Effect of aging on the human initial interaural linear vestibulo-ocular reflex

Transient whole-body surge (fore-aft) translation at 0.5 G peak acceleration was administered to six subjects with unilateral vestibular deafferentation (UVD), and eight age-matched controls. Subjects viewed eccentric targets to determine if linear vestibulo-ocular reflex (LVOR) asymmetry might lateralize otolith deficits. Eye rotation was measured using magnetic search coils. Immediately before surge, subjects viewed a luminous target 50 cm away, centered or displaced 10 degrees horizontally or vertically. The target was extinguished during randomly directed surges. LVOR gain relative to ideal velocity in subjects with UVD for the contralesional horizontally eccentric target (0.59 +/- 0.08, mean +/- SEM) did not differ significantly from normal (0.50 +/- 0.04), but gain for the ipsilesional eccentric target (0.35 +/- 0.02) was significantly less than normal (0.48 +/- 0.03, P < 0.05). Normal subjects had mean gain asymmetry for horizontally eccentric targets of 0.17 +/- 0.03, but asymmetry in UVD was significantly increased to 0.35 +/- 0.05 (P < 0.05). Four of six subjects with UVD had maximum gain asymmetry outside normal 95% confidence limits. Asymmetry did not correlate with UVD duration. Gain for 10 degrees vertically eccentric targets averaged 0.38 +/- 0.14 for subjects with UVD, insignificantly lower than the normal value of 0.75 +/- 0.15 (P > 0.05). Surge LVOR latency was symmetrical in UVD, and did not differ significantly from normal. There was no significant difference in response between dark and visible target conditions until 200 ms after surge onset. Chronic human UVD, on average, significantly impairs the surge LVOR for horizontally eccentric targets placed ipsilesionally, but this asymmetry is small relative to interindividual variation.

The effects of aging on response time are examined in 2 simple signal detection tasks with young and older subjects (age 60 years and older). Older subjects were generally slower than young subjects, and standard Brinley plot analyses of response times showed typical results: slopes greater than 1 and (mostly) negative intercepts. R. Ratcliff, D. Spieler, and G. McKoon (2000) showed that the slopes of Brinley plots measure the relative standard deviations of the distributions of response times for older versus young subjects. Applying R. Ratcliff's (1978) diffusion model to fit the response times, their distributions, and response accuracy, it was found that the larger spread in older subjects' response times and their slowness relative to young subjects comes from a 50-ms slowing of the nondecision components of response time and more from conservative settings of response criteria.

To evaluate the role of abnormal glucagon physiology in the glucose intolerance of aging, we have examined: (1) basal glucagon concentration, (2) suppression of plasma glucagon by hyperglycaemia and hyperinsulinaemia, (3) plasma glucagon response to intravenous alanine, (4) glucagon kinetics, and (5) hepatic sensitivity to glucagon (3 ng·kg-1·min-1 for 3 h) using 3-3H-glucose in young (24±1 years), middleaged (41±2 years), and older (62±2 years) subjects. Fasting plasma glucagon levels in 58 young, 21 middle-aged, and 32 older subjects were 89±10, 91±12, and 96±21 pg/ml, respectively (p=NS). Following elevation of plasma glucose to 2.2–6.9 mmol/l above basal for 2 h (hyperglycaemic clamp technique), young, middle-aged, and older subjects showed similar depressions in plasma glucagon levels during all three studies. Elevation of the plasma insulin concentration to approximately 100 mU/l while maintaining euglycaemia (insulin clamp technique) also resulted in a similar decline in plasma glucagon levels in both young and older subjects (by 25±3 and 27±3 pg/ml respectively). Following intravenous alanine infusion, the increase in plasma glucagon was not significantly different in young compared with older subjects (65±16 versus 38±7 pg/ml). Plasma insulin (7±1 versus 8±1 mU/l) and glucose (0.33±0.11 versus 0.50±0.11 mmol/l) responses were comparable in young and older subjects. During continuous glucagon infusion, the steady-state plasma glucagon concentration (267±32 versus 252±12 pg/ml) and the metabolic clearance rate of glucagon (16±1 versus 15±1 ml· kg-1·min-1) were similar in young and older subjects. However, the increase in plasma glucose concentration was significantly greater in the older than young subjects (Δ=1.17±0.11 versus 0.67±0.06 mmol/l, p<0.01). Basal glucose production in older subjects (0.13 ±0.01 mmol·kg-1·min-1) was slightly less than in the young (0.15±0.01 mmol·kg-1· min-1). However, the rise in glucose production following glucagon was significantly greater in older than young subjects (31±5 versus 18±4%, p<0.05). In conclusion, (1) basal glucagon levels are not consistently elevated in older subjects, (2) glucagon suppression by both hyperglycaemia and hyperinsulinaemia is similar in young and older subjects, (3) α cell sensitivity to alanine is not affected by age, (4) the metabolic clearance rate of glucagon is similar in young and older subjects, and (5) hepatic sensitivity to a physiological increment in plasma glucagon is increased in older subjects.

1. The spatial properties of linear vestibuloocular reflexes (LVOR) were studied in pigmented rats in response to sinusoidal linear acceleration on a sled. The orientation of the animal on the sled was altered in 15 degrees steps over the range of 360 degrees. Horizontal, vertical, and torsional components of eye movements were recorded with the magnetic field search coil technique in complete darkness. Conjugacy of the two eyes was studied in the horizontal movement plane. 2. Acceleration along the optic axis of one eye (approximately 50 degrees lateral) induced maximal vertical responses in the ipsilateral eye and, at the same time, maximal torsional responses in the contralateral eye. These vertical and torsional responses of the LVOR coincide with those obtained when the respective coplanar vertical semicircular canals are stimulated. Such a congruence suggests a common reference frame for LVOR and angular vestibuloocular reflexes (AVOR), with the result that direct combination of signals indicating apparent and real head tilt is facilitated. 3. Transformations of vertical and torsional responses into head coordinates (pitch and roll) show that these movements are compensatory in direction for any combination of apparent head tilt in pitch and roll planes. 4. Gain (rotation of the eye/apparent rotation of the gravity direction) was approximately 0.3 at 0.1 Hz and decreased to approximately 0.1 at 1.0 Hz. Vertical responses tended to have a larger gain than torsional responses. Phase lag relative to peak acceleration increased from about -9 degrees to about -47 degrees over the same frequency range. 5. Vertical linear acceleration evoked only vertical eye movements at a frequency of 1.0 Hz. 6. Horizontal responses of both eyes were symmetric or asymmetric in amplitude and in-phase (conjugate) or out-of-phase (disconjugate) with respect to each other, depending on the direction of linear acceleration. Translation in the transverse direction evoked conjugate compensatory horizontal responses. Forward-backward translation evoked movements of both eyes that were symmetric in amplitude, but 180 degrees out-of-phase. Translation along diagonal axes evoked almost no horizontal responses in the eye facing in the direction of linear motion but maximal horizontal responses in the eye facing away from the direction of linear motion. These disconjugate movements resulted in a modulation of the vergence angle of the eyes. 7. Disconjugate horizontal responses in darkness are best explained by the assumption that part of the visual consequences of a translational head displacement (i.e., change of viewing distance in light) is taken into account centrally.(ABSTRACT TRUNCATED AT 400 WORDS)

To evaluate the effects of hypertension on heart rate and left ventricular responses to beta-agonist in young and older subjects, as well as the modulating effect of the arterial baroreflex on these responses. Isoproterenol (INN, isoprenaline) alone was infused in 14 young normotensive subjects (mean age, 30 +/- 2 years), 18 older normotensive subjects (mean age, 60 +/- 2 years), 11 young hypertensive subjects (mean age, 36 +/- 1 years), and 17 older hypertensive subjects (mean age, 59 +/- 1 years); isoproterenol combined with ganglionic blockade (trimethaphan [INN, trimetaphan]) was administered to eight young normotensive subjects and eight young hypertensive subjects. Isoproterenol was infused at three to four incremental rates, each rate for 8 minutes. Left ventricular responses were assessed by echocardiography. Isoproterenol caused similar increases in heart rate in all four groups. With ganglionic blockade, heart rate responses were enhanced but were similar in the young normotensive and hypertensive subjects. In young subjects, hypertension did not affect left ventricular responses to isoproterenol alone, whereas older hypertensive subjects showed some blunting of left ventricular responses compared with older normotensive subjects. With ganglionic blockade, young hypertensive subjects also showed mild blunting of left ventricular responses. These results show that, in humans, hypertension does not lead to a decrease in chronotropic responses to infusion of the beta-agonist isoproterenol and causes only a modest decrease in left ventricular responses.

Cardiac vagal predominance increases the RR interval and RR high-frequency (HF) variability during non-rapid eye movement (non-REM) sleep (stages I through IV) in young subjects. Aging suppresses deep sleep, but effects of age-related changes in sleep architecture on RR are unknown. Whether mechanical effects of changes in the breathing pattern on the sinus node during sleep affect RR variability is unclear. Polygraphic sleep recordings and RR and RR spectral profiles were determined in 8 young (22.5+/-3.3 years) and 8 older (55.0+/-7.3 years) healthy volunteers. HF oscillations in RR of 8 cardiac-denervated heart transplant recipients determined mechanical effects of respiration on the sinoatrial node during sleep. Transition from wakefulness to non-REM sleep increased the RR interval in young and older subjects and increased the HF variability of RR in the young (P:<0.05) but not in the older subjects. Older subjects disclosed a faster RR (P:<0.01) and a lower HF variability (P:<0.05) during non-REM sleep than the young subjects. Aging did not affect light and REM sleep but decreased deep sleep (stage IV) from 39+/-23 to 6+/-6 minutes (P:<0.001). Reduction in sleep stage IV with aging blunted the increase in RR and in RR HF variability during non-REM sleep (r>0.55, P:<0.05). Transition from wakefulness to non-REM sleep doubled the markedly reduced HF variability of RR in the heart transplant recipients (P:<0.05). Disappearance of deep sleep with aging impairs nocturnal increase in cardiac vagal activity. Mechanical effects of changes in breathing pattern during sleep favor increases in HF oscillations of the RR interval during non-REM sleep.

BackgroundThe skeletal muscle system plays an important role in the independence of older adults. In this study we examine differences in the skeletal muscle transcriptome between healthy young and older subjects and (pre‐)frail older adults. Additionally, we examine the effect of resistance‐type exercise training on the muscle transcriptome in healthy older subjects and (pre‐)frail older adults.MethodsBaseline transcriptome profiles were measured in muscle biopsies collected from 53 young, 73 healthy older subjects, and 61 frail older subjects. Follow‐up samples from these frail older subjects (31 samples) and healthy older subjects (41 samples) were collected after 6 months of progressive resistance‐type exercise training. Frail older subjects trained twice per week and the healthy older subjects trained three times per week.ResultsAt baseline genes related to mitochondrial function and energy metabolism were differentially expressed between older and young subjects, as well as between healthy and frail older subjects. Three hundred seven genes were differentially expressed after training in both groups. Training affected expression levels of genes related to extracellular matrix, glucose metabolism ,and vascularization. Expression of genes that were modulated by exercise training was indicative of muscle strength at baseline. Genes that strongly correlated with strength belonged to the protocadherin gamma gene cluster (r = −0.73).ConclusionsOur data suggest significant remaining plasticity of ageing skeletal muscle to adapt to resistance‐type exercise training. Some age‐related changes in skeletal muscle gene expression appear to be partially reversed by prolonged resistance‐type exercise training. The protocadherin gamma gene cluster may be related to muscle denervation and re‐innervation in ageing muscle.

Neurophysiological correlates of age-related changes in working memory capacity

Effects of age on retrieval cue processing as revealed by ERPs

To determine effects of aging and autonomic input on interrelationships between respiratory and heart rate variability, we collected 5 min of lung volume of R-R interval data from 7 young [27 +/- 3(SD) yr] and 10 older (69 +/- 6 yr) healthy supine humans before and after double pharmacological autonomic blockade with propranolol (0.2 mg/kg iv) and atropine (0.04 mg/kg iv). Estimates of respiratory and heart rate power spectra and linear transfer functions between the two groups were generated by Fourier analysis. Age, double blockade effects, the age-drug interactions were determined by analysis of variance for repeated measures. Basal R-R intervals were unaffected by age. Double blockade decreased R-R intervals and variability in both age groups (P < 0.0001), but R-R intervals decreased less in older than in young subjects (P < 0.0001). In contrast, basal respiratory intervals and standard deviation were greater in older subjects (P = 0.05) and were unaffected by double blockade in young and older subjects. Lung volume-to-heart rate spectral coherence was highest at frequencies associated with respiration and greater in young than in older subjects (P < 0.07). Double blockade decreased lung volume-to-heart rate variability transfer function magnitude (P < 0.007) and increased phase angle (P < 0.02) without age effects or age-drug interactions. In conclusion, heart rate, respiration, and respiration-heart rate interrelations are altered by aging, and double autonomic pharmacological blockade does not eliminate all age-related differences.

Quantifying the complexity of physiologic time series has been of considerable interest. Several entropy-based measures have been proposed, although there is no straightforward correspondence between entropy and complexity. These traditional algorithms may generate misleading results because an increase in system entropy is not always associated with an increase in its complexity, and because the algorithms are based on single time scales. Recently, we introduced a new method, multiscale entropy (MSE) analysis, to calculate entropy over a wide range of scales. In this study, we sought to determine whether loss of complexity due to aging could be distinguished from that due to major cardiac pathology. We analyzed RR time series from young subjects (n = 26), elderly subjects (n = 46) and subjects with congestive heart failure (n = 43). The mean MSE measures of each of the three groups revealed characteristic curves, suggesting that they capture fundamental changes in the heart rate dynamics due to age and disease. We used Fisher's linear discriminant to evaluate the use of MSE features for classification. In discriminant tests on the training data, we found that MSE features could separate elderly, young and heart failure subjects with 92% accuracy and that older healthy subjects (mean age = 65.9) could be separated from subjects with heart failure (mean age = 55.5) with 94% accuracy. Also, we discriminated data from heart failure subjects and elderly healthy subjects with a positive predictivity of 76% and a specificity of 83% using only the MSE features. Larger databases will be needed to confirm if automatic classification results can match separation results. We conclude that MSE features capture differences in complexity due to aging and heart failure. These differences have implications for modeling neuroautonomic perturbations in health and disease.

Several recent studies have noted a blunted muscle protein synthetic response following an acute bout of resistance exercise (RE) in older individuals. Much less is known regarding the effect of age on the muscle protein breakdown response to RE. The effect of age on the regulation of muscle anabolic and catabolic signaling pathways following RE is not well characterized. We hypothesized that aging would be associated with a reduced overall muscle protein anabolic response. PURPOSE: To determine whether a differential aging response exists in skeletal muscle protein synthesis and breakdown signaling during a 24h time-course following a bout of RE. METHODS: 8 young (age=27±2 yrs) and 8 older subjects (age=70±2 yrs) performed a bout of leg-extensions at 70% 1RM. Muscle biopsies were obtained from the vastus lateralis at baseline and at 3, 6 and 24h post-exercise. Intracellular signaling was assessed with immunoblotting methods. RESULTS: We observed a significant increase in the phosphorylation of S6K1 (Thr389) (0.14+0.02 vs 0.26+0.02 AU) and rpS6 (Ser240/244) (0.04+0.0 vs 0.07+0.0) at all post-exercise time points in the young (P<0.05), with no changes in the older subjects (0.14+.01 vs 0.13+.01, S6K1) (0.05+0.0 vs 0.05+0.0, rpS6) (P>0.05). Older subjects also had a reduced S6K1/rpS6 phosphorylation compared to the young at 6 and 24h post-exercise (P<0.05). Our preliminary data for catabolic signaling shows that phospho-Akt (Thr308), an upstream effector of E3 ubiquitin ligases, increased at 3 and 6h post-exercise in the young (P<0.05) with no changes in the older subjects (P>0.05). Akt phosphorylation was also higher in young compared to old at 6 and 24h post-exercise (P<0.05). Total LC3B protein, indicative of autophagy induction, decreased at both 6 and 24h post-exercise in the young subjects (1.07+0.13 vs 0.59+0.06) (P<0.05) and decreased at all post-exercise time points in the old (1.09+0.12 vs 0.60+0.09) (P<0.05). CONCLUSIONS: We conclude that aging is associated with a dysregulation of anabolic and catabolic signaling following RE which may contribute to the blunted muscle protein anabolic response to RE in older adults. Supported by NIH/NIAMS R01AR049877, P30AG024832 and T32HD07539.

Volumetric proton magnetic resonance spectroscopic imaging (MRSI) was used to generate brain metabolite maps in 15 young and 19 elderly adult volunteers. All subjects also had structural MR scans, and a model, which took into account the underlying structural composition of the brain contributing to each metabolite voxel, was developed and used to estimate the concentration of the N-acetyl-moiety (NAc), creatine (Cr), and choline (Cho) in gray matter and white matter. NAc concentration (signal intensity per unit volume of brain) was higher in gray than white matter and did not differ between young and old subjects despite significant gray matter volume deficits in the older subjects. To the extent that NAc is an index of neuronal integrity, the available gray matter appears to be intact in these older healthy adults. Cr concentrations were much higher in gray than white matter and significantly higher in the old than young subjects. Cho concentration in gray matter was also significantly higher in old than young subjects. Independent determination of metabolite values rather than use of ratios is essential for characterizing age-related changes in brain MRS metabolites.

The present study was undertaken to examine the effect of aging on cholecystokinin (CCK) release, gallbladder emptying and their interrelationships. Therefore, 26 healthy subjects were studied, 13 younger than 40 yr (mean age 31 yr, range 21–39 yr) and 13 older than 40 yr (mean age 64 yr, range 40–78 yr). After intraduodenal administration of 60 ml corn oil, plasma CCK concentration was measured by a sensitive and specific radioimmunoassay and gallbladder emptying by cholescintigraphy. Fasting plasma CCK concentrations were similar in both groups (1.2±0.2 pmol/l in the younger and 1.5 ± 0.3 pmol/l in the older subjects), but the integrated postprandial CCK secretion was significantly (p<0.01) increased in the older subjects (214±21 pmol/l. 60 min) compared to the younger subjects (153±15 pmol/l. 60 min). However, gallbladder emptying was not significantly different between the older and younger subjects (at 60 min 55±7% vs. 61±4%). Gallbladder sensitivity to endogenous CCK was significantly (P<0.02) reduced in the older subjects when compared to the younger subjects. In conclusion, gallbladder sensitivity to CCK is diminished in older subjects but gallbladder emptying remains unchanged due to a significantly increased endogenous CCK secretion.

Objectives: The aim of this study was to compare the pharmacokinetics (PK) and safety of fimasartan (BR-A-657), an angiotensin II receptor antagonist, between healthy young (19 – 45 years) and older (≥ 65 years) male subjects.Methods: To assess the effect of age on PK and safety, fimasartan was administered as a single 240 mg tablet to 12 young and 10 older male subjects, followed by serial blood sampling over 48 h. Plasma concentrations of fimasartan were analyzed using validated HPLC-MS/MS. Clinical and laboratory adverse events were assessed.Results: After oral administration of 240 mg fimasartan, the mean area under the plasma concentration-time curve from time zero to infinity (AUC0→∞) was 2899.0 ng/ml/h in the older, which was significantly greater than in young subjects (1767.4 ng/ml/h; p = 0.03). The geometric mean AUC0→∞ was 69.4% higher in older than in young subjects. The maximum plasma concentration (Cmax), time to reach Cmax and elimination half-life for fimasartan did not differ significantly between the older and young groups. Importantly, fimasartan was well tolerated during this study.Conclusions: While some PK parameters were statistically different between the two groups, the effect of age on the PK was modest (e.g., AUC increase < twofold in older subjects).