Fight Aging! Newsletter, December 5th 2016

With age, somatic cells such as neurons lose their ability to maintain the quality of their protein content. Pluripotent stem cells, on the contrary, do not age and have increased mechanism to maintain the integrity of their proteins. The survival of an organism is linked to its ability to maintain the quality of the cellular proteins. A group of proteins called chaperones facilitate the folding of proteins and are essential to regulating the quality of the cellular protein content. This ability declines during the aging process, inducing the accumulation of damaged and misfolded proteins that can lead to cell death or malfunction. Several neurodegenerative age-related disorders such as Alzheimer's, Parkinson's or Huntington's disease are linked to a decline in protein quality control.

Human pluripotent stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity necessarily demands avoidance of any imbalance in the integrity of their protein content. "There is one chaperone system, the TRiC/CCT-complex that is responsible for folding about 10% of all the cellular proteins. By studying how pluripotent stem cells maintain the quality of their proteome, we found that this complex is regulated by the subunit CCT8. Then, we discovered a way to increase the assembly and activity of the TRiC/CCT complex in somatic tissues by modulating this single subunit, CCT8. The increase resulted in prolonged lifespan and delay of age-related diseases of the model organism Caenorhabditis elegans. For this study we combined the results from human pluripotent stem cells and C. elegans, to have both in vitro and in vivo models, providing a more convincing approach. Our results show that expressing CCT8 as the key subunit of the complex is sufficient to boost the assembly of the whole system. It is very interesting that expressing this single subunit is enough to enhance protein quality and extend longevity, even in older animals. One of our next steps will be to test our findings in mice."

Human embryonic stem cells can replicate indefinitely while maintaining their undifferentiated state and, therefore, are immortal in culture. This capacity may demand avoidance of any imbalance in protein homeostasis (proteostasis) that would otherwise compromise stem cell identity. Here we show that human pluripotent stem cells exhibit enhanced assembly of the TRiC/CCT complex, a chaperonin that facilitates the folding of 10% of the proteome. We find that ectopic expression of a single subunit (CCT8) is sufficient to increase TRiC/CCT assembly. Moreover, increased TRiC/CCT complex is required to avoid aggregation of mutant Huntingtin protein. We further show that increased expression of CCT8 in somatic tissues extends Caenorhabditis elegans lifespan in a TRiC/CCT-dependent manner. Ectopic expression of CCT8 also ameliorates the age-associated demise of proteostasis and corrects proteostatic deficiencies in worm models of Huntington's disease. Our results suggest proteostasis is a common principle that links organismal longevity with hESC immortality.

Osteoarthritis (OA) is one of the leading causes of pain and disability worldwide. It can greatly increase health care costs and reduce quality of life. The key characteristics of age-related OA in humans include damage of articular cartilage with joint space narrowing and degeneration of soft tissues. Age is the leading predictor for developing OA. However, modeling age- or senescence-associated OA, which may be distinct from injury-related OA, in mice has been challenging. So far, no disease-modifying drug has been approved to treat OA other than pain reducers, partly because etiological mechanisms of age-related OA have been poorly understood to date. Potential cellular mechanisms contributing to the development of OA include low-grade inflammation, chondrocyte alteration, mitochondrial dysfunction, loss of glycosaminoglycans, and dysregulated energy metabolism. In addition, a potential contribution by senescent cells has been suggested. Cellular senescence refers to a state of stable arrest of cell proliferation in replication-competent but apoptosis-resistant cells. Senescent cells accumulate with aging in various tissues, including the articular cartilage. One key feature of senescent cells is secretion of an array of pro-inflammatory cytokines, chemokines, and growth factors, termed the senescence-associated secretory phenotype (SASP). The SASP is observed across a number of senescent cell types, including fibroblasts and mesenchymal stem cells. Although mounting evidence suggests that cellular senescence is associated with OA, whether this link is causal remains to be determined.

To test if senescent cells cause an OA-like arthropathy, we injected either senescent or control nonsenescent fibroblasts into the knee joint region of mice. We transplanted seven mice with control cells and seven with senescent cells. Three months after cell injection, senescent and nonsenescent cell-injected knees were evaluated histologically and radiologically to assess articular cartilage and overall joint structure. We found that the senescent cells induced a phenotype with features resembling OA, including articular cartilage erosion, increased pain, and impaired function. We found that Rotarod performance was significantly decreased in the mice injected with senescent cells compared with animals injected with control nonsenescent cells or those that were not injected. In addition, we found that mice injected with senescent cells moved less and traveled shorter distances than mice injected with control nonsenescent cells. To our knowledge, this is the first evidence suggesting that cellular senescence can actually cause OA. Our findings also imply that targeting senescent cells is a promising approach for preventing or treating OA.

This both provides a new model of OA and implies that clearing senescent cells with senolytics or interfering with their pro-inflammatory SASP could be a disease-modifying therapeutic option. A next step will be to test such interventions in our senescent cell-transplanted model. One of the potential mechanisms by which senescent cells could induce an OA-like phenotype is through the SASP. OA is linked to inflammation and immune cells have been found in early stage OA. IL-6, one of the key SASP components, is highly associated with OA progression. We found that the senescent cells we transplanted secreted 20 times more IL-6 than nonsenescent cells. In addition, senescent cells can directly impair progenitor function through the SASP and spread senescence to nearby cells, both of which might contribute to dysfunction of chondrocytes and therefore to OA.

The finding that cellular senescence can drive development of an OA-like state is consistent with the geroscience hypothesis - that fundamental aging mechanisms, of which cellular senescence is one, predispose to age-related disabilities and chronic diseases, such as OA. If correct, this would imply that senescent cell accumulation may not only predispose to OA, but to multiple other age-related conditions, as is increasingly appearing to be the case. We predict that senolytics or SASP inhibitors such as ruxolitinib, which decreases IL-6 secretion and effects by senescent cells and also alleviates the senescent cell-induced stem cell dysfunction caused by TGFβ-related SASP factors, will delay, prevent, or alleviate OA. Consistent with this possibility, we found that senolytics attenuate age-related loss of glycosaminoglycans, a contributor to developing OA, from the intervertebral discs of progeroid mice. Moreover, senolytics are effective when administered periodically, likely because senescent cells do not of course divide and may be slow to re-accumulate once cleared in the absence of a strong continuing insult. We predict that senolytics may have fewer side effects than the anti-inflammatory agents currently used for controlling pain.

The new study examined aquaporin-4, a type of membrane protein in the brain. Using brains donated for scientific research, researchers discovered a correlation between the prevalence of aquaporin-4 among older people who did not suffer from Alzheimer's as compared to those who had the disease. Aquaporin-4 is a key part of a brain-wide network of channels, collectively known as the glymphatic system, that permits cerebral-spinal fluid from outside the brain to wash away proteins such as amyloid and tau that build up within the brain. These proteins tend to accumulate in the brains of some people suffering from Alzheimer's, which may play a role in destroying nerve cells in the brain over time.

The study closely examined 79 brains donated through the Oregon Brain Bank. They were separated into three groups: People younger than 60 without a history of neurological disease; people older than 60 with a history of Alzheimer's; and people older than 60 without Alzheimer's. Researchers found that in the brains of younger people and older people without Alzheimer's, the aquaporin-4 protein was well organized, lining the blood vessels of the brain. However within the brains of people with Alzheimer's, the aquaporin-4 protein appeared disorganized, which may reflect an inability of these brains to efficiently clear away wastes like amyloid beta. The study concluded that future research focusing on aquaporin-4 - either through its form or function - may ultimately lead to medication to treat or prevent Alzheimer's disease.

Since 2013, we have defined a brain wide perivascular pathway, termed the glymphatic system, that facilitates the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma and supports the clearance of interstitial solutes including amyloid-β (Aβ) and tau. Perivascular exchange of CSF and interstitial fluid is dependent on the astroglial water channel aquaporin-4 (AQP4), which is localized to perivascular astrocytic endfeet that ensheathe the cerebral vasculature. We demonstrated that perivascular CSF recirculation and Aβ clearance are impaired in the aging mouse brain, impairment that was associated with the loss of perivascular AQP4 localization. Prior studies in postmortem human tissue show that AQP4 is up regulated and that localization of AQP4 to the cerebral vasculature is disrupted in the AD cortex. This suggests that age-related mislocalization of AQP4 may slow glymphatic function and promote protein aggregation and neurodegeneration.

In this study, we assessed AQP4 expression and perivascular localization in human brain samples including individuals of different ages and with different cognitive and neuropathological AD profiles. Expression of AQP4 was associated with advancing age among all individuals. Perivascular AQP4 localization was significantly associated with AD status independent of age and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden.

The Hadza live a very different kind of lifestyle - and a very active one, engaging in significantly more physical activity than what is recommended by U.S. government standards. They also have extremely low risk of cardiovascular disease. Researchers have spent several years studying the lifestyle of the Hadza. "Our overall research program is trying to understand why physical activity and exercise improve health today, and one arm of that research program aims to reconstruct what physical activity patterns were like during the evolution of our physiology. The overarching hypothesis is that our bodies evolved within a highly active context, and that explains why physical activity seems to improve physiological health today."

The U.S. Department of Health and Human Services recommends that people engage in 150 minutes per week of moderate intensity activity - about 30 minutes a day, five times a week - or about 75 minutes per week of vigorous intensity activity, or an equivalent combination of the two. However, few Americans achieve those levels. The Hadza, on the other hand, meet those weekly recommendations in a mere two days, engaging in about 75 minutes per day of moderate-to-vigorous physical activity, or MVPA. Furthermore, and consistent with the literature identifying aerobic activity as a key element necessary to a healthy lifestyle, researchers' health screenings of Hadza people have shown that the population has extremely low risk for heart disease. "They have very low levels of hypertension. In the U.S., the majority of our population over the age of 60 has hypertension. In the Hadza, it's 20 to 25 percent, and in terms of blood lipid levels, there's virtually no evidence that the Hadza people have any kind of blood lipid levels that would put them at risk for cardiovascular disease."

While physical activity may not be entirely responsible for the low risk levels - diet and other factors may also play a role - exercise does seem to be important, which is significant because humans' physical activity levels have drastically declined as we have transitioned from hunting and gathering to farming to the Industrial Revolution to where we are today. "Over the last couple of centuries, we've become more and more sedentary, and the big shift seems to have occurred in the middle of the last century, when people's work lives became more sedentary. In the U.S., we tend to see big drop-offs in physical activity levels when people age. In the Hadza, we don't see that. We see pretty static physical activity levels with age. This gives us a window into what physical activity levels were we like for quite a while during our evolutionary history, and, not surprisingly, it's more than we do now. Perhaps surprisingly, it's a whole lot more than we do now. Going forward, this helps us model the types of physical activity we want to be looking at when we explore our physiological evolution. When we ask what kinds of physical activity levels would have driven the evolution of our cardiovascular system and the evolution of our neurobiology and our musculoskeletal system, the answer is not likely 30 minutes a day of walking on a treadmill. It's more like 75-plus minutes a day."

The maximum lifespan of mammalian species differs by more than 100-fold, ranging from ~2 years in shrews to more than 200 years in bowhead whales. While it has long been observed that maximum lifespan tends to correlate positively with body mass and time to maturity, but negatively with growth rate, mass-specific metabolic rate, and number of offspring, the underlying molecular basis is only starting to be understood. One way to study the control of longevity is to identify the genes, pathways, and interventions capable of extending lifespan or delaying aging phenotypes in experimental animals. Studies using model organisms have uncovered several important conditions, such as knockout of insulin-like growth factor 1 (IGF-1) receptor, inhibition of mechanistic target of rapamycin (mTOR), mutation in growth hormone (GH) receptor, ablation of anterior pituitary (e.g. Snell dwarf mice), augmentation of proteins of the sirtuin family, and restriction of dietary intake. While many of these genes and pathways have been verified in yeast, flies, worms, and mice, the comparisons largely involve treatment and control groups of the same species, and the extent to which they explain the longevity variations across different species is unclear. For example, do the long-lived species have metabolic profiles resembling calorie restriction? Do they suppress IGF-1 or growth hormone signaling compared with the shorter-lived species? More generally, how do the evolutionary strategies of longevity relate to the experimental strategies that extend lifespan in model organisms?

To address these questions, a popular approach has been to compare exceptionally long-lived species with closely related species of common lifespan and identify the features associated with exceptional longevity. Examples include the amino acid changes in Uncoupling Protein 1 (UCP1) and production of high-molecular-mass hyaluronan in the naked mole rat; unique sequence changes in IGF1 and GH receptors in Brandt's bat; gene gain and loss associated with DNA repair, cell-cycle regulation, and cancer, as well as alteration in insulin signaling in the bowhead whale; and duplication of the p53 gene in elephants. Again, it is important to ascertain whether these mechanisms are unique characteristics of specific exceptionally long-lived species, or whether they can also help account for the general lifespan variation.

An extension of this approach has been cross-species analyses in a larger scale. For example, several biochemical studies across multiple mammalian and bird species identified some features correlating with species lifespan. Longevity of fibroblasts and erythrocytes in vitro, poly (ADP-ribose) polymerase activity, and rate of DNA repair were found to be positively correlated with longevity, whereas mitochondrial membrane and liver fatty acid peroxidizability index, rate of telomere shortening, and oxidative damage to DNA and mitochondrial DNA showed negative correlation. The advent of high throughput RNA sequencing (RNAseq) and mass spectrometry technologies has enabled the quantification of whole transcriptomes, metabolomes, and ionomes, across multiple species and organs. These studies revealed the complex transcriptomic and metabolic landscape across different organs and species, as well as some overlaps with the changes observed in the long-lived mutants created in laboratory.

While molecular profiling of mammals at the level of tissues may better represent the underlying biology, profiling in cell culture represents more defined experimental conditions and allows further manipulation to alter the identified molecular phenotypes. In this study, we examined the transcriptomes and metabolomes of primary skin fibroblasts across 16 species of mammals, to identify the molecular patterns associated with species longevity. We report that the genes involved in DNA repair and glucose metabolism were up-regulated in the longer-lived species, whereas proteolysis and protein translocation activities were suppressed. The longer-lived species also had lower levels of lysophosphatidylcholine and lysophosphatidylethanolamine and higher levels of amino acids; and the latter finding was validated in an independent dataset of bird and primate fibroblasts.

The pro-inflammatory cytokine interleukin-1 (IL-1) is a major driver of inflammation, with well documented detrimental effects in multiple preclinical models of systemic inflammatory disease as well as in cerebral ischemia. To this end, the selective, naturally occurring competitive inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1Ra) has shown potential as a new treatment for stroke. More specifically, in a number of experimental stroke paradigms IL-1Ra reduces infarct volume and improves long term functional outcome, including in co-morbid animals. However, exact mechanisms by which IL-1Ra is neuroprotective are yet to be fully established.

While much research has focused on limiting ischemic damage in the initial stages of acute reperfusion, it is also important to understand mechanisms that underpin brain repair following injury and develop strategies that enhance reparative endogenous processes, including adult neurogenesis. Ischemic injury elicits a robust neurogenic response by stimulating production of neuronal progenitor cells (NPCs) in distinct neurogenic regions, which include the subventricular zone (SVZ) and the subgranular zone (SGZ), to generate new functional neurons. Though mechanisms underlying post-stroke neurogenesis and the influence of inflammation on these processes are still poorly understood, it has been observed in young and aged animals that inflammation impairs both basal levels of neurogenesis and attenuates the neurogenic response triggered by central nervous system (CNS) injury via induction of the pro-inflammatory cytokines. IL-1, for example, reduces the proliferation and differentiation of NPCs to neurons in pathologies such as stress and depression, effects reversed by administration of IL-1Ra.

Here, we explored how inhibition of IL-1 actions by clinically relevant, delayed administration of subcutaneous IL-1Ra affects stroke outcome and neurogenesis up to 28 days after experimental ischemia, in aged/co-morbid and young rats. All experiments were performed using 13-month-old male, lean and corpulent (Cp) rats and 2-month-old Wistar rats. Cp rats are homozygous for the autosomal recessive cp gene (cp/cp), and spontaneously develop obesity, hyperlipidemia, insulin resistance, glomerular sclerosis, and atherosclerosis. Delayed IL-1Ra administration at 3 and 6 hours reperfusion in aged lean, aged Cp and young Wistar rats induced a significant reduction in infarct volume at 24 hours and 7 days of reperfusion, and a significant reduction in cortex loss at 28d in young Wistar rats. Reductions in infarct volume at 24 hours of reperfusion were 37%, 42% and 40% in aged lean, aged Cp and young Wistar rats respectively. IgG staining at 7 days reperfusion revealed a reduction of 40%, 48% and 46% in blood-brain barrier (BBB) damage in IL-1Ra treated aged lean, aged Cp and young Wistar animals respectively, versus their placebo-treated counterparts. A reduction of 26% was also observed at 14d reperfusion in young Wistar rats treated with IL-1Ra versus their placebo counterparts.

Our findings demonstrate that subcutaneous administration of IL-1Ra is neuroprotective in young and aged animals with multiple risk factors for stroke and increases post-stroke neurogenesis. It has previously been observed that delayed administration of IL-1Ra exerts neuroprotective effects at acute time points following experimental ischemia. Here we extend these findings to show that the early beneficial effects of IL-1Ra persist for at least 7 days in aged/co-morbid animals and for 28 days in young/healthy animals. Our data show that although 13-month-old corpulent rats had a plethora of stroke associated co-morbidities, infarct volumes were of a similar size to aged leans, suggesting that the extent of ischemic damage was close to maximal and that no further increase was possible. Conversely, younger rats were more resistant. This suggests that age is the primary variable that increases the brain susceptibility to infarction following an ischemic stroke. However, despite reaching maximal levels of infarction, tissue is still salvageable under these circumstances if IL-1Ra is administered within a therapeutic window.

Furthermore, our results indicate that although the delayed administration of IL-1Ra (3 and 6 hours from reperfusion onset) reduces infarct volume, it produces an increase on cellular proliferation and migration of immature neurons versus placebo counterparts in the SVZ following stroke in young and aged/co-morbid rats, suggesting that a reduced inflammation of the tissue fosters a more efficient repair of the damaged tissue. We also show that IL-1Ra increases the number of new integrated neurons in areas surrounding the infarct lesion in young animals compared to placebo groups a result that correlates with improvements in motor and behavioral sub-acute outcomes. The benefits of IL-1Ra are therefore not limited to inducing neuroprotection, but also favor and promote neurorepair mechanisms. We conclude that further studies are required to fully elucidate the mechanisms through which IL-1Ra may be mediating its beneficial, neurogenic effects.

In the past 40 years, there has been a large increase in the number of people living with high blood pressure worldwide because of population growth and ageing - rising from 594 million in 1975 to over 1.1 billion in 2015. The largest rise in the prevalence of adults with high blood pressure has been in low- and middle-income countries (LMICs) in south Asia (eg, Bangladesh and Nepal) and sub-Saharan Africa (eg, Ethiopia and Malawi). But high-income countries (eg, Australia, Canada, Germany, Sweden, and Japan) have made impressive reductions in the prevalence of adults with high blood pressure, according to the most comprehensive analysis of worldwide trends in blood pressure to date.

Both elevated systolic (higher than 140 mmHg; first number in blood pressure reading) and diastolic (higher than 90mmHg) blood pressure can be used to make a diagnosis of high blood pressure. Recent research suggests that the risk of death from ischemic heart disease and stroke doubles with every 20 mmHg systolic or 10 mmHg diastolic increase in middle and older ages. Over the past four decades, the highest average blood pressure levels have shifted from high-income western countries (eg, Norway, Germany, Belgium, France) and Asia-Pacific countries (eg, Japan) to LMICs in sub-Saharan Africa, South Asia, and some Pacific island countries. High blood pressure remains a serious health problem in central and eastern Europe (eg, Slovenia, Lithuania). The findings come from a comprehensive new analysis of global, regional, and national trends in adult (aged 18 and older) blood pressure between 1975 and 2015. This includes trends in average systolic (the maximum pressure the heart exerts while beating) and diastolic blood pressure (amount of pressure in the arteries between beats), as well as prevalence of high blood pressure. The Non-Communicable Disease (NCD) Risk Factor Collaboration pooled data from 1479 population-based studies totalling 19.1 million men and women aged 18 years or older from 200 countries (covering more than 97% of the world's adult population in 2015).

"High blood pressure is the leading risk factor for stroke and heart disease, and kills around 7.5 million people worldwide every year. Most of these deaths are experienced in the developing world. Taken globally, high blood pressure is no longer a problem of the Western world or wealthy countries. It is a problem of the world's poorest countries and people. Our results show that substantial reductions in blood pressure and prevalence are possible, as seen in high-income countries over the past 40 years. They also reveal that WHO's target of reducing the prevalence of high blood pressure by 25% by 2025 is unlikely to be achieved without effective policies that allow the poorest countries and people to have healthier diets - particularly reducing salt intake and making fruit and vegetables affordable - as well as improving detection and treatment with blood pressure lowering drugs."

In April 2016 BioViva stated that Elizabeth Parrish, CEO, had experienced telomere lengthening in her leukocytes, as a result of an injection of two experimental therapies. These consisted of a myostatin inhibitor to protect against loss of muscle mass with age, and a telomerase inducer to battle stem cell depletion responsible for diverse age-related diseases and infirmities. While the test was designed to establish the first human safety data regarding telomerase induction, in tests conducted by SpectraCell Laboratories, data indicated that her leukocyte telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb. Further data will be released later this year. Upon further examination and testing, comparison of Parrish's data prior to the therapy and following the therapy has revealed additional positive changes. MRI scans taken before and after depict a slight increase in muscle size in conjunction with a noticeable reduction in muscle fat content. An over-accumulation of intramuscular fat, also known as 'marbling', is associated with increased insulin resistance, and as such an appropriate reduction may be linked to beneficial metabolic changes, in addition to the improved musculature. The aforementioned patient's total body weight has also not decreased during this period, and as such weight loss is not a confounding variable. The muscle growth achieved post-therapy corresponds with observed improvements in patients with Becker's Muscular Dystrophy, after receipt of myostatin inhibition gene therapy.

Researchers have noted that a significant reduction in fasting glucose was apparent in mice following telomerase gene therapy. The subject's fasting glucose has declined from previous measurements of 94 mg/dL and 86 mg/dL, to a fasting glucose level of 71 mg/dL by August 2016, as measured by Quest Diagnostics. Repeated testing will confirm the implied increase in insulin sensitivity. Previous research has also indicated that telomerase deficiency impairs glucose metabolism and insulin secretion in telomerase deficient mice, which may explain an apparent improvement in metabolic markers. In accordance with an improvement in metabolic health, triglyceride levels have also declined from 140 mg/dL in 2015 prior to the therapy, to 36 mg/dL in February 2016, subsequently rising to 80 and 84 mg/dL in August 2016. While there has been an increase in blood triglyceride content following the February reading, it is still measurably lower than before treatment. Both decreases in fasting glucose and triglycerides can be potentially explained by prior studies, of both telomerase and myostatin. Raised myostatin mRNA seen in type 2 diabetes patients is associated with impaired insulin sensitivity, raising triglyceride levels and low-grade chronic inflammation. Myostatin inhibition in mice has also been shown to reduce triglyceride levels and improve insulin sensitivity.

No negative effects have been reported, and there are no visible detrimental effects in blood analysis thus far; providing tentative evidence of safety in the first human test of BioViva's dual gene therapy strategy.

Sarcopenia has come a long way since Irwin Rosenberg first suggested the term to apply to age-related muscle mass. In 2010, the European Working Group on Sarcopenia defined sarcopenia as low muscle mass together with low muscle function (strength or performance). Subsequently, other international groups developed similar definitions for sarcopenia focusing on walking speed or distance walked in 6 min or grip strength in persons with lean muscle mass. A number of studies have confirmed the validity of these definitions. Based on the available literature, it would appear that sarcopenia is present in 5 to 10% of persons 65 years of age or older. This high quality research approach to sarcopenia has led to the recognition of sarcopenia as a disease entity with the awarding of an ICD-10-CM (M62.84) code in September, 2016. This is an important step similar to the much earlier recognition of osteoporosis as a disease state. This will lead to an accelerated interest in physicians making the diagnosis of sarcopenia and for pharmaceutical companies to accelerate the interest in developing drugs to treat sarcopenia. This research will be helped by there already being a number of biomarkers available for sarcopenia. This should also drive an increase in diagnostic tool availability for recognizing sarcopenia.

Sarcopenia is the most important cause of frailty in older persons. In addition, there is a close association between sarcopenia and bone loss and hip fracture - osteosarcopenia. Sarcopenia has also been found to be a major reason for poor outcomes in persons with diabetes mellitus. SARC-F is a simple screening test for sarcopenia. It prospectively identifies decreased walking speed, activities of daily living disability, hospitalization, and mortality. It has been shown to correlate well with the available international definitions for sarcopenia. There are numerous causes of sarcopenia including anorexia, inflammation, hypogonadism, lack of activity, hypovitaminosis D, motoneuron loss, insulin resistance, poor blood flow to muscle, mitochondrial dysfunction, and genetic causes. The established treatment for sarcopenia is resistance exercise. It appears that sarcopenia is always responsive to resistance exercise. Supplementation with leucine enriched, essential amino acid can also enhance muscle rejuvenation. Vitamin D declines with ageing, and supplementation enhances muscle function when deficient. Testosterone is the drug with the strongest record for increasing muscle mass and improving function. Anamorelin improves muscle mass but not strength. A number of other drugs are under development focusing mainly on myostatin and activin-2 receptor inhibitors. Selective androgen receptor molecules (SARMs) have also shown positive effects. Overall, the availability of an ICD-10 code for those of us who work in the area of muscle wasting disease is a very exciting time. Over the next few years, we can expect major advances in the treatment of older persons with sarcopenia.

Progress in the field of clinical research and medicine has decreased global mortality drastically. The developed countries have extended the life span of their aging population. However, the modern world is now faced with the issues of aging and age related disorders. Neurodegeneration and neurodegenerative disorders are one of the major health implications faced by the aging population. Neurodegenerative disorders have been thoroughly investigated using animal models, primary cultures, and post mortem human brain tissues. Though informative, these approaches have some limitations. Data obtained from animal models fails to directly correlate with that of humans because a rodent brain is not an exact mimic of a human brain. Despite being highly conserved evolutionarily, mammalian genomes are not identical. Therefore species difference prevents the animal data from successful validation during clinical field trials which poses a severe economic burden. Preclinical studies often do not efficiently translate to the clinic and the clinical trial failures have been reported time and again. Primary culture of neurons is challenging because these are the post mitotic differentiated cells which are difficult to sustain in the in-vitro conditions. Ethical constraints have held back human based research and thus the best possible source of human samples are the postmortem brain tissues. However, these autopsied samples depict the end stages of the disease and do not give much insight into the intricacies of the disease' developing stages. Researchers are not willing to subject the human beings to untested interventions, but the choices have been limited so far.

Majority of neurodegenerative disorders have been incurable (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis) so far but timely diagnosis can help in the management and symptom alleviation. However, researchers across the world are continuously striving to achieve the cure and hope to achieve fruitful results in the near future. Neurodegeneration studies are largely divided into two major categories. One is the experimental modeling strategy which allows for a comprehensive understanding of the disease such as the etiology, pathophysiology, genotypic-phenotypic interactions, symptomatic, and mechanistic insights. The second is the medical approach which deals with the treatment, therapy, and disease management. Stem cells and iPSCs find widespread application for both, disease modeling as well as transplantation and regenerative therapeutics. In the present review we shall discuss the applicability of stem cell research in the field of neurodegenerative disease modeling and provide the current updates of how stem cell and induced pluripotent stem cell based studies have been employed to address the diagnosis and therapy of the most common neurodegenerative disorders. We shall briefly touch upon the advances and preferable methodologies employing stem cell and iPSC culture such as the three dimensional (3D) culture which has revolutionized the current trend of in-vitro studies. The article intends to highlight the fact, that though animal based in-vivo research is absolutely necessary for the neuroscience research, one cannot wholly and solely depend upon it and human based stem cell driven research has and will open newer avenues for the neurodegenerative disorders′ modeling and treatment.

Researchers have found a promising treatment for Alzheimer's disease, by noticing a similarity in the way insulin signaling works in the brain and in the pancreas of diabetic patients. In the pancreas, the Kir6.2 channel blockade increases the insulin signaling, and insulin signaling decreases the blood glucose levels. In the brain, insulin signaling increases the acquisition of memory through CaM kinase II activation by Kir6.2 channel blockade. The research group thus concluded that Alzheimer's disease can be described as a diabetic disorder of the brain. Memantine, a drug widely used to treat Alzheimer's disease, is a well known inhibitor of the N-methyl-D-aspartate (NMDA) receptors that prevent excessive glutamate transmission in the brain. Researchers have now found that memantine also inhibits the ATP-sensitive potassium channel (Kir6.2 channel), improving insulin signal dysfunction in the brain.

In their experiment with mice, the researchers found that memantine treatment improved impaired hippocampal long-term potentiation (LTP) and memory-related behaviors in the mice through the inhibition of KATP channel Kir6.2. "Our results suggest that Kir6.2 blockade in dendritic spines by memantine regulates CaMKII activity by increasing intracellular Ca2+ mobilization, which in turn improves cognitive function by promoting AMPAR trafficking into the postsynaptic membrane. Since KATP channels Kir6.1 or Kir6.2 are critical components of sulfonylurea receptors (SURs) which is downstream insulin receptor signaling, the KATP channel inhibition by Memantine mediates the anti-diabetic drug action in peripheral tissues. And this leads to improved cognitive functions and improved memory retention among Alzheimer's patients." The researchers now hope that results of their study and the parallels drawn with diabetes, will lead to new treatments for Alzheimer's disease, using the inhibition of Kir6.2 channel.

A teenager who tragically died of cancer recently has become the latest among a tiny but growing number of people to be cryogenically frozen after death. These individuals were hoping that advances in science will one day allow them to be woken up and cured of the conditions that killed them. But how likely is it that such a day will ever come? Nature has shown us that it is possible to cryopreserve animals like reptiles, amphibians, worms and insects. Nematode worms trained to recognise certain smells retain this memory after being frozen. The wood frog (Rana sylvatica) freezes during winter into a block of ice and hops around the following spring. However, in human tissue each freeze-thaw process causes significant damage. Understanding and minimising this damage is one of the aims of cryobiology.

At the cellular level, these damages are still poorly understood, but can be controlled. Each innovation in the field relies on two aspects: improving preservation during freezing and advancing recovery after thawing. During freezing, damage can be avoided by carefully modulating temperatures and by relying on various types of cryoprotectants. One of the main objectives is to inhibit ice formation which can destroy cells and tissues by displacing and rupturing them. For that reason, a smooth transition to a "glassy stage" (vitrification) by rapid cooling, rather than "freezing", is the aim. Reviving whole bodies also poses its own challenges as organs need to commence function homogeneously. The challenges of restoring the flow of blood to organs and tissues are already well-known in emergency medicine. But it is perhaps encouraging that cooling itself does not only have negative effects - it can actually mitigate trauma. In fact, drowning victims who have been revived seem to have been protected by the cold water - something that has led to longstanding research into using low-temperature approaches during surgery.

The pacemakers of scientific innovation in cryobiology are both medical and economic. Many advances in cell preservation are driven by the infertility sector and an emerging regenerative medicine sector. Cryopreserved and vitrified cells and simple tissues (eggs, sperm, bone marrow, stem cells, cornea, skin) are already regularly thawed and transplanted. Work has also started on cryopreservation of "simple" body parts such as fingers and legs. Some complex organs (kidney, liver, intestines) have been cryopreserved, thawed, and successfully re-transplanted into an animal. While transplantation of human organs currently relies on chilled, not frozen, organs, there is a strengthening case for developing cryopreservation of whole organs for therapeutic purposes.

But there's another huge hurdle for cryonics: to not only repair the damage incurred due to the freezing process but also to reverse the damage that led to death - and in such a manner that the individual resumes conscious existence. So will it one day be possible to cryopreserve a human brain in such a manner that it can be revived intact? Success will depend on the quality of the cryopreservation as well as the quality of the revival technology. Where the former is flawed, as it would be with current technologies, the demands on the latter increase. This has led to the suggestion that effective repair must inevitably rely on highly advanced nanotechnology - a field once considered science fiction. The idea is that tiny, artificial molecular machines could one day repair all sorts of damage to our cells and tissues caused by cryonics extremely quickly, making revival possible. Given the rapid advances in this field, it may seem hasty to dismiss the entire scientific aim behind cryonics.

The development of the embryo during pregnancy is one of the most complex processes in life. Genes are strongly activated, and developmental pathways must do their job in a highly accurate and precisely timed manner. So-called Hox-genes play an important regulatory role in this process. Although remaining detectable in stem cells of adult tissues throughout life, after birth they are only rarely active. Now, however, researchers have shown that, in old age, one of these Hox-genes (Hoxa9) is strongly re-activated in murine muscle stem cells after injury; leading to a decline in the regenerative capacity of skeletal muscle. Interestingly, when this faulty gene re-activation was inhibited by chemical compounds, muscle regeneration was improved in aging mice, thus suggesting novel therapeutic approaches aimed at improving muscle regeneration in old age.

The biggest surprise from the current study is that the re-activation of Hoxa9 after muscle injury in old age impairs the functionality of muscle stem cells instead of improving it. Originally, Hoxa9-induced developmental pathways are responsible for the proper development of body axes - for example, during development of the fingers of a hand. A decline in stem cell functionality leads to an unavoidable decrease in the regenerative capacity of the whole skeletal muscle. With age, this may weaken the muscular strength after injury. The courses of stem cell and tissue aging are yet to be completely understood. It has already been recognized that signals which control the development of the embryo become activated in aging stem cells. However, the regulator-genes controlling these signals have not yet been analyzed in aging. "From an evolutionary perspective, Hox-genes are very old. They regulate organ development across almost the entire animal kingdom - from flies up to humans. It is a huge surprise that the faulty re-activation of these genes leads to stem cell aging in muscle. This finding will fundamentally influence our understanding of the courses of aging. Surprisingly, old muscle stem cells did not show a faulty activation of the epigenome in quiescence - the resting stage in non-injured muscle. Only in response to a muscle injury, do the stem cells display an abnormal epigenetic stress response, which leads to the opening of DNA and, thus, to the activation of developmental pathways."

The researchers now plan to investigate whether a similar re-activation of embryonic genes is also causative for the loss of muscle maintenance in aging humans. Medical compounds that limit alterations in the epigenome may improve the regenerative capacity of muscles in old mice. Thus far, this approach is too unspecific and affects the modification of genes in several cells and tissues. For this reason, a collaborative study is primed to investigate whether a nanoparticle-induced, target-specific inhibition of Hox-genes in muscle stem cells is feasible and, if so, would it be sufficient to improve muscle regeneration and maintenance.