Journal i>l (U'ronlold.vv 1979. Vol. 34. No. 5. 642-650

E. M. Burns, PhD,2 T. W. Kruckeberg, MS,2 L. E. Comerford, BS, 2 and MB. T. Buschmann, PhD3 Samples were obtained from the frontal and occipital cortex of Macaque monkeys at 4, 10 and 20 years of age. Electron microscopic studies revealed attenuation of capillary walls and declining numbers of endothelial mitochondria per capillary profile with increasing age. The basal lamina surrounding the capillary increased in thickness between 4 and 10 years of age; however, it did not undergo further change between 10 and 20 years. These results corroborate morphological and biochemical studies indicative of declining numbers of mitochondria, and decreasing mitochondrial ATP synthesis and ATPase activity in other tissues during aging.

y HERE have been a number of studies A dealing with changes in cerebral microvasculature with increasing age, most of which were focussed on maturational changes occurring during early postnatal life. Schwink and Wetzstein (1966) reported thinning of capillary walls in the subcommissural organ in the rat with increasing age, from birth through 18 months. Bar (1978) performed a morphometric evaluation of capillaries in the various layers of the cerebral cortex of rats during development and aging. He found that the mean diameter of the capillary lumen showed no change between 6 and 23 months of age, however decreased between 23 and 30 months, whereas the mean length of microvessels per unit volume increased with age. He noted also a decrease in the number of endothelial cells with increasing age and suggested that endo1 Supported in part by grants PHSNU 1548-03, 8TO63078 & PHSNU 500-3 (H. Werley, P.I., Univ. of Illinois Medical Ctr., Chicago) and by NIH grants RR00166 and AG62145 (D. M. Bowden, P. I., Univ. of Washington, Primate Ctr., Seattle, WA). We wish to thank Michael J. Huns, Micro Measurements, Inc., Burlington, MA, for providing access to the Optomax for this study and Janet N. Meyer for illustrations. 2 Dept. of General Nursing, College of Nursing, Univ. of Illinois Medical Ctr., Chicago, IL 60612 and Dept. of Research, Mercy Medical Ctr., Chicago, IL 60616. •'Dept. of General Nursing, College of Nursing and Dept. of Anatomy, School of Basic Medical Sciences, Univ. of Illinois Medical Ctr., Chicago, IL 60612.

642

thelial cell loss with aging may be compensated in part by elongation of remaining cells. Cerebral capillaries comprise a major portion of the blood-brain barrier (BBB), a bloodto-brain interface that regulates capillary tissue exchange. Cerebral capillaries are characterized by the presence of tight junctions (zonulae occludens, less than 2 nm in width) between contiguous cells, the absence of endothelial pores and paucity of pinocytotic vesicles (Reese & Karnovsky, 1967) and a several-fold increase in the numerical density of endothelial mitochondria as compared with capillaries from other regions of the body (Oldendorf & Brown, 1975; Oldendorf, et al., 1977). The greater work capability of the cerebral capillary, as compared with the non-barrier type capillary, is thought to be related to active transport across the BBB. The occurrence of active transport at the cerebral capillary has not been clearly established in vivo. Goldstein (1978), utilizing isolated brain capillaries, showed that active transport of Rubidium-86 (an analog of potassium with essentially identical transport properties in mammalian cells as potassium) does occur, the direction of transport being from the interstitial surface of the capillary into its lumen.

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

Thinning of Capillary Walls and Declining Numbers of Endothelial Mitochondria in the Cerebral Cortex of the Aging Primate, Macaca Nemestrina1

AGING CAPILLARY END0THEL1AL MITOCHONDRIA

643

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

A number of studies implicate the mitochon- continuously occurring in the central nervous drion as an important subcellular organelle for system. For example, K+ concentration in aging studies. Most of these studies have brain extracellular fluid (ECF) is maintained at utilized mitochondria isolated from liver, 2.8 mM against a plasma K + concentration of heart, flight muscles, and kidneys. Morphologi- 3.5 to 5.0 mM (Goldstein, 1978). Further, Goldcal studies (Herbener, 1976; Saktor & Shima- stein showed that most of the ATP consumed da, 1972; Stocco&Hutson, 1978;Tauchietal., by the metabolic pump at the capillary level 1964; Tauchi & Sato, 1968; Wilson & Franks, had its origin in oxidative metabolism. This is 1975a, b) have revealed a decrease in numbers consistent with the high density of cerebral of mitochondria with age. Early biochemical capillary endothelial mitochondria reported studies, on the other hand, reported no signifi- by Oldendorf et al. (1977). cant increase in mitochondrial ATP synthesis with increasing age (Barrows et al., 1960; Gold et al., 1968; Weinbach & Garbus, 1956, MATERIALS AND METHODS 1959; Wilson et al., 1975). However, a recent Eighteen Macaca nemestrina were included study (Vann & Webster, 1977) of mitochondria in this study: three 4-year-bld, ten 10-year-old, from aging Drosophila melanogaster, known and five 20-year-old animals. All animals were to have minimal, if any, mitochondrial turn- female except two; one male was included in over, showed a decrease in both ATP synthesis the 10-year-old group and one in the 20-yearand ATPase activity with increasing age. As old group. The design of the project in detail, pointed out by Vann and Webster (1977), including subject acquisition, presacrifice previous biochemical studies may have measures (e.g., anesthesia) specimen collecselected out younger, less fragile, mitochon- tion and distribution, and data analyses related dria, with a more efficient phosphorylative to the experimental design of the overall projmechanism and thus may have obscured the ect are described elsewhere (Bowden, 1979). effects of aging on mitochondrial function. Full-depth sections of cerebral cortex, 1 to 3 Also mitochondrial DNA was shown to de- mm thick, were removed from the frontal and crease with age in Drosophila melanogaster occipital poles of the cerebrum within three (Massie et al., 1975) and mitochondrial DNA min after cessation of respiration, and were to protein ratio decreased with age in mice immediately immersed in McDowell's fixative (Huemer etal., 1971). (McDowell & Trump, 1976). Thin sections The purpose of the present study was to (0.5 to 1.0 mm thick) were removed from the investigate changes occurring in cerebral capil- lateral surfaces of all samples, post-fixed in laries with increasing age. Specific features of osmium tetroxide, stained en bloc with uranyl the cerebral capillary measured were: the acetate (Graham & Karnovsky, 1966) dehythickness of the capillary wall and its com- drated in a graded series of ethyl alcohol and ponents (endothelium, pericytes and basal propylene oxide, and embedded in Epon. lamina) and the number of endothelial mito- Ultrathin sections of silver to gray interference chondria per capillary profile. The study of colors were made perpendicularly to the cortitight junctions was excluded because in vivo cal pial surface. Sections were further stained introduction of horseradish peroxidase as a on the grid with uranyl acetate and Reynold's marker was contraindicated in view of the fact lead. Electron micrographs were made using that other samples from each monkey were either an Elmiskop I or a Philips 300 electron needed for a variety of studies. Evaluation of microscope. A minimum of 10 capillary profiles possible changes in the thickness of capillary were photographed in a random manner in walls during aging was deemed.important since cortical layer III of each cerebral sample. capillary permeability characteristics might Capillaries sectioned lengthwise or tangentialbe affected by alterations in this parameter. ly were excluded from analysis. A diffraction Likewise, possible changes in numbers of grating was used routinely to control for endothelial mitochondria might result in an magnification. Evaluation of age-related changes in cerealtered work capability of the BBB, which could lead to a disturbance of the relative bral capillaries was based on the following constancy of the neuronal microenvironment parameters/counts: (1) cross-sectional area of required for the precise neuronal signaling the entire capillary; (2) cross-sectional area of

644

BURNS, KRUCKEBERG, COMERFORD AND BUSCHMANN

the capillary lumen; (3) thickness of the basal Measurements, Inc., Burlington, MA). The lamina surrounding the entire capillary (BL0); next three sets of measurements (3, 4 and 5 (4) cross-sectional area of pericytes; (5) cross- above) were made with a Grafacon planimeter, sectional area of the inner basal lamina (i.e., (Model #1010A, Bolt, Beranek & Newman, basal lamina between endothelial cell and peri- Inc., courtesy of Dr. Rudolph Vracko, General cyte (BLj); and (6) number of endothelial Medical Research Program, Veterans Adminmitochondria per capillary profile. The first istration Hospital, Seattle, WA). two sets of measurements (1 and 2 above) were In order to measure cross-sectional areas of made with an Optomax (courtesy of Micro capillary profiles from electron micrographs, the

Fig. 1. A diagrammatic representation of a cerebral capillary in cross-section. (A) External boundary of capillary profile delineated by the outer edge of the BL0. (B) Luminal endothelial membrane. (C) BL0, inner and outer edges outlined. (D) Portion of BLj between endothelium and preicyte. (E) Small portion of a pericyte, cross-sectional view.

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

D

AGING CAPILLARY ENDOTHELIAL MITOCHONDRIA

lucida of the BL0. The cross sectional areas of the BLj (Fig. ID) and pericytes (Fig. IE) were measured for at least four representative profiles from each sample by tracing their respective outlines with the Grafacon stylus. The number of endothelial mitochondria per cerebral capillary profile was estimated from the same electron micrographs. The criteria used in counting mitochondria were visualization of a double unit membrane and cristae. Measurements and counts included in this study were made without prior knowledge of the age of the animal. After measurements were completed, all data were arranged according to animal number, area of cerebral cortex, and age group. Statistical analyses, carried out according to standard methods, included mean, SD, SEM, Student's T-test, and linear regression. RESULTS

AH of the measurements which were made are summarized in Table 1. A regression analysis revealed a significant decrease with age in the cross-sectional areas of entire capillaries from the occipital pole (/• = 0.419;/? = 0.004), a significant attenuation with age of the crosssectional area of the capillary wall in both cortical areas (frontal pole: r = -0.545; p = 0.019 and occipital pole: /• = -0.0554; p = 0.017) as illustrated in Fig. 3, and a significant decrease in the combined endothelial cell — basal lamina component of the capillary wall in both cortical poles (frontal: /• = -0.526;/? = 0.025 and occipital: /• = -0.546; p = 0.019). No significant change occurred with age in the

LUMEN Fig. 2. A diagrammatic representation of a portion of the wall of a cerebral capillary in cross-section. T-bars indicate 3 cm intervals at which perpendicular measurements were made across the width of the basal lamina (BL0).

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

Optomax scanner was linked with a macro lens which was focussed first on the outline of the outer edge of BL0 (Fig. 1A), thus measuring the area of the entire capillary profile, and secondly was focussed on the outline of the luminal endothelial membrane (Fig. IB), similarly measuring the area of the capillary lumen. Optomax picture elements were calibrated daily. In making an area measurement, the Optomax logic after scanning the selected optical image, summed the total number of picture elements visualized. This number was multiplied by a calibration factor, which took into account the optical magnification, thus giving the area of the image under examination. Raw data were corrected for photographic magnification and areas were expressed in square microns. Points at which the width of the BL0 was to be measured were determined by placing each electron micrograph on the tablet of the Grafacon planimeter attached to a PDP-8 computer. The stylus was traced along the BLO. When 3 cm were transversed by the stylus, the computer rang a bell and the location of the stylus tip was marked. After the BL0 was marked at 3 cm intervals in all electron micrographs (Fig. 2), two-point measurements were made perpendicularly across the width of the BLO (Fig. 1C). Each marked site was measured by touching the tip of the Grafacon stylus to the plasma membrane of the endothelium or pericyte adjacent to the BLO and again at the junction of the BL 0 with the plasma membrane of the astrocytic end-feet. The BL0 measurements thus included both the lamina densa and lamina

645

BURNS, KRUCKEBERG, COMERFORD AND BUSCHMANN

646

Table 1. Mean Measurements of Microvascular Morphological Characteristics in Three Groups of Macaco Nemestrina.

4> ' . O .

Characteristic A. Cross-sectional area of entire capillary in ix2

B. Cross-sectional area of capillary lumen in fi2

in (i2

E. Total Cross-sectional area of endothelial cells and basal laminae (C-D) in /x2 F. Thickness of outer basal lamina in n2 G. Cross-sectional area of inner basal lamina in n2

H. Endothelial mitochondria per capillary profile

N

mean s.d.

frontal occipital frontal occipital frontal occipital frontal occipital frontal occipital frontal occipital frontal occipital frontal occipital

10-18 11-24 10-18 11.24 10-18 11-24 12-34 14-25 10-34 11-25 159-354 165-376 12-34 14-25 10-18 11-24

31.6 :t 8.1 36.6 :t 10.4 7.3 :t 2.7 10.4 :t 2.5 24.4 :b 5.5 26.3 :b 11.8 1.5 :t 0.2 1.3 :t 1.2 22.9 ib 5.3 25.0 :b 10.6 0.13 :t 0.02 0.11 :b 0.01 0.23 :b 0.13 0.12 dt 0.05 3.5 ib 1.0 3.8 ib 1.5

29.3 28.0 10.1 9.4 19.2 19.4 0.9 0.6 18.3 18.8 0.19 0.14 0.11 0.09 3.3 2.5

± 9.9 ± 6.2 ± 6.1 ± 4.5 ± 4.2 ± 4.6 ± 0.7 ± 0.3 ± 4.5 ± 4.3 ±0.05 ± 0.03 ± 0.06 ± 0.03 ± 0.9 ± 0.7

20 y.o. mean s.d. 22.8 20.7 6.7 6.1 15.9 14.6 0.9 0.4 15.0 14.2 0.20 0.14 0.10 0.08 2.3 2.8

± 2.2 ± 3.5 ± 3.3 ± 2.1 ± 3.2 ± 2.2 ± 0.2 ± 0.2 ± 3.0 ± 2.0 ± 0.07 ± 0.03 ± 0.03 ± 0.01 ± 0.5 ± 0.3

Significance NS

p = 0.004 NS NS

p = 0.019 p = 0.017 NS NS

p = 0.025 p = 0.019 NS NS

p = 0.052 NS

p = 0.035 NS

Means are based upon measurements from 3 four-year-old, 10 ten-year-old, and 5 twenty-year-old animals. N = range of numbers of capillary profiles sampled per animal. Significance estimate based on linear regression analysis of measurement vs age. In F, N = number of measurements taken at 3 cm intervals.

I I cross-sectional area of capillary wall {JL. [gl endothelial mitochondria per capillary profile

20 -

10 -

k 0

5

k 10

15

cross-sectional area of pericytes in the capillary wall. A regression analysis revealed a trend toward a decrease with age in the BLj of the frontal cortex (/• = -0.465; p = 0.052). There was a significant increase in thickness of the BL0 between 4 and 10 years of age with no futher change between 10 and 20 years. A regression analysis, however, revealed no significant increase in thickness of the BL 0 with increasing age. The BL 0 was found to be significantly thicker in the frontal cortex than in the occipital cortex at all ages studied, in each case p = 0.001. Note the thick BL0 of the capillary profiles shown in Fig. 4. Mean values for the number of endothelial mitochondria per capillary profile are shown in Table 1H and Fig. 3. A regression analysis revealed a significant decline with age in endothelial mitochondria per capillary profile in the frontal cortex (/• = -0.498; p = 0.035), however, no significant decline was observed in the occipital cortex.

20

AGE IN YEARS

DISCUSSION Fig. 3. Cross-sectional areas of capillary walls and numbers of endothelial mitochondria per capillary profile from the frontal pole of the cerebral cortex in M. nemestina (mean values ± S.D.).

The attenuation of cerebral capillary walls with increasing age in Macaque monkeys, as observed in this study, is in agreement with that reported for the rat (Schwink & Wetzstein,

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

C. Cross-sectional area of capillary wall (A-B) in /A2 D. Cross-sectional area of pericytes

Site

Age Group 10 y.o. mean s.d.

AGING CAPILLARY ENDOTHELIAL MITOCHONDRIA

647

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

Fig. 4. Transverse sections through capillaries from the frontal cortex of Macaca nemestr'ma of different ages. A, 4 years and B, 20 years. (Magnification 13,500 X).

648

BURNS, KRUCKEBERG, COMERFORD AND BUSCHMANN

the human, nor is it known whether aging human cerebral capillaries undergo changes similar to those observed by us in the nonhuman primate. The decline with increasing age in the number of endothelial mitochondria per capillary profile has not been reported previously. It has been shown (Oldendorf & Brown, 1975; Oldendorf et al., 1977) that in the rat the mitochondrial content of cerebral capillary endothelium amounted to 8 to 11% of the cytoplasmic volume as compared with 2 to 5% of the cytoplasmic volume in non-barrier capillaries from skin, cardiac and skeletal muscle, lung, and renal glomerulus. Their mitochondrial counts (Oldendorf & Brown, 1975) were in close agreement with their mitochondrial content studies (Oldendorf et al., 1977). Although the present study shows a decrease in mitochondrial number and in capillary wall thickness, it is not clear whether the concentration of the mitochondrial volume per unit volume of the endothelial cytoplasm has changed. If the ratio of mitochondrial volume to endothelial cytoplasmic volume has remained stable, the relative amount of energy production for transport across the endothelial wall probably would be unchanged. This implies that altered mitochondrial function may yet be adequate. On the other hand, if the concentration of mitochondria has decreased, the function of the blood-brain barrier may be impaired. Studies are currently underway to determine mitochondrial concentration in cerebral endothelial cytoplasm of aged monkey brains. The occurrence of active transport across the cerebral capillary wall in vivo has not been clearly established although it has been recently shown to occur in isolated capillaries (Goldstein, 1978). If active transport across cerebral capillaries does occur and if it can be related to the capacity for oxidative phosphorylation, which presumably is proportional to the mitochondrial content of cerebral capillary endothelial cytoplasm, then the finding in this study of a one-third decrease with age in mitochondrial counts in capillaries of the frontal pole suggests that there may be an impairment of active transport mechanisms in the BBB of the frontal cortex in older primates. This alteration could have serious consequences for endothelial functioning and indirectly for neuronal functioning. The main-

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

1966). The change in capillary lumen diameter, which we observed, although not statistically significant, is similar in magnitude and direction to that reported for the rat (Bar, 1978). The outer basal lamina increased in thickness, particularly between 4 and 10 years of age; however, there was an insignificant decrease in cross-sectional area of the inner basal lamina, between pericytes and endothelium. Thus, the observed attenuation of the capillary wall is apparently due almost entirely to a decrease in cross-sectional area of its endothelial component. Bar (1978) reported capillary endothelial cell loss with aging in rats and suggested that this may be compensated in part by elongation of remaining cells. The attenuated endothelial component of the capillary as observed by us, may indeed reflect endothelial cell loss with aging with subsequent elongation of remaining cells. The outer basal lamina of capillaries from the frontal cortex was significantly thicker than that of capillaries from the posterior cerebral cortex at all ages studied. Whether attenuation of cerebral capillary walls with aging is causally related to neurological changes during senescence is not known. Sokoloff (1966) has shown that, in the absence of disease in the human, cerebral blood flow and cerebral oxygen consumption remain essentially unchanged between young adulthood and old age. However, he found a statistically significant decrease in both parameters in elderly persons with senile psychosis. Attenuation of the capillary wall and narrowing of the capillary lumen under nprmal resting conditions, probably would not affect cerebral blood flow. However, it is not known how microvasculature thus altered would respond during stress or at a time when an increased cerebral blood flow might normally occur. For example, measurements of local blood flow in the brain of animals show that a marked increase in blood flow throughout the brain occurs during rapid eye movement (REM) sleep (Reivich et al., 1968). It may be speculated that morphological alterations of cerebral microvasculature during aging might interfere with the normal increase in cerebral bloodflowduring REM sleep and that this could lead to an altered ratio of REM to slow wave sleep. Consequently, altered sleep patterns might be reflected in behavioral change (e.g., mental confusion). However, there are no data available concerning blood flow during sleep in

AGING CAPILLARY ENDOTHELIAL MITOCHONDRIA

SUMMARY

This study of cerebral capillaries in Macaca nemestrina revealed the following significant alterations with increasing age: an attenuation of capillary walls and a decline in the number of endothelial mitochondria per capillary profile. Capillary lumen size was not significantly altered. The thickness of the outer basal lamina increased between 4 and 10 years of age, however, no further change in this param-

eter was observed between 10 and 20 years of age. A trend toward a decrease with age in the cross-sectional area of the inner basal lamina was noted primarily between 4 and 10 years of age. At all ages studied, the outer basal lamina of capillaries from the frontal cerebral cortex was significantly thicker than that of capillaries from the occipital cerebral cortex. These findings in cerebral capillaries in aging nonhuman primates confirm and extend findings previously reported for cerebral microvasculature in rats (Schwink & Wetzstein, 1966; Bar, 1978). Further, the declining numbers of cerebral capillary endothelial mitochondria with increasing age corroborate the findings of previous morphological and biochemical stujdies of mitochondria from various other tissues5 during aging. The paucity of previous studies of the BBB in aging ancj the importance of the structural integrity of the BBB to normal neurological functioning emphasize the need for continued research on the effects of aging, particularly on the tight junctions and endothelial mitochondria.

REFERENCES

Bar, T. Morphometric evaluation of capillaries in different laminae of rat cerebral cortex by automatic image analysis: Changes during development and aging. In J. Cervds-Navarro, E. Betz, G. Ebhardt, R. Ferszt, & B. Wullenweber (Eds.), Advances in Neurology, Vol. 20, Pathology of Cerebral Microcirculation, Raven Press, NY, 1978. Barrows, C. H., Falzone, J. A., & Shock, N. W. Age differences in the succinoxidase activity of homogenates and mitochondria from the liver and kidneys of rats. Journal of Gerontology, 1960,15, 130-133. Bowden, D. M. Aging in Nonhuman Primates, Van Nostrand Reinhold Co., NY, 1979. Bradbury, M. W. B., & Kleeman, C. R. Stability of the potassium content of cerebrospinal fluid and brain. American Journal of Physiology, 1967, 218, 519-528. Bradbury, M. W. B., & Stulcova, B. Efflux mechanisms contributing to the stability of potassium concentration in cerebrospinal fluid. Journal of Physiology, 1970, 208, 415-430. Davson, H. The blood-brain barrier. Journal of Physiology, 1976, 255, 1-28. Gold, O. H., Gee, M. V., & Strehler, B. L. Effect of age on oxidative phosphorylation in the rat. Journal of Gerontology, 1968, 23, 509-512. Goldstein, G. W. Metabolism of brain capillaries in relation to active ion transport. In J. Cervds-Navarro, E. Betz, G. Ebhardt, R. Ferszt, & R. Wullenweber (Eds.), Advances in Neurology, Vol. 20, Pathology of Cerebrospinal Microcirculation, Raven Press, NY, 1978. Graham, R. C , & Karnovsky, M. J. The early stages of absorption of injected horseradish peroxidase in the

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

tenance of ionic differentials between blood plasma and brain extracellular fluid (ECF) may be compromised in older primates. According to Davson (1976) K+ concentration in plasma is 4.63 m eq/Kg H2O and in cerebrospinal fluid (CSF) is 2.86. Because there is no barrier between CSF and the ECF it is assumed that the concentration of K+ in the ECF is equivalent to that in CSF. Thus, under normal circumstances, the cerebral capillary is able to maintain a lower concentration of K+ in the brain ECF than in plasma. Under experimental circumstances this steadystate level was maintained in spite of large variations in plasma K+ sustained over long time periods (Bradbury & Kleeman, 1967). Bradbury and Stulcova(1970) by ventriculo-cisternal perfusion of 42K snowed an acceleration of the efflux of K+ from CSF with increasing concentration of K+ in the perfusion. They were unable to state definitively that this pattern of efflux also occurred across the capillary wall. The maintenance of optimal levels of K+ and other ionic species (e.g., Na+, Mg+ + , Ca+ + , Cl~) is crucial to normal neuronal functioning. If these ions are able to flow down their concentration gradients because of altered capillary permeability, or, if they cannot be transported against their electrochemical gradients because of insufficient energy production for the support of active transport processes, then the elderly primate may suffer undue neurological consequences from alteration in plasma electrolytes. For example, it is not uncommon for elderly humans to develop altered plasma electrolytes as a result of poor nutrition, or of dehydration associated with a relatively mild febrile illness or with diuretic therapy. It is possible, therefore, that these seemingly subtle alterations of the BBB occurring with increasing age may indeed compromise optimal neurological functioning during senescence.

649

650

BURNS, KRUCKEBERG, COMERFORD AND BUSCHMANN

Schwink, A., & Wetzstein, R. Die Kapillaren im subcommissuralorgan der ratte. Zeitschrift fur Zellforschung und Mikroskopische Anatomie, 1966, 73, 56-88. Sokoloff, L. Cerebral circulatory and metabolic changes associated with aging. Research Publications of the Association of Nervous and Mental Diseases, 1966, 41, 237-254. Stocco, D. M., & Hutson, J. C. Quantitation of mitochondrial DNA and protein in the liver of Fischer 344 rats during aging. Journal of Gerontology, 1978, 33, 802809. Tauchi, H., & Sato, T. Age changes in size and number of mitochondria of human hepatic cells. Gerontology, 1968, 23, 454-461. Tauchi, H., Sato, T., Hoshino, M., Kubayashi, H., Adachi, F., Aoki, J.,& Masuko.T. Studies on correlation between ultrastructure and enzymatic activities of the parenchymal cells in senescence. In P. F. Hansen (Ed.), Age with a Future, Munksgaard, Copenhagen, 1964. Vann, A. C , & Webster, G. C. Age-related changes in mitochondrial function in Drosophila melanogaster. Experimental Gerontology, 1977, 12, 1-5. Weinbach, E. G., & Garbus, J. Age and oxidative phosphorylation in rat liver and brain. Nature, 1956, 178, 1225-1226. Wilson, P. D., & Franks, L. M. The effect of age on mitochondrial ultrastructure. Gerontologia, 1975, 21, 8194. (a) Wilson, P. D., & Franks, L. M. The effects of age on mitochondrial ultrastructure and enzymes. Advances in Experimental Medicine and Biology, 1975, 532, 171182. (b) Wilson, P. D., Hill, B. T., & Franks, L. M. The effects of age on mitochondrial enzymes and respiration. Gerontologia, 1975,2/, 95-101.

PhD Clinical Psychologist: with interest in working with geriatric patients in a short term facility within a large academic medical center. Training and experience in individual and family therapy required. Responsibilities include diagnostic evaluations, staff consultation and a broad range of patient care. Research is strongly encouraged and opportunities are extensive. Available July, 1979. Academic rank in College of Health Sciences and salary will be commensurate with experience. Respond with vita and three letters of reference to: Rosalind Cartwright, PhD, Dept. of Psychology and Social Sciences, RushPresbyterian-St. Luke's Medical Ctr., 1753 West Congress Parkway, Chicago, IL 60612. Equal Opportunity/ Affirmative Action Employer.

Downloaded from http://geronj.oxfordjournals.org/ at University of Western Ontario on October 30, 2014

proximal tubules of mouse kidney. Journal of Histochemistry and Cytochemistry, 1966, 14, 291-302. Herbener, G. H. A morphometric study of age-dependent changes in mitochondrial populations of mouse liver and heart. Journal of Gerontology, 1976, 31, 8-12. Huemer, R. P., Lee, K. D., Reeves, A. E., & Bickert, C. Mitochondrial studies in senescent mice —II. Specific activity, bouyant density, and turnover of mitochondrial DNA. Experimental Gerontology, 1971, 6, 327334. Massie, H. R., Baird, M. B., & McMahon, M. M. Loss of mitochondrial DNA with aging in Drosophila melanogaster. Gerontologia, 1975,2/, 231-238. McDowell, E. M., & Trump, B. F. Histologic fixatives suitable for diagnostic light and electron microscopy. Archives of Pathology and Laboratory Medicine, 1976, WO, 405-414. Oldendorf, W. H., & Brown, W. J. Greater numbers of capillary endothelial cell mitochondria in brain than in muscle. Proceedings of the Society of Experimental Biological Medicine, 1975, 149, 736-738. Oldendorf, W. H., Cornford, M. E., & Brown, W. J. The large apparent work capability of the blood-brain barrier: A study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Annals of Neurology, 1977, /, 409-417. Reese, T. S., & Karnovsky, M. J. Fine structural localization of a blood-brain barrier to exogenous peroxidase. Journal of Cell Biology, 1961,34, 207-217. Reivich, M., Isaacs, G., Evarts, E. V., & Kety, S. S. The effect of slow wave and REM sleep on regional cerebral blood flow in cats. Journal of Neurochemistry, 1968, 15, 301-306. Sactor, B., & Shimada, Y. Degenerative changes in the mitochondria of flight muscle from aging blowflies. Journal of Cell Biology, 1975,52, 465-477.

Thinning of capillary walls and declining numbers of endothelial mitochondria in the cerebral cortex of the aging primate, Macaca nemestrina.

Journal i>l (U'ronlold.vv 1979. Vol. 34. No. 5. 642-650 E. M. Burns, PhD,2 T. W. Kruckeberg, MS,2 L. E. Comerford, BS, 2 and MB. T. Buschmann, PhD3 S...
1MB Sizes 0 Downloads 0 Views