. T.; Norman, D. C. Aging and clinical practice: Infectious diseases diagnosisand treatment. New York: Igaku-ShoinMedical Publishers, Inc; 1987: 90-107.