The Asia-Pacific Clinical Practice Guidelines for the Management of Frailty.

OBJECTIVE: To develop Clinical Practice Guidelines for the screening, assessment and management of the geriatric condition of frailty. METHODS: An adapted Grading of Recommendations, Assessment, Development, and Evaluation approach was used to develop the guidelines. This process involved detailed evaluation of the current scientific evidence paired with expert panel interpretation. Three categories of Clinical Practice Guidelines recommendations were developed: strong, conditional, and no recommendation. RECOMMENDATIONS: Strong recommendations were (1) use a validated measurement tool to identify frailty; (2) prescribe physical activity with a resistance training component; and (3) address polypharmacy by reducing or deprescribing any inappropriate/superfluous medications. Conditional recommendations were (1) screen for, and address modifiable causes of fatigue; (2) for persons exhibiting unintentional weight loss, screen for reversible causes and consider food fortification and protein/caloric supplementation; and (3) prescribe vitamin D for individuals deficient in vitamin D. No recommendation was given regarding the provision of a patient support and education plan. CONCLUSIONS: The recommendations provided herein are intended for use by healthcare providers in their management of older adults with frailty in the Asia Pacific region. It is proposed that regional guideline support committees be formed to help provide regular updates to these evidence-based guidelines.

IAGG/IAGG GARN International Survey of End-of-Life Care in Nursing Homes.

This article reports the findings of a survey on end-of-life (EOL) care in nursing homes of 18 long-term care experts across 15 countries. The experts were chosen as a convenience-based sample of known experts in each country. The survey was administered in 2016 and included both open-ended responses for defining hospice care, palliative care, and "end of life," and a series of questions related to the following areas-attitudes toward EOL care, current practice and EOL interventions, structure of care, and routine barriers. Overall experts strongly agreed that hospice and palliative care should be available in long-term care facilities and that both are defined by holistic, interdisciplinary approaches using measures of comfort across domains. However, it appears the experts felt that in most countries the reality fell short of what they believed would be ideal care. As a result, experts call for increased training, communication, and access to specialized EOL services within the nursing home.

Nutrient interface with biology and aging.

PURPOSE OF REVIEW: To highlight recent conundrums in the interface of nutrition, biology and aging. RECENT FINDINGS: A Mediterranean diet with extra virgin olive oil, or similar plant-based diets, including five helpings of fruit and vegetables, exercise and nonsmoking are the mainstays of aging successfully. Recent studies have questioned the utility of weight loss in older persons, the use of antioxidant vitamin supplements as well as the appropriate level of sodium intake. The understanding of the role of ethnicity in the levels of vitamin D-binding protein has questioned the measurement of 25(OH)vitamin D by itself. Gut microbiota may also appear important for aging. SUMMARY: Continuous scientific advances are leading us to question whether some of our nutrient beliefs need to be altered in older persons.

Pharmacologic Options for the Treatment of Sarcopenia.

Sarcopenia is now clinically defined as a loss of muscle mass coupled with functional deterioration (either walking speed or distance or grip strength). Based on the FRAX studies suggesting that the questions without bone mineral density can be used to screen for osteoporosis, there is now a valid simple questionnaire to screen for sarcopenia, i.e., the SARC-F. Numerous factors have been implicated in the pathophysiology of sarcopenia. These include genetic factors, mitochondrial defects, decreased anabolic hormones (e.g., testosterone, vitamin D, growth hormone and insulin growth hormone-1), inflammatory cytokine excess, insulin resistance, decreased protein intake and activity, poor blood flow to muscle and deficiency of growth derived factor-11. Over the last decade, there has been a remarkable increase in our understanding of the molecular biology of muscle, resulting in a marked increase in potential future targets for the treatment of sarcopenia. At present, resistance exercise, protein supplementation, and vitamin D have been established as the basic treatment of sarcopenia. High-dose testosterone increases muscle power and function, but has a number of potentially limiting side effects. Other drugs in clinical development include selective androgen receptor molecules, ghrelin agonists, myostatin antibodies, activin IIR antagonists, angiotensin converting enzyme inhibitors, beta antagonists, and fast skeletal muscle troponin activators. As sarcopenia is a major predictor of frailty, hip fracture, disability, and mortality in older persons, the development of drugs to treat it is eagerly awaited.

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition.

Intranasal insulin has shown efficacy in patients with Alzheimer's disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory deficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain.

Prevalence, incidence, and clinical impact of sarcopenia: facts, numbers, and epidemiology-update 2014.

Sarcopenia is now defined as a decline in walking speed or grip strength associated with low muscle mass. Sarcopenia leads to loss of mobility and function, falls, and mortality. Sarcopenia is a major cause of frailty, but either condition can occur without the other being present. Sarcopenia is present in about 5 to 10 % of persons over 65 years of age. It has multiple causes including disease, decreased caloric intake, poor blood flow to muscle, mitochondrial dysfunction, a decline in anabolic hormones, and an increase in proinflammatory cytokines. Basic therapy includes resistance exercise and protein and vitamin D supplementation. There is now a simple screening test available for sarcopenia-SARC-F. All persons 60 years and older should be screened for sarcopenia and treated when appropriate.

Scientific overview of hormone treatment used for rejuvenation.

A search for a hormonal fountain of youth has been hotly pursued over the last century, predominately by those who wish to market hormones to a gullible public. There is little or no benefit of hormone replacement in persons who do not have a hormone deficiency. Overall, the present state of the art suggests that the findings have been disappointing. In persons who fail to get adequate sunlight, and therefore have low vitamin D levels, vitamin D replacement appears to have positive effects, including decreasing mortality. Testosterone in hypogonadal males has a number of positive effects such as improving libido and erectile capacity, increasing strength and bone mineral density, and perhaps having a small effect on cognition. These effects need to be balanced against long-term side effects, the evidence for which studies are lacking. There is little evidence to recommend DHEA, pregnenolone, growth hormone, ghrelin, or melatonin to older persons. Overall, exercise, adequate exposure to sunlight, and adequate dietary protein appear to have at least as positive an effect as any of the hormones being used to rejuvenate older persons.

Frailty consensus: a call to action.

Frailty is a clinical state in which there is an increase in an individual's vulnerability for developing increased dependency and/or mortality when exposed to a stressor. Frailty can occur as the result of a range of diseases and medical conditions. A consensus group consisting of delegates from 6 major international, European, and US societies created 4 major consensus points on a specific form of frailty: physical frailty. 1. Physical frailty is an important medical syndrome. The group defined physical frailty as "a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual's vulnerability for developing increased dependency and/or death." 2. Physical frailty can potentially be prevented or treated with specific modalities, such as exercise, protein-calorie supplementation, vitamin D, and reduction of polypharmacy. 3. Simple, rapid screening tests have been developed and validated, such as the simple FRAIL scale, to allow physicians to objectively recognize frail persons. 4. For the purposes of optimally managing individuals with physical frailty, all persons older than 70 years and all individuals with significant weight loss (>5%) due to chronic disease should be screened for frailty.

Frailty, sarcopenia, and hormones.

Frailty is now a definable clinical syndrome with a simple screening test. Age-related changes in hormones play a major role in the development of frailty by reducing muscle mass and strength (sarcopenia). Selective Androgen Receptor Molecules and ghrelin agonists are being developed to treat sarcopenia. The role of Activin Type IIB soluble receptors and Follistatin-like 3 mimetics is less certain because of side effects. Exercise (resistance and aerobic), vitamin D and protein supplementation, and reduction of polypharmacy are keys to the treatment of frailty.

From muscle wasting to sarcopenia and myopenia: update 2012.

Human muscle undergoes constant changes. After about age 50, muscle mass decreases at an annual rate of 1-2 %. Muscle strength declines by 1.5 % between ages 50 and 60 and by 3 % thereafter. The reasons for these changes include denervation of motor units and a net conversion of fast type II muscle fibers into slow type I fibers with resulting loss in muscle power necessary for activities of daily living. In addition, lipids are deposited in the muscle, but these changes do not usually lead to a loss in body weight. Once muscle mass in elderly subjects falls below 2 standard deviations of the mean of a young control cohort and the gait speed falls below 0.8 m/s, a clinical diagnosis of sarcopenia can be reached. Assessment of muscle strength using tests such as the short physical performance battery test, the timed get-up-and-go test, or the stair climb power test may also be helpful in establishing the diagnosis. Serum markers may be useful when sarcopenia presence is suspected and may prompt further investigations. Indeed, sarcopenia is one of the four main reasons for loss of muscle mass. On average, it is estimated that 5-13 % of elderly people aged 60-70 years are affected by sarcopenia. The numbers increase to 11-50 % for those aged 80 or above. Sarcopenia may lead to frailty, but not all patients with sarcopenia are frail-sarcopenia is about twice as common as frailty. Several studies have shown that the risk of falls is significantly elevated in subjects with reduced muscle strength. Treatment of sarcopenia remains challenging, but promising results have been obtained using progressive resistance training, testosterone, estrogens, growth hormone, vitamin D, and angiotensin-converting enzyme inhibitors. Interesting nutritional interventions include high-caloric nutritional supplements and essential amino acids that support muscle fiber synthesis.

Intranasal administration of PACAP: uptake by brain and regional brain targeting with cyclodextrins.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a potent neurotrophic and neuroprotectant that is transported across the blood-brain barrier in amounts sufficient to affect brain function. However, its short half-life in blood makes it difficult to administer peripherally. Here, we determined whether the radioactively labeled 38 amino acid form of PACAP can enter the brain after intranasal (i.n.) administration. Occipital cortex and striatum were the regions with the highest uptake, peaking at levels of about 2-4% of the injected dose per gram of brain region. Inclusion of unlabeled PACAP greatly increased retention of I-PACAP by brain probably because of inhibition of the brain-to-blood efflux transporter for PACAP located at the blood-brain barrier. Sufficient amounts of PACAP could be delivered to the brain to affect function as shown by improvement of memory in aged SAMP8 mice, a model of Alzheimer's disease. We found that each of three cyclodextrins when included in the i.n. injection produced a unique distribution pattern of I-PACAP among brain regions. As examples, ß-cyclodextrin greatly increased uptake by the occipital cortex and hypothalamus, α-cyclodextrin increased uptake by the olfactory bulb and decreased uptake by the occipital cortex and striatum, and (2-hydropropyl)-ß-cyclodextrin increased uptake by the thalamus and decreased uptake by the striatum. These results show that therapeutic amounts of PACAP can be delivered to the brain by intranasal administration and that cyclodextrins may be useful in the therapeutic targeting of peptides to specific brain regions.

Sarcopenia in the elderly.

Sarcopenia is the age-related loss of muscle. It leads to loss of muscle power, which in the end results in frailty and disability. There are numerous causes of sarcopenia. Treatment consists of resistance exercise and a leucine-enriched essential amino acid protein supplement. There is an emerging role for testosterone and other anabolic steroids. An activin II receptor soluble fusion protein is showing great potential to increase muscle mass and bone mineral density.

Extra virgin olive oil improves learning and memory in SAMP8 mice.

Polyphenols are potent antioxidants found in extra virgin olive oil (EVOO); antioxidants have been shown to reverse age- and disease-related learning and memory deficits. We examined the effects of EVOO on learning and memory in SAMP8 mice, an age-related learning/memory impairment model associated with increased amyloid-ß protein and brain oxidative damage. We administered EVOO, coconut oil, or butter to 11 month old SAMP8 mice for 6 weeks. Mice were tested in T-maze foot shock avoidance and one-trial novel object recognition with a 24 h delay. Mice which received EVOO had improved acquisition in the T-maze and spent more time with the novel object in one-trial novel object recognition versus mice which received coconut oil or butter. Mice that received EVOO had improve T-maze retention compared to the mice that received butter. EVOO increased brain glutathione levels suggesting reduced oxidative stress as a possible mechanism. These effects plus increased glutathione reductase activity, superoxide dismutase activity, and decreased tissue levels of 4-hydroxynoneal and 3-nitrotyrosine were enhanced with enriched EVOO (3 × and 5 × polyphenols concentration). Our findings suggest that EVOO has beneficial effects on learning and memory deficits found in aging and diseases, such as those related to the overproduction of amyloid-ß protein, by reversing oxidative damage in the brain, effects that are augmented with increasing concentrations of polyphenols in EVOO.

Nitric oxide is a central component in neuropeptide regulation of appetite.

In recent years, there have been a large number of neuropeptides discovered that regulate food intake. Many of these peptides regulate food intake by increasing or decreasing nitric oxide (NO). In the current study, we compared the effect of the food modulators ghrelin, NPY and CCK in NOS KO mice. Satiated homozygous and heterozygous NOS KO mice and their wild type controls were administered ghrelin ICV. Food intake was measured for 2h post injection. Ghrelin did not increase food intake in the homozygous NOS KO mice compared to vehicle treated NOS KO mice, whereas food intake was increased in the wild type controls compared to vehicle treated wild type controls. NPY was administered ICV and food intake measured for 2h. Homozygous NOS KO mice showed no increase in food intake after NPY administration, whereas the wild type controls did. In our final study, we administered CCK intraperitoneally to homozygous and heterozygous NOS KO mice and their wild type controls after overnight food deprivation. Food intake was measured for 1h after injection. CCK inhibited food intake in wild type mice after overnight food deprivation, however, CCK failed to inhibit food intake in the NOS KO mice. The heterozygous mice showed partial food inhibition after the CCK. The current results add further support to the theory that NO is a central mediator in food intake.

Nutritional recommendations for the management of sarcopenia.

The Society for Sarcopenia, Cachexia, and Wasting Disease convened an expert panel to develop nutritional recommendations for prevention and management of sarcopenia. Exercise (both resistance and aerobic) in combination with adequate protein and energy intake is the key component of the prevention and management of sarcopenia. Adequate protein supplementation alone only slows loss of muscle mass. Adequate protein intake (leucine-enriched balanced amino acids and possibly creatine) may enhance muscle strength. Low 25(OH) vitamin D levels require vitamin D replacement.