The Statin Mafia Censors Pharmaceutical Harm

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The first statin (lovastatin) was approved for use in the U.S. in 1987.1 Fast forward to 2020, just over three decades later, and it’s estimated that total sales for statin drugs will reach $1 trillion.2 Their usage statistics are staggering. Among U.S. adults aged 40 to 59, lipid-lowering drugs such as statins are the second most commonly prescribed drug, being taken by 13.9% of this population.

When you tailor this to adults aged 60 to 79, lipid-lowering drugs become the most common prescription, being used by 45% of Americans and 34.3% of Canadians in the same age range.3

The drugs were once only offered to people at high risk of heart disease, but in 2013, a joint task force of the American College of Cardiology and the American Heart Association released new guidelines, which increased the number of adults eligible for statin therapy by 12.8 million people — mostly older adults without heart disease.4

Statins are effective at lowering cholesterol, but whether this is the panacea for helping you avoid heart disease and extend your lifespan is up for debate and a question worthy of closer scrutiny. The pharmaceutical industry is quick to try to discredit any negative press toward the drugs, including, as explained in the video above, an ABC News in Australia segment that revealed the questionable effectiveness of the drugs.

Cholesterol Guidelines Marred by Potential Bias

Maryanne Demasi, Ph.D., a former medical scientist with the University of Adelaide, was a reporter for ABC News in Australia. In 2013, she was featured in a two-part series, with the first investigating the science behind the persistent claim that saturated fat causes heart disease by raising cholesterol. The second part focused on cholesterol drug wars and questioned the overprescription of statins and industry influence in statin trials.

Worthy of attention, the authors of the 2013 cholesterol guidelines declared conflicts of interest that should have removed them from either writing or voting on the guidelines, but didn’t. Of the 15 panelists who authored the cholesterol guidelines, six revealed ties to drug companies that produced cholesterol-lowering medications. Of the 10 expert reviewers for the guidelines, five listed relationships with drug makers.5

One of the criteria for people to take statin drugs was based on an algorithm that uses your age, gender, blood pressure, total cholesterol, high density lipoproteins (HDL), race and history of diabetes to predict the likelihood you’ll experience a heart attack in the coming 10 years.

At the time, the recommendation was that those with a risk profile over 7.5% should take statins and those with a profile near 5% should discuss their options with their physician.6 Studies looking into the tool’s accuracy, however, suggested the tool overestimated the number of people who would have a cardiovascular event “substantially.”7

Part of the statin debate also rests on a statistical tool called relative risk reduction (RRR) to amplify what amounts to trivial benefits. Writing in the journal Expert Review of Clinical Pharmacology, researchers explained:8

“Our opinion is that although statins are effective at reducing cholesterol levels, they have failed to substantially improve cardiovascular outcomes.

We have described the deceptive approach statin advocates have deployed to create the appearance that cholesterol reduction results in an impressive reduction in cardiovascular disease outcomes through their use of a statistical tool called relative risk reduction (RRR), a method which amplifies the trivial beneficial effects of statins.”

Statin News Segment Shut Down

After Demasi’s series aired, it was met with an outpouring of support from viewers, only to be quickly overcome with complaints from health organizations and drug companies, which orchestrated a campaign to discredit the segment. News commentators suggested “people will die” if they watch the program and a Sydney cardiologist went so far as to state, “ABC has blood on its hands,” Demasi said in the video above.

A study published in the Medical Journal of Australia also suggested that the ABC News program led to a reduction in statin usage that could result in up to 2,900 preventable vascular events.9 A gag order was issued, which meant Demasi and colleagues were unable to defend themselves or the program, and ABC ultimately capitulated to the scrutiny and pulled the program.

A similar smear campaign was launched in France against a cardiologist who questioned the value of statins in his book. In this case, researchers looked into what actually happens when statin use is discontinued, concluding, “it is not evidence based to claim that statin discontinuation increases mortality or saves lives” and:10

“On the contrary, one might even conclude that statin discontinuation could save lives. One possible explanation of this apparently paradoxical finding is that statin discontinuers, in the same time they stop statin therapy, likely try to adopt a healthy lifestyle.”

Statin Mafia Hiding Statin Data

Demasi also explains how the U.K.-based Cholesterol Treatment Trialists’ (CTT) Collaboration is holding all the raw data on statin side effects, then publishing meta-analyses promoting their use. Although they claim to be independent, they’ve received millions in funding from the pharmaceutical industry.

Dr. Malcolm Kendrick, a general practitioner in Cheshire, England, is the author of three books. I’ve previously interviewed him about “Doctoring Data: How to Sort Out Medical Advice From Medical Nonsense” and his latest book is “A Statin Nation: Damaging Millions in a Brave New Post-Health World,” which addresses the challenges with this conventional approach to heart disease prevention. Regarding CTT, he explained:

“They’ve got all the data … from the statin trials. They hold it. They won’t let anyone else look at it, ever. They keep producing these meta-analyses showing how wonderful statins are and that they don’t have adverse effects, and we’re supposed to believe them.

Although they run a clinical trials unit, last time I looked, they earned well over $400 million in funding from pharmaceutical companies almost entirely — those companies that produce cholesterol-lowering agents … [W]e have a completely biased organization paid hundreds of millions to hold all the data, and then tell us, ‘No one else can look at it. By the way, you should believe everything we say.’

… [H]ow on Earth can this be allowed to happen? … [S]omehow, these people have got themselves such a standing and status that we’re supposed to go, ‘Well, you said it. It must be right.’ This is ridiculous.”

The lack of transparency is clearly not in the public’s best interest. Demasi suggests looking to what happened with Tamiflu to learn a lesson, referring to the fact that drug makers hid a significant amount of negative data from the public.

Practitioners Persecuted for Breaking Statin Orthodoxy

Demasi, unfortunately, is not alone in being targeted for speaking out against the medical orthodoxy of using statins as a primary means of prevention against heart disease.

Others, like Dr. Antti Heikkilä in Finland, have also been persecuted for using other tools. In Heikkilä’s case, he’s been using low-carb, high healthy-fat and ketogenic diets to treat and prevent chronic diseases among his patients, with many able to manage their conditions without drugs — and facing attacks on his reputation as a result.11

As Demasi wrote in the British Journal of Sports Medicine, we’re in the midst of a statin war, and it’s the public who is suffering as a result:12

“A bitter dispute has erupted among doctors over suggestions that statins should be prescribed to millions of healthy people at low risk of heart disease. There are concerns that the benefits have been exaggerated and the risks have been underplayed. Also, the raw data on the efficacy and safety of statins are being kept secret and have not been subjected to scrutiny by other scientists.

This lack of transparency has led to an erosion of public confidence. Doctors and patients are being misled about the true benefits and harms of statins, and it is now a matter of urgency that the raw data from the clinical trials are released.”

Statin Side Effects Are Real

More than half of statin users stop using the drugs within a year, with 62% citing side effects as the reason.13 Fatigue, nausea, joint and muscle pain and increases in blood sugar have all been associated with statin drug use. Statins have also been shown to increase your risk of diabetes via a number of different mechanisms.

Researchers with the Erasmus Medical Center in the Netherlands analyzed data from more than 9,500 patients. Those who had ever used statins had a 38% higher risk of Type 2 diabetes, with the risk being higher in those with impaired glucose homeostasis and those who were overweight or obese.14

Further, the World Health Organization (WHO) Foundation Collaborating Centre for International Drug Monitoring receives safety reports associated with statin medications and has noted a disproportionately high number of patients with upper motor neuron lesions among those taking statin medications.15

Statins also deplete your body of coenzyme Q10 (CoQ10), which accounts for many of their devastating results. CoQ10 is used for energy production by every cell in your body. Its reduced form, ubiquinol, is a critical component of cellular respiration and production of adenosine triphosphate (ATP). ATP is a coenzyme used as an energy carrier in every cell of your body.

The depletion of CoQ10 caused by statins can actually increase your risk of acute heart failure. While this can be somewhat offset by taking a Coenzyme Q10 supplement (if you’re over 40, I would recommend taking ubiquinol instead of CoQ10), statins still come with a risk of other serious side effects, including:

  • Cancer16
  • Cataracts17
  • Musculoskeletal disorders, including myalgia, muscle weakness, muscle cramps, rhabdomyolysis and autoimmune muscle disease18
  • Depression19

Statins also inhibit the synthesis of vitamin K2, which can make your heart health worse instead of better, and reduce ketone production. Ketones are crucial nutrients to feed your mitochondria and are important regulators of metabolic health and longevity.

How to Lower Your Risk of Heart Disease

There is far more that goes into your risk of heart disease than your cholesterol levels. The suggestions that follow can help you lower your insulin resistance and restore your insulin sensitivity, among other heart-protective mechanisms:

Avoid environmental pollutants and toxins, including smoking, vaping, heavy metals, herbicides and pesticides, especially glyphosate.

Minimize your exposure to electromagnetic fields and wireless radiation from cellphones, Wi-Fi, routers, smart meters and more, as this kind of radiation has been shown to cause serious free radical damage and mitochondrial dysfunction.

Eat an unprocessed whole food-based diet low in net carbs and high in healthy fats. A ketogenic diet — which is very low in net carbohydrates and high in healthy fats — is key for boosting mitochondrial function.

When your body is able to burn fat for fuel, your liver creates water-soluble fats called ketones that burn far more efficiently than carbs, thereby creating fewer reactive oxygen species and secondary free radicals. Ketones also decrease inflammation and improve glucose metabolism.20

Eat nitrate-rich foods to help normalize your blood pressure. Good sources include arugula, cilantro, rhubarb, butter leaf lettuce, mesclun mixed greens, beet greens, fresh beet juice, kvass (fermented beet juice) and fermented beet powder.

Get plenty of nonexercise movement each day; walk more and incorporate higher intensity exercise as your health allows.

Intermittently fast. After you’ve become accustomed to intermittently fasting for 16 to 18 hours, you can try a stricter fast once or twice a week, when you eat a 300- to 800-calorie meal loaded with detox supporting nutrients, followed by a 24-hour fast. So, in essence, you’re then only eating one 300- to 800-calorie meal in 42 hours.

If you have heart disease, consider enhanced external counterpulsation (EECP). To find a provider, see EECP.com.21

If you have heart disease, you may also consider taking g-strophanthin, an adrenal hormone that helps create more parasympathetic nervous system neurotransmitters, thereby supporting your parasympathetic nervous system. It also helps flush out lactic acid. Strophanthus is the name of the plant, the active ingredient of which is called g-strophanthin in Europe, and ouabain in the U.S.

Get sensible sun exposure to optimize your vitamin D status and/or take an oral vitamin D3 supplement with magnesium and vitamin K2.

Implement heart-based wellness practices such as connecting with loved ones and practicing gratitude.

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Controlling Hypertension Slows Cognitive Decline

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The study here shows that given a population of individuals with hypertension, those who manage to control their high blood pressure go on to suffer lesser degrees of cognitive decline. Numerous mechanisms may link hypertension to structural damage in the brain: degeneration of the blood-brain barrier, allowing inappropriate molecules and cells into the brain, leading to neuroinflammation and other effects; rupture of capillaries causing microbleeds, effectively tiny strokes; outright pressure damage in tissue very close to small vessels that directly harms brain cells; and so forth. This damage adds up, but note that it is a set of physical issues that stem from increased pressure rather than the biochemistry that causes that increased pressure. Therefore these downstream issues can be suppressed by any method that reduces blood pressure consistently, even though that will leave the underlying damaged biochemistry to continue to cause other issues.


High blood pressure appears to accelerate cognitive decline among middle-aged and older adults, but treating high blood pressure may slow this down, according to a preliminary study. According to the American Heart Association’s 2017 Hypertension Guidelines, high blood pressure affects approximately 80 million U.S. adults and one billion people globally. Moreover, the relationship between brain health and high blood pressure is a growing interest as researchers examine how elevated blood pressure affects the brain’s blood vessels, which in turn, may impact memory, language, and thinking skills.

In this observational study, the researchers analyzed data collected on nearly 11,000 adults from the China Health and Retirement Longitudinal Study (CHARLS) between 2011-2015, to assess how high blood pressure and its treatment may influence cognitive decline. High blood pressure was defined as having a systolic blood pressure of 140 mmHg or higher and a diastolic blood pressure of 90 mmHg or higher, and/or taking antihypertensive treatment. According to guidelines of the American Heart Association, high blood pressure is defined as 130 mmHg or higher or a diastolic reading of 80 mmH or higher.

Researchers interviewed study participants at home about their high blood pressure treatment, education level, and noted if they lived in a rural or urban environment. They were also asked to perform cognitive tests, such as immediately recalling words as part of a memory quiz. Among the study’s findings: (a) Overall cognition scores declined over the four-year study; (b) Participants ages 55 and older who had high blood pressure showed a more rapid rate of cognitive decline compared with participants who were being treated for high blood pressure and those who did not have high blood pressure; (c) The rate of cognitive decline was similar between those taking high blood pressure treatment and those who did not have high blood pressure.

Link: https://www.mailman.columbia.edu/public-health-now/news/high-blood-pressure-treatment-may-slow-cognitive-decline

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Lipid Turnover in Fat Tissue Decreases with Age

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Researchers here show that lipid turnover in fat tissue decreases with age, and suggest that this mechanism explains some fraction of the tendency to gain weight with age. Everyone of a certain age recognizes that it takes ever more effort to evade or get rid of excess fat tissue. It remains an open question as to which underlying mechanisms cause this change in lipid turnover, though given progress in rejuvenation research we are at the point of being able to test hypotheses such as chronic inflammation resulting from senescent cells, or mitochondrial dysfunction. We shall see what new data on this topic emerges in the years ahead.


Scientists studied the fat cells in 54 men and women over an average period of 13 years. In that time, all subjects, regardless of whether they gained or lost weight, showed decreases in lipid turnover in the fat tissue, that is the rate at which lipid (or fat) in the fat cells is removed and stored. Those who didn’t compensate for that by eating less calories gained weight by an average of 20 percent, according to the study.

The researchers also examined lipid turnover in 41 women who underwent bariatric surgery and how the lipid turnover rate affected their ability to keep the weight off four to seven years after surgery. The result showed that only those who had a low rate before the surgery managed to increase their lipid turnover and maintain their weight loss. The researchers believe these people may have had more room to increase their lipid turnover than those who already had a high-level pre-surgery.

“The results indicate for the first time that processes in our fat tissue regulate changes in body weight during ageing in a way that is independent of other factors. This could open up new ways to treat obesity.” Prior studies have shown that one way to speed up the lipid turnover in the fat tissue is to exercise more. This new research supports that notion and further indicates that the long-term result of weight-loss surgery would improve if combined with increased physical activity.

Link: https://news.cision.com/karolinska-institutet/r/new-study-shows-why-people-gain-weight-as-they-get-older,c2899205

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Arguing for Extracellular Vesicles to Mediate Beneficial Effects of Parabiosis

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Cells communicate with one another constantly, and a large portion of that communication is not carried by individual secreted molecules, though there are certainly a lot of those, but rather takes the form of small membrane-bound packages of diverse molecules known as extracellular vesicles. Cells generate and secrete extracellular vesicles of various sizes, and other cells ingest them. Two important areas of active research into cell signaling are the way in which young tissue can restore the function of old cells, and the way in which senescent cells change the activity of surrounding cells for the worse. In both cases, extracellular vesicles are important in this process of communication and influence.

There is a substantial faction in the research community focused on potentially beneficial effects that derive from young blood, emerging from the study of heterochronic parabiosis in which the circulatory systems of a young and old mouse are linked. The old mouse benefits and shows some signs of reversal of the consequences of aging, the young mouse exhibits accelerated signs of aging. Is this in fact due to beneficial signals in young blood? There is good evidence that strongly supports the case that benefits result from a dilution of harmful factors in old blood, and that beneficial factors in young blood are not important. Nonetheless, there is further independent evidence in which factors or extracellular vesicles derived from young blood have been used to produce benefits in old mice. There are also a number of failures to show meaningful benefits from blood or plasma transfusion, in mice and humans. It is an interesting field, in which conflicting evidence abounds.

Extracellular vesicles circulating in young organisms promote healthy longevity


In the late 1950s, parabiosis experiments provided some scientific consistency to these beliefs. Indeed, a shared circulatory system was sufficient to increase bone weight and density of old mice when joined to younger ones. The same experimental design was applied to demonstrate a lifespan-enhancing effect of young blood. Many years later, elegant reports demonstrated a rejuvenation-promoting effect of young blood in a wide variety of cells and tissues, e.g. stem cells, muscle, brain, and the heart. However, the pursuit of the circulating factors responsible for such effects did not achieve the same success. In fact, the suggested pro-regeneration role of growth differentiation factor 11, a member of the TGFβ superfamily, has been questioned.

Extracellular vesicles (EVs) are membrane-coated nanoparticles actively released by almost all cell types. Increasing evidence indicates that both are able to shuttle and deliver functional proteins and nucleic acids in a paracrine and systemic manner. Blood contains a heterogeneous mixture of EVs of different origins, which are currently being characterized for therapeutic and diagnostic purposes. The effects of EVs are now attracting intense interest also in the context of ageing and age-related diseases (ARDs).

In particular, senescent cells (SCs) are emerging as major drivers of ageing and key contributors to inflammaging, the age-associated pro-inflammatory drift that promotes the development of ARDs. Recent evidence suggests that EVs are also central constituents of the SCs secretome. In particular, SCs secrete an increased amount of EVs, excreting pro-inflammatory DNA and possibly spreading pro-ageing signals. Conversely, a seminal paper suggests that a 4-month injection of small EVs derived from hypothalamic neural stem cells and rich in specific miRNAs into the hypothalamic third ventricle is sufficient to ameliorate some age-associated detrimental outcomes in C57BL/6 mice, including hypothalamic inflammation and the drop in physical activity.

These and other observations prompted the hypothesis that EVs are central mediators of the circulating communicosome fostering inflammaging. In that framework, we hypothesized that the chronic administration of EVs purified from a young healthy mouse to an old one should ameliorate some age-associated phenotypes. This experimental approach appeared to be enough feasible and robust to demonstrate a tangible role of EVs in the ageing process. Researchers have now shown a clear pro-longevity role for EVs isolated from young mouse plasma. Indeed, they injected EVs isolated from 4-to-12-month-old mice into 26-month-old female mice once a week until sacrifice and observed an increase of 10.2% and of 15.8% in median and maximal lifespan, respectively, in mice receiving the treatment vs. vehicle-treated mice of the same age.

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Healthy Aging: Being Mindful of Brain Health

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Healthy Aging: Being Mindful of Brain Health
Regan Jones, RD

As a registered dietitian nutritionist, I’m confronted regularly with a wide variety of people with health-related inquiries. But for all the ways we differ in our individual health needs, there is one commonality we share. Every person on this planet is aging day-by-day.

It’s true that some of us are farther along on the timeline than others, but there’s no denying that we’re all putting days behind us as we move towards the days ahead of us. The question is — what are we doing each day to support that aging process as healthfully as possible? September is Healthy Aging Month and it’s the perfect time to answer this question, especially as it relates to brain health.

Why begin with the brain?

While physical signs of aging like muscle mass decline or weight gain can be seen outwardly, prompting people to lose weight or work out, the changes happening in the brain are often simply dismissed as a natural consequence of growing older — “Oh, I’m so forgetful these days!” The truth is, maintaining cognitive function is critical to healthy aging. The decline in focus and problem solving are common age-related affects among normal aging individuals.

It’s well known that as we age brain metabolism decreases which is associated with cognitive decline.1,2,3,4 There are many factors associated with age-related cognitive decline:

• Oxidative stress and free radical damage5
• Changes in hormone levels6-8
• Poor diet quality9,10
• Stress and social isolation11,12

Is cognitive decline inevitable?

Not necessarily. There are several things you can do to support brain health and cognitive function with age.

The good news is that you can support brain health through commonly recommended practices, such as increasing physical activity, decreasing stress, improving sleep quality and ensuring adequate nutrient intake through healthy eating and supplementation.13-18 With about 90 billion neurons, the brain is a sponge waiting to soak up high-quality nutrients to help it perform optimally.19 Most of that nutrition comes from the diet we eat, but supplements can help by providing additional targeted nutrients.

Healthy Eating for a Healthy Brain

To understand how healthy eating plays a role in brain health, it’s important to look at the research and, most notably, the recent revelation in the scientific community that an eating plan known as the MIND Diet substantially slows cognitive decline with age.20

The MIND Diet (Mediterranean-DASH Intervention for Neurodegenerative Delay) emphasizes plant-based foods, specifically an increase in berries and green leafy vegetables and a decrease in saturated fats and animal-based foods. The following recommendations align with the MIND Diet21:

• At least three servings of whole grains a day
• A salad and one other vegetable a day
• One glass of wine a day
• A serving of nuts a day
• Beans every other day
• Poultry at least twice a week
• Berries at least twice a week
• Fish at least once a week
• Limiting butter (less than one tablespoon a day), cheese and fast or fried foods

Supplemental Support: Nutrients that Support Brain Health

In addition to eating a healthy diet, targeted nutritional supplementation may also support brain health.

Sage extract

Sage extract has been shown to promote healthy levels of the neurotransmitter acetylcholine and the signaling of neurotransmitters like GABA, dopamine, serotonin, and more. Also of note, in pre-clinical studies, sage extract shows promise in promoting healthy gene expression related to lipid metabolism and insulin.22

Vinpocetine

Derived from the periwinkle plant, vinpocetine has been shown to promote cognitive function, support a healthy inflammatory response and help maintain healthy blood flow, oxygen and nutrient delivery to brain cells.23

Blueberry extract

Blueberry consumption and supplementation has been shown in many studies to support brain health and cognitive function.24 AuroraBlue® is a complex of blueberry and bilberry species from across the Alaskan tundra that are known to contain powerful antioxidants.

Phosphatidylserine

Phosphatidylserine (PS) is an essential part of healthy cell membranes, critical to both brain metabolism and intra-brain connections. Furthermore, PS helps with brain-related glucose metabolism and stimulation of acetylcholine production.25-27

Ashwagandha

By promoting the healthy growth of nerve cell components that support brain and nervous system function, Ashwagandha has neuroprotective effects on the brain. It has been shown to support healthy stress adaptation and cognitive function in aging individuals.28-32

Uridine-5’-Monophosphate

In pre-clinical studies, Uridine-5’-Monophosphate (UMP) has been shown to promote healthy brain function by supporting healthy levels of both acetylcholine and dopamine.33-35

Life Extension created Cognitex® Elite, which contains the nutrients listed above, specifically to provide brain-friendly nutrient support for a healthy brain and cognitive function at any age.

Every day offers a new chance to preserve and protect our bodies and brains from the decline associated with aging. Science has shown that while the risk for decline is real, so are the benefits of lifestyle and dietary interventions. Through the right combination of stress reduction, physical activity and a nutrient dense diet through foods and supplement support, maintaining a sharp mind for many years to come is a reality we can all enjoy.

About the Author: Regan Jones is an award winning registered dietitian and host of ThisUnmillennialLife.com, an iTunes Top 30 personal journal podcast that offers women a roadmap through midlife. Jones, who began her career as an assistant editor at Cooking Light and Weight Watchers Magazines, is now frequently featured in the national media and is the 2017 winner of the Academy of Nutrition and Dietetic’s prestigious Media Excellence Award. She is also co-author of the Academy of Nutrition and Dietetic’s 2016 Practice Paper, Social Media and the Dietetics Practitioner: Opportunities, Challenges, and Best Practices. Jones enjoys manning the microphone from her home in Georgia, where she lives with her husband and two sons.

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  31. Wadhwa R, Konar A, Kaul SC. Nootropic potential of Ashwagandha leaves: Beyond traditional root extracts. Neurochem Int. 2016;95:109-118.
  32. Shah N, Singh R, Sarangi U, et al. Combinations of Ashwagandha leaf extracts protect brain-derived cells against oxidative stress and induce differentiation. PLoS One. 2015;10(3):e0120554.
  33. Cansev M, Watkins CJ, van der Beek EM, Wurtman RJ. Oral uridine-5′-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Res. 2005;1058(1-2):101-108.
  34. Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5′-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007;1182:50-59.
  35. Wang L, Albrecht MA, Wurtman RJ. Dietary supplementation with uridine-5′-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res. 2007;1133(1):42-48.

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Omega-3s Protect Your Lungs and Mitochondria

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The death toll from the terrorist attacks on September 11, 2001, included 343 firefighters and paramedics among the 2,7531 who were exposed to 10 million tons of material released in a caustic dust cloud as the twin towers were reduced to rubble.2

Since then, more than 150 have died. Of the nearly 400,000 who are eligible for the World Trade Center Health Program set up specifically to treat the physical and mental health challenges caused by exposure,3 72,000 are enrolled and 8,000 have been diagnosed with cancer.4

First responders were exposed to toxins, the result of exposure to dust containing chemicals in asbestos, glass fibers, lead and cement.5 Seventeen years later the WTC Health Program addresses care for those suffering from respiratory problems, malignant cancers, digestive problems and reproductive problems associated with the exposure.6

Utility workers, medical examiners, bus drivers and others were also affected.7 Researchers from New York University School of Medicine8 undertook an analysis to determine if there were indications that some first responders may have greater risk than others.9

Omega-3 May Protect Against Lung Damage in First Responders

The team believes their experiment is the first to suggest compounds present in first responders could prevent disease. They measured metabolites, which are chemicals the body makes as it breaks down fat, protein and carbohydrates. Metabolites are natural byproducts that result from the breakdown of these macronutrients.10

The study specifically linked 30 metabolites to first responders who had a lower incidence of obstructive airway disease. Conversely, they found those who had lower levels also had an increased risk of developing pulmonary disease.11

In a press release12 the researchers announced they had analyzed blood samples from 14,000 first responders and their lung function tests. Firefighters are a unique population since pre-exposure lung function testing was available for many of the first responders.13

Lung function testing has been done every year since 9/11. The study found specific chemicals were predictive of disease with a 93.3% accuracy. The two groups of metabolites most associated with lung injury were amino acids and lipids.14

The researchers were unsure of the biological function of the amino acids in relationship to lung injury. Increased concentration supported the hypothesis some firefighters had higher protein intakes and also enjoyed a lower risk of lung injury. However, they also felt it was unlikely that protein deficiency was an issue in active firefighters.

A number of lipid metabolites were found in higher quantities in those who were without lung injury. Eicosapentaenoic acid (EPA)15 in particular acts as a precursor for reducing your inflammatory response and immune response to any injury. This effect may have helped reduce damage in first responders triggered by exposure to toxins.

Lead investigator George Crowley discussed the importance this data could have on prevention. He also shared potential recommendations for first responders participating in disaster relief and suggested that physicians analyze their patients’ blood and use the results to help guide treatment.16

Heart Risk Factors May Be Another Predictor of Lung Damage

The same team published findings in the journal Chest17 showing heart disease risk factors may also predict persistent lung damage in 9/11 first responders.18

The data demonstrated that traits of metabolic syndrome were a stronger predictor of lung dysfunction than tobacco smoking or the amount of exposure that emergency personnel were subjected to at the site of the attack.

The symptoms of metabolic syndrome include high blood pressure, abdominal obesity and high blood triglycerides.19 Dr. Anna Nolan, a senior study contributor from NYU School of Medicine, said,20 “A third of the population in most Western countries has abdominal obesity, insulin resistance and issues with high lipids.”

The researchers also noted the syndrome is linked to an increased risk for Type 2 diabetes, stroke and heart disease. The combination of particulate matter and metabolic syndrome was interesting to the researchers since issues with air pollution and particulate matter are becoming more common.21

The team analyzed data from firefighters enrolled in the WTC Health Program and found that the 1,208 people who developed lung injury by 2017 were more likely to be overweight or obese and to have metabolic syndrome.22 The data indicate that obesity is a greater risk factor than high blood sugar and insulin resistance.

Dr. Anne Dixon from the University of Vermont Medical Center was not involved in the study, but said she found the results highly important because it shows “a clear link” between metabolic syndrome and an increased risk of pulmonary disease.23

Omega-3 Protects Against Secondary Bacterial Infections

Past research24 has also demonstrated omega-3 fatty acids can help reduce bacterial infections in the lungs of those who suffer from chronic obstructive pulmonary disease (COPD).

Research from the University of Rochester School of Medicine and Dentistry demonstrated that derivatives of omega-3 are effective in clearing non-typeable Haemophilus influenzae that may become problematic in those with COPD. Lung infections may put lives at risk in those who suffer from obstructive airway disease, such as first responders who are exposed to multiple toxins.

Richard Phipps, Ph.D., was part of the team who found that omega-3 provides precursors to help shut down excessive inflammation in the lungs. Using mice, the data show that unlike drugs used in the study, omega-3 helps reduce inflammation without stopping the animals’ capacity to clear bacteria. It may have even sped up the process of clearing bacteria overall.25

Omega-3 Fats Affect Your Mitochondrial Function

Your omega-3 levels may also affect your mitochondrial function, or dysfunction. Mitochondrial disease26 is a group of conditions attributed to the dysfunction of mitochondria rendering organelles unable to effectively generate energy. Some of the more profound effects become evident in the brain and muscle, including the heart.

Other organs affected include the liver, eyes and kidneys. Omega-3 fats are among the more promising nutritional components researchers have found that play a crucial role in the management of mitochondrial dysfunction.27 Your mitochondria are important in energy production and calcium signaling, as well as apoptosis and autophagy.28

In one animal study, the oral administration of omega-3 fats demonstrated a positive effect on mitochondrial function and neuroprotection.29 Giving omega-3 fats to cells in a lab setting demonstrated the ability to induce metabolic genes and metabolic rate, increasing mitochondrial content compared with control cells.30

One of the signs of advancing age is remodeling of the cell membranes in the heart.31 One impact on this remodeling is mitochondrial function, which plays a role in sustaining energy production. Some of the changes that occur during aging predispose heart cells to ischemic injury and cell death.

Changes in the mitochondrial membrane are exacerbated by the presence of omega-6 polyunsaturated fats. This has a significant consequence on the efficiency of cell function. Researchers have found that dietary changes involving increased amounts of omega-3 fats help with metabolic issues that affect aging and facilitate mitochondrial energy production.32

Omega-3 Index May Offer Insight Into Your Levels

The featured study points to just one of the benefits of maintaining optimal levels of omega-3 fats. Unfortunately, while most people get more than enough omega-6 from vegetable oils, salad dressings, mayonnaise and nuts,33 they don’t get enough omega-3.

Technically, omega-3 fats are found in plant and animal sources, but as I discuss below, animal sources are the most bioavailable to your body. Maintaining optimal levels of omega-3 is also associated with a reduction in levels of obesity34,35 and in the prevention of chronic diseases such as cardiovascular disease, cancer, autoimmune diseases,36 nonalcoholic fatty liver disease and Alzheimer’s disease.37

Knowing your omega-3 level helps determine the amount of change needed to get your levels in the low risk category. William Harris, Ph.D., developed the omega-3 index, a blood test that measures the amount of omega-3 in your red blood cells. This reflects the amount in the rest of your body and is not influenced by recent meals.

The test has been used to evaluate data,38 the results of which demonstrate a healthy range of omega-3 measured in blood cells is from 8% to 12%.39,40 GrassrootsHealth, an independent research organization with whom we partner, offers an omega-3 and vitamin D at home test kit.

The results are completely private and require no doctor or lab visit. Once your sample and questionnaire are mailed, your results are usually ready within 10 to 20 days after the lab receives your sample. I offer this test kit simply as a convenience and courtesy as I don’t benefit or participate in the test in anyway.

Once you have your results, you have access to knowing how much omega-3 you need to reach a low level of risk. You may use this free calculator41 to help.

Choose Your Omega-3 Source Wisely

Although your body needs both plant and animal sources of omega-3 fats, they are not interchangeable. Plant-based omega-3 provides alpha linoleic acid (ALA), which your body inefficiently converts to EPA and poorly converts to DHA.42 Plant-based sources of omega-3 include flaxseed, walnuts, pumpkin seeds and chia seeds. These help to boost your overall ALA intake.43

Fish and marine oil supplements are a direct source of EPA and DHA.44 EPA and DHA are essential in digestion, blood clotting, memory, learning and functions of cell receptors. You must get these from your diet.45 You may choose to increase your intake of wild-caught Alaskan salmon, mackerel, anchovies and herring to do so.

However, if these are not available, choose to use a krill oil supplement rather than fish oil. Since fatty acids are insoluble in water they need to be packaged in a type of lipoprotein to be transported within your blood. An unprocessed fish oil supplement is bound in triglycerides while krill oil is mostly bound in phospholipids.46

It’s the phospholipids in krill oil that make this form of omega-3 supplement easily bioavailable in the first 72 hours.47 As you consume fish oil, the liver must attach it to a phosphatidylcholine while krill already contains this substance — yet another reason krill oil demonstrates more efficient cellular uptake.48

In addition to these advantages, fish oil has a higher likelihood of oxidative damage, making it less stable than most other supplements.49 In testing 54 of the best-selling supplements,50 one lab found 59.2% of the products had levels of omega-3 that varied by more than 10% of what was labeled on the bottle.

The testing also revealed 92.5% had measurable amounts of mercury, known to damage the nervous system, digestive tract and immune system, as well as on the lungs, skin and kidneys.51

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Matthew O'Connor Presenting on Underdog Pharmaceuticals at Undoing Aging 2019

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Here Matthew O’Connor of the SENS Research Foundation talks about the research that led to founding of Underdog Pharmaceuticals, a biotech startup incubated by the foundation to commercialize a means of targeting 7-ketocholesterol in atherosclerosis and other conditions. Oxidized cholesterols, and largely 7-ketocholesterol, are the primary cause of dysfunction in the macrophage cells normally responsible for preventing the build up of fatty plaques in blood vessel walls. That dysfunction is the cause of atherosclerosis, and the fact that the presence of oxidized cholesterols increases with age is one of the reasons why atherosclerosis is an age-related disease, and why young people don’t exhibit the plaques that narrow and weaken blood vessels.

A sufficiently effective way of selectively clearing 7-ketocholesterol from the body should go a long way towards preventing and reversing atherosclerosis – and possibly other conditions as well. As noted here, there is evidence for 7-ketocholesterol to accumulate in other tissues and contribute to age-related conditions in other ways. The particular approach taken by the SENS Research Foundation scientists is to find a non-toxic molecule that selectively binds to the toxic molecule that one would like to remove, 7-ketocholesterol in this case, and deliver it to the body in volume. The bound molecules are then processed and excreted in the normal way. It will be interesting to see how the Underdog project progresses in the years ahead.

Matthew O´Connor presenting at Undoing Aging 2019


Thank you everybody. It is a real honor and a pleasure to be here today, speaking in a last minute slot. Don’t volunteer to take over to speak for someone who didn’t show up, because then you have to stay up all night, working on your slides. This slide is the SENS team from this last summer, a combination of the MitoSENS team and the team working on 7-ketocholesterol that Aubrey de Grey was just referring to, that we’re calling the Underdog team. You can see me as the chief Underdog there.

I want to just spend a minute, Aubrey had mentioned that this is the tenth anniversary of SENS Research Foundation, and it is my 9th year with SENS Research Foundation. It has been a privilege to have started so early, to help build the lab, and I wish that I could show a time lapse photography of where it started and where it has gone, and also to be involved with some of these amazing interns. So many of these projects, including this one, are very intern driven. Regarding the MitoSENS team, people may not realize that all the progress Aubrey was talking about, publishing papers all of a sudden, didn’t happen until after we hired Amutha, so you can see why that project got taken away from me and given to her. She is just a phenomenal mitochondrial biologist.

So this project that I’m about to tell you about involves a story about 7-ketocholesterol. I hope that a lot of you have heard about it. It is kind of one of the classic bad guy molecules that Aubrey has been talking about for a long time. My history with it goes back even further than SENS Research Foundation, as the foundation and Methuselah Foundation before it have been funding work on trying to get rid of this really nasty molecule 7-ketocholesterol for at least ten years, with work that we’ve funded in various places. I actually heard Aubrey give a talk about this, one of the best talks I’ve ever seen, at Rice University something like 15 years ago when I was in graduate school. So I’ve been thinking about it ever since then.

This project kind of started out as some ideas about how to think about this problem and how to get rid of this nasty molecule a different way. It started out as something that we were sort of dabbling in, and graduated from being my 20% project to something that is all-consuming now. On this slide, you can see causes of death worldwide, which probably looks familiar to you many of you. As Aubrey was just saying, atherosclerosis is the world’s biggest killer. If you risk-adjust all of these diseases for what their underlying cause is, atherosclerosis is believed by world health organizations to kill about 44% of everybody. This molecule, 7-ketocholesterol, an oxidized form of cholesterol, is thought to be one of the earliest stages leading to atherosclerosis. But not everyone simplistically believes in that model; the classic model is that you eat too many hamburgers and you get too much cholesterol in your bloodstream, and that just sort of stochastically builds up, and eventually you get plaques, and eventually they rupture and you have heart attacks and strokes, and you die.

However 7-ketocholesterol is many, many, many times more toxic than LDL cholesterol is – so I call it the really bad cholesterol. It is by far the most common product of the reaction between a free radical and cholesterol, and so more often than not you get this stable 7-ketocholesterol which is extremely toxic. It has no useful purpose in your body. It can accumulate in the lysosomes of macrophages and can be an early step in the progression towards becoming a foam cell. Foam cells build up as a layer in atherosclerotic plaques, and 7-ketocholesterol is found inside them, as well as in the necrotic core of the plaque.

Let me change gears now and reveal the class of drug, the class of molecules, that we have been playing around with for the last few years. They are called cyclodextrins. You may or may not have heard of them, but they are a huge industry, and they have a huge variety of applications. The medical applications, despite the fact that cyclodextrins have been studied and applied for many decades, are only just starting to be realized. They come in three basic flavors, alpha, beta, and gamma, which are three different sizes, and they have six, seven, or eight different sugar rings that they are made out of. There are different forms of them, probably thousands of different ones that have been invented. They are extremely customizable and modifiable. Any one of these hydroxyl groups you can stick just about anything you want on it, doing synthetic chemistry.

The slide here shows just a few examples of common cyclodextrins that are used for various industrial purposes. Medically, they are mostly now only used as excipients, meaning as carrier molecules for small hydrophobic drugs. They are used in food: alpha-cyclodextrin is approved in the European Union as a bulk fiber supplement, so maybe you ate some of it this morning. There are versions of these that are extremely low toxicity household items, like Febreze. People can use cyclodextrins, use different formulations of them mixed with other guest molecules that stick into the cyclodextrin cavity, to engineer all kinds of materials such as self-healing gels. They look like jello, and you cut it in half and put it back together and there is no seam any more. Somebody in Japan built a car out of cyclodextrins, and there is a German scientist who is making self-healing paint for cars.

Now let me summarize a bit the history of using cyclodextrins themselves as the active component of drugs. That is what we’re trying to do here, to engineer them to be drugs to target 7-ketocholesterol directly. The history here goes back to the 1990s, where this Australian group had a lot of foresight; they already knew that 7-ketocholesterol was a really toxic atherogenic molecule back then, this isn’t a new discovery. There has been tons of evidence for that for decades. Cyclodextrins were just starting to be explored in the 80s and 90s as cholesterol binding drugs; different versions of them bind cholesterol well. So they went looking for a modified cyclodextrin that can specifically bind 7-ketocholesterol with a hypothesis, and they found hydroxpropyl-beta-cyclodextrin, which I will tell you about. After they published a bunch of papers, however, they abandoned it and never went into any animal studies.

However, there was a group in Texas that seems to have picked up on this idea, and there was an orphan disease called Niemann-Pick type C, which is a lysosomal storage disease, that hyperaccumulates 7-ketocholesterol. These patients, almost always children, are very sick and die very young. There are good mouse and cat models for this disease, and if you dose them with very high doses of hydroxpropyl-beta-cyclodextrin, you can rescue the small animals. People have started to look at this for atherosclerosis because hydroxpropyl-beta-cyclodextrin is so safe, but there is some debate as to whether you are targeting 7-ketocholesterol, and I’ll present some evidence as to why I’m strongly in favor of one hypothesis over the other. For the Niemann-Pick studies, it is going into clinical trials, it is entering phase II, there is a lot of funding going into this now. Presumably because they’ve got their eyes on atherosclerosis rather than just Niemann-Pick, which is an extraordinarily rare disease.

This slide shows some older data on cyclodextrin, and this came from the Australians. They are soluablizing 7-ketocholesterol, and here is the effect that it has on cholesterol, which is to say nothing, while it does a great job soluablizing 7-ketocholesterol. I’m going to talk a lot about this assay, so if you don’t understand it, hold tight and I’ll explain it in more detail. 7-ketocholesterol is very toxic, so with increasing doses you kill cells in culture and this was work we funded at Rice University, kind of as a scientific control for the experiments that they were doing. They were playing with cyclodextrin; as I said, it has a lot of different functions. They were using it as a carrier molecule, and found that it was working better than anything else that they were using, while we were working on the earlier LysoSENS enzymatic process to rescue the cells from 7-ketocholesterol toxicity. Then more recently, work in that same lab led to a paper and a patent on the idea of using that same cyclodextrin to prevent and reverse lipofuscin from forming in cells.

So I’ll leave that there as history and show you this happy and sad video of cats with Neimann-Pick disease. All three of these cats have this disease and their phenotype is pretty similar to that of the humans. It is a devastating disease. All of these cats have it, one of these cats has been treated with hydroxpropyl-beta-cyclodextrin at a very high dose. Apparently this video is famous in the FDA for how you get something fast tracked into humans by showing a heart-tugging video like this. Because it clearly is working very dramatically to help these cats.

This slide shows the assay that we use. It is a really simplistic assay to screen through many different compounds, the many different cyclodextrins, many different modifications to cyclodextrins that we’ve made. It is a simple turbidity assay that we’ve automated. If you dump most sterols that are not water soluable into an aqueous solution, they get cloudy. Then if you managed to add something to the solution that can soluablize the sterols, then the solution turns clear. That is an indication that they are binding to your target.

So we’ve automated it, you run many of these plates, read them in a plate reader, and you get data that looks like this next slide. I’m just reporting the percent turbidity, so start at 100% and then go down, or in some cases it becomes more cloudy. So these are some cyclodextrins that have been studied for Neimann-Pick disease, as I keep talking about, hydroxpropyl-beta-cyclodextrin is one of our favorites. It doesn’t bind cholesterol, even at ridiculously high concentrations. With 7-ketocholesterol it has nice specificity. There’s another one, sulphobutyl, that has also been tested somewhat in animal models for Neimann-Pick disease but hasn’t really gone further than that, and doesn’t seem to be as effective as hydroxpropyl-beta-cyclodextrin.

The safety profile for some cyclodextrins such as hydroxpropyl-beta-cyclodextrin is just phenomenal. It is much less toxic than aspirin, or something like that. So you can dose humans or animals with grams of it and they are fine. As you can see, hydroxpropyl-gamma-cyclodextrin, a bigger one, doesn’t do anything in the assays.

We’ve checked many different cyclodextrins and run them through our screening process. This slide shows a bunch more from the catalogs. Some of them are better and some of them are worse. The point of showing this to you is to show how we gathered a ton of data about which cyclodextrins were interacting with which targets in which ways, and I deleted a whole bunch of data because I was practicing this this morning, and I had too much in the presentation. But we also screened a bunch of other targets, other sterols that you can order from the Sigma catalog. That helps us look at off-target effects.

We can also do it computationally. On this slide you see the former intern that Aubrey was bragging about before. She had the idea when she was an intern – we were already working on this project, and making some progress, and she said well why don’t you just model them, you can learn so much about them. She said I’ll figure it out. So now she’s one of the world’s experts in modeling cyclodextrins. Which is a very niche field. Only a few people in the world know how to do this.

What you see here is a molecular dynamic simulation of just a basic beta-cyclodextrin. We’ve done hundreds of different simulations on different tweaks and different cyclodextrins, mostly with just cholesterol and 7-ketocholesterol, trying to optimize selectivity binding. Also to optimize the affinity. So beta-cyclodextrin, just the core molecule, is known as a good cholesterol binding molecule, but we can learn additional things here. If you stick it in this way, both cyclodextrin and cholesterol are asymmetrical molecules and if you start with it the wrong way, it will go in the way that it prefers. It seems kind of nitty-gritty to talk about, but that kind of information is what helped us figure out all the different subtle ways in which cyclodextrins are binding their targets.

Now on this slide is a model of hydroxpropyl-beta-cyclodextrin binding 7-ketocholesterol extremely tightly and with specificity. To really get the lowdown on this, and this is all unpublished data, we’ll have a publication coming out soon, that we’re furiously writing now. Go see the posters at this conference, and grill me on this, because the author is brilliant, she’s great at explaining it. So we started optimizing cyclodextrins, making little tweaks to them, and came up with some tricks on how to improve the affinity for them, starting out with hundreds of these models. This slide shows the kind of data you’ll get from it, the geometry of how they are interacting, how closely in space they are interacting. Then the information, that I think is the most dramatic, about the affinity.

So when you find one that is actually going to grab on super-tightly, then you massively increase the free energy of interaction, or decrease it. You can see that this also corresponds with super-close, tight, and stable interaction between the two molecules. Those kinds of simulations are extremely high resolution. We do them for a whole microsecond, which is an eternity in terms of nanosecond resolution simulations of molecules. The chief way to do lots of simulations is to do molecular docking, and so using this method – this slide is, I think, 28 different simulations that are done quickly, doing just small little tweaks to a particular family of cyclodextrins. We look for areas such as here where you seem to get separation between cholesterol and 7-ketocholesterol.

That is what led us to the step shown on this slide, which is that we synthesized some new cyclodextrins and checked to see if they could increase their affinity and maintain specificity for 7-ketocholesterol. Up at the top here you have hydroxpropyl-beta-cyclodextrin, which doesn’t bind cholesterol, it binds 7-ketocholesterol a little bit. However, note the change in scale down here, we’re using lower dosing ranges. The modifications that we’re making to these that I’m showing you here today, they all work phenomenally well to massively increase the affinity for our target 7-ketocholesterol. However, all of them also increase their affinity for cholesterol. You probably can’t see all of them in this slide, but some of them are maintaining better specificity than others, and those are the ones we’re most excited about.

So there are a couple of different families of new cyclodextrins that we’ve invented that have extremely high affinity for 7-ketocholesterol. One in particular that caught our eye that we’re really excited about – again, hydroxpropyl-beta-cyclodextrin up here at the top of the slide, some nice specificity for 7-ketocholesterol. Down here, one of the new cyclodextrins that we made has an extremely high affinity for 7-ketocholesterol, and good specificity.

Like I was saying before, these are exciting molecules to work on because they are really safe, the different versions are edible, breathable, or injectable, as in happening in the Neimann-Pick trials. A classic safety test before going in vivo is to collect some blood from whatever hapless CEO or intern happens to be wandering down the wrong time, and then treat their blood with something, and if it lyses it, then it is killing their blood cells, and if it stays clear then it is not. All of the new cyclodextrins that we’ve made seem to be non-toxic in the pharmacological range, and as you go above that you get some variation. For the one we’re most excited about, that had the highest specificity for 7-ketocholesterol, we couldn’t find a dose at which we would kill any blood cells.

I’m going to try to make the case that animal models for atherosclerosis are useless, and that we should skip straight to humans. My argument is that mice, rodents, don’t get atherosclerosis naturally, and when you do give it to them by knocking out their ability to metabolize cholesterol, they are just not able to take up cholesterol, to clear it, so that it just builds up into artificial plaques. We don’t think that is a good model. So once again we’re working in humans, we’re stealing their blood, and then treating blood with the drug in concentrations that we think are realistic and for time periods that we think are realistic. We know a lot – so much work has been done on safety for cyclodextrins over the years. We know a lot about how quickly it is cleared from circulation in different animal systems and even humans.

Then what we’re doing is instead of trying to measure serum 7-ketocholesterol levels, which basically don’t exist, as 7-ketocholesterol isn’t transported in HDL or LDL, and that is part of what makes 7-ketocholesterol so toxic, as it can’t be transported out of cells. We’re measuring our ability to release 7-ketocholesterol into the serum, and measuring it by mass spectrometry. The early data on our new cyclodextrins is looking good. In this slide here is hydroxpropyl-beta-cyclodextrin that can remove some 7-ketocholesterol from human blood cells, and the first new cyclodextrin that we made can do a lot more, a lot better, and with blood from multiple donors.

So to recap, there are some big players in this area that are excited about being able to treat an orphan disease like Neimann-Pick disease. They probably have their eyes on going after bigger indications like heart disease, but they think that they are treating cholesterol, which I think is crazy. I think that they are actually treating 7-ketocholesterol, and that they are having the success that they are having because of this. However our drug blows it away in terms of affinity for the target by something like tenfold.

Beyond atherosclerosis, 7-ketocholesterol is implicated in a number of diseases, as shown on this slide. It is one of those bad guys that accumulates in different tissues with age, and we don’t even know yet everything that it is implicated in. Just as for senescent cells now that people are finding ways to kill them, all of a sudden you are finding aspects of aging that are being reversed when you kill senescent cells, and I predict that someday we’ll see the same thing with 7-ketocholesterol. However, atherosclerosis and heart failure I think are great indications. Of course familial hypercholesterolemia is just an exaggerated way to get atherosclerosis. There is Neimann Pick disease, and we think are drug would work better than the ones that are out there now.

I don’t want to try to claim that 7-ketocholesterol causes everything that has ever made everyone sick, but it does accumulate in macular degeneration and some cells in Alzheimer’s disease. Our tools that we’ve developed to make new cyclodextrins, to test them, to model them, I think that this is a great platform. There are other toxic oxysterols that we could be going after that we haven’t starting working on yet, but are good targets for this kind of technology. Basically any small hydrophobic molecule that is bioaccumulating is a potential target. So the space in this area looks crowded because there are tens of thousands of patents on cyclodextrins, however when you get down into using cyclodextrins as drugs themselves, then you are down into single digits, like four or five patents that are out there. So we think that we have pretty strong data and protections that will get there.

Because cyclodextrins have such a good regulatory profile and are so well established in how you can use them safely, industrially, in food, in medicine, we think that the pathway to turning this into an actually effective drug – that we can write a plan, and have it be realistic is good. We’re talking to experts on formulation and manufacturing, and what you see on this slide are realistic timelines. We’re developing some more assays that we think will be more effacious; assays that will demonstrate that we can reverse a foam cell phenotype for example, or remove 7-ketocholesterol from plaque samples that we’re working on getting from human patients or cadavers. So we have a detailed month by month plan on how we think that we could get a drug to clinical trials in three years.

As Aubrey said, we’re working and making great strides on turning this into a SENS Research Foundation spinout, wholly incubated and owned at the foundation. We’re calling it Underdog Pharmaceuticals.

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An Interview with Aubrey de Grey at Longevity.Technology

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It is always pleasant to see new efforts to produce longevity-focused interest sites and publications; Longevity.Technology is a recent example, here publishing an interview with Aubrey de Grey of the SENS Research Foundation that touches on recent developments in the field of rejuvenation research. There have been many such news organization initiatives over the past ten to fifteen years, and all too few of them lasted. Hopefully that will change now that an industry of rejuvenation is forming, beginning with the development of senolytic therapies, and ever greater degrees of funding and attention are directed towards this part of the life science field. If we look at larger fields, enough of that funding and attention can spill over to support a community focused on analysis, reporting, and other such work. That should happen here as well.


We’ve read a lot of very compelling reasons from you as to why we as a society should care about aging, but we’re very curious what made you care about it?

Nothing really made me care about it. It was always obvious to me that it was the number one most important problem in the world. It’s the thing that causes by far the greatest amount of suffering and everyone gets it. The astonishing thing was that other people didn’t think that way. In fact, I only discovered that others didn’t in my late 20s. I had gone through my entire life presuming that it was as obvious as the colour of the sky. It wasn’t something I would even have conversations about, so I’d never done the experiment to determine whether anyone else agreed. Then I met my ex-wife, who was quite a senior biologist at the time. And I began to discover that, actually, people didn’t think that way, not even in biology. And hardly any work was being done to deal with this problem. So I thought “Well, that won’t do.”

What is the SENS platform and why did you need to create it?

SENS stands for Strategies for Engineered Negligible Senescence. It’s a formal name for the way my organisation, the SENS Research Foundation, develops therapies for the diseases and disabilities of aging. I was able to see that there was indeed a very different, and entirely overlooked, approach to dealing with aging. And it was something the people who were studying it weren’t doing: that we should essentially be trying to repair damage in the body. When I’m feeling frivolous, I like to compare gerontologists of that era to seismologists. What they studied was bad for you, but they had no idea whatsoever how they could actually do anything about it. I stuck to my guns, stood my ground and people have gradually caught up and understood the kinds of things I’ve been saying all the time. Now it’s totally mainstream – orthodox – and people are reinventing the idea in slightly different language. So that’s all very nice.

What undeveloped areas are you working on at the moments?

One that really is a centrepiece project in-house (and has been for quite some time) is to put back-up copies of the mitochondrial DNA in the cell nucleus. For non-biologists who are reading, mitochondria are very essential parts of each cell that perform the chemistry of breathing. They combine oxygen with nutrients in order to extract energy from those nutrients. And, unlike any other part of the cell, the mitochondria have their own DNA – separate from the DNA of the nucleus.

But the process of extracting energy from nutrients using oxygen is chemically hairy, producing a load of by-products (in particular free radicals) that can damage the mitochondrial DNA and give it a really bad day. So the idea that we’ve taken, that was put forward in the mid 80s, is to essentially put copies of the mitochondrial DNA inside the nucleus, modified so that it still works in there, to shield it from this damage. It’s not as hard as it sounds, but it still is very hard! People gave up on it … they thought it was too hard. I thought that they’d given up a bit too easily. And it turns out I was right – we had to work about ten years or so before we eventually got to the point of being able to publish a single paper on this. But we eventually got there a couple of years ago, and now we have a second paper in the works demonstrating that we have done most of the job.

Link: https://www.longevity.technology/and-it-turns-out-i-was-right/

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The Longevity Associated Variant of BPIFB4

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In principle, genetic variants associated with longevity should help to point out which processes are more important in the aging process, and therefore steer researchers towards more effective approaches to interventions aimed at slowing or reversing aging. In practice, however, so few longevity-associated variants have been found that little has been accomplished on this front. One of them is examined in this open access paper. The mechanism by which it contributes to longevity may be a reduction in the burden of hypertension and consequent tissue damage.

To be clear, near any study of genetics and aging turns up all sorts of variants that correlate with longevity in the study population in question, but only a handful have ever been replicated in other study populations. This tells us that the genetics of aging is a matter of hundreds or thousands of tiny, interacting contributions, highly sensitive to environmental factors. This is why I am not optimistic that genetic studies of this nature are the road to any sort of meaningful progress towards greater human longevity. Even the variant here, if it operates via a lowering of blood pressure, is a poor substitute for long-standing drugs that achieve the same result to a greater degree, and those drugs were developed without any reference to the genetic study of longevity.


Frailty reflects the individual’s biological age and life expectancy better than chronological age. Studies in long-living individuals (LLIs), which, in spite of their exceptional biological age, are protected from and cope better with age-related diseases, confirm this concept. Moreover, several genetic factors that are reportedly implicated in the determination of exceptional longevity are also inversely related with frailty disabilities.

The Bactericidal/Permeability-Increasing Fold-Containing Family B member 4 (BPIFB4) gene encodes a secreted protein, initially found to be expressed in salivary glands, and more recently discovered to play important pathophysiological roles at systemic level. A genome wide association study (GWAS), performed on an Italian set of LLIs and controls and validated on two independent populations from Germany and USA, identified the BPIFB4 variants associate with lifespan.

The BPIFB4 protein is expressed in undifferentiated and highly proliferative cells and in fetal/stressed heart tissue (cardiac hypertrophy), which share a common hypoxic environment. Overexpression of BPIFB4 isoforms induced the activation of stress response-related heat-shock proteins (HSPs) and the modification of protein homeostatic processes (translation, ribosome biogenesis, spliceosome), two processes that are usually lost during aging.

Furthermore, the circulating levels of immunoreactive BPIFB4 protein are reportedly higher in healthy LLIs than in diseased LLIs or young controls. Similarly, CD34+ hematopoietic cells and mononuclear cells (MNCs) of LLIs expressed higher levels of BPIFB4 than corresponding cells of young controls. Studies in experimental models of cardiovascular disease confirmed that overexpression of the human LAV-BPIFB4 gene results in attenuation of hypertension, atherosclerosis, and ischemic disease, which are hallmarks of aging.

Link: https://doi.org/10.18632/aging.102209

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Resveratrol Improves Blood Sugar

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I have often written about the many benefits of resveratrol, which is a phytonutrient belonging to a class of polyphenolic stilbene compounds found in some plants. This naturally occurring substance, also known as 3,4′,5-trihydroxystilbene, functions an as antiantioxidant, providing neuroprotection against many neurodegenerative illnesses such as Alzheimer’s disease and stroke.

Yet that is hardly the limit of resveratrol’s other valuable actions. Unlike many other antiantioxidants, resveratrol crosses the blood-brain barrier which separates the brain’s blood from the extracellular fluid in the central nervous system.

This ability means resveratrol can increase cerebral blood flow and thus likely protect against stroke and vascular dementia,1 depression,2 brain inflammation,3 plaque buildup associated with Alzheimer’s disease4 bacteria and fungi,5 and may even improve learning, mood and memory.6

Recently, another apparent resveratrol benefit was confirmed by researchers –– resveratrol’s ability to improves blood sugar in those with Type 2 diabetes mellitus.7 After just eight weeks of resveratrol supplementation, subjects’ fasting blood sugar decreased, their high density lipoprotein increased and their insulin levels improved.8 Clearly this is a valuable nutrient with many benefits. I take it myself.

Important Implications for Those With Type 2 Diabetes

In a recent study in the journal Phytotherapy Research, 71 overweight patients with Type 2 diabetes (T2DM) and a body mass index between 25 and 30 either received 1,000 mg/day trans-resveratrol or methyl cellulose, used as a placebo, for eight weeks. Their lipid and glycemic profiles were measured before and after the study.

Even though subjects did not change in the size, shape or composition of their bodies during the study –– called anthropometric measurements –– here is what the researchers found:9

“In adjusted model (age, sex, and baseline body mass index), resveratrol decreased fasting blood sugar (-7.97±13.6 mg/dL, p=0.05) and increased high density lipoprotein (3.62±8.75 mg/dL, p=0.01) levels compared with placebo.

Moreover, the mean difference in insulin levels reached significance (-0.97±1.91, μIU/mL, p= 0.02) … It was found that 8-week resveratrol supplementation produced useful effects on some cardio-metabolic parameters in patients with T2DM.”

Another study with similar, encouraging results put 56 subjects who had both T2DM and coronary heart disease (CHD) on either resveratrol or placebo for only four weeks. The researchers said:10

“Resveratrol reduced fasting glucose, insulin and insulin resistance and significantly increased insulin sensitivity when compared with the placebo. Resveratrol also significantly increased HDL-cholesterol levels and significantly decreased the total-/HDL-cholesterol ratio when compared with the placebo.

Additionally, resveratrol caused a significant increase in total antioxidant capacity (TAC) and a significant reduction in malondialdehyde (MDA) levels when compared with the placebo.

Four-week supplementation of resveratrol in patients with T2DM and CHD had beneficial effects on glycemic control, HDL-cholesterol levels, the total-/HDL-cholesterol ratio, TAC and MDA levels. Resveratrol also upregulated PPAR-γ and SIRT1 in the PBMCs of T2DM patients with CHD.”

Resveratrol May Prevent Type 2 Diabetes Complications

Certainly, selling synthetic antidiabetic agents is a lucrative enterprise for the drug industry. But phytonutrients such as resveratrol and other natural treatments are clearly preferable for those with diabetes because they lack the many side effects of these prescription drugs and are also often more affordable. So when a natural substance like resveratrol can help prevent diabetic side effects, as a recent issue of the journal Current Diabetes Reviews suggests, it is good news.

The journal researchers report that resveratrol and several other phytonutrients may hold great promise in addressing diabetic side effects and that more research is should be conducted:11

“Most of the reported findings focus on one aspect of several biochemical processes e.g. enhancement of glucose utilization, anti-oxidation, induction of insulin production, antiglycation etc. An in-depth study of phytonutrients with respect to functional, immunological as well as biochemical factors suggesting their efficacy, as well as safety in the management of diabetes, is rarely reported …

Our study thus highlights the abundance of clinical evidence of the efficiency of phytonutrients, and at the same time, the scarcity of clinically approved and marketed phytonutrients, as drugs, for the management of diabetes and related complications.”

The researchers are right. Natural treatments for diabetes complications are urgently needed. Deaths from diabetes complications and chronic respiratory diseases are only preceded by deaths from cardiovascular diseases and cancer in the developed world.12Resveratrol’s antidiabetic properties as well as its potential antiaging effects, which I have written about before, were noted in the journal Cell.13

Resveratrol Noted for Chemoprevention of Many Cancers

Many natural substances have strong scientific indications of their ability to reduce the risk of cancer, but resveratrol may be one of the most impressive. In the United States National Library of Medicine at the National Institutes of Health, which maintains what is known as the “Pubmed” database, in 2019 there were 3,362 references for resveratrol as it relates to general cancer,14 546 to breast cancer,15 263 to colon cancer,16 249 to prostate cancer,17 230 to lung cancer18 and 106 to ovarian cancer.19

In 2018, researchers at the University of Geneva in Switzerland discovered that resveratrol could actually prevent lung cancer in some mice given lung cancer producing carcinogens.20

“We tried to prevent lung cancer induced by a carcinogen found in cigarette smoke by using resveratrol … in a mouse model,” said Muriel Cuendet, associate professor in the University of Geneva’s School of Pharmaceutical Sciences. A 45 percent decrease in tumor formation per mouse in the treated mice was seen, suggesting that, “resveratrol could therefore play a preventive role against lung cancer.”

The University of Geneva researchers surmised that the chemoprevention mechanism seen with resveratrol was likely related to the process by which cells program their own death and from which cancer cells escape, a mechanism called apoptosis.

Resveratrol May Protect Patients During Cancer Treatment

Imagine a natural substance that not only can prevent the risk of cancer, but minimize some of the notorious side effects of cancer treatments. Again, there is evidence favoring the benefits of resveratrol. Chemotherapy and radiotherapy, two common treatments for cancer, are often associated with depression, fatigue, anorexia, neuropathic pain and sleep disorders — and resveratrol may help. Researchers in a 2011 study in the journal Experimental Biology and Medicine wrote:21

“During the past decade, increasing evidence has shown that the dysregulation of inflammatory pathways contributes to the expression of these symptoms. Cancer patients have been found to have higher levels of proinflammatory cytokines such as interleukin-6. The nuclear factor (NF)-κB is a major mediator of inflammatory pathways.

Therefore, anti-inflammatory agents that can modulate the NF-κB activation and inflammatory pathways may have potential in improving cancer-related symptoms in patients.

Because of their multitargeting properties, low cost, low toxicity and immediate availability, natural agents have gained considerable attention for prevention and treatment of cancer-related symptoms. How NF-κB and inflammatory pathways contribute to cancer-related symptoms is the focus of this review.

We will also discuss how nutritional agents such as curcumin, genistein, resveratrol, epigallocatechin gallate and lycopene can modulate inflammatory pathways and thereby reduce cancer-related symptoms in patients.”

Resveratrol May Reverse Side Effects of Chemotherapy

Chemotherapy can cause ovarian aging, early menopause and, in young women, infertility –– terrible side effects on top of the cancer itself. Yet, some research shows that resveratrol can reverse some of these deleterious effects.22 This is what researchers wrote in the journal Aging:

“We demonstrated that resveratrol (30 mg/kg/d) relieved oogonial stem cells loss and showed an attenuating effect on Bu/Cy-induced oxidative apoptosis in mouse ovaries, which may be attributed to the attenuation of oxidative levels in ovaries.

Additionally, we also showed that Res exerted a dose-dependent effect on oogonial stem cells and attenuated H2O2-induced cytotoxicity and oxidative stress injury by activating Nrf2 in vitro. Therefore, resveratrol could be of a potential therapeutic drug used to prevent chemotherapy-induced ovarian aging.”

Resveratrol Boosts a Chemotherapy Drug

In 2018, researchers found other cancer-related resveratrol benefits. “Pancreatic cancer (PC) is one of the top five leading causes of cancer-related deaths,” wrote researchers in the journal Cell Proliferation, yet “chemotherapeutic drugs can barely reach the tumour due to lack of blood supply.”

While the preferred chemotherapy drug is gemcitabine, resistance, both intrinsic and acquired, often occurs, even when little of the drug reaches the pancreatic tumor write the researchers. Resveratrol proves useful here too.23

Resveratrol enhances chemotherapy by suppressing the gemcitabine-induced “stemness” –– cancer cells that proliferate, differentiate, self-renew and resist anticancer therapies24 –– write the Cell Proliferation researchers:25

“A previous study reported that resveratrol enhanced the sensitivity of PC cells to gemcitabine via activating the AMPK signalling pathway. Moreover, a study performed in nude mice determined the effect of resveratrol plus gemcitabine in vivo.

According to that study, resveratrol potentiated the effect of gemcitabine on tumour growth. In our present study, we found that resveratrol enhanced the sensitivity of PC cells to gemcitabine via down‐regulating SREBP1 expression.

Meanwhile, down-regulation of SREBP1 by resveratrol overcame the stemness induced by gemcitabine in both PC cell lines and the KPC mouse model.

Overall, our data provide evidence that resveratrol enhances sensitivity to gemcitabine and reverses the stemness induced by gemcitabine via down‐regulating SREBP1 expression. These findings suggest that resveratrol is a potent chemotherapy sensitizer and that SREBP1 is a notable target for cancer treatment.”

Cleary, with its cancer-related properties and its recently confirmed ability to improve blood sugar, resveratrol is a valuable, natural substance with myriad wonderful uses.

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