The Gary Null Show

The Gary Null Show - 10.23.20

October 23, 2020


Vitamin A boosts fat burning in cold conditions

The conversion of white into brown adipose tissue is a promising target for obesity treatment

Medical University of Vienna, 21 October 2020


 A recent study conducted by a research team led by Florian Kiefer from MedUni Vienna's Division of Endocrinology and Metabolism shows that cold ambient temperatures increase vitamin A levels in humans and mice. This helps convert "bad" white adipose tissue into "good" brown adipose tissue which stimulates fat burning and heat generation. This "fat transformation" is usually accompanied by enhanced energy consumption and is therefore considered a promising approach for the development of novel obesity therapeutics. The study has now been published in the leading journal Molecular Metabolism.

In humans and mammals, at least two types of fatty depots can be discerned, white and brown adipose tissue. During obesity development, excess calories are mainly stored in white fat. In contrast, brown fat burns energy and thereby generates heat. More than 90% of the body fat depots in humans are white which are typically located at the abdomen, bottom, and upper thighs. Converting white into brown fat could be a new therapeutic option to combat weight gain and obesity. 

A research group led by Florian Kiefer from the Division of Endocrinology and Metabolism, Department of Medicine III at MedUni Vienna demonstrated now that moderate application of cold increases the levels of vitamin A and its blood transporter, retinol-binding protein, in humans and mice. Most of the vitamin A reserves are stored in the liver and cold exposure seems to stimulate the redistribution of vitamin A towards the adipose tissue. The cold-induced increase in vitamin A led to a conversion of white fat into brown fat ("browning"), with a higher rate of fat burning. 

When Kiefer and his team blocked the vitamin A transporter "retinol-binding protein" in mice by genetic manipulation, both the cold-mediated rise in vitamin A and the "browning" of the white fat were blunted: "As a consequence, fat oxidation and heat production were perturbed so that the mice were no longer able to protect themselves against the cold," explains Kiefer. In contrast, the addition of vitamin A to human white fat cells led to the expression of brown fat cell characteristics, with increased metabolic activity and energy consumption. 

"Our results show that vitamin A plays an important role in the function of adipose tissue and affects global energy metabolism. However, this is not an argument for consuming large amounts of vitamin A supplements if not prescribed, because it is critical that vitamin A is transported to the right cells at the right time," explains the MedUni Vienna researcher. "We have discovered a new mechanism by which vitamin A regulates lipid combustion and heat generation in cold conditions. This could help us to develop new therapeutic interventions that exploit this specific mechanism."


High flavanol diet may lead to lower blood pressure

First study to use objective measure to look at 25,000 people's diet

University of Reading (UK), October 21, 2020


People who consume a diet including flavanol-rich foods and drinks, including tea, apples and berries, could lead to lower blood pressure, according to the first study using objective measures of thousands of UK residents' diet. 

The findings, published in Scientific Reports, studied the diet of more than 25,000 people in Norfolk, UK and compared what they ate with their blood pressure. In contrast to most other studies investigating links between nutrition and health, the researchers did not rely on study participants reporting their diet, but instead measured flavanol intake objectively using nutritional biomarkers - indicators of dietary intake, metabolism or nutritional status that are present in our blood.

The difference in blood pressure between those with the lowest 10% of flavanol intake and those with the highest 10% of intake was between 2 and 4 mmHg. This is comparable to meaningful changes in blood pressure observed in those following a Mediterranean diet or Dietary Approaches to Stop Hypertension (DASH) diet. Notably, the effect was more pronounced in participants with hypertension.

Professor Gunter Kuhnle, a nutritionist at the University of Reading who led the study said: 

"Previous studies of large populations have always relied on self-reported data to draw conclusions, but this is the first epidemiological study of this scale to objectively investigate the association between a specific bioactive compound and health. We are delighted to see that in our study, there was also a meaningful and significant association between flavanol consumption and lower blood pressure. 

"What this study gives us is an objective finding about the association between flavanols - found in tea and some fruits - and blood pressure. This research confirms the results from previous dietary intervention studies and shows that the same results can be achieved with a habitual diet rich in flavanols. In the British diet, the main sources are tea, cocoa, apples and berries. 

"The methodology of the study is of equal importance. This is one of the largest ever studies to use nutritional biomarkers to investigate bioactive compounds. Using nutritional biomarkers to estimate intake of bioactive food compounds has long been seen as the gold standard for research, as it allows intake to be measured objectively. The development, validation and application of the biomarker was only possible because of the long-term commitment of all collaborators. In contrast to self-reported dietary data, nutritional biomarkers can address the huge variability in food composition. We can therefore confidently attribute the associations we observed to flavanol intake."

An international team from the University of Reading, Cambridge University, the University of California Davis, and Mars, Incorporated studied 25,618 participants from the European Prospective Investigation into Cancer (EPIC) Norfolk study and found that the biggest difference was observed in participants with the highest blood pressure. This suggests if the general public increased its flavanol intake, there could be an overall reduction in cardiovascular disease incidence.

Hagen Schroeter, Chief Science Officer at Mars Edge, said: 

"This study adds key insights to a growing body of evidence supporting the benefits of dietary flavanols in health and nutrition. But, perhaps even more exciting was the opportunity to apply objective biomarkers of flavanol intake at a large scale. This enabled the team to avoid the significant limitations that come with past approaches which rely on estimating intake based on self-reported food consumption data and the shortcomings of current food composition databases."


Researchers discover molecular link between diet and risk of cancer

Tel Aviv University, October 22, 2020


An international team of researchers has identified a direct molecular link between meat and dairy diets and the development of antibodies in the blood that increase the chances of developing cancer. This connection may explain the high incidence of cancer among those who consume large amounts of dairy products and red meat, similar to the link between high cholesterol and an increased risk of heart disease.

The study was led by Dr. Vered Padler-Karavani of the Department of Cell Research and Immunology at the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University's George S. Wise Faculty of Life Sciences. The results of the research were published on September 23, 2020, in BMC Medicine.

Neu5Gc is a sugar molecule found in the tissues of mammals but not in poultry or fish. Humans develop antibodies to Neu5Gc in infancy, when they are first exposed to dairy and meat products. While it is known that these antibodies increase the risk of cancer, especially colorectal cancer, no direct link had been found between the antibodies and meat and dairy consumption.

For the study, the researchers used samples from NutriNet-Santé, an extensive national nutritional survey conducted in France. Salam Bashir, a PhD student in Dr. Padler-Karavani's lab, together with other team members measured the amount of Neu5Gc sugar in a variety of dairy and meat foods common in the French diet and calculated the daily Neu5Gc intake of 19,621 adults aged 18 and over, who reported all of their food intake online over a period of several days.

The research team then took a representative sample of 120 participants and tested the levels of the anti-Neu5Gc antibodies in their blood.

Based on these findings and the quantification of Neu5Gc sugar in various food products from France, Dr. Padler-Karavani and her team created an index called the Gcemic index. This index ranks foods whose excessive consumption can lead to an increase in the antibodies - and possibly to an increase in the risk of cancer.

"We found a significant correlation between high consumption of Neu5Gc from red meat and cheeses and increased development of those antibodies that heighten the risk of cancer," Dr. Padler-Karavani says. "For years there have been efforts to find such a connection, but no one did. Here, for the first time, we were able to find a molecular link thanks to the accuracy of the methods used to measure the antibodies in the blood and the detailed data from the French diet questionnaires."

Dr. Padler-Karavani adds that this combination of methods allowed the researchers to predict that those who eat a lot of red meat and cheese will develop high levels and a different variety of the antibodies, and therefore may be at higher risk for cancer - especially colorectal cancer, but other cancers as well.



Study finds association between lignan and stilbene intake and improvements in cognitive function

Navarra Institute for Health Research (Spain), October 20, 2020


According to news reporting from Pamplona, Spain, research stated, “The global growing rates of cognitive decline and dementia, together with the absence of curative therapies for these conditions, support the interest in researching potential primary prevention interventions, with particular focus on dietary habits. The aim was to assess the association between the intake of polyphenols, lignans and stilbene (primarily found in grapes and berries) and 6-year change in cognitive function in the ‘Seguimiento Universidad de Navarra’ (SUN) Project, a Spanish prospective cohort study.”

The news correspondents obtained a quote from the research from Navarra Institute for Health Research, “Changes (final -initial) in cognitive function were evaluated in a subsample of 806 participants (mean age 66 years (SD 5), 69.7% male) of the SUN Project using the validated Spanish Telephone Interview for Cognitive Status-modified (STICS-m) score. Polyphenol intake was derived from a validated semi-quantitative food-frequency questionnaire and matching food composition data from the Phenol Explorer database. Multivariable linear regression models were used to evaluate the association between total polyphenol intake, polyphenol subclasses and cognitive changes. No significant association between total polyphenol intake and changes in cognitive function was found. However, a higher intake of lignans (bQuintile (Q) 5 vs. Q1 0.81; 95% CI 0.12, 1.51; p trend=0.020) and stilbenes (bQ5 vs. Q1 0.82; 95% CI 0.15, 1.49; p trend 0.028) was associated with more favorable changes in cognitive function over time, particularly with respect to immediate memory and language domains. Olive oil and nuts were the major sources of variability in lignan intake; and wine  in stilbene  intake.”

According to the news reporters, the research concluded: “The results suggest that lignan and stilbene intake was associated with improvements in cognitive function.”

This research has been peer-reviewed.



Bacterial metabolism of dietary soy may lower risk factor for dementia

University of Pittsburgh, Oct. 22, 2020


A metabolite produced following consumption of dietary soy may decrease a key risk factor for dementia--with the help of the right bacteria, according to a new discovery led by researchers at the University of Pittsburgh Graduate School of Public Health.

Their study, published today in the journal Alzheimer's & Dementia: Translational Research & Clinical Interventions, reports that elderly Japanese men and women who produce equol--a metabolite of dietary soy created by certain types of gut bacteria--display lower levels of white matter lesions within the brain.

"White matter lesions are significant risk factors for cognitive decline, dementia and all-cause mortality," said lead author Akira Sekikawa, M.D., Ph.D., associate professor of epidemiology at Pitt Public Health. "We found 50% more white matter lesions in people who cannot produce equol compared to people who can produce it, which is a surprisingly huge effect."

To obtain this result, Sekikawa's research team measured equol levels within the blood of 91 elderly Japanese participants with normal cognition. Participants were sorted by their equol production status, and then six to nine years later underwent brain imaging to detect levels of white matter lesions and deposits of amyloid-beta, which is the suspected molecular cause of Alzheimer's disease. 

The researchers found that while equol production did not appear to impact levels of amyloid-beta deposited within the brain, it was associated with reduced white matter lesion volumes. Sekikawa's team also discovered that high levels of isoflavones--soy nutrients that are metabolized into equol--had no effect on levels of white matter lesions or amyloid-beta when equol wasn't produced.

According to Sekikawa, the ability to produce equol from soy isoflavones may be the key to unlocking protective health benefits from a soy-rich diet, and his team has previously shown that equol production is associated with a lower risk of heart disease. As heart disease is strongly associated with cognitive decline and dementia, equol production could help protect the aging brain as well as the heart.

Epidemiological studies in Japan, where soy is regularly consumed, have shown that dietary intake of soy isoflavones has been linked to a lower risk for heart disease and dementia. However, most clinical trials in America have failed to show this.

Sekikawa believes that this discrepancy may be due to the microbiome--40-70% of Japanese harbor gut bacteria that can convert dietary isoflavones into equol compared to only 20-30% of Americans.

Sekikawa said that equol supplements could one day be combined with existing diet-based prevention strategies that appear to lower the risk of dementia, particularly the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets.

Though Sekikawa hopes to evaluate the neuroprotective effects of equol supplements in a future randomized clinical trial, in the meantime, he urges caution to anyone who might be tempted to purchase equol supplements to stave off dementia.

"This type of study always catches people's attention, but we cannot prove that equol protects against dementia until we get a randomized clinical trial with sufficient evidence," he said.



Serum creatinine-to-cystatin C ratio predicts mortality

Yonsei University (South Korea), October 21, 2020

In patients initiating continuous renal replacement therapy for acute kidney injury, higher serum creatinine-to-cystatin C ratios were associated with lower mortality.

Identifying risk factors for mortality in patients with acute kidney injury (AKI) receiving intensive care and continuous renal replacement therapy (CRRT) is useful for improving assessment of prognosis. In this study of 1,588 patients who underwent CRRT in a single tertiary center intensive care unit, the 30- and 90-day mortality risks were significantly lower in patients with higher creatinine:cystatin C ratio at the time CRRT was begun. This association remained after adjustment for confounding factors. These findings suggest that creatinine:cystatin C ratio may be a simple, useful tool for mortality risk assessment in critically ill patients who develop AKI.


Glutathione precursor GlyNAC reverses premature aging in people with HIV

Baylor College of Medicine, October 16, 2020

Premature aging in people with HIV is now recognized as a new, significant public health challenge. Accumulating evidence shows that people with HIV who are between 45 to 60 years old develop characteristics typically observed in people without HIV that are more than 70 years of age. For instance, declining gait speed, physical function and cognition, mitochondrial aging, elevated inflammation, immune dysfunction, frailty and other health conditions are significantly higher in people with HIV when compared to age- and sex-matched uninfected people.

At Baylor College of Medicine, endocrinologist Dr. Rajagopal Sekhar, associate professor of medicine-endocrinology, and his team have found themselves in the right place at the right time to study premature aging in people with HIV. For the last 20 years, they have been studying natural aging in older humans and aged mice in the Section of Endocrinology, Diabetes and Metabolism of the Department of Medicine. Also, for the last 17 years, Sekhar has been active in HIV research, and has been providing clinical care for patients at the HIV clinic at Thomas Street Health Center, a part of Houston's Harris Health System, where he runs the sole endocrinology and metabolism clinic.

Sekhar's years-long expertise, knowledge and interest in metabolic disorders affecting HIV patients and a parallel track investigating non-HIV people have resulted in the publication of significant discoveries regarding the metabolic complications in aging, HIV and diabetes, and has guided numerous clinical trials that together provide a better understanding of why we age. 

"The work presented here, published in the journal Biomedicines, builds a bridge between laboratory bench and bedside by showing proof-of-concept that supplementing people with HIV specifically with a combination of glycine and N-acetylcysteine, which we call GlyNAC, as precursors of glutathione, a major antioxidant produced by the body, improves multiple deficits associated with premature aging," said Sekhar.

Why we age?

For several decades, experimental evidence has supported two theories for aging. The free radical theory and the mitochondrial theory propose that elevated free radicals (oxidative stress) and mitochondrial dysfunction, respectively, are at the core of geriatric aging. Both, elevated oxidative stress and mitochondrial dysfunction, are present in people with HIV.

Free radicals, such as reactive oxygen species, and the mitochondria are physiologically connected. The mitochondria are like the batteries of the cell, they produce the energy needed for conducting cellular functions. The body transforms the food we eat into sugar and fat, which the mitochondria burns as fuel to produce energy.

However, one of the waste products of cellular energy generation is free radicals, which are highly reactive molecules that can damage cells, membranes, lipids, proteins and DNA. Cells depend on antioxidants, such as glutathione, to neutralize these toxic free radicals. When cells fail to neutralize free radicals, there is an imbalance between the radicals and the antioxidant responses, leading to harmful and damaging oxidative stress.

"The free radicals produced during fuel burning in the mitochondria can be compared to some of the waste products produced by a car's combustion engine, some of which are removed by the oil filter," Sekhar said. "If we don't change the oil filter periodically, the car's engine will diminish its performance and give less mileage."

Similarly, if the balance between free radical production and antioxidant response in cells consistently favors the former, in time cellular function could be disrupted. Glutathione helps cells keep oxidative stress in balance, it keeps the oil filter clean. GlyNAC helps the cell make glutathione.

Sekhar and his colleagues have been studying mitochondrial function and glutathione for more than 20 years. Their findings, and those of other researchers, have shown that glutathione is the ultimate natural antioxidant. 

Interestingly, compared to those in younger people, glutathione levels in older people are much lower, and the levels of oxidative stress are much higher. Glutathione levels also are lower and oxidative stress is higher in conditions associated with mitochondrial dysfunction, including ageing, HIV infection, diabetes, neurodegenerative disorders, cardiovascular disorders, neurometabolic diseases, cancer, obesity and other conditions. 

"When the mitochondrial batteries are running low on power, as a medical and scientific community, we do not know how to recharge these batteries," Sekhar said. "Which raised the question, if the levels of glutathione were restored in cells, would the mitochondria be recharged and able to provide power to the cell? Would restoring mitochondrial functioning improve conditions associated with mitochondrial dysfunction?"

Restoring glutathione

Restoring glutathione in cells was not straightforward because glutathione cannot work if taken orally for the same reasons that diabetic patients cannot eat insulin. It would be digested before it reached the cells. Also, providing glutathione in the blood cannot correct glutathione deficiency because every cell makes its own.

"Glutathione is a small protein made of three building blocks: amino acids cysteine, glycine and glutamic acid. We found that people with glutathione deficiency also were deficient in cysteine and glycine, but not glutamic acid," Sekhar said. "We then tested whether restoring deficient glutathione precursors would help cells replenish their glutathione. But there's another catch, because cysteine cannot be given as such, we had to supplement it in another form called N-acetylcysteine."

In past studies, Sekhar and his colleagues determined that supplementing GlyNAC, a combination of glycine and N-acetylcysteine, corrected glutathione deficiency inside the cells of naturally aged mice to the levels found in younger mice. Interestingly, the levels of glutathione and mitochondrial function, which were lower in older mice before taking GlyNAC, and oxidative stress, which was higher before GlyNAC, also were comparable to those found in younger mice after taking GlyNAC for six weeks. 

The same results were observed in a small study in older humans who had high oxidative stress and glutathione deficiency inside cells. In this case, taking GlyNAC by mouth for 2-weeks corrected the glutathione deficiency and lowered both oxidative stress and insulin resistance (a pre-diabetic risk factor).

In past clinical trials, Sekhar provided GlyNAC to small groups of people to correct a nutritional deficiency, and produced encouraging evidence supporting further studies of the value of this approach to restoring mitochondrial function in clinical trials.

Improving premature aging in people with HIV

In the current study, Sekhar and his colleagues conducted an open-label clinical trial that included six men and two women with HIV, and eight age-, gender- and body mass index-matched uninfected controls, all between 45 and 60 years old. The people with HIV were on stable antiretroviral therapy and had not been hospitalized for six months prior to the study.

Before taking GlyNAC, the group with HIV, compared with the controls, was deficient in glutathione and had multiple conditions associated with premature aging, including higher oxidative stress; mitochondrial dysfunction; higher inflammation, endothelial dysfunction and insulin resistance; more damage to genes; lower muscle strength; increased belly fat and impaired cognition and memory.

The results are encouraging. GlyNAC supplementation for 12 weeks improved all the deficiencies indicated above. Some of the improvements declined eight weeks after stopping GlyNAC.

"It was exciting to see so many new beneficial effects of GlyNAC that have never been described before. Some of the most encouraging findings included reversal of some measures of cognitive decline, a significant condition in people with HIV, and also improved physical strength and other hallmark defects," Sekhar said.

"It was encouraging to see that GlyNAC can reverse many of these hallmark defects in people with HIV as there is no current treatment known to reverse these abnormalities. Our findings could have implications beyond HIV and need further investigation," Sekhar said.

Overall, these findings in HIV patients provide proof-of-concept that dietary supplementation of GlyNAC improves multiple hallmarks of aging and that glutathione deficiency and oxidative stress could contribute to them. 

Encouraged by these results, Sekhar has continued his investigations by testing the value of GlyNAC supplementation for improving the health of the growing older population, and has completed an open label trial, and another NIH-funded, double-blind, placebo-controlled trial in older adults. 

"The results from these recently completed trials support the findings of the HIV study," said Sekhar, who is currently the Principal Investigator of two NIH-funded randomized clinical trials studying the effect of GlyNAC in older humans with mild cognitive impairment, and with Alzheimer's disease.



Greater adherence to aspects of Mediterranean diet associated with lower mortality risk among men during seven-year follow-up

IRCCS Foundation National Cancer Institute (Italy), October 22, 2020


According to news originating from Milan, Italy, research stated, “The present study analyzes the relation between diet and all-cause mortality in a cohort of Italian men residing in different regions of Italy. The cohort was established using the members of the Associazione Nazionale Alpini, a voluntary organization that enlists individuals who have served in the Alpine troup; a mountain warfare infantry corps of the Italian Army.”

Our news journalists obtained a quote from the research from IRCCS Foundation National Cancer Institute, “For the purpose of these analyses a total of 5049 participants were followed for an average of seven years. At baseline information was collected regarding age, education, life style habits, with special emphasis on diet (with the use of a validated dietary questionnaire), smoking and alcohol use. A total of 190 deaths were ascertained. In multivariate analyses the consumption of a Mediterranean type diet was inversely associated with mortality. Additional findings of relevance include: an inverse association between mortality and intake of vegetable fats and proteins, monounsaturated (MUFA) fats of vegetable origins, starch and folic acid. Positive association were evident between mortality and intake of animal fats, MUFA of animal origins and sugar. This study, focusing on a homogenous cohort characterized by a varied intake and high intake of monounsaturated fats, confirms the inverse association between a Mediterranean type diet and mortality and points out that the nature of the MUFA may be relevant for their effects on health.”

According to the news editors, the research concluded: “In addition, the study confirms that fats of animal origins and dietary sugar are associated with an overall deleterious effect on mortality.”



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