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PubMed2006

A web-based study concept designed to progress clinical research for 'orphan' disease areas in haematological oncology in the elderly: the SHIELD programme.

Clinical randomised trials (RCT) in elderly populations with haematological malignant disease are rare and difficult to perform. This paper describes the methodology and process of organising an internet-based international programme for Hodgkin's lymphoma in the >60 years age group in a format which is compliant with the European Clinical Trials Directive (EUCTD). International agreement was obtained on the need for a web-based data collection system for basic registration and evaluation which incorporated an electronic case report system (eCRF) for a Phase II Study. Objective assessments of co-morbidity, activities of daily living (ADL) and instruments of daily living (IADL) were built-in to define objective frailty, linked to physician treatment choice or inclusion on the Study protocol. The programme is now operating effectively in the UK and Germany and provides an organisational model of how research in 'orphan' disease areas of haematological and solid tumour oncology, previously considered very difficult, might be overcome.

Activities of Daily Living↗

PubMed2005

Pharmacological and clinical aspects of antiepileptic drug use in the elderly.

In this article, epidemiological and clinical aspects related to the use of antiepileptic drugs (AEDs) in the elderly are highlighted. Studies have shown that people with epilepsy receiving AED treatment show important deficits in physical and social functioning compared with age-matched people without epilepsy. To what extent these deficits can be ascribed to epilepsy per se or to the consequences of AED treatment remains to be clarified. The importance of characterizing the effects of AEDs in an elderly population is highlighted by epidemiological surveys indicating that the prevalence of AED use is increased in elderly people, particularly in those living in nursing homes. Both the pharmacokinetics and the pharmacodynamics of AEDs may be altered in old age, which may contribute to the observation that AEDs are among the drug classes most commonly implicated as causing adverse drug reactions in an aged population. Age alone is one of several contributors to alterations in AED response in the elderly; other factors include physical frailty, co-morbidities, dietary influences, and drug interactions. Individualization of dosage, avoidance of unnecessary polypharmacy, and careful observation of clinical response are essential for an effective and safe utilization of AEDs in an elderly population.

Aged↗

PubMed2005

Muscle mass loss in Rhesus monkeys: age of onset.

Sarcopenia, the decline in skeletal muscle mass and function with age, contributes to increased frailty and decreased functional performance in the aging human population. The negative health consequences of muscle mass loss emphasize the need for development of a nonhuman primate model for the prevention or attenuation of sarcopenia. The age of onset for muscle mass loss in Rhesus macaques was determined using three datasets; (i) dual-energy X-ray absorptiometry (DXA) data from a cross-sectional study of 90 adult Rhesus monkeys; (ii) lean tissue mass and estimated skeletal muscle mass (ESM) from 727 DXA scans taken in 38 monkeys in a long-term, longitudinal aging study; and, (iii) quadriceps weights taken at necropsy from 13 male and 28 female Rhesus monkeys. These data indicate that both male and female Rhesus monkeys develop sarcopenia with age. The onset of sarcopenia is 14.1 +/- 2.8 years in females and 15.8 +/- 2.5 years in males. Muscle loss reaches 20% in males by 23.2 years of age and in females by 24.5 years of age. Furthermore, our data indicate percentage declines in ESM similar to those seen in humans with advancing age. These data support the suitability of the Rhesus monkey as a primate sarcopenia model.

Absorptiometry, Photon↗

PubMed2006

Sarcopenia in the Caenorhabditis elegans pharynx correlates with muscle contraction rate over lifespan.

In muscles, sarcopenia, the loss of muscle mass, is the major cause of aging-related functional decline and frailty. Several factors are correlated with sarcopenia during aging, including contraction-related cellular injury, oxidative stress, endocrine changes and reduced regenerative potential. However the involvement of these factors has not been experimentally investigated. Here, we report that contraction-related injury may significantly promote the progression of sarcopenia in the pharynx of the nematode, Caenorhabditis elegans, a model of aging in non-regenerative tissues. Both functional and structural declines in the pharynx during aging were significantly delayed in mutants with reduced muscle contraction rates. We also examined the role of bacteria in pharynx muscle decline during aging, as previous studies reported that antimicrobial treatments could extend C. elegans lifespan. Although microbial infection may have enhanced functional decline in the pharynx during aging, it was not the sole cause of decreased pumping rates in old animals. This study identifies contraction-related injury as a factor affecting the initiation and progression of sarcopenia during aging. Further, characterization of the specific types of damage induced by muscle contraction will be helpful for understanding the underlying causes of sarcopenia.

Aging↗

PubMed2006

A cross-national study of transitions in deficit counts in two birth cohorts: implications for modeling ageing.

Generally, health does not improve with age, and many physical and physiological functions are known to decline. These changes do not occur uniformly, however; for many reasons, some people experience significant improvement in their health over non-trivial time intervals. Earlier, we showed that 5-year transitions in health status in elderly people (age 65+ years) can be modeled as a stochastic process, using a modified Poisson distribution with four readily interpretable parameters. The original description was based on follow-up of a single cross-sectional study, thus mixing age and cohort effects. Here, we again used a multistate Markov chain to model 5-year deficit accumulation in relation to frailty in both a Swedish birth cohort (aged 70 years at inception) and, from the original cross-sectional study, a Canadian birth cohort, aged 69-71. In both datasets, we found again that a modified Poisson describes the transition in health status with high precision. The parameters of the model though different, are close to each other, even though the cohorts are from different countries, were assembled 20 years apart, and counted different deficits. The model suggests that all health transitions, including health improvement, worsening, and death, can be summarized in a unified stochastic model with a few interpretable parameters.

Aged↗

PubMed2006

Age associated differences in postural equilibrium control: a comparison between EQscore and minimum time to contact (TTC(min)).

Increased postural instability and the subsequent elevation in fall incidence with increasing age are important contributors for hip fractures and developing frailty. When testing for such instability, most studies characterize balance in terms of center-of-mass (COM) deviation from a finite point, the "equilibrium point", located at the center of a subject's stance. For example, the clinically accepted equilibrium score (EQscore) represents instability as the maximum peak-to-peak sway about the "equilibrium point". An alternative theory views balance as being controlled within a "stability margin" in which all corrective actions are based on the time to contact (TTC) of the body's COM with that margin. This study examines the differences offered by evaluating balance control using the EQscore and TTC approach across several age groups and sessions. Consenting subjects from the Baltimore Longitudinal Study of Aging were recruited (N=155) from each age decade (20s-80s) who were generally healthy and free from neurological diagnoses. Results showed TTC tests detected significant variations in eyes open versus eyes closed testing that were unpredictable by EQscore. Further, TTC produced differences in age-related stability threats not seen using EQscore. The TTC data also provided a discriminating difference between subjects who fell in the difficult tests and those who maintained posture. Overall, these data suggest EQscore might not sufficiently account for dynamic control components the body may be using to maintain balance. TTC may offer a more accurate estimate of postural stability (functional ability) than EQscore based on its inclusion of a velocity component to detect dynamic changes.

Accidental Falls↗

PubMedDate not supplied

How do self-care routines of nursing home residents compare with past self-care practices?

This article compares the self-care routines of nursing home residents with those customarily practiced when individuals were able to care for themselves. Participants were 20 nursing home residents, their spouses, and nursing assistants. Self-care routines were assessed using the Self-maintenance Habits and Preferences in Elderly (SHAPE) questionnaire. More items change than remain the same. Items most likely to change are those dealing with timing or duration. Routines become more simplified after admission and reflect the increased frailty of residents. Self-care becomes more important overall. Spouses are unable to indicate whether current and past self-care practices are the same slightly over half of the time, but nursing assistants are almost totally lacking in the knowledge of previous self-care routines. Knowledge of changes in self-care routines can be used to guide interventions to bring past and current practices into greater concordance.

Activities of Daily Living↗

PubMed2006

Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia.

Some cytokines have been involved in the pathogenesis of late onset Alzheimer's disease (LOAD). A possible increase in plasma cytokines levels has been reported in LOAD and vascular dementia (VD), but the results of previous studies are conflicting. We evaluated the plasma levels of IL-6, TNF-alpha, IL-1beta, and IL-10 in four groups of older individuals: 60 patients with LOAD, 80 patients with VD, 40 subjects with cerebrovascular disease but without dementia (CDND), and 42 controls (C). By analysis of covariance (adjustment for age, gender, coronary heart disease, diabetes, hypertension, smoking, and alcohol consumption) we found that: *IL-1beta was higher in VD, LOAD, and CDND compared with controls (p<0.005). *TNF-alpha was higher in VD and LOAD compared to C (p<0.05), and in VD compared to LOAD (p<0.03). *IL-6 was higher in VD compared with LOAD (p<0.03). No differences in IL-10 values were found (Kruskal-Wallis, Asymp. Sig. 0.14). By logistic regression analysis, we demonstrated that high levels (defined as above the median) of IL-1beta and TNF-alpha, but not of IL-6, were associated with increased likelihood of having VD and LOAD compared to C, while high IL-6 levels were associated with a increased probability of having VD, compared with LOAD. Our study support the notion of a low-grade systemic inflammation in older patients with LOAD or VD, characterized by an increase in plasma IL-1beta and TNF-alpha levels. The high IL-6 levels found in VD might be not a specific finding, as it might come from several conditions including atherosclerosis and related vascular risk factors, comorbidity, and frailty.

Aged↗

PubMed2006

Modeling human mortality using mixtures of bathtub shaped failure distributions.

Aging and mortality is usually modeled by the Gompertz-Makeham distribution, where the mortality rate accelerates with age in adult humans. The resulting parameters are interpreted as the frailty and decrease in vitality with age. This fits well to life data from 'westernized' societies, where the data are accurate, of high resolution, and show the effects of high quality post-natal care. We show, however, that when the data are of lower resolution, and contain considerable structure in the infant mortality, the fit can be poor. Moreover, the Gompertz-Makeham distribution is consistent with neither the force of natural selection, nor the recently identified 'late life mortality deceleration'. Although actuarial models such as the Heligman-Pollard distribution can, in theory, achieve an improved fit, the lack of a closed form for the survival function makes fitting extremely arduous, and the biological interpretation can be lacking. We show, that a mixture, assigning mortality to exogenous or endogenous causes, using the reduced additive and flexible Weibull distributions, models well human mortality over the entire life span. The components of the mixture are asymptotically consistent with the reliability and biological theories of aging. The relative simplicity of the mixture distribution makes feasible a technique where the curvature functions of the corresponding survival and hazard rate functions are used to identify the beginning and the end of various life phases, such as infant mortality, the end of the force of natural selection, and late life mortality deceleration. We illustrate our results with a comparative analysis of Canadian and Indonesian mortality data.

Adolescent↗

PubMed2005

The voyage to healthy longevity: from experimental models to the ultimate goal.

Understanding mechanisms underlying longevity, and endeavor towards the specific goals of alleviating frailty in old age, require a comprehensive approach that considers the various theoretical and experimental approaches, as well as compiling the data on humans. This logistic has underlined the program of the conference, and is reflected in the present special issue. Considerable volume of data now point to distinct genes that are associated with exceptional longevity in humans, as reflected from the articles in this volume. However, this symposium also highlighted non-genetic effects, including physical, mental and social activities, and elucidate the relevant underlying mechanisms. The symposium focused on understanding the basis of human longevity coupled to extended health-span and function into old age.

Aged↗

PubMed2005

1267 HSP70-2 polymorphism as a risk factor for carotid plaque rupture and cerebral ischaemia in old type 2 diabetes-atherosclerotic patients.

Patients with type 2 diabetes mellitus (NIDDM) are at risk for macrovascular disease complications, such as myocardial infarction (MI) or stroke from plaque rupture. Cytokines play a key role in plaque vulnerability. IFN-gamma inhibits collagen synthesis thereby affecting plaque stability. High IL-6, TNF-alpha, and dyslipidemia are risk factors for thrombosis. Abnormal increments of HSP70 in atherosclerotic plaques might lead to plaque instability and rupture caused by chronic inflammation, which up-regulates the expression of pro-inflammatory cytokines (IL-6 and TNF-alpha) in human monocytes. Studies of a polymorphic PstI site lying in the coding region at position 1267 of the HSP70-2 gene have shown that the BB genotype is associated with NIDDM. We screened 60 old NIDDM patients with carotid stenosis and 107 old healthy controls for 1267 HSP70-2 polymorphism in order to establish if an association with plaque frailty exists. Different genotypic distributions were observed between patients and healthy controls. An increased relative risk was associated with the B allele (p = 0.0107; odds ratio = 1.861). HSP70-2, IL-6, IFN-gamma, TNF-alpha gene expressions within the plaques and serum levels of triglyceride, total cholesterol and LDL cholesterol were tested from patients stratified according to their B+ (AB and BB) and B- (AA) genotypes. Plaque morphology (soft or fibrous-calcified) and the incidence of cerebral ischaemia were also assessed. B+ patients showed increased HSP70-2, IL-6, IFN-gamma, TNF-alpha and dyslipidemia as compared to B- carriers. The frequency of soft plaques increased in B+ in comparison to B- patients (67% versus 13%; odds ratio 13.0, p = 0.0006). A higher frequency of cerebral ischaemia (ictus or transient ischaemic attack (TIA)) was present in B+ than in B- genotype (53% versus 20%; odds ratio 4.57, p < 0.05) Hence, 1267 HSP70-2 polymorphism may be of use in identifying B+ NIDDM patients at risk for carotid plaque rupture and cerebral ischaemia.

Aged↗

PubMed2006

Accumulation of health disorders as a systemic measure of aging: Findings from the NLTCS data.

BACKGROUND: An index of age-associated health/well-being disorders (deficits), called the "frailty index" (FI), appears to be a promising characteristic to capture dynamic variability in aging manifestations among age-peers. In this study we provide further support toward this view focusing on the analysis of the FI age patterns in the participants of the National Long Term Care Survey (NLTCS). METHODS: The NLTCS assessed health and functioning of the U.S. elderly in 1982, 1984, 1989, 1994, and 1999. Detailed information for our sample was assessed from about 26,700 interviews. The individual FI is defined as a proportion of health deficits for a given person. RESULTS: The FI in the NLTCS exhibits accelerated age patterns. The acceleration is larger for elderly who, at younger ages, had a lower FI (low FI group) than for those who showed a higher FI at younger ages (high FI group). Age-patterns for low and high FI groups tend to converge at advanced ages. The rate of deficit accumulation is sex-sensitive. CONCLUSIONS: The accelerated FI age patterns suggest that FI can be considered as a systemic measure of aging process. Convergence of the (sex-specific) FI age patterns for low and high FI groups by extreme ages might reflect the limit of the FI-specific (or systemic) age as well as the limit of adaptation capacity in aging individuals.

Age Distribution↗

PubMed2006

Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans.

A large part of the aging phenotype, including immunosenescence, is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status we proposed to call inflammaging. Within this perspective, healthy aging and longevity are likely the result not only of a lower propensity to mount inflammatory responses but also of efficient anti-inflammatory networks, which in normal aging fail to fully neutralize the inflammatory processes consequent to the lifelong antigenic burden and exposure to damaging agents. Such a global imbalance can be a major driving force for frailty and common age-related pathologies, and should be addressed and studied within an evolutionary-based systems biology perspective. Evidence in favor of this conceptualization largely derives from studies in humans. We thus propose that inflammaging can be flanked by anti-inflammaging as major determinants not only of immunosenescence but eventually of global aging and longevity.

Aging↗

PubMed2006

Cumulative index of health disorders as an indicator of aging-associated processes in the elderly: results from analyses of the National Long Term Care Survey.

BACKGROUND: We employ an approach based on the elaborated frailty index (FI), which is capable of taking into account variables with mild effect on the aging, health and survival outcomes, and investigate the connections between the FI, chronological age and the aging-associated outcomes in the elderly. METHODS: Cross-sectional analysis of pooled data from the National Long Term Care Survey (NLTCS) assessing health and functioning of the U.S. elderly in 1982, 1984, 1989, 1994, and 1999. RESULTS: Distributions of frequency, residual life span, mortality rate, and relative risk of death are remarkably similar over age and FI. Coefficients of correlation between FI and age are low both for males (0.127, p<.01) and females (0.221, p<.01). The FI-specific age patterns show deceleration at advanced ages. The FI can provide order of magnitude better resolution in estimating mean remaining life span compared to age. Males have smaller FI than females while males' mortality risks are higher. For short-time horizons, the FI and age are largely independently associated with mortality risks. CONCLUSIONS: The FI: (i) can be considered as an adequate sex-specific indicator of the aging-associated processes in the elderly, (ii) can characterize these processes independently of age, and (iii) is a better characteristic of the aging phenotype than chronological age.

Age Factors↗

PubMed2005

A random effects model for multistate survival analysis with application to bone marrow transplants.

We present an extension of the non-homogeneous Markov model for a bone marrow transplant recovery process which allows for possible associations between the transition intensities. The associations between intensities are modeled by a correlated gamma frailty model. Based on a parametric model for the conditional transition intensities, we obtain estimates of the model parameters. We use these estimates to make predictions of patient's eventual prognosis given the current medical history of the patient. Estimates of the uncertainty in our predictions are obtained by a modified bootstrap technique.

Bone Marrow Transplantation↗

PubMed2006

The older cancer patient.

Providing effective and tolerable cancer treatment for the growing number of older adult patients who have cancer will require an understanding of the role of aging, comorbidity, functional status, and frailty on treatment outcomes. The incorporation of CGA into the care of older patients who have cancer will ensure that the heterogeneity of this population is considered in the development of treatment plans. It also may improve outcomes by identifying and optimally treating comorbid conditions and functional impairments. Optimal treatment of the older adult patient who has cancer starts with careful delineation of goals through conversation. The treatment plan should be comprehensive and address cancer-specific treatment, symptom-specific treatment, supportive treatment modalities, and end-of-life care.

Aged↗

PubMed2006

Cardiovascular dysautonomia as a cause of falls in Parkinson's disease.

Parkinson's disease (PD) patients have a ninefold increased risk of recurring falls compared to healthy controls. The risk of falling due to cardiovascular dysautonomia (CVD) is not quantifiable. But, CVD is an integral part of the disease and at least 20% of PD patients suffer from orthostatic hypotension, an expression of CVD. One way to reduce falls due to CVD in PD patients could be to give adequate information on the relationship between falling risks and cardiovascular dysautonomia to patients and their caregivers. Moreover, drugs given for PD might contribute to OH and we propose that education and non-pharmacological strategies for its treatment might be preferable, especially because of the low efficacy of drugs available for the treatment of OH and the frailty of elderly PD patients.

Accidental Falls↗

PubMed2005

The effectiveness of a bibliotherapy in increasing the self-management ability of slightly to moderately frail older people.

OBJECTIVE: Self-management ability (SMA) is the ability to obtain those resources necessary for the production of well-being. With age, SMA becomes increasingly important, if one has a large variety of resources, physical and psychosocial losses due to the aging process can be substituted or compensated for. This study examined whether an increase in SMA would ensure sustainable levels of positive well-being among slightly to moderately frail older people. METHODS: A bibliotherapy was developed to increase the SMA of slightly to moderately frail older people, and to help these persons to sustain a certain level of well-being. The effectiveness of this bibliotherapy was examined by comparing the SMA, mastery, and subjective well-being of 97 older people participating in the bibliotherapy to those of 96 older people in a delayed-treatment control condition. RESULTS: The bibliotherapy resulted in a significant increase in SMA and mastery compared to the delayed-treatment control condition, and for SMA, this effect still existed 6 months after the intervention. The increase in SMA among older people who received the bibliotherapy prevented a decline in well-being as expected, but only in the short-term. CONCLUSION: The current findings show that it is possible to counteract an age-related decline in well-being, even with only slight to moderate levels of frailty. PRACTICE IMPLICATIONS: Cheap and easily accessible interventions, like the self-management bibliotherapy described in this article, may provide a useful addition to more traditional gerontological interventions.

Activities of Daily Living↗