[Validity of the "Kaigo-Yobo Check-List" as a frailty index].

OBJECTIVES: A frailty index for Japanese older people is not yet available. This study examined the validity of "Kaigo-Yobo Check-List" (CL) as a frailty index. METHODS: The study site was Kusatsu town, Gunma prefecture. Out of 612 older persons aged 65 years and over who undertook a comprehensive geriatric assessment in 2007, results from 526 who had no missing data were used to examine the cross-sectional relationship between frailty as defined by Fried's criteria (= external criteria) and CL scores in order to evaluate concurrent and construct validity. Further, 916 older individuals aged 70 years and over who responded to the baseline survey in 2001 were followed for the subsequent 4 years and 4 months regarding the onset of ADL disability, service use under the Long Term Care Insurance program, and mortality. We examined the predictive validity of the CL for such adverse outcomes after adjustment for gender, age, and comorbidity. RESULTS: The CL (cut-off point = 3/4) discriminated frailty from non-frailty at the sensitivity of 70.0% and specificity of 89.3%. The higher the CL score, the higher the prevalence of frailty; the trend was highly significant (P < 0.001). The Multitrail Multimethod Model showed that there were significant associations among three components of CL (homeboundness, falling, and lower nutrition) and four out of five components of Fried's frailty criteria (shrinking, exhaustion, low activity, and slowness), whereas those components of the CL did not have an association with the weakness component of Fried's frailty criteria. As compared with older persons who had CL scores of 3 points or below, those who had CL scores of 4 or more points had a significantly higher risk for developing adverse outcomes. Multivariate-adjusted odds ratios for ADL disability at 2 and 4 years after baseline were 5.25 (95% confidence interval, 2.79-9.89) and 3.42 (1.79-6.54), respectively. Likewise, multivariate-adjusted hazard ratios for the onset of service use under the Long Term Care Insurance program and mortality during the follow-up period of 4 years and 4 months were 3.50 (2.41-5.07) and 2.43 (1.70-3.47), respectively. Although the construct validity remained inconclusive, the "Kaigo-Yobo Check-List" showed CONCLUSION: good concurrent and predictive validity as a frailty index. Since it comprises 15 easy-to-answer questions, it could be widely used for research on frailty and its preventive intervention.

[Prevalence and characteristics of frailty among community-dwelling older people in Japan].

OBJECTIVE: To examine the prevalence and characteristics of frailty in community-dwelling people over 70 years of age. METHODS: Data collected from in-home interviews conducted in 2001 were used to determine the prevalence of frailty. A total of 916 out of 1,039 older adults responded, and the data of 914 were eligible. Secondly, data collected from a comprehensive health examination undertaken in two areas in 2005 were used to identify the characteristics of frailty. 1,005 older adults participated and the data of 974 were eligible. We used a frailty index (Kaigo-Yobo Checklist) developed by Shinkai et al. (2010) to divide data into Frail and Non-frail groups. RESULTS: The prevalence of frailty was 24.3% for men and 32.4% for women. The prevalence showed a tendency to rapidly increase after age 80 in men and 75 in women. Even after controlling for age, study area, ADL disability and comorbidity, a number of variables showed significant associations with frailty. The results showed poor functional status in physical, mental and social areas in the Frail group. The Frail group was more likely to have comorbid geriatric syndromes than the Non-frail group, such as lower MMSE scores, higher prevalence of depression, higher prevalence of hearing impairment in men, and urinary incontinence and walking impairment in women. In contrast, almost no associations with frailty were detected on routine clinical tests such as blood pressure or blood examination. CONCLUSIONS: Overall, frailty was identified as a multifactorial syndrome which was strongly related to other geriatric syndromes. The symptoms of frailty manifested as poor functioning in multiple areas. Routine clinical tests may not be useful for detecting frailty.

[Predictors of frailty development in a general population of older adults in Japan using the Frailty Index for Japanese elderly patients].

AIM: To identify predictors for the onset of frailty in Japanese older adults using the Frailty Index for Japanese elderly people, we focused on subjects who participated in a routine health check. METHODS: Of 357 older people (age, ≥70 years) who participated in a routine health check-up in Kusatsu, Japan in 2005, 334 individuals were identified as non-frail and were followed up 2 years later. A logistic regression model using the stepwise method was used to identify predictors for the onset of frailty, after controlling for age and gender. RESULTS: A total of 45 subjects (13.5%) had developed symptoms of frailty at follow-up. Even after multiple adjustment for controlling factors, a history of hypertension, hand grip strength, and albumin were significantly associated with frailty 2 years later (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.24-5.25; OR per 1 kg decrease, 1.08; 95% CI, 1.00-1.16; OR per 0.1 g/dl decrease, 1.22; 95% CI, 1.03-1.46, respectively). CONCLUSION: These results supported a definition of frailty which includes geriatric symptoms such as vascular disease and sarcopenia in Japanese older adults. Undernutrition was strongly associated with the onset of frailty and is an important target for prevention.

Plasma adenosine triphosphate and heat shock protein 72 concentrations after aerobic and eccentric exercise.

The endolysosome pathway has been proposed for secretion of heat shock protein (Hsp)72 with a regulatory role for extracellular adenosine triphosphate (ATP). Here, we tested the hypothesis that extracellular ATP mediates the increase in plasma Hsp72 after exercise. We measured plasma ATP Hsp72, cathepsin D, norepinephrine, free fatty acid, glucose, and myoglobin in 8 healthy young males (mean +/- SE: age, 22.3 +/- 0.3 years; height, 171.4 +/- 0.8 cm; weight, 68.8 +/- 3.1 kg; body mass index, 23.5 +/- 1.1 kg/cm2; VO2 max, 44.1 +/- 3.8 mL/kg/min) before and at 0, 10, 30, and 60 min after aerobic exercise (cycling) and elbow flexor eccentric exercise. Subjects cycled for 60 min at 70-75% VO2 max (mean +/- SE; 157.4 +/- 6.9 W). Eccentric strength exercise consisted of flexing the elbow joint to 90 degrees with motion speed set at 30 degrees/sec at extension and 10 degrees/sec at flexion. Subjects performed 7 sets of 10 eccentric actions with a set interval of 60 sec. The motion range of the elbow joint was 90 degrees-180 degrees. Compared with the levels of Hsp72 and ATP in plasma after bicycle exercise, those after eccentric exercise did not change. A significant group x time interaction was not observed for Hsp72 or ATP in plasma. A significant correlation was found between Hsp72 and ATP in plasma (r=0.79, P<0.05), but not between Hsp72 and norepinephrine (r=0.64, P=0.09) after bicycle exercise. A significant correlation between ATP and norepinephrine in plasma was found (r=0.89 P<0.01). We used stepwise multiple-regression analysis to determine independent predictors of exercise-induced elevation of eHsp72. Candidate predictor variables for the stepwise multiple-regression analysis were time (Pre, Post, Post10, Post30, Post60), exercise type (aerobic, eccentric), ATP, cathepsin D, norepinephrine, epinephrine, glucose, and FFA. In the regression model for Hsp72 in plasma, increased ATP and glucose were the strongest predictors of increased Hsp72 (ATP: R2=0.213, beta=0.473, P=0.000; ATP and glucose: R2=0.263, beta=0.534, P=0.000). Collectively, these results imply that ATP in plasma is a trigger of Hsp72 release after exercise.

[The validity of the "Kihon Check-list" as an index of frailty and its biomarkers and inflammatory markers in elderly people].

AIM: The present study was designed to assess the validity of the "Kihon ("basic") Check-list (KCL)" as a frailty index, and to investigate its biomarkers in an elderly population. METHODS: We enrolled 420 elderly persons aged 65 years and over in comprehensive geriatric assessments in 2007 and 2008. We examined the temporal relationship between the Fried frailty criteria (external criteria) and KCL items 1-20 to evaluate concurrent validity. In 2008, 665 elderly people aged 65 years and over who participated in the comprehensive geriatric assessment in 2008 were assessed based on their frailty and non-frailty using the KCL. We compared biomarkers, including TNF-α, IL-6, CRP and ß(2)-microglobulin (ß(2)-MG) between frail and non-frail groups. RESULTS: The KCL items 1-20 showed good concurrent validity against the Fried criteria in terms of frailty. When using a cut-off point of 5/6, the KCL items 1-20 showed a sensitivity of 60.0% and a specificity of 86.4% for the Fried frailty criteria. Overall, 34 males (12.3%) and 74 females (19.0%) were defined as frail. Among varying biomarkers, IL-6 (odds ratio [OR] of highest tertile vs. lowest tertile, 2.05; 95% confidence interval [CI]: 1.15-3.64), grip strength (OR: 0.19; 95% CI: 0.07-0.46) and walking speed (OR: 0.23; 95% CI: 0.12-0.45) were significantly associated with risks of frailty. The highest tertile of IL-6 and ß(2)-MG combined highly increased the risk of frailty (OR: 5.61; 95% CI: 2.34-13.11) compared with those in the lowest tertile of the 2 markers combined. CONCLUSIONS: The KCL items 1-20 can be used as a frailty index for Japanese elderly population. IL-6 and ß(2)-MG are potential candidates for biomarkers of frailty.

[A randomized controlled trial of the effects of a comprehensive intervention program for community-dwelling older adults].

AIM: The objective of this study was to evaluate the effects of a comprehensive intervention program named SPRING, which utilizes a hot spring facility, in community-dwelling older adults in a randomized controlled trial. METHODS: A total of 60 community-dwelling elderly people (mean age, 72.7±6.0 years) participated in this program. After baseline investigation, participants were randomly assigned to an intervention group (n=31) or a control group (n=29). The intervention group participated in a comprehensive intervention program (including exercise classes, nutrition classes and bathing) twice a week for 3 months. After 3 months and 6 months, we evaluated the effects of the intervention. RESULTS: The attendance rate of the intervention group was 76%, and there were no accidents or injuries associated with this program. After 3 months, grip strength and one-leg standing with eyes-open scores significantly improved among the intervention group, compared with the control group (p=0.028; p=0.003, respectively). On follow-up, grip strength, one-leg standing with eyes-open scores and the World Health Organization Well-Being Index (WHO-5) scores were statistically significantly maintained or had improved in the intervention group (p=0.001; p=0.024; p=0.027, respectively). CONCLUSION: The comprehensive intervention program SPRING may improve physical function among community-dwelling older adults. In addition, SPRING may have long-term beneficial effects for older adults.

Oral intake of Lactobacillus pentosus strain b240 accelerates salivary immunoglobulin A secretion in the elderly: A randomized, placebo-controlled, double-blind trial.

BACKGROUND: Immunoglobulin A (IgA) secretion in saliva decreases with age and may be the cause of increased vulnerability of the elderly to respiratory infections. The effect of oral intake of lactic acid bacteria on salivary secretory IgA (SIgA) in the elderly has not been reported. The objective of this study was to demonstrate the acceleration of salivary SIgA secretion by oral intake of Lactobacillus pentosus strain b240 (b240) in the elderly. RESULTS: A total of 80 healthy elderly individuals were randomly allocated to either an intervention (i.e., b240) or a control (i.e., placebo) group. The elderly individuals in the b240 group were given a sterile water beverage (125 mL) containing heat-killed b240 (4 × 109 cells), while those in the placebo group were given only a sterile water beverage (125 mL); both groups received their respective beverages once daily for 12 weeks. Saliva was collected before initiation of the study and every 2 weeks thereafter. Saliva flow rate and SIgA concentration were determined, and the SIgA secretion rate was calculated. The mean salivary SIgA secretion rate in the b240 group steadily increased until week 4 (exhibiting a 20% elevation relative to that at week 0), and then remained stable until week 12. Changes in SIgA secretion rate over the intervention period were significantly greater in the b240 group than in the placebo group. The treatment groups exhibited no significant differences in adverse events. CONCLUSIONS: Oral intake of L. pentosus strain b240 for 12 weeks significantly accelerated salivary SIgA secretion, thereby indicating its potential utility in the improvement of mucosal immunity and resistance against infection in the elderly.

Resistance exercise training-induced muscle hypertrophy was associated with reduction of inflammatory markers in elderly women.

Aging is associated with low-grade inflammation. The benefits of regular exercise for the elderly are well established, whereas less is known about the impact of low-intensity resistance exercise on low-grade inflammation in the elderly. Twenty-one elderly women (mean age ± SD, 85.0 ± 4.5 years) participated in 12 weeks of resistance exercise training. Muscle thickness and circulating levels of C-reactive protein (CRP), serum amyloid A (SAA), heat shock protein (HSP)70, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, monocyte chemotactic protein (MCP-1), insulin, insulin-like growth factor (IGF)-I, and vascular endothelial growth factor (VEGF) were measured before and after the exercise training. Training reduced the circulating levels of CRP, SAA (P < .05), HSP70, IGF-I, and insulin (P < .01). The training-induced reductions in CRP and TNF-α were significantly (P < .01, P < .05) associated with increased muscle thickness (r = -0.61, r = -0.54), respectively. None of the results were significant after applying a Bonferroni correction. Resistance training may assist in maintaining or improving muscle volume and reducing low-grade inflammation.

The association of elevated reactive oxygen species levels from neutrophils with low-grade inflammation in the elderly.

BACKGROUND: Reactive oxygen species (ROS), including free radicals, oxygen ions, and peroxides, are implicated in cell damage. The objective of this study was to investigate whether the spontaneous production of ROS from neutrophils changes with age and is associated with the conventional inflammatory markers. RESULTS: Thirty-seven elderly subjects (median age, 87, range 70-95 years) and 22 young subjects (median age, 26, range 21-37 years) participated in this study. Circulating levels of C-reactive protein, serum amyloid A, tumor necrosis factor-alpha, interleukin (IL)-1, IL-6, IL-8, monocyte chemotactic protein-1, and heat shock protein (HSP)70 were measured with enzyme-linked immunosorbent assays. The N-formyl-methionyl-leucyl-phenylalanine and lipopolysaccharide-stimulated ROS of neutrophils were quantified by flow cytometry. Both spontaneous ROS production and circulating levels of inflammatory markers were higher in the elderly group than in the younger group. In addition, spontaneous ROS production by neutrophils was negatively associated with HSP70 in plasma. We could not find the association between spontaneous ROS production by neutrophils and the other inflammatory markers including cytokines. CONCLUSION: The results suggest that spontaneous ROS production from neutrophils may increase with age and represent the different aspect of age-associated immune dysregulation.

Serum ethanolamine plasmalogens improve detection of cognitive impairment among elderly with high excretion levels of urinary myo-inositol: A cross-sectional study.

BACKGROUND: Several reports have implicated myo-inositol (MI) in myelin formation. We hypothesized that MI is involved in this process through facilitating the biosynthesis of ethanolamine plasmalogens (PlsEtns), which are the major component of myelin membranes, and essential for myelin formation and function. Excessive MI urinary excretion possibly causes PlsEtn deficiency, leading to demyelinating diseases including dementia. METHODS: We examined the association between cognitive impairment, serum levels of PlsEtn, and baseline levels of urinary MI excretion, in the enrollment of 55 memory clinic outpatients and 107 cognitively normal elderly. RESULTS: Serum PlsEtns were independently associated with cognitive impairment, and significantly reduced in memory clinic outpatients, especially in those with high urinary MI, as compared to normal elderly. On the other hand, there was no direct association between urinary MI and cognitive impairment, but urinary MI was significantly associated with serum hemoglobin A1c and amyloid ß 1-40. The interaction between PlsEtn and urinary MI for cognitive impairment was statistically confirmed, and their combined usage improved diagnosis of cognitive impairment. CONCLUSIONS: We proposed the involvement of MI and PlsEtn in cognitive impairment pathology. In conclusion, serum PlsEtn may be useful in detecting cognitive decline among elderly with hyperglycemia.

Habitual exercise did not affect the balance of type 1 and type 2 cytokines in elderly people.

The purpose of this study was to test the hypothesis that regular exercise training in elderly people affects the type 1/type 2 balance. Nine elderly women who train by walking (mean+/-S.E.M., age 63+/-1 years, VO2 peak 32.2+/-1.0 ml kg(-1) min(-1)), 12 age-matched untrained women (63+/-1 years, 27.8+/-0.9 ml kg(-1) min(-1)), and nine young untrained women (26+/-1 years, 37.8+/-1.3 ml kg(-1) min(-1)) participated in the study. We measured interferon gamma (IFN-gamma), IL-2, and IL-4 in CD4+ and CD8+ T cells, to compare type 1 and type 2 T cells. The number of CD4+ cells expressing intracellular IFN-gamma (CD4+/IFN-gamma cell) significantly higher in the elderly trained than in the young (P<0.01). The number of CD8+/IL-2 cells was significantly higher in the elderly trained than in the elderly untrained (P<0.05). The number of CD8+/IL-4 cells was significantly higher in the young than in the elderly untrained (P<0.01). No significant differences were apparent in the IFN-gamma/IL-4 ratio within CD4+ and CD8+ cells from the three groups. These results might indicate that the effect of age on the balance of type 1/type 2 T cells was stronger than the effect of physical training.

Cardiovascular disease delay in centenarian offspring: role of heat shock proteins.

Cardiovascular disease is a major cause of morbidity and mortality of older Americans. We have demonstrated recently that centenarian offspring, when compared with age-matched controls, avoid and/or delay cardiovascular disease and cardiovascular risk factors. Given recent evidence suggesting that higher circulating levels of HSP70 predict the future development of cardiovascular disease in established hypertensives and a recent study demonstrating a decrease in HSP60 and HSP70 with advancing age, we hypothesized that HSP70 levels would be lower in centenarian offspring compared with controls. The circulating serum concentration of HSP70 in 20 centenarian offspring and 9 spousal controls was analyzed using a modified HSP70 ELISA method. Centenarian offspring showed approximately 10-fold lower levels of circulating serum HSP70 compared with spousal controls (P <.001). The exact biological significance of the extremely low levels of circulating serum HSP70 observed in centenarian offspring thus far is not clear. However, circulating HSP has been shown to correlate in diseases or disorders in which there is destruction or damage to target tissues or organs, including cardiovascular diseases and numerous autoimmune disorders. We hypothesize that low levels of circulating serum HSP70 may be an indicator of a healthy state and point to longevity of the host; therefore, our results suggest that levels of circulating serum HSP70 may be a marker for longevity.

Effects of a comprehensive intervention program, including hot bathing, on overweight adults: a randomized controlled trial.

AIM: The objective of this study was to evaluate the effects of a comprehensive overweight intervention program, which utilizes hot bathing, on overweight, community-dwelling middle-aged and older adults in a randomized controlled trial. METHODS: The program was carried out in a hot bath facility and included 66 community-dwelling middle-aged and older Japanese adults (mean age 61.6 years, SD 7.5, 77.3% were women). The participants were randomly assigned to an exercise, diet and hot bathing intervention group (group A), exercise and diet intervention group (group B), a hot-bathing intervention group (group C) and a control group (group D). The participants in groups A and B participated in a comprehensive intervention program (including exercise and diet classes) twice a week for 3 months, and groups A and C had hot bathing. RESULTS: After 3 months, the participants in group A showed a reduction in weight, abdominal circumference, body mass index and body fat percentage compared with the other intervention groups. And the lower extremity function (i.e. walking speed) had greater improvement in the participants in groups A and B compared with groups C and D. In group C, in which only hot bathing was the intervention, there were no significant improvements in measurement items. CONCLUSIONS: Our study provides preliminary evidence that a comprehensive intervention program, including hot bathing, is useful for community residents with a tendency toward overweight.

Plasma heat shock protein 72 as a biomarker of sarcopenia in elderly people.

Sarcopenia is a geriatric syndrome in which there is a decrease of muscle mass and strength with aging. In age-related loss of muscle strength, there are numerous observations supporting the assertion that neural factors mediate muscle strength. A possible contributing cause may be that aging changes systemic extracellular heat shock protein (eHsp)72 activity. The present study was designed to assess the plasma levels of eHsp72 in elderly people and to investigate its potential interaction with components of sarcopenia. A total of 665 men and women participated in an official medical health examination and an integrated health examination, including psychological and physical fitness tests. Blood samples were assayed for levels of plasma Hsp72, serum C-reactive protein, interleukin 6, tumor necrosis factor α, and regular biomedical parameters. We found that higher Hsp72 in plasma is associated with lower muscle mass, weaker grip strength, and slower walking speed, and may be a potential biomarker of sarcopenia in elderly people. This finding was supported by other results in the present study: (1) older age and shrinking body and lower hemoglobin levels, all of which characterize sarcopenia, were related to higher eHsp72 tertiles and (2) the ORs of the highest tertile of eHsp72 for the lowest tertiles of muscle mass, grip strength, and walking speed were 2.7, 2.6, and 1.8, respectively. These ORs were independent of age, sex, and the incidence of related diseases. Our results would reveal that eHsp72 in plasma is linked to sarcopenia factors and is a potential biomarker or predictor of sarcopenia.

Mechanisms for Hsp70 secretion: crossing membranes without a leader.

Heat shock protein 70 (Hsp70) is released from cells of many types and plays a significant signaling role, particularly in the inflammatory and immune responses. However, Hsp70 does not contain a consensus secretory signal and thus cannot traverse the plasma membrane by conventional mechanisms. However, Hsp70 can be released from cells by active mechanism that are independent of de novo Hsp70 synthesis or cell death. This pathway is similar to one utilized by the leaderless protein interleukin 1beta. Hsp70 release involves transit through an endolysosomal compartment and is inhibited by lysosomotropic compounds. In addition, the rate of Hsp70 secretion correlates well with the appearance of the lysosomal marker LAMP1 on the cell surface, further suggesting the role for endolysosomes. The entry of Hsp70 into this secretory compartment appears to involve the ABC-family transporter proteins. While the cell signals involved in triggering Hsp70 release through this lysosomal pathway are largely unknown, recent data suggest a regulatory role for extracellular ATP. These mechanisms are also shared by interleukin 1beta secretion. Following release it has been shown that Hsp70 binds to adjacent cells, suggesting that the secreted protein participates in paracrine or autocrine interactions with adjacent cell surfaces. Thus an outline is beginning to of the mechanisms of Hsp70 secretion. Much further study will be required to fully elucidate mechanisms involved in targeting Hsp70 towards the non-canonical secretion pathways and its regulation.

A single bout of exercise influences natural killer cells in elderly women, especially those who are habitually active.

The purpose of our study was to examine the effects of a single exercise bout on the natural killer (NK) cell count and activity in physically active elderly people, sedentary elderly people, and sedentary young people. Eight elderly women who trained by walking (age, 64 +/- 1 years; Vo(2peak), 32.2 +/- 1.1 ml.kg(-1).min(-1)), 8 age-matched untrained women (63 +/- 1 years, 28.8 +/- 1.0 ml.kg(-1).min(-1)), and 8 young untrained women (25 +/- 1 years, 37.6 +/- 1.6 ml.kg(-1).min(-1)) were studied. Blood samples were taken before, immediately after, and 2 hours after a 30-minute bout of exercise at an intensity equivalent to 70-75% of Vo(2peak). Peripheral blood mononuclear cells were isolated and the NK cell count and activity were analyzed. The NK cell count of the elderly sedentary group immediately after exercise was significantly higher than those of the elderly women who walked and young sedentary women, whereas no significant interaction was detected in NK cell activity and NK cell activity per cell number among the 3 groups. Consequently, an intrinsic defect in the cytotoxic ability of NK cells appeared in sedentary elderly people but not in active elderly people who perform habitual exercise.