Editorial: Obesity and Accelerated Aging.

Through shared pathophysiologic mechanisms, obesity exacerbates the age-related decline in physical function, which leads to frailty and disability. Obesity and aging are characterized by chronic low-grade inflammation, which contributes to reduced muscle quality and protein control mechanisms as well as to diminished muscle anabolic response. Obesity causes oxidative stress and inflammation, which increases telomere shortening. Calorie excess increases ROS formation, which damages nucleus, endoplasmic reticulum, and mitochondria and promotes cellular senescence. Given the persistence of DNA damage associated with altered DNA repair proteins in obesity and aging, it is thought that inability to repair DNA may be the principal molecular event that underlies accelerated aging. Calorie restriction in combination with exercise slows biological aging by protecting against the molecular and cellular damages that occur in obesity and aging. Promising approaches such as Time Restricted Eating, Mediterranean Diet, and Senolytics need further investigation.

Effect of Diet, Exercise, or Both on Biological Age and Healthy Aging in Older Adults with Obesity: Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVES: To determine the effect of diet, exercise, and diet-exercise in combination on measures of biological age. DESIGN: Secondary analysis of a 1-year randomized, controlled trial. SETTING: University-based Medical Center. PARTICIPANTS: One-hundred-seven older (age≥65 yrs.) adults with obesity (BMI≥30 kg/m2) were randomized and 93 completed the study. Analyses used intention-to-treat. INTERVENTIONS: Participants were randomized to a control group, a weight-management (diet) group, an exercise group, or a weight-management-plus-exercise (diet-exercise) group. MAIN OUTCOME MEASURES: We calculated Klemera-Doubal Method (KDM) biological age, Homeostatic Dysregulation (HD) score, and Health Aging Index (HAI) score at baseline, and changes at 6- and 12-months. RESULTS: Diet and diet-exercise decreased KDM biological age more than exercise and control (-2.4±0.4, -2.2±0.3, -0.2±0.4, and 0.2±0.5, respectively, P<0.05 for the between group-differences). Diet and diet-exercise also decreased HD score more than exercise and control (-1.0±0.3, -1.1±0.3, 0.1±0.3, and 0.3±0.3 respectively, P<0.05). Moreover, diet-exercise decreased HAI score more than exercise, diet, or control (-1.1±0.2, -0.5±0.2, -0.5±0.2, and 0.0±0.2, respectively, P<0.05). CONCLUSIONS: These findings suggest that diet and diet-exercise are both effective methods of improving biological age, and that biological age may be a valuable method of assessing geroprotective interventions in older humans.

Truncal Fat and Frailty Are Important Predictors of Cognitive Performance among Aging Adults with Obesity.

OBJECTIVES: To explore associations among cognition, frailty, and obesity in older adults. DESIGN: Descriptive, secondary analysis of baseline data from two related lifestyle intervention trials. SETTING: Clinical study open to civilian population through the Center for Translational Research on Inflammatory Diseases at the Veterans Affairs Medical Center in Houston, TX. PARTICIPANTS: One hundred eight community-dwelling adults with obesity, aged 65 or older, recruited consecutively from two lifestyle intervention trials. MEASUREMENTS: Cognition was assessed using Composite Age-Adjusted Scale Score from the National Institutes of Health Toolbox Cognition Battery: Obesity was assessed by body mass index (BMI) and also by truncal fat mas via dual energy x-ray absorptiometry. Frailty was assessed using the Physical Performance Test. RESULTS: A significant linear regression model for cognition revealed frailty as the strongest predictor, followed by sex, and then truncal fat (R2=0.340, p<0.001). CONCLUSION: Cognition among community-dwelling older adults with obese BMI may worsen with greater truncal fat mass. Frailty appears to be an important predictor of cognitive performance in this population.

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines.

The human ageing process is universal, ubiquitous and inevitable. Every physiological function is being continuously diminished. There is a range between two distinct phenotypes of ageing, shaped by patterns of living - experiences and behaviours, and in particular by the presence or absence of physical activity (PA) and structured exercise (i.e., a sedentary lifestyle). Ageing and a sedentary lifestyle are associated with declines in muscle function and cardiorespiratory fitness, resulting in an impaired capacity to perform daily activities and maintain independent functioning. However, in the presence of adequate exercise/PA these changes in muscular and aerobic capacity with age are substantially attenuated. Additionally, both structured exercise and overall PA play important roles as preventive strategies for many chronic diseases, including cardiovascular disease, stroke, diabetes, osteoporosis, and obesity; improvement of mobility, mental health, and quality of life; and reduction in mortality, among other benefits. Notably, exercise intervention programmes improve the hallmarks of frailty (low body mass, strength, mobility, PA level, energy) and cognition, thus optimising functional capacity during ageing. In these pathological conditions exercise is used as a therapeutic agent and follows the precepts of identifying the cause of a disease and then using an agent in an evidence-based dose to eliminate or moderate the disease. Prescription of PA/structured exercise should therefore be based on the intended outcome (e.g., primary prevention, improvement in fitness or functional status or disease treatment), and individualised, adjusted and controlled like any other medical treatment. In addition, in line with other therapeutic agents, exercise shows a dose-response effect and can be individualised using different modalities, volumes and/or intensities as appropriate to the health state or medical condition. Importantly, exercise therapy is often directed at several physiological systems simultaneously, rather than targeted to a single outcome as is generally the case with pharmacological approaches to disease management. There are diseases for which exercise is an alternative to pharmacological treatment (such as depression), thus contributing to the goal of deprescribing of potentially inappropriate medications (PIMS). There are other conditions where no effective drug therapy is currently available (such as sarcopenia or dementia), where it may serve a primary role in prevention and treatment. Therefore, this consensus statement provides an evidence-based rationale for using exercise and PA for health promotion and disease prevention and treatment in older adults. Exercise prescription is discussed in terms of the specific modalities and doses that have been studied in randomised controlled trials for their effectiveness in attenuating physiological changes of ageing, disease prevention, and/or improvement of older adults with chronic disease and disability. Recommendations are proposed to bridge gaps in the current literature and to optimise the use of exercise/PA both as a preventative medicine and as a therapeutic agent.

International Clinical Practice Guidelines for Sarcopenia (ICFSR): Screening, Diagnosis and Management.

OBJECTIVES: Sarcopenia, defined as an age-associated loss of skeletal muscle function and muscle mass, occurs in approximately 6 - 22 % of older adults. This paper presents evidence-based clinical practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR). METHODS: To develop the guidelines, we drew upon the best available evidence from two systematic reviews paired with consensus statements by international working groups on sarcopenia. Eight topics were selected for the recommendations: (i) defining sarcopenia; (ii) screening and diagnosis; (iii) physical activity prescription; (iv) protein supplementation; (v) vitamin D supplementation; (vi) anabolic hormone prescription; (vii) medications under development; and (viii) research. The ICSFR task force evaluated the evidence behind each topic including the quality of evidence, the benefit-harm balance of treatment, patient preferences/values, and cost-effectiveness. Recommendations were graded as either strong or conditional (weak) as per the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Consensus was achieved via one face-to-face workshop and a modified Delphi process. RECOMMENDATIONS: We make a conditional recommendation for the use of an internationally accepted measurement tool for the diagnosis of sarcopenia including the EWGSOP and FNIH definitions, and advocate for rapid screening using gait speed or the SARC-F. To treat sarcopenia, we strongly recommend the prescription of resistance-based physical activity, and conditionally recommend protein supplementation/a protein-rich diet. No recommendation is given for Vitamin D supplementation or for anabolic hormone prescription. There is a lack of robust evidence to assess the strength of other treatment options.

Designing Drug Trials for Frailty: ICFSR Task Force 2018.

To reduce disability and dependence in older adults, frailty may represent an appropriate target for intervention. While preventing frailty through lifestyle interventions may be the optimal public health approach for many population groups, pharmacological approaches will likely be needed for individuals who meet frailty criteria or who have comorbid conditions that contribute to and complicate the frailty syndrome, and for those who are not compliant with lifestyle interventions. Barriers to successful development of drug treatments for frailty include variability in how the frailty syndrome is defined, lack of agreement on the best diagnostic tools and outcome measures, and the paucity of sensitive, reliable, and validated biomarkers. The International Conference on Frailty and Sarcopenia Research Task Force met in Miami, Florida, on February 28, 2018, to consider the status of treatments under development for frailty and discuss potential strategies for advancing the field. They concluded that at the present time, there may be a more productive regulatory pathway for adjuvant treatments or trials targeting specific functional outcomes such as gait speed. They also expressed optimism that several studies currently underway may provide the insight needed to advance drug development for frailty.

Reversible States of Physical and/or Cognitive Dysfunction: A 9-Year Longitudinal Study.

OBJECTIVES: To determine 1) age-adjusted transition probabilities to worsening physical/cognitive function states, reversal to normal cognition/physical function, or maintenance of normal state; 2) whether these transitions are modulated by sex, BMI, education, hypertension (HTN), health status, or APOE4; 3) whether worsening gait speed preceded cognition change, or vice versa. DESIGN: Analysis of 9-year prospective cohort data from the New Mexico Aging Process Study. SETTING: Healthy independent-living adults. PARTICIPANTS: 60+ years of age (n= 598). MEASUREMENTS: Gait speed, cognitive function (3MSE score), APOE4, HTN, BMI, education, health status. RESULTS: Over 9 years, 2129 one-year transitions were observed. 32.6% stayed in the same state, while gait speed and cognitive function (3MSE scores) improved for 38% and 43% of participants per year, respectively. Transitions to improved function decreased with age (P< 0.001), APOE4 status (P=0.02), BMI (P=0.009), and health status (P=0.009). Transitions to worse function were significantly increased for the same factors (all P<0.05). Times to lower gait speed and cognitive function did not precede each other (P=0.91). CONCLUSIONS: Transitions in gait speed and cognition were mutable with substantial likelihood of transition to improvement in physical and cognitive function even in oldest-old, which may have clinical implications for treatment interventions.

Sarcopenia Trials in Specific Diseases: Report by the International Conference on Frailty and Sarcopenia Research Task Force.

Muscle atrophy occurs as a consequence of a number of conditions, including cancer, chronic obstructive pulmonary disease (COPD), diabetes mellitus, heart failure, and other chronic diseases, where it is generally a predictor of poor survival. It also occurs as a consequence of disuse and an age-related loss of muscle mass and strength (sarcopenia). The aims of the 2016, International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force were to examine how these specific chronic conditions have been employed in treatment trials thus far and how future trials using these patient groups might be designed for efficient identification of effective sarcopenia interventions. Functional limitations assessed as gait speed, distance walked over a set time period, or other attributes of physical performance have been suggested as outcome measures in sarcopenia trials. Indeed, such measures have already been used successfully in a number of trials aimed at preventing disability in older adults.

Effect of Lifestyle Intervention on the Hormonal Profile of Frail, Obese Older Men.

OBJECTIVE: Obesity-associated hypogonadism is hypothesized to be due to the suppressive effect of high estradiol (from an increase in aromatase activity present in the abundant adipose tissue) on the hypothalamic-pituitary-gonadal unit resulting in low testosterone production. Although weight loss has been found to be effective in reducing estradiol and raising testosterone levels in studies of younger men, its effect in frail, obese older men is understudied. Thus, the objective of this study was to determine the effect of lifestyle intervention on hormone levels in frail, obese older men. DESIGN: Randomized controlled trial of lifestyle intervention in frail, obese older men (≥65 yo) for 1 year. SETTING: University hospital. METHODS: Forty frail, obese elderly men were randomized, for a 52-week study, to any of the following treatment groups: (1) control group, (2) diet-induced weight loss group (diet group), (3) exercise training group (exercise group), and (4) diet-induced weight loss and exercise training group (diet-exercise group). The objective was to achieve a ~10 % weight loss at 6 months and maintain this weight for an additional 6 months. Physical function was assessed by the modified physical performance testing (modified PPT). Estradiol was measured by radioimmunoassay, testosterone by automated immunoassay, and sex hormone-binding globulin by enzyme-linked immunoassay. RESULTS: After 12 months of intervention, diet alone resulted in a weight loss of -10.1 ± 1.9 kg in the diet group and -9.1 ± 0.9 kg in the diet-exercise group. This resulted in a significant decrease (both p<0.05) in total estradiol compared to baseline among subjects in the diet (-2.5 ± 1.3 pg/ml) and diet-exercise group (-2.2 ± 4.0 pg/ml). Free estradiol index also significantly decreased (both p <0.05) in both the diet (-0.39 ± 0.14 pmol/nmol) and diet-exercise (-0.52 ± 0.12 pmol/nmol) group. Total testosterone significantly increased (p<0.05) in response to diet (71.0 ± 21.0 ng/dl) and diet-exercise (49.9 ± 15.5 pg/ml) resulting in values of 287.0 ± 28.1 ng/dl in the diet and 317.6 ± 33.1 ng/dl in the diet-exercise group. However, because there was a significant increase in sex hormone-binding globulin levels in both the diet and diet-exercise groups, free testosterone index and the changes in free testosterone index were not significant compared to baseline. Regardless of changes in hormonal levels, patients in the diet, exercise, and diet-exercise groups experienced significant improvements in the modified PPT from baseline. CONCLUSION: Weight loss from lifestyle intervention resulted in significant decreases in total and free estradiol levels in frail, obese older men, but this did not result in a clinically important increase in total testosterone nor a significant increase in free testosterone. Thus, alternative forms of treatment in addition to lifestyle intervention may be necessary to improve the hormonal profile among these patients. Nevertheless, whether further improvement in hormonal profile would result in better physical performance than what can be achieved by lifestyle alone in these subjects remains uncertain.

Sexually dimorphic patterns of nutritional intake and eating behaviors in community-dwelling older adults with normal and slow gait speed.

OBJECTIVES: Assess sex-specific nutritional intake and dietary habits of independently living older adults with normal and slow gait speeds. DESIGN: New Mexico Aging Process Study, cross-sectional, secondary data analysis. SETTING: Albuquerque, New Mexico USA. PARTICIPANTS: Three-hundred fifteen adults 60 years and older (194 women and 121 men). MEASUREMENTS: Gait speed test, 3-day diet records, Mini-Mental State Examination, and body mass index. RESULTS: Slow gait speed was associated with lower total calories (-154 kcal/day) and zinc (1 mg/day) (.05 < p < .1). Slower men consumed less protein (-4.1 g/day), calcium (-140 mg), fiber (-2.8 g/day) and iron (-2.5 mg/day) (p≤.05). Slower women consumed less, protein (-5.5 g/day), carbohydrate (-19.1 g/day), fiber (-2.7 gm/day), vitamin C (-18.4 mg/day) and higher fat intake (p=0.03). Slower women snacked less, had trouble chewing/biting, and lived alone (p= .04). Slower men were less likely to snack. CONCLUSIONS: We found sex-specific nutritional differences associated with gait speed. Those presenting with slow gait speed may need encouragement to increase meat and whole grain breads/cereal. Those with trouble eating should be advised on adapting diet to maintain adequate nutrition and encouraged on regular snacking to achieve higher nutrient intake. Prospective and randomized controlled studies are needed to confirm these findings and provide further evidence for putting these suggestions into practice.

Changes in thigh muscle volume predict bone mineral density response to lifestyle therapy in frail, obese older adults.

UNLABELLED: We studied the relationships among strength, muscle mass, and bone mineral density (BMD) with lifestyle change. Lifestyle therapy consisted of exercise, diet, and diet plus exercise. Diet was by caloric restriction to induce and maintain a weight loss of 10 % from baseline body weight. Exercise attenuated weight loss-induced muscle and bone losses. Exercise improved strength despite muscle loss in patients on diet and exercise. Changes in strength did not correlate with changes in BMD. However, changes in thigh muscle volume correlated with, and predicted changes in hip BMD. INTRODUCTION: Losses of hip BMD and lean body mass are major complications of lifestyle therapy in frail, obese older adults; however, the contribution of mechanical strain loss from muscle loss is poorly defined. We determined the effect of changes in thigh muscle volume and muscle strength on BMD in frail, obese older adults undergoing lifestyle therapy aimed at intentional weight loss with or without exercise. METHODS: One hundred seven obese older adults were randomized to control, diet, exercise, and diet-exercise groups for 1 year. Thigh muscle volume was measured by magnetic resonance imaging, BMD by DXA, knee strength by dynamometry, total strength by one-repetition maximum (1-RM), and bone markers by immunoassay. RESULTS: Thigh muscle volume decreased in the diet group (-6.2 ± 4.8 %) and increased in the exercise group (2.7 ± 3.1 %), while it was not significantly different from the control in the diet-exercise group. Changes in hip BMD followed similar pattern as those in thigh muscle volume. Knee extension and flexion increased in the exercise group (23 ± 20 %; 25 ± 19 %) and diet-exercise group (20 ± 19 %; 20.6 ± 27 %) but were unchanged in the control and diet groups. Changes in thigh muscle volume correlated with changes in hip BMD (r = 0.55, P = <0.001) and were an independent predictor of changes in hip BMD (ß = 0.12, P = 0.03) in the multiple regression analyses after accounting for demographic factors and changes in weight and physical activity. There were no correlations between BMD changes and knee strength, 1-RM, and sclerostin changes. CONCLUSIONS: Changes in thigh muscle volume predict hip BMD changes in obese older patients undergoing lifestyle therapy. The effect of exercise in attenuating thigh muscle loss when added to diet may in part account for the reduction in weight loss-induced bone loss in the diet-exercise group.

Weight loss, exercise or both and cardiometabolic risk factors in obese older adults: results of a randomized controlled trial.

BACKGROUND: Obesity exacerbates the age-related decline in insulin sensitivity and is associated with risk for cardiometabolic syndrome in older adults; however, the appropriate treatment for obese older adults is controversial. OBJECTIVE: To determine the independent and combined effects of weight loss and exercise on cardiometabolic risk factors in obese older adults. DESIGN: One-hundred and seven obese (body mass index (BMI)≥30 kg m(-2)) older (≥65 years) adults with physical frailty were randomized to control group, diet group, exercise group and diet-exercise group for 1 year. Outcomes for this study included changes in insulin sensitivity index (ISI), glucose tolerance, central obesity, adipocytokines and cardiometabolic syndrome. RESULTS: Although similar increases in ISI occurred in the diet-exercise and diet groups at 6 months, the ISI improved more in the diet-exercise than in the diet group at 12 months (2.4 vs 1.2; between-group difference, 1.2; 95% confidence interval, 0.2-2.1); no changes in ISI occurred in both exercise and control groups. The diet-exercise and diet groups had similar improvements in insulin area under the curve (AUC) (-2.9 and -2.9 × 10(3) mg min dl(-1)), glucose AUC (-1.4 and -2.2 × 10(3)mg min dl(-1)), visceral fat (-787 and -561 cm(3)), tumor necrosis factor (-17.0 and -12.8 pg ml(-1)), adiponectin (5.0 and 4.0 ng ml(-1)), waist circumference (-8.2 and -8.4 cm), triglyceride (-30.7 and -24.3 g dl(-1)) and systolic/diastolic blood pressure (-15.9 and -13.1/-4.9 and -6.7 mm Hg), while no changes in these parameters occurred in both exercise and control groups. The cardiometabolic syndrome prevalence decreased by 40% in the diet-exercise and by 15% in the diet group. Body weight decreased similarly in the diet-exercise and diet groups (-8.6 and -9.7 kg) but not in the exercise and control groups. CONCLUSIONS: In frail, obese older adults, lifestyle interventions associated with weight loss improve insulin sensitivity and other cardiometabolic risk factors, but continued improvement in insulin sensitivity is only achieved when exercise training is added to weight loss.

Long-term maintenance of weight loss after lifestyle intervention in frail, obese older adults.

OBJECTIVES: To determine if long-term weight loss with associated improvement in physical and metabolic health can be maintained after lifestyle intervention in frail, obese older adults. DESIGN: Thirty-month follow-up pilot study of a 1-year lifestyle intervention trial. SETTING: Community. PARTICIPANTS: Sixteen frail, obese (body mass index=36±2 kg/m2) older (71±1 yr.) adults. MEASUREMENTS: Body weight and composition, physical function, markers of the metabolic syndrome, glucose and insulin response to an oral glucose tolerance test, bone mineral density (BMD), liver and renal function tests, and food diaries. RESULTS: At 30-month follow-up, weight (101.5±3.8 vs. 94.5±3.9 kg) and BMI (36.0 ±1.7 vs. 33.5±1.7 kg/m2) remained significantly below baseline (all p<0.05). No significant change in fat-free mass (56.7±2.1 vs. 56.9±2.2 kg) or appendicular lean mass (24.1±1.0 vs. 24.1±1.1kg, all p>0.05) occurred between 12 months (end of trial) and 30 months. Improvements in the physical performance test (PPT 27±0.7 vs. 30.2±0.6), insulin sensitivity (4.1±0.8 vs. 3.0±0.6), and insulin area under the curve (12484±2042 vs. 9270±1139 min.mg/dl) remained at 30 months compared to baseline (all p<0.05). Waist circumference (116±3 vs. 109±3 cm) and systolic blood pressure (134±6 vs. 123±5 mm HG) remained decreased at 30 months compared to baseline (all p<0.05). Whole body and lumbar spine BMD did not change; however, total hip BMD progressively decreased at 30 months compared to baseline (0.985±.026 vs. 0.941±.024 g/cm2; p<0.05). There were no adverse effects on liver or renal function. Food frequency questionnaire data showed lower overall caloric intake (-619±157 kcal/day) at 30 months compared to baseline (p<0.05). CONCLUSION: These findings suggest that long-term maintenance of clinically important weight loss is possible in frail, obese older adults. Weight maintenance appears to be achieved through continued caloric restriction. Larger, long-term studies are needed to follow up on these findings and investigate mechanisms and behaviors underlying maintenance of weight loss and physical function.

Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial.

CONTEXT: Although hormone replacement therapy (HRT) is an established approach for osteoporosis prevention, little is known about the osteoprotective effects of HRT in frail elderly women. OBJECTIVE: To determine whether HRT increases bone mineral density (BMD) in frail elderly women. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted in a US university-based research center from September 1995 to August 2000. PARTICIPANTS: Sixty-seven women aged 75 years or older with mild-to-moderate physical frailty. INTERVENTION: Participants were randomly assigned to receive conjugated estrogens, 0.625 mg/d, plus trimonthly medroxyprogesterone acetate, 5 mg/d for 13 days (n = 45), or matching placebo (n = 22), for 9 months. MAIN OUTCOME MEASURES: The primary outcome measure was 9-month change in BMD of the lumbar spine and hip, measured by dual-energy x-ray absorptiometry. Secondary outcomes were changes in markers of bone turnover. RESULTS: Based on intention-to-treat analyses, HRT resulted in significantly larger increases in BMD of the lumbar spine than placebo (mean change, 4.3% vs 0.4%; between-group difference, 3.9%; 95% confidence interval [CI], 3.5%-4.3%) and total hip (mean change, 1.7% vs -0.1%; between-group difference, 1.8%; 95% CI, 1.5%-2.1%). Compared with placebo, HRT resulted in significant decreases in serum bone-specific alkaline phosphatase levels (mean change, -24% vs 6%; between-group difference, -30%; 95% CI, -26% to -33%) and urine N-telopeptide levels (mean change, -48% vs 4%; between-group difference, -52%; 95% CI, -47% to -55%). CONCLUSIONS: In physically frail elderly women, 9 months of HRT significantly increased BMD compared with placebo in clinically important skeletal regions. Further studies are needed to determine whether these osteogenic effects of HRT in elderly women are associated with a reduction in osteoporotic fractures.

Effects of DHEA replacement on bone mineral density and body composition in elderly women and men.

OBJECTIVE: Dehydroepiandrosterone (DHEA) is a precursor for both oestrogens and androgens. Its marked decline with ageing may influence age-related changes in tissues influenced by sex hormones. The aim of this study was to determine the effects of DHEA replacement on bone mineral density (BMD) and body composition in elderly women and men with low serum DHEA sulphate (DHEAS) levels. DESIGN: Prospective 6 month trial of oral DHEA replacement, 50 mg/day. PATIENTS: Experimental subjects were 10 women and eight men, aged 73 +/- 1 years. Control subjects were 10 women and eight men, aged 74 +/- 1 years. MEASUREMENTS: BMD, body composition, serum markers of bone turnover, serum lipids and lipoproteins, oral glucose tolerance, serum IGF-I, total serum oestrogens and testosterone. RESULTS: BMD of the total body and lumbar spine increased (mean +/- SEM; 1.6 +/- 0.6% and 2.5 +/- 0.8%, respectively; both P < or = 0.05), fat mass decreased (- 1.3 +/- 0.4 kg; P < 0.01) and fat-free mass increased (0.9 +/- 0.4 kg; P < or = 0. 05) in response to DHEA replacement. DHEA replacement also resulted in increases in serum IGF-I (from 108 +/- 8 to 143 +/- 7 microg/l; P < 0.01) and total serum testosterone concentrations (from 10.7 +/- 1.2 to 15.6 +/- 1.8 nmol/l in the men and from 2.1 +/- 0.2 to 4.5 +/- 0.4 nmol/l in the women; both P < or = 0.05). CONCLUSIONS: The results provide preliminary evidence that DHEA replacement in those elderly women and men who have very low serum DHEAS levels can partially reverse age-related changes in fat mass, fat-free mass, and BMD, and raise the possibility that increases in IGF-I and/or testosterone play a role in mediating these effects of DHEA.

The diagnosis of Alzheimer's disease.

Dementia constitutes a growing public health crisis. Early and accurate diagnosis of dementia is essential in order to provide patient and family counseling and appropriate treatment, including with specific antidementia drugs as they become increasingly available. Age-related cognitive decline, as compared with dementia, does not seriously interfere with usual activities. The optimal approach to early detection of dementia is clinical examination that incorporates information from a reliable collateral source about how the patient's cognitive abilities have declined relative to past performance. Alzheimer's disease (AD), the most common cause of dementia, can be diagnosed clinically with high accuracy (=85%) using standardized criteria. Even incipient AD can be detected with clinical methods alone. Although the typical picture of AD is characterized by gradual onset and progression of memory and other cognitive deficits, in other respects the disease is marked by heterogeneity. Early and late-onset AD represent the most easily recognized subtypes. Research continues towards characterizing a biologic marker but, as of yet, no candidate marker surpasses the high diagnostic accuracy of clinical assessments alone. At present, the diagnosis of AD rests primarily in the hands of the clinician.

Measurement of nitric oxide synthase and its mRNA in genetically obese (ob/ob) mice.

Recent studies have suggested a role for nitric oxide (NO) in the regulation of food intake. The obese (ob/ob) mouse is a genetic model of obesity. Previously, it has been demonstrated that ob/ob mice show a marked weight reduction when treated with a nitric oxide synthase inhibitor. In the studies reported here, we demonstrate increased levels of nitric oxide synthase (NOS) and its mRNA in the hypothalamus of genetically obese (ob/ob) mice compared to their lean littermate controls (ob/c). NOS levels were 0.016 +/- 0.001 nmol/mg/min in ob/ob compared to 0.009 +/- 0.001 in ob/c (p < 0.01) and NOS mRNA was 32.0 +/- 5.0 pg NOS mRNA/mg total RNA in ob/ob compared to 12.4 +/- 4.0 in ob/c (p < 0.05). These studies further support the possibility of a role for nitric oxide in the regulation of food intake.

Trophic factors in aging. Should older people receive hormonal replacement therapy?

The aging process is associated with significant declines in the levels of many hormones and trophic factors including estrogen, testosterone, growth hormone (somatropin, somatotropin) and insulin-like growth factor-1 (IGF-1, somatomedin-1, somatomedin-C). Since the classic age-related changes resemble the signs and symptoms of endocrine deficiency, it has been hypothesised that some of the negative effects of aging are due to these hormonal deficits. Consequently, the potential role of hormonal replacement in reversing the deleterious effects of aging deserves investigation. In old hypogonadal men, preliminary studies have shown that testosterone replacement not only improves libido but also significantly increases musculoskeletal mass and strength. However, adverse effects have included increases in haematocrit and prostate specific antigen. Similarly, short term studies with growth hormone replacement have shown substantial bodyweight gain, particularly in severely malnourished older adults, but longer studies have been limited by adverse effects such as gynaecomastia and carpal tunnel syndrome in a few people. Thus, though both testosterone and growth hormone may have potential roles for frailty syndromes in the elderly, long term clinical trials are needed to confirm these positive effects and assess their safety. On the other hand, the multiple beneficial effects of estrogen replacement in older women such as relieving acute menopausal symptoms and preventing postmenopausal osteoporosis are well recognised. Observational studies also suggest that estrogen may decrease cardiovascular disease. However, the optimum duration of treatment and the best way to administer this hormone are still unknown. Also, estrogen may be less effective in senile osteoporosis which primarily results from age-related bone loss. Traditionally, age-related bone loss has been attributed to impaired vitamin D activation and decreased calcium absorption. Thus, it was thought that such bone losses may be ameliorated by calcium supplementation. However, recent studies suggest that alterations in local factors affecting bone cell function may also be important in the pathogenesis of osteoporosis. An increase in potent bone resorbing factors, such as the cytokines interleukin-1 and interleukin-6, has been recently demonstrated in elderly patients with osteoporosis. In these patients, it has been suggested that there may also be a decrease in bone growth factors such as IGF-1 and transforming growth factor-beta. Accordingly, studies are underway to determine whether these factors may be useful in the prevention of osteoporosis. Other growth factors recently identified which may be important in aging include epidermal growth factor, nerve growth factor and fibroblast growth factor.(ABSTRACT TRUNCATED AT 400 WORDS)

IL-1-induced murine osteoblast IL-6 production is mediated by the type 1 IL-1 receptor and is increased by 1,25 dihydroxyvitamin D3.

IL-1-induced osteoblast IL-6 production represents one possible mechanism by which IL-1 augments bone resorption. In this report, we show that the murine osteoblastic cell line (MC3T3-E1) expresses type 1 IL-1 receptors based on 125I-HrIL1 alpha binding, blocked by type 1 IL-1R antibodies (35F5), and analysis of MC3T3 RNA by reverse transcription (RT)-DNA amplification and Northern analysis. MC3T3 cells do not express detectable type 2 IL-1R mRNA by RT-DNA amplification. IL-1 induces (IL-1 ED50, 0.1 pM) IL-6 production through the type 1 IL-1R as 35F5 antibodies block IL-1-stimulated IL-6 production. Vitamin D3 increases IL-1R expression dose- and metabolite-dependently, with 1,25-(OH)2D3 having the greatest potency, and also enhances IL-1's capacity to stimulate IL-6 production at low IL-1 levels. Both IL-1 and 1,25-(OH)2D3 induce type 1 IL-1R and not type 2 IL-1R upregulation based on ligand binding and RT-DNA amplification. Increased IL-1R expression requires a 5-7-h treatment and is protein/RNA synthesis dependent. These observations imply that IL-1-induced IL-6 production in osteoblasts is mediated by type 1 IL-1Rs and that increased IL-1R expression could play a role in mediating IL-1-induced skeletal responses.