Category: Biomed/Longevity

An FDA-approved exploratory clinical trial of a prototype wearable artificial kidney (WAK) — a miniaturized, wearable hemodialysis machine —  at the University of Washington Medical Center in Seattle has been completed, the researchers reported June 2 in an open-access paper in JCI Insight.

The seven patients enrolled in the study reported “significantly greater treatment satisfaction during the WAK treatment period compared with ratings of care during periods of conventional in-center hemodialysis treatment,” according to the researchers.

“During the study, hemodynamic parameters remained stable, ultrafiltration was achieved as intended, and there were no unexpected adverse treatment effects.” The study was led by the device inventor, Victor Gura, M.D., of Cedars-Sinai Medical Center in Los Angeles and Blood Purification Technologies Inc.

The trial was stopped after the seventh subject due to device-related technical problems, including excessive carbon dioxide bubbles in the dialysate circuit and variable blood and dialysate flows, which the scientists plan to fix.

More than 2 million people worldwide experience end-stage renal disease (ESRD), which is currently treated with hemodialysis therapies that require patients to adhere to restrictive dietary and fluid intake limitations and are associated with a high pill burden, according to the researchers. Adjusted rates of all-cause mortality are up to 8 times greater for dialysis patients compared with age-matched individuals in the general population, they note.

The WAK is designed to be worn and used by patients for up to 24 hours per day. The hope is that treatment can be administered at the patients’ homes either by the patients themselves or caretakers.  Being able to be ambulatory while undergoing dialysis, if further proven in additional studies, “would liberate patients from the need to be tethered to a stationary machine during dialysis treatments,” according to the researchers.

The researchers caution that “long-term safety of continuous treatment with the WAK has not been established yet. Longer-term studies treating patients in the outpatient and home environment are necessary to address safety issues during ambulation and the home operation of the device by patients and to incorporate additional human factor elements.”

To learn more or donate, contact Wearable Artifical Kidney Foundation, which funded the study along with Blood Purification Technologies Inc.

UWMedicineHealth | Wearable Artificial Kidney: first U.S. clinical trial

 

A meta-analysis of 45 studies (64 publications) of consumption of whole grain by an international team of researchers, led by Dagfinn Aune, PhD, at Imperial College London, found lower risks of coronary heart disease and cardiovascular disease overall, as well as deaths from all causes and from specific diseases, including stroke, cancer, diabetes, infectious and respiratory diseases.

The researchers say these results “strongly support dietary recommendations to increase intake of whole grain foods in the general population to reduce risk of chronic diseases and premature mortality.”

The results have been published in an open-access paper in the British Medical Journal (BMJ).

The greatest benefit was seen for people who increased from no intake of whole grain to two servings per day, equivalent to 32 g/day, such as 32 g of whole grain wheat, or to 60 g product/day, such as 60 g of whole grain wheat bread.

Further reductions in risks were observed up to 7.5 servings a day, equivalent to 225 g/day of whole grain products, and suggest additional benefits at higher intakes.

Relation to specific types of disorders

A large body of evidence has emerged on the health benefits of whole grain foods over the last 10–15 years. Grains are one of the major staple foods worldwide and provide on average 56% of energy intake and 50% of protein intake.

But recommendations on the daily amount and types of whole grain foods needed to reduce risk of chronic disease and mortality have often been unclear or inconsistent. So the researchers carried out a systematic review and meta-analysis of 45 published studies on whole grain consumption in relation to several health outcomes and all-cause mortality.*

They found reductions in the relative risk of coronary heart disease (19%), cardiovascular disease (22%), all cause mortality (17%), and mortality from stroke (14%), cancer (15%), respiratory disease (22%), infectious disease (26%), and diabetes (51%) per 90 g/day of whole grain product (one serving equals 30g of whole grain product).

Reductions in risks of cardiovascular disease and all-cause mortality were associated with intake of whole grain bread, whole grain breakfast cereals, and added bran, as well as total intake of bread and breakfast cereals.

There was little evidence of an association with intake of refined grains, white rice, total rice or other grains.

Caveats and recommendations

Few people may have total grain intake of three or more servings a day, so the authors recommend “increasing intake of whole grains, and as much as possible to choose whole grains rather than refined grains.”

However, the researchers noted that systematic reviews and meta-analyses involving observational research cannot be used to draw conclusions about cause and effect.

They call for more research to determine health benefits of different types of whole grain in different geographical regions, as most of the current evidence is from the U.S. and fewer studies have been conducted in Europe, Asia and other regions. Studies of specific diseases, and less common causes of deaths, are needed.

They caution that it’s important that “great care” should be taken not to promote whole grain foods with high sugar and salt content, and call for more research on the “biological mechanisms of health effects and contribution to health of different grain types.”

A related study published in The Journals of Gerontology, Series A (recently described on KurzweilAI — see Dietary fiber has biggest influence on successful aging, research reveals) found that fiber that made the biggest difference to what the researchers termed “successful aging,” meaning “the absence of disability, depressive symptoms, cognitive impairment, respiratory symptoms, and chronic diseases including cancer, coronary artery disease, and stroke.”

* They included more than 7,000 cases of coronary heart disease, 2,000 cases of stroke, 26,000 cases of cardiovascular disease, 34,000 deaths from cancer, and 100,000 deaths among 700,000 participants.

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Abstract of Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies

Objective To quantify the dose-response relation between consumption of whole grain and specific types of grains and the risk of cardiovascular disease, total cancer, and all cause and cause specific mortality.

Data sources PubMed and Embase searched up to 3 April 2016.

Study selection Prospective studies reporting adjusted relative risk estimates for the association between intake of whole grains or specific types of grains and cardiovascular disease, total cancer, all cause or cause specific mortality.

Data synthesis Summary relative risks and 95% confidence intervals calculated with a random effects model.

Results 45 studies (64 publications) were included. The summary relative risks per 90 g/day increase in whole grain intake (90 g is equivalent to three servings—for example, two slices of bread and one bowl of cereal or one and a half pieces of pita bread made from whole grains) was 0.81 (95% confidence interval 0.75 to 0.87; I²=9%, n=7 studies) for coronary heart disease, 0.88 (0.75 to 1.03; I²=56%, n=6) for stroke, and 0.78 (0.73 to 0.85; I²=40%, n=10) for cardiovascular disease, with similar results when studies were stratified by whether the outcome was incidence or mortality. The relative risks for morality were 0.85 (0.80 to 0.91; I²=37%, n=6) for total cancer, 0.83 (0.77 to 0.90; I²=83%, n=11) for all causes, 0.78 (0.70 to 0.87; I²=0%, n=4) for respiratory disease, 0.49 (0.23 to 1.05; I²=85%, n=4) for diabetes, 0.74 (0.56 to 0.96; I²=0%, n=3) for infectious diseases, 1.15 (0.66 to 2.02; I²=79%, n=2) for diseases of the nervous system disease, and 0.78 (0.75 to 0.82; I²=0%, n=5) for all non-cardiovascular, non-cancer causes. Reductions in risk were observed up to an intake of 210-225 g/day (seven to seven and a half servings per day) for most of the outcomes. Intakes of specific types of whole grains including whole grain bread, whole grain breakfast cereals, and added bran, as well as total bread and total breakfast cereals were also associated with reduced risks of cardiovascular disease and/or all cause mortality, but there was little evidence of an association with refined grains, white rice, total rice, or total grains.

Conclusions This meta-analysis provides further evidence that whole grain intake is associated with a reduced risk of coronary heart disease, cardiovascular disease, and total cancer, and mortality from all causes, respiratory diseases, infectious diseases, diabetes, and all non-cardiovascular, non-cancer causes. These findings support dietary guidelines that recommend increased intake of whole grain to reduce the risk of chronic diseases and premature mortality.

Small electrical currents appear to activate certain immune cells to jumpstart or speed wound healing and reduce infection when there’s a lack of immune cells available, such as with diabetes, University of Aberdeen (U.K.) scientists have found.

In a lab experiment, the scientists exposed healing macrophages (white blood cells that eat things that don’t belong), taken from human blood, to electrical fields of strength similar to that generated in injured skin. When the voltage was applied, the macrophages moved in a directed manner to Candida albicans fungus cells (representing damaged skin) to facilitate healing (engulfing and digesting extracellular particles). (This process is called “phagocytosis,” in which macrophages clean the wound site, limit infection, and  allow the repair process to proceed.)

The electric fields enhanced the uptake and clearance of a variety of targets known to promote inflammation and impair healing in addition to Candida albicans, including latex beads and expended white blood cells.*

“These findings raise the prospect that EF-based therapies could be extended beyond tissue repair and ultimately, be exploited to modulate the function of macrophages in other inflammatory diseases where these cells are dysregulated,” the researchers note in a report appearing in the June 2016 issue of the Journal of Leukocyte Biology.

“This new work identifies previously unappreciated opportunities to tune immune system function with electrical fields and has potentially wide-reaching implications for wound repair for a variety of diseases where macrophages play a role, including infectious disease, cancer and even obesity,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology.

The research extends previous research reported by KurzweilAI (New evidence that electrical stimulation accelerates wound healing).

* The experiments also showed that electric fields selectively augmented the production of protein modulators associated with the healing process, enhancing cytokine (growth factor) production and phagocytic activity essential for clearance of infection and for tissue repair and confirming that macrophages are tuned to respond to naturally generated electrical signals in a manner that boosts their healing ability.

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Abstract of Electric fields are novel determinants of human macrophage functions

Macrophages are key cells in inflammation and repair, and their activity requires close regulation. The characterization of cues coordinating macrophage function has focused on biologic and soluble mediators, with little known about their responses to physical stimuli, such as the electrical fields that are generated naturally in injured tissue and which accelerate wound healing. To address this gap in understanding, we tested how properties of human monocyte-derived macrophages are regulated by applied electrical fields, similar in strengths to those established naturally. With the use of live-cell video microscopy, we show that macrophage migration is directed anodally by electrical fields as low as 5 mV/mm and is electrical field strength dependent, with effects peaking ∼300 mV/mm. Monocytes, as macrophage precursors, migrate in the opposite, cathodal direction. Strikingly, we show for the first time that electrical fields significantly enhance macrophage phagocytic uptake of a variety of targets, including carboxylate beads, apoptotic neutrophils, and the nominal opportunist pathogen Candida albicans, which engage different classes of surface receptors. These electrical field-induced functional changes are accompanied by clustering of phagocytic receptors, enhanced PI3K and ERK activation, mobilization of intracellular calcium, and actin polarization. Electrical fields also modulate cytokine production selectively and can augment some effects of conventional polarizing stimuli on cytokine secretion. Taken together, electrical signals have been identified as major contributors to the coordination and regulation of important human macrophage functions, including those essential for microbial clearance and healing. Our results open up a new area of research into effects of naturally occurring and clinically applied electrical fields in conditions where macrophage activity is critical.

Insilico Medicine and Life Extension announced today an exclusive collaboration to identify novel biomarkers of human aging through the use of big-data analytics and AI, with the ultimate goal of discovery and formulation of nutrients to support health and longevity.

Insilico Medicine* is a big-data analytics company specializing in applying advances in deep learning to discovery of biomarkers and drugs. Life Extension**, a Florida-based organization established in the early 1980s, is a dietary-supplement innovator dedicated to extending healthy human longevity.

Insilico Medicine will focus on applying advanced signaling pathway activation analysis techniques and deep-learning algorithms to find nutraceuticals that mimic the tissue-specific transcriptional response of many known interventions and pathways associated with health and longevity.

Life Extension will use this information to develop novel nutraceutical products to support health and longevity, such as “geroprotectors” — precision natural organic small-molecule formulations that slow down or even reverse age-associated conditions and damage.

“Senescence is accompanied by a shift in cellular signaling that initiates and promotes a system-wide degenerative condition,” William Faloon, co-founder of the Life Extension Foundation, told KurzweilAI. “By turning back ‘on’ youthful signaling pathways while suppressing those that emerge during normal maturation, we expect to gain significant control over what are now thought to be inevitable pathologies of old age.”

“This collaboration means a lot to our team. For many years I was buying a range of supplements from Life Extension, and saw how passionate they are about extending healthy human life and supporting cutting-edge research in the field,” said Alex Zhavoronkov, PhD, CEO of Insilico Medicine, Inc. and the chief science officer of the Biogerontology Research Foundation in the UK. “Life Extension’s discovery research and product development teams have decades of experience in the pharmaceutical and nutraceutical research and have set very high standards for science-based nutraceutical discovery.”

Insilico Medicine scientists will present the results of this collaboration at RAADFest in San Diego in August, a longevity-focused conference.

Applying deep-learning techniques to aging

Insilico Medicine scientists have recently authored key papers on applying deep-learning techniques to biomedical applications in influential peer-reviewed journals, including “Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic,” published in Aging Cell.

Other papers include “Deep learning applications for predicting pharmacological properties of drugs and drug repurposing using transcriptomic data” in Molecular Pharmaceutics, a journal published by the American Chemical Society; “Applications of Deep Learning in Biomedicine“, also in Molecular Pharmaceutics; and “Deep biomarkers of human aging: Application of deep neural networks to biomarker development” in Aging, a high-impact journal in aging research.

“We believe that accelerating the rate of progress in novel biomarker identification, as well as precision nutrient formulation development, is critical,” said Andrew G. Swick, Ph.D., senior vice president of scientific affairs, discovery research and product development for Life Extension.

“Life Extension aims to improve health and human longevity by utilizing the experience of noted research scientists and engaging in academic and industry collaborations. Artificial intelligence is one of the promising areas, where years of experience in the nutraceutical industry combined with sophisticated biologically inspired algorithms and high-performance computing may produce unprecedented results.”

* Insilico Medicine, Inc. is a bioinformatics company located at the Emerging Technology Centers at the Johns Hopkins University Eastern campus in Baltimore, with R&D resources in Belgium, Russia, and Poland. It utilizes advances in genomics, big-data analysis, and deep learning for in silico drug discovery and drug repurposing for aging and age-related diseases. The company pursues internal drug discovery programs in cancer, Parkinson’s, Alzheimer’s, sarcopenia, and geroprotector discovery. Through its Pharma.AI division, the company provides advanced machine-learning services to biotechnology, pharmaceutical, and skin-care companies.

** A trailblazer in the $35 billion U.S. dietary supplement industry for the past 36 years, Life Extension’s core mission is to extend the healthy human life span using an integrative approach by reporting on and funding cutting-edge scientific research. Life Extension Buyers Club (Life Extension) offers a full-range of premium-quality vitamins, minerals, and hormones as well as unique, specially made formulas. The company’s products are developed based on the latest scientific studies from peer-reviewed medical journals and are continually updated as new information occurs.

Eating the right amount of dietary fiber from breads, cereals, and fruits can help us avoid disease and disability into old age, according to an open-access paper published in The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences by scientists from The Westmead Institute for Medical Research in Australia.

Using data compiled from the Blue Mountains Eye Study, a benchmark population-based study that examined a cohort of more than 1,600 adults aged 50 years and older for long-term sensory loss risk factors and systemic diseases, the researchers found that out of all the factors they examined — including a person’s total carbohydrate intake, total fiber intake, glycemic index, glycemic load, and sugar intake — it was, surprisingly, fiber that made the biggest difference to what the researchers termed “successful aging.”

Successful aging was defined as including an absence of disability, depressive symptoms, cognitive impairment, respiratory symptoms, and chronic diseases including cancer, coronary artery disease, and stroke.

Fiber, or roughage, is the indigestible part of plant foods that pushes through the digestive system, absorbing water along the way and easing bowel movements.

According to lead author of the paper, Associate Professor Bamini Gopinath, PhD, from the Institute’s Centre for Vision Research, “Out of all the variables that we looked at, fiber intake —- which is a type of carbohydrate that the body can’t digest — had the strongest influence,” she said. “Essentially, we found that those who had the highest intake of fiber or total fiber actually had an almost 80 percent greater likelihood of living a long and healthy life over a 10-year follow-up. That is, they were less likely to suffer from hypertension, diabetes, dementia, depression, and functional disability.”

While it might have been expected that the level of sugar intake would make the biggest impact on successful aging, Gopinath pointed out that the particular group they examined were older adults whose intake of carbonated and sugary drinks was quite low.

Although it is too early to use the study results as a basis for dietary advice, Gopinath said the research has opened up a new avenue for exploration. “There are a lot of other large cohort studies that could pursue this further and see if they can find similar associations. And it would also be interesting to tease out the mechanisms that are actually linking these variables,” she said.

This study backs up similar recent findings by the researchers, which highlight the importance of the overall diet and healthy aging.

In another study published last year in The Journals of Gerontology, Westmead Institute researchers found that, in general, adults who closely adhered to recommended national dietary guidelines reached old age with an absence of chronic diseases and disability, and had good functional and mental health status.

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Abstract of Association Between Carbohydrate Nutrition and Successful Aging Over 10 Years

Background: We prospectively examined the relationship between dietary glycemic index (GI) and glycemic load (GL), carbohydrate, sugars, and fiber intake (including fruits, vegetable of breads/cereals fiber) with successful aging (determined through a multidomain approach).

Methods: A total of 1,609 adults aged 49 years and older who were free of cancer, coronary artery disease, and stroke at baseline were followed for 10 years. Dietary data were collected using a semiquantitative Food Frequency Questionnaire. Successful aging status was determined through interviewer-administered questionnaire at each visit and was defined as the absence of disability, depressive symptoms, cognitive impairment, respiratory symptoms, and chronic diseases (eg, cancer and coronary artery disease).

Results: In all, 249 (15.5%) participants had aged successfully 10 years later. Dietary GI, GL, and carbohydrate intake were not significantly associated with successful aging. However, participants in the highest versus lowest (reference group) quartile of total fiber intake had greater odds of aging successfully than suboptimal aging, multivariable-adjusted odds ratio (OR), 1.79 (95% confidence interval [CI] 1.13–2.84). Those who remained consistently below the median in consumption of fiber from breads/cereal and fruit compared with the rest of cohort were less likely to age successfully, OR 0.53 (95% CI 0.34–0.84) and OR 0.64 (95% CI 0.44–0.95), respectively.

Conclusions: Consumption of dietary fiber from breads/cereals and fruits independently influenced the likelihood of aging successfully over 10 years. These findings suggest that increasing intake of fiber-rich foods could be a successful strategy in reaching old age disease free and fully functional.

Scientists from the Gladstone Institutes have identified a new pathway by which salicylic acid — a key compound in aspirin (acetylsalicylic acid) — stops inflammation and cancer.

In a study published in eLife, the researchers found that both salicylic acid — and also diflunisal, a cousin of aspirin — suppress two key proteins (p300 and CREB-binding protein or CBP) that help control gene expression throughout the body.

These proteins are epigenetic regulators that control the levels of proteins that cause inflammation or are involved in cell growth.

So by suppressing these proteins, these compounds can prevent cellular damage caused by inflammation. This study provides the first concrete demonstration that both p300 and CBP can be targeted by drugs and may have important clinical implications.

“Salicylic acid is one of the oldest drugs on the planet, dating back to the Egyptians and the Greeks, but we’re still discovering new things about it,” said senior author Eric Verdin, MD, associate director of the Gladstone Institute of Virology and Immunology. “Uncovering this pathway of inflammation that salicylic acid acts upon opens up a host of new clinical possibilities for these drugs.”

Shrinking tumors

Scientists at Gladstone and Sylvester Comprehensive Cancer Center, at the University of Miami Miller School of Medicine, worked together to test whether suppressing p300 with diflunisal would suppress leukemia growth in mice. As predicted, diflunisal stopped cancer progression and shrunk the tumors in the mouse model of leukemia.

“We have conducted a clinical trial of salicylic acid in patients with hematologic cancers and found it to be safe,” said Sylvester director and co-author Stephen D. Nimer, MD. “Thus, this collaborative effort to develop novel epigenetic therapies is an important next step in our journey to find more effective treatment for leukemia patients.”

The scientists are now pursuing a clinical trial that will test the ability of salicylic acid to treat patients with leukemia as part of novel combination therapies. Other possible clinical applications for salicylic acid include other forms of cancer, type 2 diabetes, inflammatory diseases, and even neurodegenerative disorders, such as Alzheimer’s disease.

Prior Gladstone research showed that another drug containing salicylic acid prevented the accumulation of tau in neurons and protected against cognitive decline in a mouse model of dementia.

Researchers from the University of Miami, University of Pennsylvania, and the National Cancer Institute also took part in the study.

Funding was provided by the University of California, San Francisco-Gladstone Institute of Virology and Immunology Center for AIDS Research (CFAR), the University of California, Berkeley Fogarty International AIDS Training Program, the American Cancer Society, the Larry L. Hillblom Foundation, the John A. Hartford Foundation, the National Cancer Institute, and the UCSF Geriatric Research Training Program.

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Abstract of Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity

Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-κB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs.