The role of thigh muscle and adipose tissue in knee osteoarthritis progression in women: data from the Osteoarthritis Initiative.

OBJECTIVE: To determine whether loss in thigh muscle strength in women concurrent with knee osteoarthritis progression is associated with reductions of muscle anatomical cross-sectional area (ACSA) or specific-strength (i.e., isometric force÷ACSA), and to explore relationships with local adiposity. DESIGN: Female participants from the Osteoarthritis Initiative with Kellgren-Lawrence grade ≤3, thigh isometric strength measurements, and thigh magnetic resonance images at year-two (Y2) and year-four (Y4) (n = 739, age 62 ± 9 years; body mass index measurements (BMI) 28.8 ± 5.9 kg/m2) were grouped into: (1) those with vs without symptomatic progression (≥9 increase in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-pain [scale: 0-100]); and (2) those with vs without radiographic progression (≥0.7 mm reduction in minimum joint space width). The change in knee extensor and flexor ACSA and specific-strength, and subcutaneous and intermuscular fat (IMF) ACSAs were compared between progressors and non-progressors using analysis of covariance. RESULTS: Symptomatic progression was associated with a significantly greater loss (p < 0.001) of knee extensor ACSA (-2.0%, 95%CI -2.5, -1.5) compared to those without progression (-0.7%, 95%CI -1.0, -0.4), and greater loss (p = 0.020) of knee flexor specific-strength (-7.6%, 95%CI -11.5, -3.7; vs -2.4%, 95%CI -4.8, 0.0). Radiographic progression was associated with a significantly greater increase (p = 0.023) in IMF (+1.7%, 95%CI -0.1, +3.6) compared to those without progression (-0.6%, 95%CI -1.6, +0.3). CONCLUSION: The significant reduction in thigh muscle strength concurrent with symptomatic progression in women appears to be associated with loss of extensor muscle ACSA and flexor specific-strength. In contrast, radiographic progression appears to be unrelated to muscle properties, but to be associated with local (intermuscular) adiposity gains.

Longitudinal change in thigh muscle strength prior to and concurrent with symptomatic and radiographic knee osteoarthritis progression: data from the Osteoarthritis Initiative.

OBJECTIVE: To investigate whether symptomatic and/or radiographic knee osteoarthritis (KOA) progression is associated with prior and/or concurrent change in thigh muscle strength in men or women. DESIGN: Osteoarthritis Initiative (OAI) participants with isometric muscle strength measurements at baseline, 2- and 4-year follow-up (n = 1785: 1016 women) were grouped into 1) those with vs without symptomatic progression (i.e., increase ≥9 in WOMAC-pain [scale: 0-100]); and 2) those with vs without radiographic progression (i.e., decrease in minimum joint space width (JSW) ≥0.7 mm) between year-two and year-four follow-up. Sex-specific changes in thigh muscle strength concurrent (between year-two and year-four follow-up) and prior to (between baseline and year-two follow-up) symptomatic and radiographic progression were compared between groups (progression vs no progression) using analysis of covariance, with adjustment for age and body mass index. RESULTS: In women, but not in men, loss in knee extensor and flexor strength was greater concurrent with symptomatic progression (extensors: -3.7%, 95% confidence interval [CI] -6.4, -0.9; flexors: -7.2% 95% CI -10.7, -3.7) than in women without symptomatic progression (extensors: -0.3%, 95% CI -1.9, 1.3, P = 0.030; flexors: -2.6%, 95% CI -4.7, -0.6, P = 0.018). No association was found between extensor or flexor strength loss concurrent to radiographic progression, in either men or women, nor any statistically significant association between prior change in muscle strength with symptomatic or radiographic progression. CONCLUSION: These findings suggest that there is concurrent but not prior longitudinal association between loss in muscle strength and symptomatic KOA progression that is specific to women.

Changes in blood chemistry and hematology variables during aging in captive rhesus macaques (Macaca mulatta). J Med Primatol 30:161-173, 2001.

The Primate Aging Database (PAD) is being developed to assist research using nonhuman primate models for various gerontological applications. We provide now an update of an earlier report providing data on hematological and blood chemistry values for rhesus monkeys across the adult lifespan. These data were collected from several research colonies and have been submitted to rigorous statistical analyses to identify relationships with chronological age.

Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys.

Many age-associated pathophysiological changes are retarded by caloric restriction (CR). The present study has investigated the effect of CR on plasma lipoprotein (a) [Lp(a)], an independent risk factor for the age-associated process of atherosclerosis. Rhesus monkeys were fed a control diet (n=19 males, 12 females) or subjected to CR (n=20 males, 11 females fed 30% less calories) for >2 years. All female animals were premenopausal. Plasma Lp(a) levels in control animals were almost two fold higher for males than females (47+/-9 vs 25+/-5mg/dl mean+/-SEM, p=0.05). CR resulted in a reduction in circulating Lp(a) in males to levels similar to those measured in calorie-restricted females, (27+/-5 vs 24+/-4 mg/dl mean+/-SEM). For all animals, plasma Lp(a) was correlated with total cholesterol (r=0.27, p=0.03) and LDL cholesterol (r=0.50, p=0.0001) whether unadjusted or after adjustment for treatment, gender or group. These studies introduce a new mechanism whereby CR may have a beneficial effect on risk factors for the development of atherosclerosis in primates.

Dietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr.

In a longitudinal study of the effects of moderate (70%) dietary restriction (DR) on aging, plasma glucose and insulin concentrations were measured from semiannual, frequently sampled intravenous glucose tolerance tests (FSIGTT) in 30 adult male rhesus monkeys. FSIGTT data were analyzed with Bergman's minimal model, and analysis of covariance revealed that restricted (R) monkeys exhibited increased insulin sensitivity (S(I), P < 0.001) and plasma glucose disappearance rate (K(G), P = 0.015), and reduced fasting plasma insulin (I(b), P < 0.001) and insulin response to glucose (AIR(G), P = 0.023) compared with control (C; ad libitum-fed) monkeys. DR reduced the baseline fasting hyperinsulinemia of two R monkeys, whereas four C monkeys have maintained from baseline, or subsequently developed, fasting hyperinsulinemia; one has progressed to diabetes. Compared with only the normoinsulinemic C monkeys, R monkeys exhibited similarly improved FSIGTT and minimal-model parameters. Thus chronic DR not only has protected against the development of insulin resistance in aging rhesus monkeys, but has also improved glucoregulatory parameters compared with those of otherwise normoinsulinemic monkeys.

Changes in blood chemistry and hematology variables during aging in captive rhesus macaques (Macaca mulatta).

Identifying changes with age in physiological variables of captive nonhuman primates will aid in the proper treatment and clinical diagnosis of these animals, as well as enhance our understanding of nonhuman primate models for human aging. Information for 33 physiological variables was obtained from the Primate Aging Database, a multi-centered database being developed for clinical and research use. Using multiple regression analyses, we investigated the relationship of age to hematological variables, blood chemistry and body weight in 345 captive rhesus monkeys (age range 7-30 years) from three different primate research facilities. The analyses revealed that 15 of these variables show a significant relationship with chronological age and are altered in older as compared with adult animals. Here we present the first phase of a project that will: a) identify changes with age in physiological variables among adult captive rhesus macaques; and b) characterize normative values for the aging rhesus population.

Toward developing a genome-wide microsatellite marker set for linkage analysis in the rhesus macaque (Macaca mulatta): identification of 76 polymorphic markers.

Linkage analysis can be problematic in humans because of the lack of large, multigenerational pedigrees and the difficulties in obtaining phenotypic data on all family members. In contrast, large, captive colonies of rhesus macaque are a potentially valuable resource for linkage studies because detailed phenotypic and genealogical data are kept, inbreeding is avoided, and DNA samples can usually be obtained. Microsatellite marker sets for genome-wide screening are available in a number of species, but not for the rhesus macaque. We tested primers to 400 human microsatellite markers from a genome-wide mapping set using DNA from nine unrelated female rhesus macaques. We found that 76 (19%) of the primers amplified a polymorphic product using the standard protocols for human DNA. The average heterozygosity of the markers in humans was 0.80, compared to 0.65 in the rhesus macaques. This study provides preliminary data, which could be used toward the development of a linkage mapping set in this species. There would be a need, however, to confirm the Mendelian inheritance of the markers.

Caloric restriction mimetics: physical activity and body composition changes.

As the only paradigm that has consistently increased life span and inhibited the onset and/or progression of disease, dietary restriction has multiple effects on a variety of organ systems. In this brief review, the goal of the panel was to attempt to understand the role of changes in physical activity and body composition as possible modulators of the life span in experimental animals and humans. We focus on whether changes in exercise behavior and body composition produce similar changes as those found in dietary restriction and whether these changes can be used to either replace or enhance the beneficial effects of dietary restriction. The complexity of the two stimuli is emphasized in our report, with suggestions offered on how to better interpret existing research. Our panel briefly examines evidence in experimental animals and humans about the specific contributions of each of these factors to altering life span and age-related pathologies. We also discuss additional animal studies and/or human intervention studies that could be performed to clarify these issues. Finally, we provide suggested avenues for future research in this area of changes in physical activity and body composition as dietary restriction mimetics.

Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study.

Dietary restriction (DR) retards aging and extends the maximum lifespan of laboratory mice and rats. To determine whether DR has similar actions in a primate species, we initiated a study in 1989 to investigate the effects of a 30% DR in 30 adult male rhesus monkeys. In 1994, an additional 30 females and 16 males were added to the study. Although the animals are still middle-aged, a few differences have developed between the control and DR animals suggesting that DR may induce physiologic changes in the rhesus monkey similar to those observed in rodents. Fasting basal insulin and glucose concentrations are lower in DR compared to control animals while insulin sensitivity is higher in the restricted animals. DR has also altered circulating LDL in a manner that may inhibit atherogenesis. These results suggest that DR may be slowing some age-related physiologic changes. In addition to measures of glucose and lipid metabolism, the animals are evaluated annually for body composition, energy expenditure, physical activity, hematologic indices, and blood or urinary hormone concentrations. In the next few years, the first animals will reach the average lifespan ( approximately 26 years) of captive rhesus monkeys and it will become possible to determine if DR retards the aging process and extends the lifespan in a primate species.

[Effectiveness and tolerance of depot leuprorelin acetate for preoperative endometrium flattening before endometrial ablation. German Leuprorelin Study Group]. / Wirksamkeit und Verträglichkeit von Leuprorelinacetat-Depot zur präoperativen Endometriumabflachung vor Endometriumablation. Deutsche Leuprorelinstudiengruppe.

OBJECTIVE: In order to assess the efficacy and tolerability of leuprorelin acetate depot in pre-operative flattening of the endometrium prior to hysteroscopic endometrial ablation, 94 patients from eight centres were included in the per protocol analysis. MATERIAL AND PATIENTS: The patients included were pre- or peri-menopausal, had completed their family planning and had intractable uterine bleeding. The primary target criterion was the reduction in maximum endometrial thickness after two injections of leuprorelin acetate depot with an interval of four weeks between injections. Surgery took place two weeks after the second injection. RESULTS: Sufficient pre-treatment was achieved in 91.5% of the patients with > 50% decrease and/or a type 1 endometrium according to sonographic and/or endometrial atrophy (Score 11) according to the central histological evaluation. The endometrium was flattened by a mean of 4.0 +/- 4.1 mm. In terms of clinical response, amenorrhoea, hypomenorrhoea or normal menstruation were achieved after endometrial ablation. Hence 91.5% of patients benefited from the overall treatment after six weeks and still 83% after six months. The trial medication was well tolerated overall. The most common side-effect described was hot flushes which could be attributed to the deliberate oestrogen withdrawal. CONCLUSION: In view of the good study results, hormone-suppressive pretreatment of the endometrium can be recommended prior to elective ablation. Surgery should take place during the oestrogen-suppressed phase.

In vitro oxidation of low-density lipoprotein in two species of nonhuman primates subjected to caloric restriction.

Caloric restriction (CR), which increases longevity and retards age-associated diseases in laboratory rodents, is being evaluated in nonhuman primate trials. CR reduces oxidative stress in rodents and appears to improve risk factors for cardiovascular disease in nonhuman primates. We tested the hypothesis that low-density lipoprotein (LDL) oxidizability is reduced in two monkey species (rhesus and cynomolgus) subjected to chronic CR. In both species, no significant differences occurred between CR and control animals on total, LDL, or high-density lipoprotein (HDL) cholesterol. In rhesus monkeys, triglycerides were higher in controls than CR (139 +/- 23 vs 66 +/- 8 mg/dl,p < .01, respectively). LDL from CR rhesus monkeys was reduced in triglyceride content and molecular weight compared to controls, whereas LDL composition in cynomolgus monkeys was similar in CR and control animals. In keeping with minor deviations in lipids, antioxidants, and LDL composition, no consistent differences in in vitro LDL oxidizability were apparent between CR and controls in either species.

Age and gender differences in body composition, energy expenditure, and glucoregulation of adult rhesus monkeys.

The purpose of this study was to examine the relationship of age to body composition, glucoregulation, activity, and energy expenditure in male and female rhesus monkeys. The animals were studied in three groups, young adults (YA, 7-9 years), middle-aged adults (MA, 13-17 years), and older adults (OA, > 23 years) adults. OA had a lower (P < 0.05) lean body mass than the YA and MA. OA also had the lowest values (P < 0.06) for energy expenditure (kJ/minute). Age-related differences (P < 0.05) were observed in time spent resting and moving. The OA spent the most time resting and the least time in vertical movement. There was a trend towards an age-related decrease in acute insulin response to glucose, while other glucoregulatory parameters were not changed with age. These results are similar to findings in humans, providing further evidence that the rhesus monkey is an appropriate model of human aging.

Effect of long-term caloric restriction on GLUT4, phosphatidylinositol-3 kinase p85 subunit, and insulin receptor substrate-1 protein levels in rhesus monkey skeletal muscle.

Caloric restriction (CR), a reduction in calorie intake without malnutrition, improves insulin sensitivity in various species, including mice, rats, rhesus and cynomolgus monkeys, and humans. Skeletal muscle is quantitatively the most important tissue for blood glucose clearance. Therefore, we assessed the effect of 6 years of CR (30% reduction in calorie intake) in male rhesus monkeys (14-20 years old) on muscle expression of several proteins involved in insulin action. Whole body insulin sensitivity (assessed by Modified Minimal Model) was significantly increased in CR relative to Control monkeys. CR did not alter the expression of GLUT4 glucose transporter or phosphatidylinositol-3 kinase p85 subunit (PI3K). Insulin receptor substrate-1(IRS-1) abundance tended to be greater for CR compared to Control monkeys (p = .051), but correlational analysis revealed no association between IRS-1 and insulin sensitivity (r2 = .075, p = .271). These findings indicate that the CR-induced increase in insulin sensitivity in rhesus monkeys is unrelated to alterations in GLUT4, P13K, and IRS-1 abundance.

Timing of prenatal androgen excess determines differential impairment in insulin secretion and action in adult female rhesus monkeys.

This study determined whether timing of prenatal androgen excess resulted in differential impairment of insulin-glucose homeostasis in adult female rhesus monkeys. Ten female rhesus monkeys exposed to testosterone propionate starting on gestational day 40 (early treated), 9 females exposed to testosterone propionate starting between gestational days 100-115 (late treated), and 15 control females were studied. The modified minimal model was used to examine various measures derived from an i.v. glucose tolerance test, with regression analysis performed between these variables and body mass index. In addition, the disposition index (DI) and the hyperbolic relationship between insulin sensitivity (S(I)) and acute insulin response to glucose were examined. Early treated females demonstrated impaired pancreatic beta-cell function, as shown by diminished DI and decreased percentile ranking for the hyperbolic relationship between S(I) and acute insulin response to glucose. In contrast, late treated females exhibited both an increase in DI and a negative relationship between body mass index and S(I). These results suggest that prenatal androgen excess in female rhesus monkeys, regardless of gestational timing, perturbs insulin-glucose homeodynamics, with androgen excess in early and late gestation impairing pancreatic beta-cell function and altering insulin sensitivity, respectively.

Short-term calorie restriction improves disease-related markers in older male rhesus monkeys (Macaca mulatta).

Calorie restriction (CR) is widely known for its effects on life span, physiological aging and age-related disease in laboratory rats and mice. Emerging data from CR studies in rhesus monkeys suggest that this nutritional intervention paradigm may also have beneficial effects in long-lived mammals. Studies from our laboratory and others have suggested that young- or adult-onset CR might have beneficial effects on cardiovascular disease and diabetes. For example, long-term CR reduced body fat and serum triglycerides, and increased a subfraction of HDL cholesterol associated with decreased cardiovascular disease risk. These studies suggested that long-term CR begun in young or adult animals might have important effects on markers relevant to age-related disease. Few studies have examined the effects of CR initiated in older animals (rodents or monkeys), and the temporal nature of some potentially beneficial effects of CR is unknown. The present study examined several markers related to diabetes and cardiovascular disease in thirteen older adult (> 18 year) non-obese (body fat < 22%), male rhesus monkeys during a short-term CR paradigm. Specifically, we collected these data at baseline (ad libitum feeding), 10, 20, and 30% CR, and at 6 and 12 months on 30% CR. Fasting and peak insulin were significantly reduced as were the acute and second-phase insulin responses. CR also marginally reduced triglycerides (50% reduction), but had no effect on total serum cholesterol or blood pressure. Interestingly, the observed glucoregulatory changes emerged prior to any evidence of a change in body composition suggesting that certain effects of CR may not be wholly dependent on changes in body composition in older monkeys.

Serum dehydroepiandrosterone sulfate concentrations across the life span of laboratory-housed rhesus monkeys.

Cross-sectional studies of humans have shown that dehydroepiandrosterone sulfate (DHEAS) peaks shortly after sexual maturation and declines thereafter, suggesting that the progressive reduction in DHEAS may play a role in the aging process and in the development of age-related morbidity. The present study examines changes in DHEAS concentrations across the life span of rhesus monkeys as part of the development of this primate model for studies of aging. Serum concentrations of DHEAS were measured in 792 laboratory-housed rhesus monkeys (Macaca mulatta) aged 0.5-36 years (527 females, 265 males). DHEAS concentrations in all monkeys were used to formulate an equation that describes two levels of decline of DHEAS with age. The most rapid decline occurs from infancy until approximately 5 years of age. The decline then occurs gradually with increasing age. There were no signs of an andrenarche just prior to sexual maturation, as is seen in humans or the great apes. This equation can be used to predict the expected mean serum DHEAS concentration and normal ranges of male or female rhesus monkeys at any age greater than 5 months.

Skeletal effects of aging and menopausal status in female rhesus macaques.

To further define the nonhuman primate as a model of the adult human skeleton, we explored the impact of growth, natural menopause, and osteoarthritis on bone mass, serum markers of bone turnover (osteocalcin and C-terminal telopeptide of type I collagen) and measures of skeletal relevance (PTH, 25-hydroxyvitamin D, total alkaline phosphatase, calcium, phosphorus, creatinine, and albumin). Fifty-eight female (aged 4-30 yr) rhesus macaques were defined as growing (G; n = 12; < or = 10 yr old), adult premenopausal (APre; n = 30; > 10 yr old; eumenorrheic, high serum estradiol and low FSH), or postmenopausal (Post; n = 16; amenorrheic for at least 1 yr, with low serum estradiol and high FSH). Total body and posterior-anterior spinal bone masses were lower in G than APre animals (P < 0.05). Post females had lower total body, distal radius, and spinal bone mass than premenopausal animals (P < 0.05). Osteocalcin was higher in Post than APre animals (P < 0.01). Other measures showed no relationship with menopausal status. In older monkeys, spinal osteoarthritis became common, causing increased dual-energy x-ray absorptiometry-measured bone mass in the lumbar spinal posterior-anterior projection. In conclusion, after natural menopause, rhesus monkeys have lower bone mass and higher skeletal turnover without alteration of the calcium-vitamin D axis. As such, they are an excellent model of human estrogen-depletion bone loss.

Body fat distribution with long-term dietary restriction in adult male rhesus macaques.

Dietary restriction (DR) is the only intervention that has been shown to increase average and median life span in laboratory rodents. The effect of long-term, moderate DR on body composition and fat distribution was evaluated in male rhesus monkeys. Thirty animals (8-14 years of age)fed either 30% less than baseline intake (R, n = 15) or allowed to eat to satiety (C, n = 15), have been assessed semiannually using somatometrics and dual-energy alpha-ray absorptiometry (DXA)for 7.5 years. R subjects have reduced body weight (p <.0001), total body fat (p < .0001), and percentage body fat located in the abdominal region (p < .05). In addition, there has been a sustained reduction in plasma leptin concentrations (p <.001). These findings suggest reduced risk for common morbidities, such as insulin resistance, dyslipidemia, and type 2 diabetes mellitus, that are associated with advancing age and increased levels of bodyfat, especially in the visceral depot.

Reduced water intake but normal response to acute water deprivation in elderly rhesus monkeys.

The ability to compensate for acute water deprivation was studied in young adult (YA, 7-9 years), middle aged (MA, 13-17 years), and older adult (OA, 20-36 years) rhesus monkeys of both sexes (N = 6/group). Water intake and urine volume were measured during three 7-day trials: 3 days of baseline measurement, 1 day of deprivation and 3 days of compensation. OA drank less during baseline (380 +/- 63 mL/day) than MA (679 +/- 92 mL/day, p < 0.05) or YA (750 +/- 128 mL/day, p < 0.01). All groups drank more following deprivation than at baseline and the OA drank significantly less than the younger groups (both p < 0.01), but the increase above baseline did not differ among groups when expressed as a cumulative percentage of baseline (89% for OA; 77% for MA; 83% for YA). Urine volume of all groups decreased by similar percentages on the day of deprivation (56% overall) and this reduction represented a similar proportion (58% overall) of baseline water intake. Urine concentration increased significantly during deprivation (p < 0.05) and returned to baseline values during compensation with no differences among age groups. OA water balance appears to have been maintained at lower levels of intake and excretion. In conclusion, responses to acute hydrational challenges in the elderly should be interpreted in the context of customary fluid intake.

A comparison of dual-energy X-ray absorptiometry and somatometrics for determining body fat in rhesus macaques.

OBJECTIVE: Various approaches have been used to assess fat and fat distribution in nonhuman primates, including measurements of body weight, body dimensions, and estimates derived from these, such as body mass index. Methods such as tritiated water dilution and dual-energy X-ray absorptiometry (DXA) have also been used. The aim of the present study was to evaluate and compare DXA measurements and somatometrics. RESEARCH METHODS AND PROCEDURES: Body composition of 15 adult male rhesus macaques was measured by DXA and somatometrics at four time-points over a 4-year period. Additionally, DXA precision and somatometric variability were analyzed by repeated measurements of the same subjects. RESULTS: DXA estimates of body fat were positively correlated with body weight, body mass index, body circumferences, and abdominal skinfold thicknesses. DXA assessments of soft tissue composition were precise, with coefficients of variation below 3.3% for all compartments analyzed. The majority of the observed variability in somatometrics was explained by subject variance, rather than by inter- or intraobserver variability, or by observer experience level. DISCUSSION: We conclude that noninvasive DXA technology provides precise estimates of nonhuman primate body composition that correlate well with the traditional somatometric measures used in primate studies.