Predicting cognitive ability in ageing cohorts using Type 2 diabetes genetic risk.

AIMS: To investigate whether there is overlap in the genetic determinants of Type 2 diabetes and cognitive ageing by testing whether a genetic risk score for Type 2 diabetes can predict variation in cognitive function in older people without dementia. METHODS: Type 2 diabetes genetic risk scores were estimated using various single nucleotide polymorphism significance inclusion criteria from an initial genome-wide association study, the largest in Type 2 diabetes to date. Scores were available for 2775-3057 individuals, depending on the cognitive trait. RESULTS: Type 2 diabetes genetic risk was associated with self-reported diabetes mellitus. Across varying single nucleotide polymorphism-inclusion levels, a significant association between Type 2 diabetes genetic risk and change in general cognitive function was found (median r = 0.04); however, this was such that higher Type 2 diabetes genetic risk related to higher cognitive scores. CONCLUSIONS: To investigate more fully the source of the often observed comorbidity between Type 2 diabetes and cognitive impairment, one direction for future research will be to use cognitive ability polygenic risk scores to predict Type 2 diabetes in line with the reverse causation hypothesis that people with lower pre-morbid cognitive ability are more likely to develop Type 2 diabetes.

Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels.

The cellular and molecular mechanisms underlying the effects of aging on human cutaneous wound healing are poorly understood, and the possible role of reproductive hormones in this process has never been investigated. We report that aging in healthy females was associated with a reduced rate of cutaneous wound healing, but an improved quality of scarring both microscopically and macroscopically, and with reduced levels of transforming growth factor-beta1 (TGF-beta1) immunostaining and steady-state mRNA in the wound. These age-related changes were reversed by the systemic administration of hormone replacement therapy (HRT). Moreover, ovariectomized young female rodents exhibited a marked delay in repair of acute incisional wounds, which was reversed by the topical application of estrogen. The cellular mechanism underlying these changes appears to involve an estrogen-induced increase in latent TGF-beta1 secretion by dermal fibroblasts. These results suggest that both the rate and quality of wound healing depend on reproductive hormone levels.

Relationship between self-reported prevalence of diabetes mellitus using the Cornell Medical Index (CMI) and prevalence determined by glycosylated hemoglobin (HbA(1c)) in an elderly community-dwelling population.

Reports of diabetes mellitus samples in community-dwelling unselected populations suggest a prevalence of 6%. A further 3% of unknown diabetes mellitus subjects are suggested when using formal biochemical methods of diagnosis. In this study, we present the prevalence of diabetes mellitus by self-reports using the CMI and concomitant biochemical detection in 436 community-dwelling older adults who have participated in a 20-year-study of age and cognitive performance in Manchester, UK. Twenty-three of the group reported that they had diagnosed diabetes mellitus, three individuals had a raised HbA(1c) of greater than 7.0% on random testing, but no knowledge of having diabetes mellitus. These individuals were re-contacted and three said they subsequently had a diagnosis of diabetes mellitus made within the two years following the questionnaire. We conclude that in an older population of community-dwelling subjects the numbers of undiagnosed cases of diabetes mellitus is lower than anticipated, based on large unselected population samples. The greater opportunity to interact with health care professionals who may consider screening for diabetes mellitus may explain these findings.

Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model.

The concept that aging impairs wound healing is largely unsubstantiated, the literature being contradictory because of poor experimental design and a failure to adequately characterize animal models. This study tested the hypothesis that aging retards the rate of wound repair using standardized cutaneous incisional wounds in a well-characterized aging mouse colony. Against the background of age-related changes in normal dermal composition, marked differences in healing were observed. Immunostaining for fibronectin was decreased in the wounds of the old mice, with a delay in the inflammatory response, re-epithelialization, and the appearance of extracellular matrix components. Heparan sulfate and blood vessel staining were both unexpectedly increased in the wounds of the old animals at late time points. Despite an overall decrease in collagen I and III deposition in the wounds of old mice, the dermal organization was surprisingly similar to that of normal dermal basket-weave collagen architecture. By contrast, young animals developed abnormal, dense scars. Intriguingly, some of these age-related changes in scar quality and inflammatory cell profile are similar to those seen in fetal wound healing. The rate of healing in young animals appears to be increased at the expense of the scar quality, perhaps resulting from an altered inflammatory response.

Ageing and the immune response--a unifying hypothesis?

In this article we review the abnormalities in immune function which have been described in relation to ageing. It is suggested that thymic involution may not be the only underlying cause. Many similar changes can be induced by the endotoxins from the cell walls of Gram-negative bacteria. The colon is a large repository for these organism and bacterial breakdown products are found in portal venous blood. Spillover into the peripheral circulation is prevented by the hepatic Kupffer cells degrading these substances. A waning in Kupffer cell function is well documented in association with ageing and there may be spillover of endotoxins into the peripheral circulation in elderly individuals. It is suggested that such spillover of endotoxins may contribute to some of the immunological changes previously attributed to ageing.

Assessment of neutrophil function in the elderly using antibody coated polyacrylamide gel (immunobeads) and nitroblue tetrazolium (NBT) reduction as a combined test.

Neutrophil function was assessed in 35 elderly individuals (age greater than 75) and 20 normal young individuals (age 20-45) by combining ingestion of antibody coated polyacrylamide gel and nitroblue tetrazolium reduction in a single test. This test evaluates phagocytosis and metabolic integrity simultaneously and appears to be a sensitive and reliable test of neutrophil function. No significant difference was found (by using this test) between neutrophils from healthy elderly people and the neutrophils from young controls, or between the sexes in either age group.

Changes in endotoxin sensitivity in ageing. Absorption, elimination and mortality.

In this paper we describe the influence of ageing on responses to intravenously-injected endotoxin in two rat strains. Old age had no apparent effect on the absorption of 51Cr-labelled endotoxin from either jejunum or colon. Notwithstanding, aged animals appeared much more sensitive than their young counterparts to the lethal effects of intravenously injected endotoxin. Old animals exhibited virtually 100% mortality over the dose range 1-4 mg/100 g body weight while only sporadic deaths were seen in young animals. One consistent feature of dying animals was a profound and progressive hypothermia. At post mortem examination, the major findings were in the liver (leukocyte infiltrates and hepatocellular necrosis) and kidneys (acute tubular necrosis). Ageing was associated with slower removal of endotoxin from the circulation but not to an extent that could reasonably account for the enhanced sensitivity to endotoxin toxicity.

Endotoxin-induced liver injury in aged and subacutely hypervitaminotic A rats.

The plasma disappearance of endotoxin and endotoxin-induced hepatic injury were studied in two rat models: the aging rat and the subacutely hypervitaminotic A rat. The choice of these models was based on their respective association with a decreased or increased Kupffer cell endocytic activity. The half-life of endotoxin (E. coli O26: B6, phenol extracted) in plasma was significantly prolonged in aged rats as measured by both the Limulus assay (t1/2 = 2.1 +/- 0.1 h in 3-6-month-old, and 3.3 +/- 0.3 h in 24-36-month-old rats) and 51Cr-labeled endotoxin radioactivity assay (t1/2 = 5.3 +/- 0.3 h in 3-6-month old and 7.7 +/- 0.6 h in 24 36-month-old rats). In subacute hypervitaminosis A, the half-life of endotoxin was significantly decreased in the Limulus assay (t1/2 = 2.1 +/- 0.1 h in 3-6-month old and 1.4 +/- 0.2 h in subacutely hypervitaminotic A rats), but not in the radioactivity assay (t1/2 = 5.3 +/- 0.3 h in 3-6-month-old and 5.0 +/- 0.4 h in subacutely hypervitaminotic A rats). Hundred percent mortality was observed at a dose of 2 mg endotoxin/100 g body wt. in old rats, but not in young rats. Only 1 of 7 young subacutely hypervitaminotic A rats died following injection of this dose of endotoxin. The dose of endotoxin which caused only minimal parenchymal liver cell injury in young rats induced substantial parenchymal cell injury in old rats and subacutely hypervitaminotic A rats as determined by both histological and biochemical parameters. It is concluded that some basic characteristics of experimental animals, such as age and nutritional status, can dramatically influence the sensitivity to endotoxin and this is not necessarily correlated with the rate of endotoxin clearance.

On the fibrinolytic system in aged rats, and its reactivity to endotoxin and cytokines.

Aged rats are more susceptible to endotoxin-induced effects, including microthrombosis and platelet aggregation, than are young rats. To investigate whether changes in the fibrinolytic system might be involved, we investigated the fibrinolytic activity in plasma euglobulin fractions and tissues (lung and heart) of young (6-months old) and aged (24-months old) rats under baseline conditions and after challenge with endotoxin. Aged rats had lower plasma levels of tissue-type plasminogen activator (t-PA) and of urokinase-type PA (u-PA) activity. PA inhibitor (PAI) activity was higher in the plasma of aged rats, as was t-PA activity in lung and heart. Rats were treated with either a low dose (1 microgram/kg) or a high dose (10 mg/kg) of endotoxin. Both treatments induced a transient phase of increased blood fibrinolytic activity, as evidenced by higher levels of tissue-type plasminogen activator (t-PA) activity and decreased levels of PA inhibitor (PAI) activity. Over time, the fibrinolytic activity decreased, probably due to increased levels of PA inhibitor. Both the early increase in t-PA activity, and the subsequent increase in PAI activity, were more pronounced in the aged rats, as compared with the younger rats, after the high dose of endotoxin. The aged rats also responded to an injection of interleukin-1 beta or tumor necrosis factor-alpha with a larger increase of PAI activity than did the younger rats. Together the data suggest that, compared to young rats, aged rats have a decreased base-line plasma fibrinolytic activity, while their fibrinolytic system is more responsive to challenge by endotoxin and cytokines.

The relationship between phenazone (antipyrine) metabolite formation and theophylline metabolism in healthy and frail elderly women.

The influence of aging on the metabolism of phenazone (antipyrine), and the relationship between the formation of 3 phenazone metabolites and the metabolic clearance of theophylline in healthy and frail elderly women, were examined. Whereas the elimination half-life did not change, clearance of phenazone decreased by about 50% with age in healthy women receiving phenazone without theophylline. However, the summation of the urinary recovery of phenazone and the measured metabolites, expressed as percentage of the phenazone dose, was lower in the healthy elderly (37 +/- 9% vs 74 +/- 15%). In both healthy and frail females the clearance of formation of 4-hydroxy-phenazone and the metabolic clearance of theophylline correlated strongly (r = 0.93 and 0.90, respectively). In non-healthy elderly females, strong correlations were also observed between the other metabolic pathways of phenazone and the metabolic clearance of theophylline. Coadministration of theophylline in the elderly increased the percentage of the phenazone dose excreted as the measured metabolites. A considerably higher interindividual variability in the disposition of phenazone and theophylline was observed in the frail elderly women. This high degree of variability in drug metabolism may be one of the explanations for the problems often occurring after drug prescription in the elderly.

Ageing and the sensitivity of the adrenal gland to physiological doses of ACTH in man.

Healthy men and women aged 19-38 or 67-83, in whom endogenous ACTH secretion was suppressed with dexamethasone, were given successive injections of 60 ng, 150 ng and 250 micrograms ACTH(1-24) at hourly intervals, and blood samples for measurement of plasma cortisol were taken every 10 min. The response to each injection was taken as the increase in cortisol concentration 20 min later, when there was a peak with the lower doses, with allowance for disappearance of cortisol produced after the previous injection. On average, the responses to 60 and 150 ng ACTH were about 0.4 and 0.7 respectively of the response to 250 micrograms. There were no consistent effects of age or sex on any index of adrenocortical sensitivity or responsiveness, but some groups showed isolated differences from both their age- and sex-matched counterparts: the response to 60 ng ACTH was low in young men, maximal responsiveness was low in elderly men and the slope of the dose-response curve was high in elderly women. In most of the elderly subjects, plasma ACTH was determined separately under normal conditions. It was negatively correlated with the cortisol responses to 60 and 150 ng ACTH, suggesting that differences in adrenal sensitivity between subjects contribute to the variability of plasma ACTH.

Changes in body composition, brown adipose tissue activity and thermogenic capacity in BN/BiRij rats undergoing senescence.

Metabolic rate, thermogenesis, brown adipose tissue (BAT) activity, and body composition were followed in ageing rats (female BN/BiRij) at 3 to 35.5 months of age. Colonic temperatures were similar in rats at 3 to 23 months of age (37.1-37.6 degrees C), but significantly reduced (36.3 degrees C) in those aged 36 months. Resting oxygen consumption (VO2), corrected for body size, was comparable in all groups, but the thermogenic response to noradrenaline was significantly reduced with age. BAT mass was unaffected by age, but brown fat protein content, specific mitochondrial cytochrome oxidase activity, and thermogenic activity (assessed from mitochondrial purine nucleotide binding) all declined markedly with age. Carcass analysis revealed a fall in body protein in very old (35.5 month) rats, but body fat content increased up to 23 months of age and thereafter declined.

Sensitivity of mononuclear leucocytes to glucocorticoids in elderly hip-fracture patients resistant to suppression of plasma cortisol by dexamethasone.

OBJECTIVE: Elderly women with proximal femur fracture show a prolonged increase in plasma cortisol, which could have undesirable catabolic effects. Suppression of cortisol by dexamethasone is impaired, suggesting resistance to glucocorticoid effects at feedback inhibitory sites. We therefore wished to find out whether peripheral glucocorticoid sensitivity is normal. DESIGN: Peripheral blood mononuclear leucocytes were used as a model tissue. Blood samples were taken from elderly women about 2 weeks after hip fracture and from elderly control women. Each patient was then given 1 mg dexamethasone at 2300 h followed by further sampling at 0800 and 1600 h the next day. METHODS: Glucocorticoid-receptor binding parameters were measured by incubating whole cells with [3H]dexamethasone for 2 h at 37 degrees C. Inhibition of cell proliferation by dexamethasone was assessed by addition of [3H]thymidine to cells cultured for 65 h with concanavalin A. Cortisol and dexamethasone concentrations were measured in the dexamethasone suppression test. RESULTS: As expected, the hip-fracture patients had raised morning cortisol concentrations and impaired suppression by dexamethasone. The cells of the patients had similar numbers of glucocorticoid receptors to those of the control subjects but higher values for Kd (i.e. a lower binding affinity). The cells of the patients incorporated less [3H]thymidine than the control cells in the absence of dexamethasone. The percentage inhibition by a saturating concentration of dexamethasone was unchanged but the concentration giving half-maximal inhibition was decreased (sensitivity was increased) at the higher of the two concanavalin A concentrations used. CONCLUSIONS: These experiments in mononuclear leucocytes give no evidence of peripheral resistance to glucocorticoids in hip-fracture patients with impaired suppression of cortisol by dexamethasone.

Gynecologic sepsis as a cause of covert infection in old age.

Three cases of endometritis, which presented covertly in elderly women, are described. All three patients were in a poor state of nutrition, and two had serious intercurrent disease. It is believed that cyclical shedding of the endometrium and "normal" vaginal flora (under the influence of estrogen) are the major defenses against infection. These are lost after the menopause, and were therefore absent in the three patients described here. The waning of the immune response associated with aging, particularly the progesterone-stimulated uptake of polymeric IgA in the endometrium, may be important, as may the immunosuppressive effect of malnutrition. It is suggested that a nonspecific deterioration in an elderly woman or infection of uncertain site should prompt a careful re-examination, including a thorough pelvic examination.

The white nails of old age (neapolitan nails).

Nail changes similar to those reported by Terry and Lindsay were defined in an elderly inpatient population. Two hundred fifty-eight patients were studied, and an overall incidence of 19 per cent was found. There was no significant difference between men and women. The only significant correlations in this study were with osteoporosis and thin skin. Eight men with nail changes were compared with seven men without such changes by calculating the metacarpal index of cortical bone mass. The index was much lower in patients with nail changes (t = 2.64; P less than 0.01). All patients with nail changes had thin skin. No correlations were found with serum albumin, liver function, or kidney function. These nail changes are less frequent in the "less frail" elderly living in the community. Changes of the Terry type are common in children but disappear by early adult life. It is suggested that the nail changes are age-related phenomena and that they may reflect an underlying disturbance of collagen being manifested as changes in the nail bed, skin, and bone.

The frequency of physical signs usually attributed to meningeal irritation in elderly patients.

Nuchal rigidity, which may be a sign of meningitis, was found in 35 per cent of geriatric patients on acute-care and rehabilitation wards and in 13 per cent of younger patients on an acute-care ward. It was significantly associated with cerebrovascular disease, confusion, abnormal plantar responses, and primitive reflexes. Elderly patients who have nuchal rigidity with no history of neurologic or cognitive disorders should be investigated for meningitis.

The effect of aging on skeletal muscle capillarization in a murine model.

Capillarization of skeletal muscle has been reported to be both maintained and reduced with advancing age. This conflict may represent methodological differences between biopsy studies. We have examined capillarization throughout two muscles, soleus and extensor digitorum longus (EDL), from a well-established colony of aging mice, and related this to fiber number (C/F ratio) and type. Labeling of muscle capillaries was performed with the biotinylated Griffonia (Bandeiraea) simplicifolia lectin (GSL 1) using immunochemistry. The results showed a significant increase in the C/F ratio in the aged mice when compared with the younger (6-month mice soleus = 1.296, 95% CI 1.226-1.366 vs 28-month mice soleus = 1.530, 95% CI 1.488-1.572, p <.001; 6-month mice EDL = 0.881, 95% CI 0.751-1.011 vs 28-month mice EDL = 1.124, 95% CI 1.028-1.220, p = .017). These differences could not be accounted for by changes in fiber type but may reflect loss of fibers. Alternatively, there may be increased angiogenic drive or a failure of downregulation of angiogenesis.

New approach to risk determination: development of risk profile for new falls among community-dwelling older people by use of a Genetic Algorithm Neural Network (GANN).

BACKGROUND: Falls risk in older people is multifactorial and complex. There is uncertainty about the importance of specific risk factors. Genetic algorithm neural networks (GANNs) can examine all available data and select the best nonlinear combination of variables for predicting falls. The aim of this work was to develop a risk profile for operationally defined new falls in a random sample of older people by use of a GANN approach. METHODS: A random sample of 1042 community-dwelling people aged 65 and older, living in Nottingham, England, were interviewed at baseline (1985) and survivors reinterviewed at a 4-year follow-up (n = 690). The at-risk group (n = 435) was defined as those survivors who had not fallen in the year before the baseline interview. A GANN was used to examine all available attributes and, from these, to select the best nonlinear combination of variables that predicted those people who fell 4 years later. RESULTS: The GANN selected a combination of 16 from a potential 253 variables and correctly predicted 35/114 new fallers (sensitivity = 31%; positive predictive value = 57%) and 295/321 nonfallers (specificity = 92%; negative predictive value = 79%); total correct = 76%. The variables selected by the GANN related to personal health, opportunity, and personal circumstances. CONCLUSIONS: This study demonstrates the capacity of GANNs to examine all available data and then to identify the best 16 variables for predicting falls. The risk profile complements risk factors in the current literature identified by use of standard and conventional statistical methods. Additional data about environmental factors might enhance the sensitivity of the GANN approach and help identify those older people who are at risk of falling.

Correlates of tumor size, gender, cell type, and metastasis of resected non-small cell lung cancer and age.

The purpose of this retrospective study was to examine the relationship between tumor volume and age in resected non-small cell lung cancer (NSCLC). Differences exist in the behavior, growth rate, and metastatic potential of solid tumors in both aged humans and experimental animal models. Data from 669 cases of NSCLC resected between 1980 and 1992 were reviewed (445 males; 224 females; median age 67 years, range 16-86). Measurements of the resected tumor in-situ were made in three dimensions, and these were multiplied to give an estimate of the tumor volume. Multiple regression analysis was used to examine the relationship between the tumor volume, age, gender, histological cell type, and TNM nodal score. No direct relationship existed between patient age and tumor volume or nodal score. However, there was a significant relationship between patient gender and tumor volume, i.e., smaller volume tumors in female patients (p = .02). Considering all variables, two relational subgroups were identified: younger male patients with large adenocarcinomas and older female patients with small squamous cell carcinomas (p = .05). We conclude that the relationship between tumor volume and age is complex and dependent on patient gender and tumor cell type.

Effects of the beta 2-adrenoceptor agonist, clenbuterol, on muscle atrophy due to food deprivation in the rat.

The effects of a beta 2-adrenoceptor agonist, clenbuterol, on body weight and protein metabolism of gastrocnemius muscle, heart, and liver were studied in rats subjected to 50% food restriction or fasting. Food restriction by 50% for 7 days caused a complete cessation of growth and reductions in the mass, protein, and RNA content of muscle, heart, and liver. The ratio of RNA to protein content was also suppressed in muscle and heart, but not in liver. Fasting for 3 days caused loss of body weight (BW), reductions in the mass, protein, and RNA content, and the ratio of RNA to protein of gastrocnemius muscle, heart, and liver. Oral administration of clenbuterol (approximately 0.6 mg/kg BW/d) to food-restricted animals did not affect BW, but did increase in the mass, protein, and RNA content, and the ratio of RNA to protein of gastrocnemius muscle. The protein content of heart was also increased. Twice-daily injections of clenbuterol (2 mg/kg body weight/d) to fasting animals had no effect on BW or the mass or protein content of gastrocnemius muscle or liver, but both parameters were stimulated in heart. The results indicate that the anabolic action of clenbuterol are maintained when substrate availability is reduced by food restriction, but this effect is lost during severe protein and energy deficit (fasting).