D. Platt

Age-dependent changes of the kidneys: pharmacological implications.

About 40% of the intoxications after drug administration occur in the elderly. A significant proportion of the disease states in elderly patients is related to adverse reactions to prescribed drugs. Declining renal function, a reduction in both renal blood flow and glomerular filtration rate, is a major contributor to drug toxicity in the elderly. Therefore, a review (based on newer papers from Medline) of age-dependent changes of the kidneys and their consequences for drug therapy in geriatric patients is presented. Renal changes that occur with aging are: a decrease of renal weight, a thickening of the intrarenal vascular intima, sclerogenous changes of the glomeruli, and infiltration of chronic inflammatory cells and fibrosis in the stroma. Altered renal tubular function, including impaired handling of water, sodium, acid, and glucose, is also frequently present in old age. Impaired ‘endocrinologic’ functioning manifested by changes of the renin-angiotensin system, vitamin D metabolism, and antidiuretic hormone responsiveness has been reported. The aging kidney is constantly exposed to the effects of a variety of potential toxic processes, i.e., drugs and chronic illnesses including hypertension, diabetes, and atherosclerotic disease. Renal changes that occur with aging also consist of impairment in the ability to concentrate urine and to conserve sodium and water. These physiological changes increase the risks of volume depletion and prerenal type of acute renal failure. A frequent cause of acute renal failure in the elderly is drug-induced nephropathy. Nonsteroidal anti-inflammatory drugs, antibiotics, and diuretics are most often involved. Due to the age-dependent decline of renal function, the pharmacokinetics of many drugs are altered in elderly patients. Therefore, the most important renal function to monitor with aging is the creatinine clearance. Changes in pharmacokinetics of many drugs and most decisions on drug dosage can be based on this information alone, as tubular functions of the kidney decrease at rates paralleling the age-dependent decrease in glomerular filtration rate (which is approximately measured by the creatinine clearance). As a conclusion, age-dependent changes of renal function are not only responsible for changes in pharmacokinetics and pharmacodynamics. In many cases, the kidneys are the target organ of adverse drug reactions too.

The Aging Liver

Background/Objective: Numerous age-related changes in hepatic structure and function have been described, although liver function seems to be quite well maintained in old age. Few consistent and reproducible observations and a lack of correlation between structural and functional data characterize the present state of our knowledge. In contrast to renal clearance, no equally reliable method exists to estimate hepatic drug clearance. The contribution of age to altered drug clearance in the elderly is difficult to assess as drug interactions, numbers and types of drugs taken at a time, underlying disease and increased interindividual variability are superimposed to the aging process. Methods: A comprehensive computer-assisted search of the literature. Results: A decline in liver volume and blood flow and a reduction in in vitro and in vivo metabolic capacity have been shown in older subjects, and the physiologic basis of reduced hepatic drug clearance in this age group. Conclusions: After decades of research into the matter, the old and well-known aphorism ‘start lower – go slower’ is valid more than ever in the field of geriatric prescribing. Not only renally excreted drugs but also substances which are metabolized and excreted by the liver should be used at a starting dose which is 30–40% smaller than the average dose used in middle-aged adults.

THE BIOLOGICAL SIGNIFICANCE OF PLASMALOGENS IN DEFENSE AGAINST OXIDATIVE DAMAGE

The phospholipid class of plasmalogens is ubiquitously found in considerable amounts as a constituent of mammalian cell membranes and of plasma lipoproteins. Plasmalogens are more susceptible to oxidative reactions compared to their fatty acid ester analogues, due to the reactivity of their enolether function. Studies on plasmalogen-deficient cell lines lead to the proposal that these ether lipids serve as endogenous antioxidants. No clear conclusions regarding the antioxidative effects of plasmalogens could be drawn from studies in patients of different ages with peroxisomal deficiency disorders. A defective peroxisomal plasmalogen synthesis is not necessarily associated with other defects in the metabolism of peroxisomes, as has been established in a cell line recently. In different mammalian tissues a decrease of plasmalogens with age was described. Moreover, an accumulation of plasmalogen oxidation products was measured in brain of old cattle compared to young ones. In pathologic conditions associated with oxidative stress like in spinal cord ischemia and reperfusion, plasmalogen levels varied inversely according to the oxidative burden. Oxidation products of plasmalogens increased with time of ischemia in infarcted porcine heart tissue. Enrichment of lipoproteins with plasmalogens increased their oxidative resistance, which was diminished in the case of LDL particles in patients with coronary arteriosclerosis. In red cell membranes plasmalogens were reduced with donor age and in hyperlipidemia. Under lipid lowering therapy with lovastatin an increase was observed, indicating a possible antioxidative impact of this treatment. Taken together, there is good evidence that plasmalogens are effective as endogenous antioxidants. However, more experimental approaches not confounded by other lipolytic processes are needed to establish this role of plasmalogens.

Fibrin degeneration product concentrations (D-dimers) in the course of ageing.

D-dimers, cross-linked fibrin split products, have been found to be an indicator of thromboembolic disease and may predict, as fibrinogen or other factors of hemostasis, a higher risk of cerebro- and cardiovascular diseases. D-dimers rose with advancing age in healthy elderly subjects and reached values well above the upper limit of the normal test values. The increase is considered to be the result of several causes, i.e. higher fibrinogen concentrations in the elderly, a slower urinary excretion, more frequent fibrin generation, (occult) diseases, risk factors, inflammatory reactions and degenerative vascular damage. In the elderly, moderately elevated D-dimers are therefore an unspecific finding. The specificity of the D-dimer test for diagnosing thromboembolic diseases can be expected to be lower than in young subjects.

Effect of borage oil consumption on fatty acid metabolism, transepidermal water loss and skin parameters in elderly people

Human skin is not able to biosynthesize gamma-linolenic acid (GLA, 18:3omega6) from the precursor linoleic acid (LA), or arachidonic acid (AA) from dihomo-gamma-linolenic acid (DHGLA). Dietary supplementation with GLA-rich seed oil of borage skips the step of hepatic 6-desaturation of fatty acids (FA) and, therefore, compensates the lack of these essential FA in conditions with impaired activity of delta 6-desaturase. Twenty-nine healthy elderly people (mean age 68.6 years), received a daily dose of 360 or 720 mg GLA for 2 months, using Borage oil in gelatine capsules (Quintesal 180, manufacturer Galderma Laboratorium GmbH, Freiburg, Germany). The effects of fatty acids derived from ingested borage oil capsules on skin barrier function were assessed by measurement of transepidermal water loss (TEWL). The consumption of borage oil induced a statistically significant improvement of cutaneous barrier function in the elderly people, as reflected in a mean decrease of 10.8% in the transepidermal water loss. Thirty-four percent of the people noted itch before borage oil consumption and 0% afterwards. Dry skin was claimed to be reduced from 42 to 14%, but no significant alteration of skin hydration was measured. The FA-composition of erythrocyte membrane phospholipids demonstrated an increase of GLA (+70%) and DHGLA (+18%) and a reduction of saturated and monounsaturated FA. There was no significant alteration in nervonic acid or in AA content, but an increase in the DHGLA/AA ratio (+23%). Thus, the consumption of borage oil by elderly people lead to alteration of FA metabolism and improved skin function.

Complement C1q and C3 mRNA expression in the frontal cortex of Alzheimer's patients

The levels and cellular localization of mRNA for complement C1q and C3 were examined by RNA gel blot and nonradioactive in situ hybridization in the frontal cortex of patients with Alzheimers disease (AD) and age-matched controls. We found that the hybridization signal for C1q mRNA was markedly increased (approx. 3.5-fold) in the frontal cortex of AD patients compared to that in age-matched controls. In contrast to previous reports we also found that the levels of C3 mRNA, although well expressed, did not differ significantly between AD cases and age-matched controls. Nonradioactive in situ hybridization using digoxigenin-labeled riboprobes revealed that transcripts coding for both C1q and C3 were closely associated with neurons. These results support the hypothesis that complement could play a role in neuronal degeneration which has been observed in the brain of AD patients.

Blood coagulation factors in the elderly

To investigate causes of the age-dependent increase of thromboembolic events, plasma coagulation parameters were determined in healthy elderly blood donors in comparison with young, and elderly diseased blood donors. Partial thromboplastin and thrombin clotting times were slightly shortened, whereas prothrombin and reptilase clotting times were unaltered. Plasma concentration of clotting factors like F I, VII, VIII: C, X, HMW-kininogen and prekallikrein were increased, whereas the coagulation inhibitor antithrombin III was decreased. Concerning fibrinolysis, plasminogen and alpha-2-antiplasmin were not affected by age, but plasminogen activators in the euglobulin fraction were lower. This shift in the pattern of coagulation factors favors enhanced fibrin formation and delayed fibrinolysis in the elderly. Higher intermediary products demonstrate that activation of coagulation and fibrinolysis happen more often in elderly healthy people. Together with blood stasis and vessel wall damage, this shift of the hemostatic balance contributes to a higher incidence of thromboembolic disorders in the aged.

Temporal Dynamics of Degenerative and Regenerative Events Associated with Cerebral Ischemia in Aged Rats

Background and Purpose: The age-related decline in plasticity of the brain may be one factor underlying the poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity could be the result of an age-related reduction in the upregulation of factors promoting brain plasticity (microtubule-associated protein 1B [MAP1B], β-amyloid precursor protein [βAPP]), and an age-related increase in glial reactivity and the accumulation of Aβ, a proteolytic cleavage product of βAPP with neurotoxic properties. Methods: Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests 3, 7, 14 and 28 days after surgery. At the indicated time points, brains were removed and immunostained for glial cells. Aβ, as well as the markers of brain plasticity, βAPP and MAP1B. Results: Histologically, in young rats there was a gradual activation of both microglia and astrocytes that peaked by days 14–28 with the formation of a glial scar. In contrast, aged rats showed an accelerated astrocytic and microglial reaction that peaked in the first week after stroke. The expression patterns of a growth-associated phenotype of βAPP as well as with MAP1B accumulation in varicosities along axons in cortical areas affected by stroke peaked between days 14 and 28 in young animals. In aged rats their expression was both delayed (28 days) and reduced. In addition the carboxy terminal fragment of βAPP steadily accumulated over time and reached a maximum by day 14 in aged rats as compared to 28 days in young rats. Conclusions: These results suggest that a temporally anomalous gliotic reaction to cerebral ischemia in aged rats in conjunction with a late and limited upregulation of neuronal plasticity proteins as well as a diminished neurogenesis potential lead to the prevalence of scar tissue that impedes functional recovery from stroke.

Seizure induced c-fos mRNA in the rat brain: comparison between young and aging animals

The molecular mechanisms associated with age-related alterations in the pharmacological and physiological properties of hippocampal and cortical neurons in response to chemically induced seizure are largely unknown. Administration of pentylenetetrazole (PTZ) (50 mg/kg body weight) to rats of various ages evoked tonic-colonic seizures. Using RNA gel blot analysis we found that 1 h after the onset of seizure, the mRNA for the protooncogene c-fos was increased in the hippocampus and cortex of 3-month-old rats. The levels of c-fos mRNA in the hippocampus and cortex of 3-month-old rats returned to control levels by 3 h after PTZ administration. The levels of c-fos mRNA in the hippocampus and cortex of 20-month-old and 30-month-old rats peaked at 3 h and returned to basal levels by 15 h following PTZ treatment. These results suggest that the induction of immediate-early gene expression, as exemplified by c-fos, is not impaired in the aged rat brain. However, the aged rat brain responded more slowly to chemically induced seizure and the levels of c-fos mRNA induction are decreased by about 49% in the cortex and by 27% in the hippocampus of 30-month-old rats, as compared to the levels expressed by 3-month-old rats.

ABO blood group system, age, sex, risk factors and cardiac infarction

In a retrospective study in 3100 patients of different ages the relationship between blood group and cardiac infarction was investigated in 450 patients. The patients were divided in two age groups: those who were 65 yr old and older and younger patients (age less than 65 yr). The predominance of blood group A in patients with cardiac infarction was highly significant in both age groups (P less than 0.005, two-tailed Chi-square test). Step-wise excluding all patients with at least one of the risk factors, hypertension, hyperuricemia, diabetes mellitus, smoking, and hyperlipemia similar results were found: the predominance of blood group A in the elderly patients with cardiac infarction was even higher than before excluding the risk factors (P less than 0.001). The predominance of blood group A was also demonstrated at a lower level in younger patients with cardiac infarction (P less than 0.05). Our investigation strongly suggests the existence of a genetic factor associated with blood group A and independent of the other risk factors which is also responsible for a greater incidence of cardiac infarction.