More Supporting Evidence for Pancreatic Fat to be the Cause of Type 2 Diabetes

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Type 2 diabetes is, for the vast majority of patients, a condition caused by being significantly overweight. Age does has an influence on the risk of being overweight leading to metabolic syndrome and then type 2 diabetes; it is reasonable to say that type 2 diabetes is an age-related condition. In essence, the younger you are, the more fat tissue it requires to push your metabolism over the red line. A few years back, researchers demonstrated that it is specifically fat in the pancreas that causes type 2 diabetes. Of course the only way to put that fat into the pancreas in the normal course of affairs is to become very overweight, creating fat tissue around all of the organs important to metabolism, and negatively influencing their function.

Now, a few years down the line, and as a result of the rapid growth of interest in senescent cells as a cause of aging and age-related disease, we know that (a) excess visceral fat tissue produces chronic inflammation through, among other mechanisms, a more rapid generation of senescent cells, and (b) much of the detrimental effects of type 2 diabetes appear to be mediated by the presence of senescent cells in the pancreas. Treating animals with senolytic drugs reverses many of the effects of the condition. So this all ties together quite nicely as a view of how and why type 2 diabetes occurs. Given that cellular senescence becomes more prevalent in older individuals, that also fits.

While I’m sure that there will be, soon enough, tremendous interest in senolytic therapies from the sizable overweight and diabetic population of the wealthier portions of the world, it remains the case that the most reliable approach to reversing type 2 diabetes, even at the later stages, is to lose the excess weight. Excess visceral fat tissue is required to maintain that harmful fat in the pancreas, and losing weight removes it. Fasting and very low calorie diets also seem quite effective at removing fat from the pancreas, perhaps more rapidly than would occur just by losing the visceral fat tissue via the usual, slow calorie deficit method, based on human trials of this approach.

Promising approach: Prevent diabetes with intermittent fasting

Fatty liver has been thoroughly investigated as a known and frequently occurring disease. However, little is known about excess weight-induced fat accumulation in the pancreas and its effects on the onset of type 2 diabetes. Researchers have now found that overweight mice prone to diabetes have a high accumulation of fat cells in the pancreas. Mice resistant to diabetes due to their genetic make-up despite excess weight had hardly any fat in the pancreas, but instead had fat deposits in the liver.

The team of scientists divided the overweight animals, which were prone to diabetes, into two groups: The first group was allowed to eat ad libitum – as much as they wanted whenever they wanted. The second group underwent an intermittent fasting regimen: one day the rodents received unlimited chow and the next day they were not fed at all. After five weeks, the researchers observed differences in the pancreas of the mice: Fat cells accumulated in group one. The animals in group two, on the other hand, had hardly any fat deposits in the pancreas.

In order to find out how fat cells might impair the function of the pancreas, researchers isolated adipocyte precursor cells from the pancreas of mice for the first time and allowed them to differentiate into mature fat cells. If the mature fat cells were subsequently cultivated together with the Langerhans islets of the pancreas, the beta cells of the islets increasingly secreted insulin. “We suspect that the increased secretion of insulin causes the Langerhans islets of diabetes-prone animals to deplete more quickly and, after some time, to cease functioning completely. In this way, fat accumulation in the pancreas could contribute to the development of type 2 diabetes.”

Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice

Ectopic fat accumulation in the pancreas in response to obesity and its implication on the onset of type 2 diabetes remain poorly understood. Intermittent fasting (IF) is known to improve glucose homeostasis and insulin resistance. However, the effects of IF on fat in the pancreas and β-cell function remain largely unknown. Our aim was to evaluate the impact of IF on pancreatic fat accumulation and its effects on islet function.

New Zealand Obese (NZO) mice were fed a high-fat diet ad libitum (NZO-AL) or fasted every other day (intermittent fasting, NZO-IF) and pancreatic fat accumulation, glucose homoeostasis, insulin sensitivity, and islet function were determined and compared to ad libitum-fed B6.V-Lepob/ob (ob/ob) mice. To investigate the crosstalk of pancreatic adipocytes and islets, co-culture experiments were performed.

NZO-IF mice displayed better glucose homeostasis and lower fat accumulation in both the pancreas (-32%) and the liver (-35%) than NZO-AL mice. Ob/ob animals were insulin-resistant and had low fat in the pancreas but high fat in the liver. NZO-AL mice showed increased fat accumulation in both organs and exhibited an impaired islet function. Co-culture experiments demonstrated that pancreatic adipocytes induced a hypersecretion of insulin and released higher levels of free fatty acids than adipocytes of inguinal white adipose tissue.

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Applying Bacterial Homing Strategies to Target Stem Cells to Heart Tissue

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Most classes of therapy benefit from some form of targeting or selectivity, helping to direct them to the tissue of interest, and away from other places where they might cause side-effects. Cells are difficult to work with, but they are also much more capable of selective targeting, since they can migrate. Many types of cell reliably find their way from one part of the body to another in the course of their functions, but where no suitable mechanism exists in human biochemistry, it is sometimes possible to look elsewhere. Here, researchers adapt a bacterial targeting system and apply it to the stem cells that might be used in regenerative therapies for damaged heart tissue.

To date, trials using stem cells, which are taken and grown from the patient or donor and injected into the patient’s heart to regenerate damaged tissue, have produced promising results. However, while these next generation cell therapies are on the horizon, significant challenges associated with the distribution of the stem cells have remained. High blood flow in the heart combined with various ’tissue sinks’, that circulating cells come into contact with, means the majority of the stem cells end up in the lungs and spleen.

“We know that some bacterial cells contain properties that enable them to detect and ‘home’ to diseased tissue. For example, the oral bacterial found in our mouths can occasionally cause strep throat. If it enters the blood stream it can ‘home’ to damaged tissue in the heart causing infective endocarditis. Our aim was to replicate the homing ability of bacteria cells and apply it to stem cells.” The team developed the technology by looking at how bacterial cells use a protein called an adhesin to ‘home’ to heart tissue. Using this theory, the researchers were able to produce an artificial cell membrane binding version of the adhesin that could be ‘painted’ on the outside of the stem cells. In an animal model, the team were able to demonstrate that this new cell modification technique worked by directing stem cells to the heart in a mouse.

“Our findings demonstrate that the cardiac homing properties of infectious bacteria can be transferred to human stem cells. Significantly, we show in a mouse model that the designer adhesin protein spontaneously inserts into the plasma membrane of the stem cells with no cytotoxity, and then directs the modified cells to the heart after transplant. To our knowledge, this is the first time that the targeting properties of infectious bacteria have been transferred to mammalian cells.”


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OncoSenX Raises $3 Million to Adapt the Oisin Biotechnologies Platform to Cancer

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Oisin Biotechnologies uses a form of programmable suicide gene therapy to target senescent cells for destruction. The therapy can be triggered by expression of specific genes inside a cell, and so beyond senescent cells there is a long, long list of possibly harmful cell populations in aging and disease that it would be beneficial to remove. The obvious first choice is cancerous cells with a mutation in one of the common cancer suppressor genes, such that the gene is expressed but not helping. Thus Oisin Biotechnologies spun out OncoSenX last year. The company is moving forward towards trials, and recently raised a seed round to fund the work of the next few years.

OncoSenX, Inc., a late preclinical-stage company developing therapeutics to kill cancer cells based on their genetics, today announced it has raised $3 million in pre-seed funding to advance its pipeline. “These funds will allow us to accelerate the preclinical research necessary for us to begin phase 1 clinical development. We believe our non-viral gene therapy for solid tumors represents the first in a new class of cancer therapeutics. The OncoSenX team is diligently working to bring this new approach into the clinic for the benefit of a global oncology community clearly in need of new options.”

OncoSenX is developing a highly selective tumor-killing platform with two main components: a proprietary lipid nanoparticle (LNP) for cellular delivery and a highly selective DNA payload. The LNP is designed to deliver its non-integrating DNA payload to solid tumors, while an engineered promoter drives expression of a potent, inducible death protein only in the target cell population. The goal is to precisely target cell populations based on their genetic activity without harming nearby cells. The platform can be effectively programmed to implement logic gates (IF/OR/AND) to provide selectivity to any target cell based on its genetics.

“Our preclinical studies suggest the OncoSenX approach has the potential to precisely kill cancer cells based on the mutations they harbor. If substantiated in the clinic, the platform could deliver reduced toxicity and improved tolerability over conventional chemotherapy, with the potential for superior targeting over biologics or even CAR-T therapy.”


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Statins double diabetes rates

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Statins are a type of medication prescribed to lower cholesterol levels. They work by blocking an enzyme in the liver your body uses to make cholesterol.1 Although vilified for many years as causing heart attacks and stroke,2 your body makes cholesterol as it is needed to produce hormones, build cell membranes and produce substances used to digest food.3

Cholesterol is found in foods from animals, such as dairy products and meats.4 Your body makes the fatty substance cholesterol, but it cannot travel in the bloodstream alone.5 The body encases small particles of cholesterol inside protein particles that are able to mix easily with the blood. These are called lipoproteins and they’re responsible for transporting cholesterol.6

One of the main types of lipoproteins is high-density lipoprotein (HDL), sometimes called the “good” cholesterol as its job is to collect cholesterol and deliver it to your liver where it’s removed.7

Low density lipoprotein (LDL) and very low-density lipoprotein (VLDL) are often referred to as “bad.”8 It’s important to remember that only 20% of the cholesterol in your body is acquired from the food you eat, while the rest is made by your body.9

Prescriptions for statins are written to reduce the levels of cholesterol made by the body.10 However, since your body is so complex, changing one factor often results in unintended events, sometimes called side effects or adverse reactions.11 As suggested by one study, one adverse reaction from statin drugs may be doubling your risk of Type 2 diabetes.12

Risk of diabetes doubles with cholesterol medication

Past studies have demonstrated that statins increase the risk of diabetes.13 A new study led by a graduate researcher at The Ohio State University14 explored this link in research published in Diabetes Metabolism Research and Reviews. The study was a retrospective evaluation of medical records using employees and spouses from a private insurance plan.

Yearly biometric screening, health surveys, medical claims and pharmacy data were gathered from 2011 through 2014.15 Individuals who had indications for statin use, or who had a previous cardiovascular event, were enrolled. Adults who had Type 2 diabetes before the study or who acquired it in the first 90 days were excluded.

Records were classified as belonging to a statin user if they had two or more prescriptions filled, but individuals using statins before January 2011 or within the first 90 days of enrollment in the insurance were excluded. Data were collected from 755 individuals using statins and 3,928 who were not.16

After accounting for factors such as age, gender, ethnicity, education and body mass index, the researchers found those who used statins during the study were two times as likely to be diagnosed with diabetes than those who did not take statin medications.17

Interestingly, individuals who used statin drugs longer than two years experienced an increased risk of more than three times as likely to get the disease.18 The data also indicated that individuals taking statin medications had a 6.5% increased risk of high blood sugar as measured by hemoglobin A1c values.

The hemoglobin A1c blood test is an average level of blood sugar measuring the past 60 to 90 days.19 The test measures how much sugar is bound to hemoglobin on red blood cells. Since red blood cells live for up to 90 days, the test is an average of your blood glucose level during this time.

Take one medicine for the side effects of another, and so on

In 2012, the FDA20 approved changes to labels on statin medications to provide information on adverse events, including reports of increased blood sugar and higher A1c testing. Other side effects listed on the label included cognitive effects such as memory loss and confusion.

While there had been reports of rare but serious liver conditions in those taking statin medications,21 in the same announcement, the FDA22 removed the need for routine monitoring of liver enzymes and recommended they should be performed before starting therapy and then as clinically necessary. Since severe injury was rare, they concluded routine monitoring would not be effective.

The NHS, National Health Services from England, recommends23 statins should not be used in those with severe liver disease since they affect your liver and are “more likely to cause serious problems if you already have a severely damaged liver.”

In 2014,24 one team of researchers discovered adding Glyburide to a statin regimen suppressed the immune response they believed was responsible for the development of Type 2 diabetes. The team led by Jonathan Schertzer, Ph.D., from McMaster University, believed this finding may lead to a next generation of statins. As reported in a press release:25

“Recently, an increased risk of diabetes has been added to the warning label for statin use. This was perplexing to us because if you are improving your metabolic profile with statins you should actually be decreasing the incidence of diabetes with these drugs, yet, the opposite happened.

We found that statins activated a very specific immune response, which stopped insulin from doing its job properly. So we connected the dots and found that combining statins with another drug on top of it, Glyburide, suppressed this side effect.”

In other words, to offset a significant adverse event from one drug, the team recommended the addition of a second drug, which comes with an additional list of side effects including vasculitis, hyponatremia (low blood sodium associated with confusion, seizures and muscle weakness),26 alopecia and liver damage.27

One journalist for commented on this turn of events, saying: “However, as glyburide stimulates insulin production, using a type 2 diabetes drug to prevent type 2 diabetes seems a peculiar treatment.”28

Statins trigger high number of side effects

Statin medications deplete your body of coenzyme Q10 (CoQ10), which may account for some of the devastating long-term results. It was strongly suggested29 the FDA add a black box warning to statin medications to advise patients and physicians about this, but in 2014 the FDA decided against it.30

The reduction in CoQ10 may be responsible for an increased risk of acute heart failure31 and atherosclerosis, as reported in a 2015 scientific investigation.32 The study addressed physiological mechanisms in the reduction of CoQ10, including the inhibition of the synthesis of vitamin K2 necessary to protect against arterial calcification.

A reduction in vitamin K2 may contribute to osteoporosis,33heart disease,34 brain disease35 and inappropriate calcification.36 Statins have also been associated with an increased risk of neurodegenerative diseases,37 cataracts,38 cancer.39,40 and musculoskeletal disorders.41

In one study,42 a research team evaluated the use of statins in patients with terminal illnesses who had a high likelihood of dying within one year. They found those who stopped taking statins had a mean survival of 39 more days than those who continued to take statins — 229 days without statins and 190 days with statins.

Although the FDA calls liver complications rare, one physician’s43 search of MedWatch, the FDA’s Adverse Event Reporting Program, found 5,405 individuals reporting hepatitis or liver function abnormalities associated with just two statin medications between 2006 and 2013.

Effectiveness of statins lower than publicized

How effective a medication may or may not be is expressed as relative risk or absolute risk.44 If the type of risk is not identified it may be difficult to determine whether taking action would affect you.

For instance, if a medication under investigation to prevent prostate cancer enrolls 200 men and splits them into two equal groups, one is likely to receive a placebo and the other is likely to receive the experimental drug. In the placebo group, two men may develop prostate cancer; in the treatment group, perhaps only one man develops it. When compared, the researchers find there’s a 50% reduction in relative risk.

Relative risk is determined by comparing the number between two groups. One man developed it in the treatment group and two in the control group. Since one is half of 2, there’s a 50% reduction in the development of the disease. The absolute risk is far smaller.

The risk of developing prostate cancer in the control group was 2%, since two out of 100 developed prostate cancer, but in the treatment group it was 1%. This means there’s a 1% absolute risk of developing prostate cancer with the medication as compared to 2%. Your absolute risk is not 50% less but rather just 1% less when taking the medication.

Knowing the difference between relative risk and absolute risk is necessary when balancing the benefits of statin medications against the side effects and adverse events. If you are in a position of needing to decide to use statin medications, it’s important to note the relative reduction in risk of a major cardiac event while using statins was between 20% and 25%.

In the case of having to decide whether the potential benefits of statins are worth the known risks, for example, it’s important to consider a report from 2016. In an Expert Analysis article, it was noted that a meta-analysis45 of 27 randomized trials revealed that “[F]or every ~40mg/dL LDL-C reduction with statin therapy, the relative risk of major adverse events is reduced by ~20-25%, and all-cause mortality is reduced by 10%.”

While another study found a similar relative risk, the actual difference in rates of coronary death in the population was 9% in the placebo group and 6.7% in those who were treated with statins.46

Researchers therefore found the difference between the treated and untreated groups was a mere 2.3% and not the inflated relative risk of 28%. They wrote that while the reduction in relative risk appears impressive to some readers, this form of data presentation is misleading.47

Simple strategies to normalize your cholesterol levels

Before becoming concerned about your cholesterol levels, it’s important to evaluate whether you really need a statin drug to reduce your risk of a cardiovascular event. Updated guidelines published by the American Heart Association and the American College of Cardiology are based on a personalized risk assessment.48

However, the U.S. Department of Health and Human Services critically evaluates those with cholesterol levels over 200 milligrams per deciliter.49 I believe this total cholesterol measurement has little benefit in evaluating your risk for heart disease unless the number is over 300.

In some instances, high cholesterol may indicate a problem, provided it’s your LDL or triglycerides and you have low HDL. A better evaluation of your risk of heart disease are these two ratios in combination with other lifestyle factors, such as your iron level and diet.

  • HDL/Cholesterol ratio — Divide your HDL level by your cholesterol. This ratio should ideally be above 24 percent.
  • Triglyceride/HDL ratio — Divide your triglyceride level by your HDL. This ratio should ideally be below 2. Data demonstrate a ratio greater than four is a powerful predictor of coronary artery disease.50

You have control over your health and may protect your heart and lower your risk of heart disease by following suggestions affecting your lifestyle and exposure to environmental toxins. In my article, “Cholesterol managers want to double statin prescriptions,” I share a list of suggestions to help minimize your toxic exposure and improve your body’s ability to maintain good heart health.

Additionally, in my article “Nearly half of American adults have cardiovascular disease,” I summarize additional strategies you may use to improve microcirculation in your heart. I also talk about mitochondrial function and insulin resistance, which are related to strong heart health.

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Live Foreverish Podcast: Men’s Health Series with Michael A. Smith, M.D. & Christopher Mohr, Ph.D., R.D.

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Live Foreverish Podcast: Men’s Health Series with Michael A. Smith, M.D. & Christopher Mohr, Ph.D., R.D.

National Men’s Health Month

Did you know that June was National Men’s Health Month? If not, that’s okay. We’ve got you covered with important information on men’s health topics in our new podcast series. While these dedicated health months are helpful to build awareness, men should be focused on their health year-round! The series is available for download, or you can listen now on

In this special Live Foreverish podcast series, you’ll hear from Christopher Mohr, Ph.D., R.D., a nationally recognized Registered Dietitian and sports nutritionist who has worked with professional athletes, including the Cincinnati Bengals and WWE Wrestlers. Featured in this three-part series:

Episode 1: Maintaining Muscle Mass for Longevity
Exercises for increasing muscle and best times to work out

Episode 2: Nutrition for Men: Protein, Minerals and Supplementation
Healthy fats, fruits & vegetables and protein intake (types and how much for men)

Episode 3: Personalize Your Preventative Health Care Regimen with Lab Testing
Hormone testing: testosterone and estrogen balance and thyroid function

About Live Foreverish: Join Dr. Mike and Dr. Crystal as they sit down with some of today’s leading medical, health and wellness experts to discuss a variety of health-related topics. From whole-body health to anti-aging and disease prevention, you’ll get the latest information and helpful advice to help you live your life to the fullest. If you like what you hear, please take a moment to give Live Foreverish a 5-star rating on iTunes!

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Vascular Calcification and Inflammation in Chronic Kidney Disease

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Kidney degeneration goes hand in hand with cardiovascular disease and neurodegeneration in aging; kidney function is one of the better examples of the way in which deterioration in one organ system causes issues in many others. Nothing in our biology exists in isolation. Researchers here discuss the present state of knowledge regarding vascular calcification in the context of age-related chronic kidney disease. There is a particular focus on the role of chronic inflammation, given the way in which it disrupts all sorts of essential tissue maintenance processes. The accumulation of senescent cells is one of the more important contributions to chronic inflammation, and there is evidence for these cells to be influential in the calcification of blood vessels, and corresponding loss of flexibility.

Low kidney function is linked to poor health outcomes, with clinical manifestations in a wide variety of other organ systems, and is associated to a much higher risk of cardiovascular disease. The risk of cardiovascular disease exponentially increases as kidney function declines, being the major contributor to the high incidence of cardiovascular complications and death in this population. This is partially due to vascular calcification (VC) and accelerated atherosclerosis, as a result of the mineral and bone disorder that often accompanies low kidney function and complicates chronic kidney disease (CKD).

In addition to the complexity of mechanisms involved in VC initiation and progression, it is currently accepted that it cannot be regarded as an isolated pathological process, with several studies providing compelling evidence that VC is highly interconnected with inflammation. In fact, it has been suggested that pathological calcification and chronic inflammation are involved in a positive feedback loop driving disease progression.

Early stages of CKD are already associated with up-regulation of proinflammatory and pro-osteogenic molecules in the vascular wall and calcification of the aortic media. In fact, several lines of evidence indicate that inflammation triggers and precedes osteogenic conversion of vascular smooth muscle cells (VSMCs) and the release of calcifying extracellular vesicles (EVs), promoting the calcification process. It is likely that the effect of inflammation on VC occurs at multiple and interconnected levels. It has been proposed that inflammation might regulate VC, at least in part, through activation of an endoplasmic reticulum stress pathway, which in turn may increase inorganic phosphate uptake, leading to increased VSMCs osteogenic differentiation and increased mineral deposition.

Remarkably, this inflammation/vascular calcification crosstalk described in CKD pathology shares many similarities with the aging process in the general population, including the inflammaging and VSMCs senescence. Inflammaging is a recently adopted term do define a state of low grade chronic inflammatory condition, associated with a significant risk factor for morbidity and mortality in the elderly. Cellular senescence, in general, has been proposed as a potential mechanism of aging and age-related diseases, which can be triggered by a number of mechanisms and leading to an altered secretome, termed the senescence-associated secretory phenotype (SASP). In the particular case of VSMCs, senescence has been shown to enhance vascular calcification and inflammation, with pro-calcific and pro-inflammatory SASPs.

VSMCs senescence and associated SASP have been suggested to contribute to chronic vascular inflammation and calcification, loss of arterial function, and the development of age-related diseases. Thus, it has been suggested that altered vascular health under CKD settings might represent an example of premature aging. In this context, it could be conceivable that new knowledge about molecular mechanisms, such as the crosstalk between VC and inflammation, in CKD, might shed new light on the aging process, and vice versa.


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A Potential Approach to Reducing TDP-43 Proteopathy in the Aging Brain

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Most neurodegenerative conditions are associated with the build up of damaging protein aggregates that degrade cell function or kill cells in the brain. The amyloid-β and tau of Alzheimer’s disease and α-synuclein of Parkinson’s disease are well known, but TDP-43 is not as well recognized beyond the that part of the research community focused on it. Here, scientists outline a potential approach to small molecule drugs that might reduce the tendency of TDP-43 to form aggregates. That is a first step on the road to therapies capable of slowing the progression of conditions such as amyotrophic lateral sclerosis (ALS) that are associated with TDP-43 pathology, but it is still a way removed from a full solution to the problem.

Researchers discovered that prolonged cellular stress, such as exposure to toxins, triggers TDP-43 clumping in the cytoplasm of human motor neurons grown in a laboratory dish. Even after the stress is relieved, TDP-43 clumping persists in ALS motor neurons, but not in healthy neurons. The team then screened and identified chemical compounds (potential precursors to therapeutic drugs) that prevent this stress-induced, persistent TDP-43 accumulation. These compounds also increased the survival time of neurons with TDP-43 proteins containing an ALS-associated mutation.

The researchers generated motor neurons from induced pluripotent stem cells (iPSCs) that had been converted from human skin cells. To mimic cellular aspects of ALS, they exposed these laboratory motor neurons to toxins such as puromycin, which stressed the cells and led to TDP-43 clumps. Normally, TDP-43 proteins help process molecules called messenger RNA, which serve as the genetic blueprints for making proteins. But when they clump outside the nucleus, TDP-43 proteins can’t perform their normal duty, and that can have a profound effect on many cellular functions.

The researchers tested thousands of chemical compounds for their effects on RNA-protein aggregation. They were surprised to find compounds that not only reduced the overall amount of clumping by up to 75 percent, but also varied clump size and number per cell. Some of the compounds tested were molecules with extended planar aromatic moieties – arms that allow them to insert themselves in nucleic acids, such as DNA and RNA. TDP-43 must bind RNA in order to join ALS-associated clumps. Thus it makes sense that a compound that interacts with RNA would prevent TDP-43 from clumping.


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Rate of Telomere Shortening Correlates with Species Average Life Span

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Researchers here report on data showing a correlation between species life span and pace of telomere shortening. Telomeres are the repeated DNA sequences at the ends of chromosomes. A little is lost with each cell division, during replication of DNA, and cells with very short telomeres become senescent or self-destruct. This is how the vast majority of cells in the body are limited in their replicative capacity, in order to lower the risk of damaged cells becoming cancerous to an evolutionarily acceptable level. Not a personally acceptable level, of course.

With age, average telomere length tends to shorten in most species, and this is most likely a reflection of loss of stem cell function. Stem cells maintain long telomeres via use of telomerase, and thus the daughter somatic cells they provide to support surrounding tissue also have long telomeres. Given fewer such daughter cells, average telomere length diminishes, along with tissue function – but that loss of telomere length isn’t the cause of loss of tissue function.

Nonetheless, telomerase gene therapy extends life in mice, most likely by inducing damaged cells to greater activity in tissue maintenance. Since the immune system is most likely improved as well, this treatment doesn’t lead to a greater incidence of cancer, which would be the usual outcome of making damage cells do more work. This hypothesis on what takes place in telomerase gene therapy is still not a suggestion that telomere shortening is a cause of aging. In this view telomerase gene therapy is conceptually similar to stem cell therapies or signaling therapies that increase native cell activity without repairing the underlying damage that caused the decline. As noted in the publicity materials, this particular research group is generally in favor of the opposite viewpoint, that telomere shortening is an important causative mechanism of aging, rather than a largely downstream reflection of other issues.

Researchers discover that the rate of telomere shortening predicts species lifespan

After analyzing nine species of mammals and birds, researchers found a very clear relationship between the lifespan of these species and the shortening rate of their telomeres, the structures that protect the chromosomes and the genes they contain. The fit is better when using the average lifespan of the species – 79 years in the case of humans – rather than the maximum lifespan -the 122 documented years lived by the Frenchwoman Jeanne Calment.

Until now, however, no relationship had been found between telomere length and lifespan of each species. There are species with very long telomeres that are short-lived and vice versa. The researchers decided not to compare the absolute length of the telomeres, but rather their rate of shortening. It is the first large-scale study that compares this highly variable parameter between species: human telomeres lose on average about 70 base pairs – the building blocks of the genetic material – per year, whereas those of mice lose about 7,000 base pairs per year.

“This study confirms that telomeres play an important role in aging. There are people who are not convinced, and they say that for example mice live two years and have very long telomeres, while humans live much longer and have short telomeres; but we have shown that the important thing is not the initial length but the rate of shortening and this parameter predicts the longevity of a species with a high degree of precision.”

Telomere shortening rate predicts species life span

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin’s gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus).

We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

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Inducing the Heat Shock Response as a Potential Treatment for Atherosclerosis

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The heat shock response is one of a number of cellular maintenance processes that works to keep cells functional under circumstances of stress. As the name implies, heat is one of those stresses in this case, but the heat shock response is also triggered by other stresses as well. Further, the heat shock response has a role in resolving inflammation. Researchers here note that the heat shock response is suppressed in atherosclerosis, possibly as a result of the chronic inflammation induced by the presence of senescent cells, possibly due to other mechanisms, and that this might be an important factor in the progression of the condition. The study shows that upregulating the heat shock response via heat treatment produces benefits in atherosclerotic mice, and the authors suggest this might function via reductions in cholesterol levels and reductions in inflammation.

While acute inflammatory responses evolved to protect organisms against pathogens and to provide tissue repair under sterile injuries, they are rapidly resolved by several physiological feedback systems aimed at avoiding the perpetuation of inflammation. In this sense, the heat shock (HS) response, i.e., the anti-inflammatory program mainly centered in heat shock factor-1 (HSF1)-dependent expression of heat shock proteins (HSPs) and other anti-aggregative protein chaperones, powerfully resolves acute inflammation by shutting off nuclear factor κB (NF-κB) and other downstream pro-inflammatory signals.

Nevertheless, if injuring stimuli become chronic, HSF1 expression is severely blunted and cells stop producing cardioprotective HSPs (e.g., HSP27, HSP72), which are anti-inflammatory. This is the case of many (if not all) chronic degenerative diseases of inflammatory nature. In contrast, inducers of the HS response clearly reverse vascular lesions in atherosclerotic models. However, the development of atherosclerotic lesions is also associated with the blockade of the expression and activity of sirtuin-1 (SIRT1), which, in turn, underlies both HSF1 expression and transcribing activity. Therefore, in an atherosclerotic milieu, the physiological resolution of inflammation is critically jeopardized thus contributing to foam cell formation and vascular senescence observed in atherosclerosis.

These observations led us to hypothesize that disruption of the anti-inflammatory and anti-senescent HS response pathways could underlie the perpetuation of vascular inflammation in atherosclerosis, as observed in other chronic inflammatory diseases, and that in vivo heat treatment, the most powerful trigger of the HS response, should be effective in re-establishing SIRT1-HSF1-HSP axis in atherosclerotic mice.

Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal healthy counterparts, which was paralleled by increased expression of NF-κB-dependent VCAM1 adhesion molecule. Conversely, heat treatment completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of triacylglycerols, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose, and insulin resistance while rising HDL-cholesterol levels. Heat treatment also decreased body weight gain, visceral fat, cellular infiltration, and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance indices. Remarkably, heat-treated mice stopped dying after the third heat treatment session, suggesting a curative effect.


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Why coffee affects metabolism

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Many people struggle with obesity and being overweight. According to the CDC,1 the prevalence of both conditions was measured nationally in 2015-2016, finding 71.6% of the U.S. population were either overweight or obese. Although some corporations, like Coca-Cola2 propose you may out-exercise a poor diet, research has found it is a combination of a healthy diet and exercise that has the greatest benefit.3

In mid-2015 The New York Times4 reported on the activities of Global Energy Balance Network, a nonprofit organization funded by Coca-Cola to promote the argument that exercise is more important than diet. The organization disbanded by the end of the year.5

Weight loss and weight management is worth $66 billion each year according to a report in late 2017 by market research firm Marketdata, LLC.6 In their press release7 they reported that the number of active dieters had fallen by 10% since 2015. Some of the products used in the weight loss industry include diet pills, shakes and supplements, medical weight loss clinics, frozen entrees and online services.

There are several factors contributing to your ability to lose weight, including getting enough quality sleep each night,8 supporting a healthy gut microbiome9 and choosing to eat more whole food and less processed food.10 A recent study published in Scientific Reports11 has demonstrated coffee may affect your metabolism and mobilize metabolically active brown fat.

Study shows coffee stimulates brown fat

Brown adipose tissue (BAT) may generate heat (thermogenesis)12 and burn glucose and fats through a mitochondrial reaction mediated by mitochondrial uncoupling protein 1 (UCP1).13 Energy balance prevents the development of obesity, and while physical activity may dissipate some energy, the body also uses a system of thermogenesis, or the production of heat through the burning of energy.

Upregulation of UCP1 may reduce the potential for obesity and improve insulin sensitivity as it is one of the systems of thermogenesis in brown fat.14 In the Scientific Reports study, researchers looked at the effect of caffeine on BAT both in the test tube and in humans.

They wrote that past studies demonstrated the activation of BAT through nutrients or cold exposure. Caffeine demonstrated an upregulation of UCP1 in obese mice but the extent that it directly affected BAT in humans was not known. The researchers first used cells from mice and human bone marrow stem cells cultured in a test tube and then introduced caffeine.

Their analysis was performed using several tests, including mitochondrial staining, transmission electron microscopy and gene expression analysis. Next, nine healthy human volunteers with a mean body mass index of 23,15 within normal range,16 were engaged to participate. They either drank a caffeinated beverage or water and then remained sitting for 30 minutes.

The researchers found treatment of the cell cultures with caffeine increased the expression of UCP1. They also analyzed and compared the thermal imaging done 30 minutes after drinking the beverages against those done before.17

The images showed an increased temperature of BAT in the subclavicular area in adults after drinking coffee. This reflected an increase in heat production in BAT not demonstrated after drinking water.

Standard cup of coffee may help weight management

The Scientific Reports researchers said this is the first study to demonstrate caffeine’s stimulation on UCP1 in vitro that could be projected to the ingestion of caffeine by humans through a standard sized cup of coffee. Michael Symonds, Ph.D., from the School of Medicine at the University of Nottingham, co-directed the study. As reported in a press release from the university, he commented:18

“From our previous work, we knew that brown fat is mainly located in the neck region, so we were able to image someone straight after they had a drink to see if the brown fat got hotter. The results were positive and we now need to ascertain that caffeine as one of the ingredients in the coffee is acting as the stimulus or if there’s another component helping with the activation of brown fat.”

The researchers believe this suggested that caffeine in a standard cup of coffee could increase the metabolic rate and enhance BAT function. They theorize this activity has the potential to contribute to weight loss. They wrote:19

“In conclusion, these results provide new complementary in vitro and in vivo evidence that caffeine (and a coffee beverage) can promote BAT function at doses compatible with human use.”

Daily coffee affects metabolism in multiple ways

New discoveries about coffee and the impact it has on health are reported frequently. Some reports state that caffeine helps you live longer,20 while others associate caffeine with increasing your potential risk to danger.21 It can be difficult to know what to believe.

In a study published by Northwestern Medicine,22 scientists discovered coffee changed significantly more metabolites in the body than had been known. After eating or drinking, your body produces metabolites, or chemicals. A higher number of affected metabolites may explain, in part, the number of effects coffee has on the body.

The researchers gathered 47 habitual coffee drinkers and ask them to stop drinking coffee for one month.23 In the following month the participants drank four cups of coffee each day and in the last month they drank eight cups of coffee each day. During the study, the researchers collected samples of their blood, evaluating for the number and type of metabolites.

They found that the levels of 115 metabolites were altered by drinking coffee, 82 of which were known to affect 33 biological pathways. They also discovered three novel links to coffee including steroid metabolites, fatty acid metabolism and the effect it had on the endocannabinoid system.24

Your body normally has cannabinoid receptors in the neurological system.25 The researchers found the neurotransmitters related to this system were reduced after drinking four to eight cups of coffee each day. The effect is opposite of what would be expected when cannabis is ingested.

The researchers point out the body’s endocannabinoid system regulates cognition, immunity, sleep, appetite and energy functions to name a few.26 Additionally, they found the metabolites related to the androsteroid system, suggesting to the researchers coffee may help eliminate steroids from the body.

This may help in cancers significantly affected by steroid levels. Lead author Marilyn Cornelis, Ph.D., assistant professor of preventive medicine, commented:27

“These are entirely new pathways by which coffee might affect health. Now we want to delve deeper and study how these changes affect the body. The increased coffee consumption over the two-month span of the trial may have created enough stress to trigger a decrease in metabolites in this system. It could be our bodies’ adaptation to try to get stress levels back to equilibrium.”

Regarding the association among coffee, weight loss and a reduced risk of Type 2 diabetes, she said:28

“This is often thought to be due to caffeine’s ability to boost fat metabolism or the glucose-regulating effects of polyphenols (plant-derived chemicals). Our new findings linking coffee to endocannabinoids offer alternative explanations worthy of further study.”

Brown, beige or white?

Three different types of fat perform different functions in your body. Researchers in the featured study were interested in the effect caffeine would have on activating BAT, and thus increase thermogenesis and energy metabolism. Symonds commented:29

“Brown fat works in a different way to other fat in your body and produces heat by burning sugar and fat, often in response to cold. Increasing its activity improves blood sugar control as well as improving blood lipid levels and the extra calories burnt help with weight loss. However, until now, no one has found an acceptable way to stimulate its activity in humans.

This is the first study in humans to show that something like a cup of coffee can have a direct effect on our brown fat functions. The potential implications of our results are pretty big, as obesity is a major health concern for society and we also have a growing diabetes epidemic and brown fat could potentially be part of the solution in tackling them.”

The most common type of fat cells are white adipocytes, where excess energy is stored, increasing the risk of obesity. Overloading these cells leads to related conditions, such as Type 2 diabetes and cardiovascular disease.30 On the other side of the spectrum are brown adipocytes, which are thermogenically active31 and more prevalent in children than adults.32

Researchers have discovered white fat cells may be programmed to turn brown, but this programming is suppressed by the FLCN protein. The function to suppress brown fat programming is performed in cooperation with another pathway,33 which is active during cell processes, including tumor formation, insulin resistance and fat cell growth.34

That particular pathway, called mTOR, is activated by amino acids and insulin,35 as well as growth factors, which in turn help suppress brown fat programming.36 The conversion of white fat to BAT cells is known as “brite” or “beige” fat cells.

The body’s sympathetic nervous system is capable of doing this on a small scale but since white fat cells are connected to other organ systems, on a large scale within the body it is not possible.37 Scientists are experimenting with conversion of white fat outside the body to beige fat and then reintroducing to help fight obesity.38

Fat location makes a difference

Where fat is located on your body makes a difference to your health. White fat performs two important functions: It stores excess calories and releases hormones that control metabolism.39 Fat may be stored directly under the skin, called subcutaneous fat, or deep in the abdomen around your organs, called visceral fat.40

Subcutaneous fat is often found on the thighs and buttocks and does not usually cause as many problems as visceral. According to Harvard Health, 90% of body fat in most individuals is subcutaneous,41 which might be described as the fat you can pinch. It accumulates in the lower body, creating a pear shape.42

The remaining 10% is intra-abdominal or visceral fat, beneath the abdominal wall and surrounding your organs.43 This type of fat is strongly associated with metabolic syndrome and insulin resistance.44 In a study45 from the University of Illinois, researchers found a regulatory molecule produced a bodily response leading to higher amounts of visceral fat with increased caloric intake.46

Activate your brown fat stores

One way the mTOR pathway is stimulated is through excessive protein intake. This stimulation helps suppress white fat to BAT programming. To discover how to determine your optimal protein intake, see my article, “Precision Matters When It Comes to Protein.”

There are additional ways of activating your brown fat to burn more energy and convert some of your white fat to beige, also increasing thermogenesis, without drugs or surgery. Here are five additional strategies you may consider:

Exercise — In a study from The Ohio State University Wexner Medical Center,47 researchers found one reason exercise may boost metabolism is through increasing levels of a lipokine molecule that had been linked to cold temperatures in the past.48

The researchers found the function of brown fat during exercise was to tell the muscle to use more fatty acids as fuel. They confirmed their results in an animal study during which they found lipokines after the mice exercised, but once BAT was removed from the mice there was no evidence of exercise-induced increase.

Cold — Several studies have demonstrated that exposure to cold temperatures increases glucose burning in brown fat and upregulates UCP1 proteins.49 It also increases BAT activation, reduces fat50 and changes mitochondria in skeletal muscle and BAT.51 Daily exposure increases the volume of BAT and the oxidative capacity.52

Sleep — One method53 studied to expose participants to a cool environment was to reduce the ambient temperature during sleep. Researchers engaged five men over four months. The participants did their regular activities during the day and then returned to their rooms each evening.

The temperature in the room was set to 75 degrees Fahrenheit (F) during the first month, 66 F in the following two months, and 81 F in the final month. After one month of exposure to mild cold temperatures the researchers measured a 42% increase in BAT volume and 10% rise in metabolic activity in the participants.54

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