Leptin levels recover normally in healthy older adults after acute diet-induced weight loss.

OBJECTIVES: Involuntary weight loss affects 20% of community dwelling older adults. The underlying mechanism for this disorder is unknown. Objective is to determine if failure of older persons to regain weight is associated with elevated pro-inflammatory cytokine and leptin levels. DESIGN: Prospective diet intervention study. SETTING: University of Washington Medical Center from 2001-2005. PARTICIPANTS: Twenty-one younger (18-35 years old) and nineteen older (>or= 70 years old) men and women. INTERVENTION: Each subject was placed for two weeks on a weight-maintaining diet, followed in sequence by 2 weeks of 30% caloric restriction, then 4 weeks of ad libitum food intake. MEASUREMENTS: Plasma leptin levels, fasting serum pro-inflammatory cytokine levels, and peripheral blood mononuclear cell cytokine levels were measured. RESULTS: Leptin levels in the two cohorts decreased after caloric restriction and increased after ad-libitum food consumption resumed. Plasma TNF alpha levels were higher in older subjects compared to younger adults. However, there was no association between changes in TNF alpha levels and changes in AUC leptin. CONCLUSION: Leptin levels in healthy older individuals responded appropriately in a compensatory manner to changes in body weight. These data do not support a cytokine dependent elevation in leptin levels as being responsible for the failure of older adults to regain weight.

Cholesterol modulation of beta-adrenergic receptor characteristics.

Cholesterol, a major structural component of plasma membranes, has a profound influence on cell surface receptor characteristics and on adenylate cyclase activity. beta-Adrenergic receptor number, adenylate cyclase activity, and receptor-cyclase coupling were assessed in rat lung membranes following preincubation with cholesteryl hemisuccinate. beta-Adrenergic receptor number increased by 50% without a change in antagonist affinity. However, beta-adrenergic receptor affinity for isoproterenol increased 2-fold as a result of an increase in the affinity of the isoproterenol high-affinity binding site. The increase in agonist affinity did not potentiate hormone-stimulated adenylate cyclase activity, which decreased 3-fold following cholesterol incorporation. However, the ratio of isoproterenol to GTP-stimulated activity was unchanged with cholesterol. Stimulation distal to the receptor by GTP, NaF, GppNHp, Mn2+ and forskolin also demonstrated 50-80% reduced enzyme activity following cholesterol incorporation. These data suggest that membrane cholesterol incorporation decreases catalytic unit activity without affecting transduction of the hormone signal.

The effect of age and cholesterol on the rat lung beta-adrenergic system.

To assess the influence of membrane lipid composition on beta-adrenergic receptor number and adenylate cyclase activity in aging, we investigated the effect of cholesteryl hemisuccinate on these parameters in lung membranes of 3-, 12-, and 24-month-old CDF (F-344) rats. When cholesteryl hemisuccinate (0.5 mg/ml) was incubated with lung membranes, beta-adrenergic receptor density was increased by 70%. This effect was the same for each age group studied and indicated that the density of both basal and CHS-sensitive receptors is unaltered in rat lung with age. Forskolin, NaF, p[NH]ppG, and isoproteronol-stimulated adenylate cyclase activity is 30% lower in lung membranes from aged rats. Since enzyme activity is affected by the lipid environment and membrane composition often changes with age, we assessed adenylate cyclase activity following cholesteryl hemisuccinate incorporation. There was up to a 75% decrease in adenylate cyclase activity following cholesteryl hemisuccinate incorporation in lung membranes in each of the three age groups. In untreated membranes, there was no significant difference in cholesterol or lipid phosphate content with age. These data suggest that cholesterol content does not account for alterations in senescent rat lung adenylate-cyclase activity.

Thyroid hormone regulation of rat heart, lymphocyte, and lung beta-adrenergic receptors.

In the rat, exogenous hyperthyroidism is associated with increased myocardial beta-adrenergic receptors. In man, however, despite the hyperadrenergic manifestations of thyrotoxicosis, lymphocyte beta-adrenergic receptors are unaltered. To test the hypothesis that lymphocytes do not reflect changes in myocardial beta-adrenergic receptors with hyperthyroidism, we characterized and quantified lymphocyte, myocardial, and lung (as another marker tissue) beta-adrenergic receptors in T3-treated rats. In T3-treated rats (500 microgram T3/kg.day for 3 days), myocardial beta-adrenergic receptors, as measured by [3H]dihydroalprenolol binding, increased by 60% over controls. In contrast, lymphocyte and lung beta-adrenergic receptors were unaltered. However, while lymphocyte adenylate cyclase activity was also unaltered with T3 treatment, lung adenylate cyclase activity was increased. Our data demonstrate that in rats, as in humans, hyperthyroidism is not associated with an increase in lymphocyte beta-adrenergic receptors. The differences in lymphocyte and myocardial receptors and lymphocyte and lung adenylate cyclases suggest that the response to T3 is a tissue-specific phenomenon. The data also suggest that despite the lack of increase in lymphocyte beta-adrenergic receptors in human hyperthyroidism, myocardial beta-adrenergic receptors may be increased.

Glucocorticoid regulation of myocardial beta-adrenergic receptors.

One action of glucocorticoids is to enhance the tropic effect of catecholamines on heart muscle. To test the hypothesis that this action of glucocorticoids is mediated by modulation of beta-adrenergic receptors, we characterized and quantified myocardial beta-adrenergic receptors in adrenalectomized and glucocorticoid-replaced rats. Adrenalectomy was associated with an increase in myocardial beta-adrenergic receptors, as measured by [3H]dihydroalprenolol binding (P less than 0.001). This increase occurred by 6 h, with no difference over time to 7 days. The administration of cortisol (80 mg/kg.day) to adrenalectomized rats prevented the increase in beta-adrenergic receptors (P less than 0.01). The data indicate that glucocorticoids modulate myocardial beta-adrenergic receptors. However, these results do not support the hypothesis that glucocorticoid enhancement of catecholamine action is mediated by these changes, suggesting that glucocorticoids exert this action at a level other than the beta-adrenergic receptor site.

Thyroid hormone regulation of beta-adrenergic receptor number in aging rats.

To evaluate the capacity of the myocardium in aged rats to respond to hyperthyroidism, we quantified myocardial beta-adrenergic receptors in female Fischer 344 rats of 3, 12, and 24 months of age. In T3-treated rats (500 microgram T3/kg . day for 3 days), myocardial beta-adrenergic receptors, as measured by [3H]dihydroalprenolol binding, were significantly increased (P less than 0.01) over controls in 3-, 12-, and 24-month-old animals. The data demonstrate that senescent rats retain the capacity to increase myocardial beta-adrenergic receptors in response to exogenous hyperthyroidism. In the myocardium, the mechanism of decreased catecholamine responsiveness in aging appears to be at other than the beta-adrenergic receptor site, since receptor density is unaltered with age, as is receptor modulation in response to hyperthyroidism.

Exercise training delineates the importance of B-cell dysfunction to the glucose intolerance of human aging.

Aging has been associated with glucose intolerance, insulin resistance, hyperinsulinemia, and diminished islet B-cell function. The relative contribution of these factors to the aging-associated changes in glucose tolerance has been difficult to discern, particularly so for B-cell function, since insulin sensitivity itself is a determinant of B-cell function and, therefore, comparisons of insulin levels and responses between old and young subjects are difficult. To reduce this effect, we compared B-cell function in 14 healthy older men (aged 61-82 yr; body mass index, 21-30 kg/m2), who were exercise trained for 6 months to improve insulin sensitivity, to that of 11 healthy young men (aged 24-31 yr; body mass index, 19-31 kg/m2), who were also trained. Insulin-glucose interactions were assessed by measuring indices of insulin sensitivity (SI) and glucose effectiveness at zero insulin (GEZI) using Bergman's minimal model. B-Cell function was assessed by determining the acute insulin responses (AIR) to glucose (AIRgluc) and arginine at 3 different glucose levels: fasting, approximately 14 mM, and greater than 28 mM (AIRmax). AIRmax provides a measure of B-cell secretory capacity, while the glucose level at which 50% of AIRmax occurs is termed PG50 and is used to estimate B-cell sensitivity to glucose. The insulin sensitivity and glucose effectiveness at zero insulin of the trained older subjects was similar to that of the trained young [SI: old, 5.1 +/- 0.6; young, 6.5 +/- 0.7 x 10(-5) min-1/pM (mean +/- SEM; P = NS); GEZI: old, 1.3 +/- 0.2; young, 1.7 +/- 0.2 x 10(-2) min (P = NS)]. Under these conditions, the fasting glucose levels (old, 5.4 +/- 0.2; young, 5.1 +/- 0.1 mM) and basal insulin levels (old, 49 +/- 6; young, 63 +/- 11 pM) were also similar in the two groups. AIRgluc values were lower in the exercised elderly (old, 253 +/- 50; young, 543 +/- 101 pM; P = 0.01). This decrease in stimulated insulin release was due solely to a reduction in the AIRmax (old, 1277 +/- 179; young, 2321 +/- 225 pM; P less than 0.005); the PG50 was not different (old, 8.9 +/- 0.4; young, 8.8 +/- 0.2 mM; P = NS). These differences in the older subjects were associated with a reduction in iv glucose tolerance (old, 1.49 +/- 0.15; young, 1.95 +/- 0.13%/min; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Alpha- and beta-adrenergic receptor function in the brain during senescence.

Alpha- and beta-adrenergic receptors and their second messengers play an important role in brain neurotransmission. Changes in receptor function with age may be involved in the age-related changes in arousal, mood and memory. The predominance of data indicates there is decreased beta-adrenergic receptors in all areas of the brain with the exception of the cortex. Evidence suggests a decreased rate of receptor synthesis may be contributing to this loss of receptors with age. Alpha-adrenergic receptor synthesis is also diminished with age. The modulation of receptor concentrations by hormonal factors is impaired with age, especially the time to recover from receptor down-regulation.

A study of training in clinical pharmacology of the elderly.

Training of physicians in geriatrics is essential to improving health care for the elderly. Considering the frequent use, cost, and side effects of drugs in the elderly, knowledge in clinical pharmacology is an important component of that training. The present study surveyed 68 geriatric medicine, 27 geropsychiatry, and 46 clinical pharmacology fellowship programs in the United States for the clinical geropharmacology content of their programs. In geriatric medicine, 73% of the programs had formal didactic material, 58% had formal training in this area during clinical experiences, and 43% formally interacted with clinical pharmacology faculty or fellows. In geropsychiatry these numbers were 79%, 67%, and 31%, respectively. In clinical pharmacology, 34% of the programs had formal didactic content, 9% had clinical experience on a specific geriatrics unit, and 14% had clinical experiences in a long-term care facility. Although some training in clinical geropharmacology exists in fellowship training programs, clearly there is much room for expansion and improvement in this important area of health care of the elderly.

Beta-adrenergic agonist-mediated desensitization in senescent rats.

The capacity of senescent rats to develop the catecholamine refractory state was investigated in CDF (F-344) rats of 3 and 24 months of age. Beta-adrenergic receptor number, receptor-agonist affinity, and adenylate cyclase activity in heart membranes were assessed, following the chronic in vivo administration of the beta-adrenergic agonist, metaproterenol. Drug treatment leads to marked myocardial hypertrophy, receptor down-regulation, and reduced isoproterenol-stimulated adenylate cyclase activity. The extent of catecholamine-refractoriness was not different in the older rats, indicating the catecholamine desensitization of myocardial beta-adrenergic responsiveness is not impaired in senescence. Receptor agonist affinity and the percent of receptors in the high-affinity state decrease with age. These parameters are further reduced by agonist treatment but to a lesser extent in the older animals. Thus, the effects of age and agonist desensitization are not additive and suggest that aged animals may already be partially desensitized.

Age-associated decrease of adenylate cyclase activity in rat myocardium.

Myocardial inotropic and chronotropic responses to beta-adrenergic agonists are diminished with aging. Since myocardial beta-adrenergic receptors are unaltered with age, we tested the hypothesis that this decreased responsiveness is related to a defect in the adenylate cyclase system. Isoproterenol-stimulated adenylate cyclase activity was assessed in myocardial membranes from Fischer 344 rats of 3, 12, and 24 months of age. Basal, as well as F-, GTP-, and hormone-stimulated adenylate cyclase activity was decreased by 20-30% with age. The Km of the enzyme for ATP was not found to be statistically different for any age group studied. These data support the hypothesis that the diminished responsiveness seen in senescence is a result of an alteration in either the catalytic subunit or the coupling protein (N) of the adenylate cyclase complex.

Age-associated decrease in the catalytic unit activity of rat myocardial adenylate cyclase.

Two techniques were employed to define the site of diminished adenylate cyclase activity observed in age-rat myocardium. We previously reported no change in beta-adrenergic receptor number or affinity but decreased NaF- and 5'-guanylylimidodiphosphate (GppNHp)-stimulated adenylate cyclase activity with age in the rat myocardium. These data suggest a defect in either N-protein or the catalytic unit component of adenylate cyclase. N-protein activity was assessed by the ability of myocardial membrane extracts from 3-, 12, and 24-month-old Fischer 344 rats to complement the N-protein deficient cyc- S49 mouse lymphoma cell line. Catalytic unit activity was assessed by the ability of forskolin to stimulate adenylate cyclase in myocardial membranes from young and old rats. The results demonstrate that both N-protein activity and catalytic unit activity are diminished with age in the rat myocardium. However, since N-protein is present in excess relative to catalytic unit, the data are consistent with the hypothesis that the loss of catalytic unit activity accounts for the loss of overall enzyme activity. The effect is tissue-specific, since erythrocyte membranes do not show the same age-dependent loss of adenylate cyclase activity.

Enhanced cell proliferation and biosynthesis mediate improved wound repair in refed, caloric-restricted mice.

Aged mice that have undergone long-term caloric-restriction (CR) have improved health and enhanced longevity in comparison to aged mice that are ad libitum-fed (AL). However, caloric-restriction does not benefit the impaired wound healing of aged mice. To test the hypothesis that CR mice have the capacity for enhanced wound repair, but require a short-term period of additional nutrient intake to show this advantage, we assessed wound healing in CR mice that had been refed (RF) an ad libitum diet for 4 weeks prior to wounding. Two strains of AL young (Y AL) (4-6 months), AL middle-aged (M AL) (15-17 months), and three different, matched cohorts of old mice (O) (30-33 months): O AL, O CR, and O RF were studied. Two full-thickness 4 mm diameter punch biopsy skin wounds were created on the dorsum of each mouse. Animals were sacrificed and wounds were harvested at 1,2,3,5, and 7 days post-wounding. Repair of wounds was slower in O AL and O CR mice compared to Y AL and M AL animals. In contrast, the O RF mice healed similarly to that of the Y AL and M AL mice, as assessed by measures of wound area and histologic criteria. O RF mice demonstrated enhanced synthesis of type I collagen mRNA in comparison to O AL and O CR mice. A greater number of endothelial cells and fibroblasts at the wound edge of the O RF mice exhibited replication in vivo as measured by uptake of BrdU. O RF mice had higher levels of insulin-like binding protein 3 (IGFBP-3). Furthermore, fibroblasts derived from the explant of the punch biopsy of O CR mouse skin revealed enhanced proliferation and contraction in vitro, in comparison to fibroblasts from the O AL mice. In conclusion, O RF mice demonstrate an enhanced capacity to undergo wound repair in comparison to O AL mice. This effect appears to be mediated, in part, by enhanced cell proliferation, contraction, and collagen biosynthesis. In addition, short-term refeeding induced an increase in the serum level of IGFBP-3, the major binding protein for IGF-1. These data confirm that cells from O CR animals have a preserved proliferative, biosynthetic, and contractile capacity, but that an adequate source of nutrients is necessary to demonstrate this advantage in wound healing.

Effects of metoprolol on rest and exercise cardiac function and plasma catecholamines in chronic congestive heart failure secondary to ischemic or idiopathic cardiomyopathy.

To define the effects of 2 months of metoprolol therapy on cardiac function, aerobic performance and sympathetic nervous system activity, metoprolol (75 to 100 mg/day) was administered to 10 patients with chronic congestive heart failure (CHF). Metoprolol was discontinued in 2 patients because of worsening CHF. In the remaining 8 patients, peak oxygen uptake increased significantly (14.8 +/- 3.0 to 16.1 +/- 2.5 ml/kg/min, p less than 0.05) as did the oxygen pulse (9.0 +/- 2.2 to 12.6 +/- 1.8 ml/beat, p less than 0.02). Resting heart rate (87 +/- 18 to 62 +/- 9 beats/min, p less than 0.05) and peak exercise heart rate (133 +/- 13 to 105 +/- 30 beats/min, p less than 0.02) were both reduced. Mean resting ejection fraction increased from 0.15 +/- 0.06 to 0.25 +/- 0.11 and peak exercise ejection fraction also tended to increase (0.19 +/- 0.11 to 0.28 +/- 0.15, difference not significant). Both resting plasma norepinephrine (613 +/- 706 to 303 +/- 142 pg/ml, p less than 0.05) and epinephrine (71 +/- 50 to 40 +/- 21 pg/ml, p less than 0.05) were reduced. Circulating lymphocyte beta-adrenergic receptor number was unchanged (1,334 +/- 292 to 1,344 +/- 456 receptors/cell, difference not significant). It is concluded that metoprolol therapy is associated with improvements in rest and exercise ventricular performance and maximal aerobic capacity. These improvements are associated with a decline in resting sympathetic nervous system activity.

Effect of endurance exercise training on heart rate variability at rest in healthy young and older men.

Heart rate variability (HRV) (SD of the RR interval), an index of parasympathetic tone, was measured at rest and during exercise in 13 healthy older men (age 60 to 82 years) and 11 healthy young men (age 24 to 32 years) before and after 6 months of aerobic exercise training. Before exercise training, the older subjects had a 47% lower HRV at rest compared with the young subjects (31 +/- 5 ms vs 58 +/- 4 ms, p = 0.0002). During peak exercise, the older subjects had less parasympathetic withdrawal than the young subjects (-45% vs -84%, p = 0.0001). Six months of intensive aerobic exercise training increased maximum oxygen consumption by 21% in the older group and 17% in the young group (analysis of variance: overall training effect, p = 0.0001; training effect in young vs old, p = NS). Training decreased the heart rate at rest in both the older (-9 beats/min) and the young groups (-5 beats/min, before vs after, p = 0.0001). Exercise training increased HRV at rest (p = 0.009) by 68% in the older subjects (31 +/- 5 ms to 52 +/- 8 ms) and by 17% in the young subjects (58 +/- 4 ms to 68 +/- 6 ms). Exercise training increases parasympathetic tone at rest in both the healthy older and young men, which may contribute to the reduction in mortality associated with regular exercise.

Improved care for patients on a new geriatric evaluation unit.

An analysis is presented of a geriatric evaluation unit (GEU) established at the Sepulveda VA Medical Center in 1979 to provide comprehensive interdisciplinary assessment and treatment of geriatric inpatients. The data on 74 patients admitted during the first year show that major improvements can occur in several outcome areas. Placement location was improved over expectations in 48.4 percent of patients, thus permitting a higher level of independence with a lower level of care requirements. Functional status (Katz ADL scale) improved in two-thirds of the patients who could have shown improvement. An average of almost four new treatable disorders not noted by previous physicians were diagnosed per patient. The mean daily number of prescribed drugs was reduced by 32 percent per patient, and the total number of drug doses by 43 percent. Though limited by the unique aspects of the vA situation and by lack of a control group, the findings lend support to the efficacy and value of the GEU concept. (A randomized controlled study is in progress.)

The Sepulveda VA Geriatric Evaluation Unit: data on four-year outcomes and predictors of improved patient outcomes.

Data from its first four operating years indicate that the Sepulveda VA Geriatric Evaluation Unit is having consistent beneficial effects on patient care. These benefits include improved diagnostic accuracy, reduced use of drugs, improved functional status, and improved placement location. However, not all patients benefit equally, and differences between patient responses highlight the need to select those who will benefit most from relatively costly Geriatric Evaluation Unit services. Discriminant and regression analyses were performed on 98 consecutive patients to determine which patients admitted to the Geriatric Evaluation Unit would show greatest improvement in terms of placement, functional status, one-year survival, and living location, and which patients would be treated most efficiently in terms of length of stay. Patient characteristics on admission significantly associated with discharge home included a relatively high functional and cognitive status, the absence of an unstable medical problem, and not being expected to need nursing home placement by the referring physician. The latter two factors alone predicted actual placement location on the next 101 patients admitted to the Geriatric Evaluation Unit with high predictive accuracy (88.5 per cent). Factors predictive of patients whose functional status would improve on the Geriatric Evaluation Unit included absence of an unstable medical problem and being over 75 years old (predictive accuracy was 82.5 per cent). Two major factors associated with long patient stays on the Geriatric Evaluation Unit were low functional status scores and not living in own home or with family. These analyses indicate criteria that may be useful in selecting patients for inpatient geriatric evaluation and rehabilitation programs.

The Seattle FICSIT/MoveIt study: the effect of exercise on gait and balance in older adults.

While exercise is generally recommended for older adults, the specific role of exercise in preventing falls and frail health is unclear. The Seattle FICSIT/MoveIt study is a population-based, randomized, controlled trial comparing the effects of three 6-month exercise interventions (endurance training, strength training, or combined endurance and strength training), and three 3-month endurance training interventions (stationary cycle, walking, or aerobic movement). Primary study outcomes are aerobic capacity, strength, gait, balance, and physical functional status. The study enrolls adults age 68-85 who have leg weakness and impaired gait. It differs from most previous community-based exercise studies in several respects: recruitment of subjects from a defined population; eligibility criteria based upon physiologic and functional status deficits; random assignment to exercise groups; assessment of both physiologic and functional status outcomes; follow-up beyond the completion of supervised exercise; and a large sample size (Total N = 180).

Beta-adrenergic receptor downregulation and recovery in heart and lung in the Fischer 344 rat: effects of aging and correlation with mRNA levels.

Using indirect methods to downregulate beta-adrenergic receptor (BAR) density, several investigators have observed an aging-related delay in the recovery of BAR density after downregulation and suggested this finding may in part explain the decreased beta-adrenergic responsiveness associated with aging. We downregulated BAR density in male Fischer 344 rats ages 3, 12, and 24 months using the direct BAR agonist, metaproterenol. Lung and heart BAR density and BAR mRNA levels were measured daily for 5 days during recovery. Heart BAR density was downregulated significantly more in the 24-month compared to the 3-month-old animals (ANOVA p < .05). The rate of recovery of heart BAR density was greater in the 24-month compared to the 3-month-old animals (ANOVA, p = .05). Lung BAR density showed no significant age-related differences at baseline, after downregulation, or during recovery. There was no significant change in lung or heart BAR mRNA levels observed in association with downregulation of BAR density. The previously documented decrease in myocardial beta-adrenergic responsiveness with aging in this animal appears to not be related to delayed or incomplete recovery of BAR density after agonist-induced downregulation, but may be associated with greater initial downregulation of heart BAR density.

The effect of intensive endurance exercise training on body fat distribution in young and older men.

Little is known about the effects of exercise interventions on the distribution of central and/or intra-abdominal (IA) fat, and until now there were no studies in the elderly. Therefore, in this study we investigated the effects of an intensive 6-month endurance training program on overall body composition (hydrostatic weighing), fat distribution (body circumferences), and specific fat depots (computed tomography [CT]), in healthy young (n = 13; age, 28.2 +/- 2.4 years) and older (n = 15; age, 67.5 +/- 5.8 years) men. At baseline, overall body composition was similar in the two groups, except for a 9% smaller fat free mass in the older men (P less than .05). The thigh and arm circumferences were smaller (P = .001 and P less than .05, respectively), while the waist to hip ratio (WHR) was slightly greater in the older men (0.92 +/- 0.04 v 0.97 +/- 0.04, P less than .01). Compared with the relatively small baseline differences in body composition and circumferences, CT showed the older men to have a twofold greater IA fat depot (P less than .001), 48% less thigh subcutaneous (SC) fat (P less than .01), and 21% less thigh muscle mass (P less than .001). Following endurance (jog/bike) training, both the young (+18%, P less than .001) and the older men (+22%, P less than .001) significantly increased their maximal aerobic power (VO2max). This was associated with small but significant decrements in weight, percent body fat, and fat mass (all P less than .001) only in the older men.(ABSTRACT TRUNCATED AT 250 WORDS)