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Month: May 2019

Repair Biotechnologies Raises a $2.15M Seed Round to Fight Age-Related Diseases

Repair Biotechnologies Raises a $2.15M Seed Round to Fight Age-Related Diseases

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As many of you know, Bill Cherman and I founded Repair Biotechnologies in 2018 with the intent of developing promising lines of rejuvenation research into clinical therapies. There are many opportunities given the present state of the science and far too few people working on them. This remains true even as large amounts of venture funding are entering the space; our field needs more entrepreneurs. I’m pleased to note that we’re making progress in our pipeline at Repair Biotechnologies, and have recently closed a seed round from notable investors in order to power us through to the next phase of our work.

What does the Repair Biotechnologies team work on? When we initially set out, after a survey of the field, we settled upon regeneration of the thymus via FOXN1 upregulation as the lowest of low-hanging fruit, a project with good evidence in the literature and the potential of a sizable upside to health in later life when realized. The thymus atrophies with age, and this is a major factor in the age-related decline of the immune system, as the thymus is where T cells mature. Reductions in the supply of new T cells eventually leads to an immune system packed with malfunctioning, senescent, and overspecialized cells that are incapable of defending effectively against pathogens and errant cells.

A little later we picked up development of a fascinating line of research relating to the vulnerability of macrophages to cholesterol. The pathologies of atherosclerosis are caused when macrophage cells become ineffective at clearing out cholesterol from blood vessel walls. They are overwhelmed by oxidized cholesterol in particular, but too much cholesterol in general will also do the trick. Macrophages become inflammatory or senescent, and die, adding their debris to a growing fatty plaque that will eventually rupture or block the blood vessel. By giving macrophages the ability to degrade cholesterol, we can in principle reverse atherosclerosis by making macrophages invulnerable to the cause of the condition. This is, we believe, a much better approach that that of trying to reduce cholesterol in the bloodstream.

Repair Biotechnologies Raises $2.15M Seed Round to Develop Drugs for Age-Related Diseases

Repair Biotechnologies, Inc. announced today $2.15 million in seed venture funding, to accelerate the preclinical development of its pipeline of drugs targeting thymus regeneration, cancer, and atherosclerosis. The $2.15 million in funding was led by Jim Mellon, the billionaire investor and chairman of Juvenescence Ltd. Also participating in the round are Emerging Longevity Ventures, Thynk Capital, and SENS Research Foundation.

“We are committed to developing treatments for the root causes of aging and its associated diseases through the damage repair approach,” said Reason, co-founder and CEO. “With this funding round, we will be able to further develop our therapies and validate them in animal models, bringing them closer to the clinic and patients.”

The thymus gland is vital to the adaptive immune system, but with age, the thymus shrinks, leading to a decreased immune cell production and a compromised immune system. Repair Biotechnologies is developing a therapy with the aim of reverting this atrophy of the thymus, which the company believes can be an effective treatment against some forms of cancer. Repair Biotechnologies’ second major project relates to atherosclerosis, which is caused by the accumulation of intracellular waste in arteries. While present therapies focus on reducing cholesterol, Repair Biotechnologies has licensed a technology to make the macrophage cells responsible for repairing arteries resilient to excess cholesterol, and thus able to repair atherosclerotic damage.

“SENS Research Foundation was founded to push forward proof-of-concept work demonstrating the validity of the SENS paradigm to the point at which people can actually do something with it. Now we’re seeing some of these technologies getting the recognition from investors that they deserve, which in turn is driving critical growth in the private-sector side of the field,” said Aubrey de Grey, co-founder and Chief Science Officer of SENS Research Foundation. “I’m thrilled to see Repair Biotechnologies taking things in this area to the next level.”

Nothing in this post should be construed as an offer to sell, or a solicitation of an offer to buy, any security or investment product. Certain information contained herein may contains statements, estimates and projections that are “forward-looking statements.” All statements other than statements of historical fact in this post are forward-looking statements and include statements and assumptions relating to: plans and objectives of Repair Biotechnologies’ management for future operations or economic performance; conclusions and projections about current and future economic and political trends and conditions; and projected financial results and results of operations. These statements can generally be identified by the use of forward-looking terminology including “may,” “believe,” “will,” “expect,” “anticipate,” “estimate,” “continue”, “rankings” or other similar words. Repair Biotechnologies does not make any representations or warranties (express or implied) about the accuracy of such forward-looking statements. Accordingly, you should not place reliance on any forward-looking statements.

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Why Children Are Getting Fatty Liver Disease

Why Children Are Getting Fatty Liver Disease

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Fatty liver disease is caused by excess fat in your liver. The medical term is hepatic steatosis. Your liver normally contains some fat, but when greater than 10% of the weight of the liver is fat, it’s called fatty liver. There are two main types: nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease, also called alcoholic steatohepatitis.1

NAFLD may be suspected if a blood test shows higher levels of liver enzymes than expected. While the disease is found more frequently in adults, researchers are finding NAFLD is a growing concern in the pediatric community, which triggered at least one intervention study weaning participants off sugar to reduce obesity and Type 2 diabetes.2

Chief of gastroenterology, hepatology and nutrition at University of Southern California and Children’s Hospital of Los Angeles (CHLA), Dr. Rohit Kohli, commented,3 “Fatty liver disease is ripping through the Latino community like a silent tsunami and especially affecting children.”

While research demonstrates 25% in the U.S. have fatty liver disease,4 in the Latino community the rate is much higher. One study in Dallas, Texas5 examined 2,287 subjects from a multi-ethnic population and found 45% of Hispanics suffered from fatty liver disease. The ethnic differences in the frequency of disease in this study mirrors those in past studies for NAFLD-related cirrhosis.

Key Facts About Fatty Liver Disease

NAFLD is the type not related to heavy alcohol use and in this category there are two types: simple fatty liver, in which your liver has additional fat but little to no inflammation or damage, and nonalcoholic steatohepatitis (NASH), in which you suffer from inflammation and damage in the liver cells, as well as excess fat in your liver.

NASH may cause fibrosis or scarring of the liver and lead to cirrhosis or liver cancer. Researchers have not been able to point to a single cause of NAFLD, but they do know it occurs more commonly in those who have specific risk factors, including:6,7

Type 2 diabetes or prediabetes

Metabolic disorders, including metabolic syndrome

High levels of fats in the blood


Middle-aged or older

High blood pressure

Rapid weight loss

Infections, such as hepatitis C

Exposure to some toxins

Gallbladder removal


NAFLD affects nearly 25% globally.8 However, as the rates of obesity and Type 2 diabetes rise, so do the rates of NAFLD. NAFLD is usually a silent disease, meaning most are unaware of the condition and have few or no symptoms. When symptoms are present, individuals may feel greater fatigue or have discomfort in the upper right-hand side of the abdomen.

It is important to distinguish between simple fatty liver disease and NASH since those with NASH experience damage to their liver cells, which increases the risk of progression to fibrosis, cirrhosis and liver cancer. According to Harvard Health Publishing,9 NASH cirrhosis is expected to top the reasons for liver transplants.

Sugar Passed in Breast Milk Predisposes Infants to Obesity

A new study10 is being led by Michael Goran, Ph.D., director of the diabetes and obesity program at Children’s Hospital Los Angeles. Last year, he discovered high fructose corn syrup (HFCS) sweetened beverages were passed through breast milk, potentially predisposing infants to fatty liver and obesity.11

Six weeks after giving birth, 41 participating women were randomized into two groups. One group consumed a readily available HFCS sweetened beverage and the other group consumed an artificially-sweetened control beverage. At each testing session, the mothers expressed milk every hour for six consecutive hours.

The researchers then measured the concentration of fructose, glucose and lactose in the breast milk. Changes were significant only for measurements of fructose, with comparisons showing HFCS beverages increased breast milk fructose at hour two, three, four and five hours after consumption. It is important to note breast milk normally does not contain fructose.12 Goran commented:13 

“Lactose is the main source of carbohydrate energy and breast milk is very beneficial, but it’s possible that you can lose some of that beneficial effect depending on maternal diet and how that may affect the composition of breast milk.

Other studies have shown that fructose and artificial sweeteners are particularly damaging during critical periods of growth and development in children. We are beginning to see that any amount of fructose in breast milk is risky.”

Dr. Robert Lustig, professor in the division of endocrinology at the University of California, is a pioneer in decoding sugar metabolism. He was among the first to bring attention to the fact that processed fructose is far worse for your metabolic system than other sugars. Fructose is broken down like alcohol in your body,14 triggering liver damage and causing mitochondrial and metabolic dysfunction.

This damage is very similar to that caused by ethanol and other toxins. Fructose also triggers severe metabolic dysfunction as it is readily metabolized into fat, far more so than other sugars. Researchers are finding exposure before birth may increase an infant’s risk of obesity leading to a higher risk of Type 2 diabetes and NAFLD.15

Gene Variant Increases Risk of Fatty Liver Disease

Before 2006, few knew children could develop NAFLD. Dr. Jeffrey Schwimmer, professor of pediatrics at the University of California San Diego, reviewed 742 autopsies of children and teenagers who had died from traumatic injury. He found an incidence of 13% with fatty liver disease, and 38% in those who were obese.16

The researchers concluded NAFLD was the most common liver abnormality in children aged 2 to 19. They suggested the identified risk factors should be considered in the development of protocols to screen children and adolescents who are at risk.

A study released in 200817 by a group of researchers from the University of Texas demonstrated a gene variant called PNPLA3 could increase the risk of fatty liver disease. Nearly 50% of Latinos have at least one copy of this high-risk gene, and 25% have two copies according to Goran.18

Goran then undertook another study, eventually demonstrating children as young as 8 who had two copies of PNPLA3 and who consumed high amounts of sugar had 2.36 times as much fat in their livers as children without the gene.19 In the clinical trial20 currently underway, his team first tests participating children for the gene and then uses an MRI to measure liver fat percentage.

The sugar consumption of the child is measured and cataloged and then a dietitian educates the family on the impact of sugar. The team does another MRI four months later to measure liver fat and assess the impact of the intervention.

Goran’s research and past studies21 have demonstrated early exposure to sugar and fructose likely contribute to obesity, diabetes and fatty liver disease as fructose enhances the body’s capacity to store fat.

Excess Fructose Triggers Obesity and Fatty Liver Disease

Results of a meta-review in Mayo Clinic Proceedings22 confirmed that not all calories are equal. The dogmatic belief that a calorie is a calorie has driven the weight loss industry and contributed to an ever-worsening history of health in the Western world.

Unfortunately, it continues to be a concept taught in schools, even though we now know it’s false. The source of the calories does indeed have a significant impact on your health and weight. In the review, the researchers evaluated how different calories affected health. As reported by Time Magazine:23

“What they found was that the added sugars were significantly more harmful. Fructose was linked to worsening insulin levels and worsening glucose tolerance, which is a driver for prediabetes. It caused harmful fat storage — visceral fat on the abdomen — and promoted several markers for poor health like inflammation and high blood pressure.

‘We clearly showed that sugar is the principal driver of diabetes,’ says lead study author James J. DiNicolantonio, a cardiovascular research scientist at Saint Luke’s Mid America Heart Institute. ‘A sugar calorie is much more harmful.'”

Another more recent study published in 201724 found fructose promotes complications in glucose metabolism and alters lipid profiles associated with an inflammatory response. The researchers found this implied a systemic picture of insulin resistance.

Choline Deficiency Also Plays a Key Role in Fatty Liver Disease

Choline is a compound in living tissue and is important in the synthesis and transportation of lipids (fats). It was discovered in 186225 and officially recognized as an essential nutrient in 1998.26

Several studies27,28 have linked higher intake of choline to a range of benefits and, in fact, it appears to be a key factor in preventing the development of fatty liver disease. By enhancing secretion of very low density lipoproteins (VLDL)29 in your liver, required to safely transport fat out, choline may protect your liver health.

Epigenetic mechanisms30 of choline also explain how it helps maintain healthy liver function. Dietary choline is an important modifier of DNA and modulates expression of many of the pathways involved in liver function.

Chris Masterjohn, who has a Ph.D. in nutritional sciences,31 proposes choline deficiency is a significant trigger of NAFLD and believes the rise in NAFLD is largely the result of rejecting liver and egg yolks in the diet:

“More specifically, I currently believe that dietary fat, whether saturated or unsaturated, and anything that the liver likes to turn into fat, like fructose and ethanol, will promote the accumulation of fat as long as we don’t get enough choline.”

In a 2010 article,32 Masterjohn reviews the medical literature supporting this view. The link between choline and fatty liver initially emerged from research into Type 1 diabetes. Studies in the 1930s demonstrated lecithin found egg yolk (containing high amounts of choline) could cure fatty liver disease in Type 1 diabetic dogs. They later found choline alone provided the same benefit.

More Ways to Support Your Liver Health

Hints to additional ways of supporting your liver health may be found in the commonly identified risk factors for NAFLD. In addition to reducing or eliminating processed fructose from your diet and including foods with choline, other modifiable factors that can have a significant impact on the development of NAFLD include:33,34

  • Maintaining a healthy weight — Managing a healthy weight requires more than monitoring your calorie intake and energy expenditure. For a full explanation of one of the master keys to healthy eating, see “My Updated Nutrition Plan — Your Guide to Optimal Health.”
  • Exercising regularly — Regular movement and exercise benefits your body by improving insulin sensitivity, supporting your metabolism and mitochondrial health, helping to manage weight and blood pressure, toning muscle and improving your balance. Exercise also improves your sleep quality, mood and mental health. There is a long list of benefits — including reducing your risk of NAFLD.
  • Limiting medications — Limit any medications to those necessary and follow dosing recommendations. Some medications increase your risk of NAFLD and other health conditions. Reduce those risks by making lifestyle changes to minimize your dependence on medications.
  • Managing high blood pressure — High blood pressure increases your risk of cardiovascular disease, dementia and NAFLD. There are several natural methods of reducing high blood pressure while working with your physician to wean off medication.
  • Reducing insulin resistance — Insulin resistance may lead to metabolic syndrome, prediabetes and Type 2 diabetes, all precursors to NAFLD. For an overview of insulin resistance and how to reduce your risk of metabolic disease, see my previous article, “Research Proves Causation — Sugar Consumption Increases Risk for Chronic Disease.”

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Why Splenda Is Not So Splendid, and Safety Has Been Questioned

Why Splenda Is Not So Splendid, and Safety Has Been Questioned

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Are artificial sweeteners such as Splenda still part of your daily diet? If so, I would strongly recommend reconsidering. It’s important to realize that while artificial sweeteners have no (or very few) calories, they are still metabolically active,1 and not in a beneficial way.

For example, research2,3 published in the online version of the Journal of Toxicology and Environmental Health August 21, 2018, shows sucralose — sold under brand names such as Splenda, Splenda Zero, Zero-Cal, Sukrana, Apriva, SucraPlus, Candys, Cukren and Nevella — is metabolized and accumulates in fat cells.

Remarkably, artificial sweeteners have become so ubiquitous, research4 published in the April 2019 issue of Ecotoxicology and Environmental Safety refers to them as an “emerging” environmental contaminant, noting they have “high water persistence.”

According to this paper, artificial sweeteners are chemically stable in the environment and water supplies appear to be at greatest risk for contamination. The researchers looked at 24 environmental studies assessing the presence of artificial sweeteners in the environment from 38 locations around the world, including Europe, Canada, the U.S. and Asia.

“Overall, the quantitative findings suggested that the occurrence of non-nutritive artificial sweeteners is present in surface water, tap water, groundwater, seawater, lakes and atmosphere,” the paper states. What the ultimate ramifications for wildlife, especially marine life, and human health might be are still anyone’s guess.

Artificial Sweeteners Promote Obesity, Diabetes and Metabolic Syndrome

As explained in the 2016 paper,5 “Metabolic Effects of Non-Nutritive Sweeteners,” many studies have linked artificial sweeteners to an increased risk for obesity, insulin resistance, Type 2 diabetes and metabolic syndrome. This is in stark contrast to what you’re told by industry, which continues to promote artificial sweeteners as a way to lower your risk of those conditions.

The paper presents several mechanisms by which artificial sweeteners promote metabolic dysfunction:

1. They interfere with learned responses that contribute to glucose control and energy homeostasis — Studies have demonstrated that when sweet taste and caloric intake are mismatched, your body loses its ability to properly regulate your blood sugar.

2. They interact with sweet-taste receptors expressed in digestive system that play a role in glucose absorption and trigger insulin secretion, thereby inducing both glucose intolerance and insulin resistance, which raises your risk of obesity. Sweet taste without calories also increases appetite6 and subjective hunger ratings.7

3. They destroy your gut microbiota — A 2008 study8 revealed sucralose (Splenda) reduced gut bacteria by as much as 49.8%, preferentially targeting bacteria known to have important human health benefits. Consuming as few as seven little Splenda packets may be enough to have a detrimental effect on your gut microbiome.

More recent research,9 published in the journal Molecules in October 2018, confirmed and expanded these findings, showing that all currently approved artificial sweeteners (aspartame, sucralose, saccharin, neotame, advantame and acesulfame potassium-k) disrupt the gut microbiome — in part by damaging the bacteria’s DNA, and in part by interfering with their normal activities.

Another 201810 found Splenda consumption may exacerbate gut inflammation and intensify symptoms in people with Crohn’s disease by promoting harmful gut bacteria. These results echoed those published in 2014,11 where they found Splenda may exacerbate symptoms of Crohn’s disease by augmenting “inflammatory activity at the biochemical level” and altering microbial-host interactions within the intestinal mucosa.

Similarly, research12 published in 2017 implicated sucralose in chronic liver inflammation by altering “the developmental dynamics of the gut microbiome.”

Why You Should Never Cook With Splenda

Splenda (sucralose) is frequently recommended for cooking and baking,13 and is often used in processed foods in which high heat was involved. This, despite the fact that scientists have warned about the dangers of heating sucralose for years.

In the 2013 paper,14 “Sucralose, a Synthetic Organochloride Sweetener: Overview of Biological Issues,” the authors state that “Cooking with sucralose at high temperatures … generates chloropropanols, a potentially toxic class of compounds.” This paper also warns the acceptable daily intake set for sucralose may in fact be hundreds of times too high to ensure safety.

The German Federal Institute for Risk Assessment (BfR) recently issued a report15 on the available data on sucralose, confirming that cooking with sucralose is likely a terrible idea, as chlorinated compounds are formed at high temperatures. As reported by MedicalXpress:16

“When sucralose (E 955) is heated to temperatures higher than 120 degrees C a gradual — and with further continuously increasing temperature — decomposition and dechlorination of the sweetener occurs.

Temperatures of between 120 degrees C [248 degrees Fahrenheit] and 150 degrees C [302 degrees F] are possible during industrial manufacturing and processing of foods, and are also reached in private households during cooking and baking of foods containing sucralose.

This may lead to the formation of chlorinated organic compounds with a health-damaging potential, such as polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF) and chloropropanols.”

Chloropropanols, while still poorly understood, are believed to have adverse effects on your kidneys and may have carcinogenic effects.17 One good reason to be suspicious of chloropropanols is because they’re part of a class of toxins known as dioxins, and dioxins are known to cause cancer and endocrine disruption.

The fact that sucralose creates toxic dioxins when heated is also a concern for those who use vaping liquid containing this artificial sweetener. A 2017 study18 found sucralose contributes sweet taste only when used in a cartridge system, and chemical analysis showed the use of a cartridge system also raised the concentration of sucralose in the aerosol.

I find it interesting that these studies are now confirming what I suspected and published in my book, published over 10 years ago — “Sweet Deception” — which was an expose on Splenda.

Sucralose Shown to Have Carcinogenic Potential

Research19 published in 2016 in the International Journal of Occupational and Environmental Health tested the carcinogenic potential of sucralose by adding it to mouse feed, at various concentrations, starting at 12 days of gestation and continuing throughout their natural life span.

Results showed male mice experienced a significant dose-related increase in malignant tumors and hematopoietic neoplasias (cancer of the blood, bone marrow and the lymphatic system). The dosages tested were 0, 500, 2,000, 8,000 and 16,000 parts per million (ppm). The worst results occurred in males given 2,000 ppm and 16,000 ppm. According to the authors:

“These findings do not support previous data that sucralose is biologically inert. More studies are necessary to show the safety of sucralose, including new and more adequate carcinogenic bioassay on rats. Considering that millions of people are likely exposed, follow-up studies are urgent.”

Pregnant Women Beware

More recent research,20 published in 2018, revealed the artificial sweeteners sucralose and acesulfame-potassium transfer into breast milk — a crucial fact that pregnant women need to be mindful of, considering the harmful effects of these compounds. To determine whether the sweeteners could transfer into breast milk, the researchers enrolled 34 women who were exclusively breastfeeding.

Each of the women drank 12 ounces of Diet Rite Cola, which contains 68 milligrams (mg) of sucralose and 41 mg of acesulfame-potassium, before breakfast. Habitual use of artificial sweeteners was also assessed via a diet questionnaire. Breast milk samples were collected before ingestion and every hour thereafter for six hours. As reported by the authors:

“Owing to one mother having extremely high concentrations, peak sucralose and acesulfame-potassium concentrations following ingestion of diet soda ranged from 4.0 to 7387.9 ng/mL and 299.0 to 4764.2 ng/mL, respectively.”

This is believed to be the first time researchers have demonstrated that infants are in fact exposed to artificial sweeteners even when exclusively breastfed (if the mother consumes them). An accompanying commentary21 by pediatric experts notes:

“NNS [non-nutritive sweeteners] were present in the breast milk of all subjects in physiologically significant amounts, and … at concentrations well above the taste thresholds. Why is this important?

NNS or non-caloric artificial sweeteners (NCAS) are ubiquitous in the modern diet … Despite the approval by the FDA and European Food Safety Authority, concerns, admittedly largely unproven, persist about their safety … The concerns about NNS are three-fold.

First, that they may adversely alter taste preferences. Second, that the ultimate effect may be contrary to what is intended and their ingestion may increase food consumption. Third, that they may adversely alter the gut bacterial microbiome and its metabolites.

All of these concerns are magnified with early exposure in life. The evidence to support these concerns is either inductive or based on experimental models and emerging human data.”

‘Diet’ Beverages Linked to Increased Risk of Stroke and Heart Attack

Another 2018 study22 by the American Heart Association (AHA) found that, compared to drinking none or just one “diet” drink per week, women over 50 who drank two or more artificially sweetened beverages per day had a:23

  • 31% increased risk for ischemic stroke
  • 29% increased risk of coronary heart disease
  • 23% increased risk of all types of stroke
  • 16% increased risk of early death

The risk is particularly high for women with no previous history of heart disease, those who are obese and/or African-American women. The study included more than 81,714 women from the Women’s Health Initiative Observational Study, a longitudinal study of the health of 93,676 postmenopausal women between the ages of 50 and 79. The mean follow-up time was close to 11.9 years. According to the authors:

“In women with no prior history of cardiovascular disease or diabetes mellitus, high consumption of ASB [artificially-sweetened beverages] was associated with more than a twofold increased risk of small artery occlusion ischemic stroke … High consumption of ASBs was associated with significantly increased risk of ischemic stroke in women with body mass index ≥30 …”

In an accompanying editorial,24 “Artificial Sweeteners, Real Risks,” Hannah Gardener, assistant scientist in the department of neurology at the University of Miami, and Dr. Michell Elkind at Columbia University, suggest drinking pure water instead of no-calories sweetened beverages, as it is by far the safest and healthiest low-calorie drink there is.

If you want some flavor, just squeeze a little bit of fresh lemon or lime into mineral water. In instances where your cooking, baking or beverage needs a little sweetener, be mindful of your choice.

Sucralose Linked to Liver, Kidney and Thymus Damage

Other recent research25 published in the journal Morphologie found sucralose caused “definite changes” in the liver of treated rats, “indicating toxic effects on regular ingestion.” The researchers warn these findings suggest sucralose should be “taken with caution to avoid hepatic damage.”

In other words, regularly using Splenda could damage your liver. Here, adult rats were given a much higher (yet nonlethal) oral dose of sucralose — 3 grams (3,000 mg) per kilo body mass per day for 30 days, after which the animals’ livers were dissected and compared to the livers of unexposed controls. According to the authors:

“Experimental rats showed features of patchy degeneration of hepatocytes along with Kupffer cells hyperplasia, lymphocytic infiltration, sinusoidal dilatation and fibrosis indicating a definite hepatic damage on regular ingestion of sucralose. Sinusoidal width was also found to be increased in experimental animals as compared to controls.”

Studies have also linked sucralose consumption to liver and kidney enlargement26,27 and kidney calcification.28,29 Another organ affected by sucralose is your thymus, with studies linking sucralose consumption to shrinkage of the thymus (up to 40%30,31) and an increase in leukocyte populations (immune system cells) in the thymus and lymph nodes.32

Sucralose Safety Has Been Repeatedly Questioned

At the time of this writing, there are 27,400 references to sucralose in the scientific search engine Google Scholar, so there’s no shortage of studies to review if you’re curious. Here’s a small sampling of papers raising questions about the safety of this artificial sweetener.

Artificial Sweetener Such as Sucralose May Promote Inflammation in Human Subcutaneous Fat-Derived Mesenchymal Stromal Cells, 2017 33 Research presented at GW Annual Research Days in 2017 shows sucralose consumption caused an increase in superoxide accumulation and cellular inflammation.

The sweetener also Increased expression of a specific sweet taste receptor. According to the researchers, “upregulation of adipogenic genes … cultured in near physiological concentrations of sucralose, indicate possible causality between increased fat deposition and sweetener use.”

The Non-Caloric Sweeteners Aspartame, Sucralose and Stevia sp. Induce Specific but Differential Responses to Compartmentalized Adipose Tissue Accumulation, 201734 In this study, consumption of sucralose resulted in weight gain, elevated blood glucose and body fat accumulation.

Sucralose Activates an ERK1/2–Ribosomal Protein S6 Signaling Axis, 201635 Sucralose was found to stimulate insulin secretion much like glucose, but through completely different and poorly understood pathways. According to the authors, these findings “will have implications for diabetes.”

Changes in the Expression of Cell Surface Markers in Spleen Leukocytes in a Murine Model of Frequent Sucralose Intake, 201636 This study found frequent sucralose intake may affect your immune function. According to the authors:

“Our results show a decrease in the frequency of B lymphocyte population and T lymphocytes in comparison to the control group. In B and T lymphocytes the analysis of co-stimulatory molecules show a lower frequency compared to the control group. The immune response depends on the differentiation and activation of cellular populations.

We hypothesized that chronic ingestion of commercial sucralose might be affecting the immune response by modifying the frequencies of cellular populations, as well as the expression of co-stimulatory and inhibitory molecules … by decreasing the ability of co-stimulation between B an T lymphocytes, with a probable effect on the immune response.

It is necessary to further determine if sucralose intake affects the efficiency of the immune response.”

Popular Sweetener Sucralose as a Migraine Trigger, 200637 As noted by the authors, “This observation of a potential causal relationship between sucralose and migraines may be important for physicians to remember this can be a possible trigger during dietary history taking.

Identifying further triggers for migraine headaches, in this case sucralose, may help alleviate some of the cost burden (through expensive medical therapy or missed work opportunity) as well as provide relief to migraineurs.”

Healthier Sugar Substitutes

Two of the best sugar substitutes are Stevia and Lo Han Kuo (also spelled Luo Han Guo). Stevia, a highly sweet herb derived from the leaf of the South American stevia plant, is sold as a supplement. It’s completely safe in its natural form and can be used to sweeten most dishes and drinks.

Lo Han Kuo is similar to Stevia, but is my personal favorite. I use the Lakanto brand vanilla flavor which is a real treat for me. The Lo Han fruit has been used as a sweetener for centuries, and is about 200 times sweeter than sugar.

A third alternative is to use pure glucose, also known as dextrose. Dextrose is only 70% as sweet as sucrose, so you’ll end up using a bit more of it for the same amount of sweetness, making it slightly more expensive than regular sugar. It is safer than regular sugar, which is 50% fructose.

Still, it’s well worth it for your health as it does not contain any fructose whatsoever. Contrary to fructose, glucose can be used directly by every cell in your body and as such is a far safer sugar alternative.

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Weekly Health Quiz: Zinc, Stress and Back Pain

Weekly Health Quiz: Zinc, Stress and Back Pain

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1 The following nutrient has been shown to contribute to improved behavior in children with attention deficit-hyperactivity disorder (ADHD):

  • Zinc

    A number of studies have found children afflicted with attention deficit-hyperactivity disorder (ADHD) are more likely to be zinc-deficient than other children, and zinc supplementation has been shown to contribute to improved behavior in children with ADHD. Learn more.

  • Vitamin C
  • Carbohydrates
  • Lectins

2 Cellular repair and regeneration occurs during which of the following fasting phases?

  • Within first 12 hours of fasting
  • The initial refeeding

    Cellular repair and regeneration occur when you start eating again, which is why cycling in and out of fasting and feasting is so imperative. The breakdown process occurs in the absence of food, while rebuilding occurs when food is reintroduced. Learn more.

  • Within first 16 to 18 hours of fasting
  • Several days after refeeding

3 BPA, dioxin, atrazine, phthalates, fire retardants, lead, mercury, PFCs and organophosphate pesticides are all examples of:

  • Volatile organic compounds
  • Radioactive materials
  • Endocrine disrupting chemicals

    BPA, dioxin, atrazine, phthalates, perchlorate, fire retardants, lead, mercury, arsenic, PFCs, organophosphate pesticides and glycol ethers are 12 of the worst and most widely used endocrine disrupting chemicals. Learn more.

  • Warfare agents

4 The following condition has been scientifically linked to an increased risk of cardiovascular disease, heart attack and stroke:

  • Autism
  • Eating disorders such as anorexia and bulimia
  • Narcissistic personality disorder
  • Chronic stress and stress related disorders such as acute stress reaction, post-traumatic stress disorder and adjustment disorder

    Stress can raise your risk of heart disease, heart attack and stroke via several different mechanisms. Recent research shows people with stress related disorders are 37 percent more likely to develop cardiovascular disease compared to the general population. Learn more.

5 The following is an independent risk factor for ill health and premature death and a primary contributor to back pain:

  • Prolonged sitting

    Excessive sitting contributes to back pain and is an independent risk factor for ill health and premature death. Foundation Training exercises — simple yet powerful structural movements that help strengthen and realign your posture — can help compensate for long hours spent sitting and significantly reduce back pain. Learn more.

  • Prolonged standing
  • Daily running
  • Strength training at the exclusion of aerobic training

6 Recent research shows outbreaks of this disease is spreading into areas in the U.S. and other countries where it has not been prevalent before:

  • Measles
  • Lyme disease

    Since Lyme disease became a nationally notifiable condition in 1991, the number of U.S. counties considered at high risk for Lyme disease has increased by more than 300 percent. The disease is also expanding rapidly all over the world, as new research presented in April 2019 shows that the outbreaks are creeping steadily into northern countries with less temperate climates. Learn more.

  • Ebola
  • West Nile virus

7 The following is a major reason why sun exposure lowers your risk of heart disease:

  • Sun exposure triggers release of serotonin.
  • Sun exposure raises your blood pressure.
  • Sun exposure triggers your body’s production of nitric oxide.

    Many of the benefits of sunlight, such as a decreased risk of heart disease, have to do with its ability to increase nitric oxide production in your body. Learn more.

  • Sunlight decreases your body’s production of nitric oxide.


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Boosting Levels of NAD+ May Make Senescent Cells More Aggressively Inflammatory

Boosting Levels of NAD+ May Make Senescent Cells More Aggressively Inflammatory

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Enhancing levels of NAD+ in mitochondria via delivery of various precursor compounds as supplements is growing in popularity as an approach to boost faltering mitochondrial function and thus modestly slow the progression of aging. A human trial demonstrated improved vascular function as a result of nicotinamide riboside supplementation, for example. Researchers here show that increased NAD+ will likely make worse the inflammatory signaling of senescent cells, however. Senescent cells accumulate with age, and are an important cause of the chronic inflammation of aging that drives the progression of many age-related diseases.

The results here suggest that efficient senolytic treatments to selectively destroy senescent cells should proceed any of the current approaches to raising levels of NAD+ in older individuals – and it is an open question as to whether any of the existing available options are efficient enough to make NAD+ enhancement safe in the longer term. Those people self-experimenting with NAD+ precursor supplementation should consider keeping a close eye on markers of inflammation.

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest.

NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.


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Giving a Name to Age-Related TDP-43 Proteopathy

Giving a Name to Age-Related TDP-43 Proteopathy

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Much of the spectrum of age-related neurodegenerative conditions is associated with, and at least partly caused by, the accumulation of abnormal proteins or protein aggregates in the brain. These include the α-synuclein associated with Parkinson’s disease, the amyloid-β and tau of Alzheimer’s disease, and so forth. This sort of condition, in which malformed proteins are a contributing cause, is termed a proteopathy. A more recently recognized neurodegenerative proteopathy involves the TDP-43 protein, and the evidence for its relevance to age-related dementia has reached the point at which researchers and administrators now feel that they can advocate for greater recognition and funding for research and development in this part of the field.

Alzheimer’s is the most common form of dementia, which is the loss of cognitive functions – thinking, remembering, and reasoning – and everyday behavioral abilities. In the past, Alzheimer’s and dementia were often considered to be the same. Now there is rising appreciation that a variety of diseases and disease processes contribute to dementia. Each of these diseases appear differently when a brain sample is examined at autopsy. However, it has been increasingly clear that in advanced age, a large number of people had symptoms of dementia without the telltale signs in their brain at autopsy. Emerging research seems to indicate that the protein TDP-43 – though not a stand-alone explanation – contributes to that phenomenon.

TDP-43 (transactive response DNA binding protein of 43 kDa) is a protein that normally helps to regulate gene expression in the brain and other tissues. Prior studies found that unusually misfolded TDP-43 has a causative role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. However, these are relatively uncommon diseases. A significant new development seen in recent research is that misfolded TDP-43 protein is very common in older adults. Roughly 25 percent of individuals over 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities.

TDP-43 pathology is also commonly associated with hippocampal sclerosis, the severe shrinkage of the hippocampal region of the brain – the part of the brain that deals with learning and memory. Hippocampal sclerosis and its clinical symptoms of cognitive impairment can be very similar to the effects of Alzheimer’s. “Recent research and clinical trials in Alzheimer’s disease have taught us two things: First, not all of the people we thought had Alzheimer’s have it; second, it is very important to understand the other contributors to dementia.” Scientists have now described the newly-named pathway to dementia as Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE.

LATE is an under-recognized condition with a very large impact on public health. Researchers emphasized that the “oldest-old” are at greatest risk and, importantly, they believe that the public health impact of LATE is at least as large as Alzheimer’s in this group. The clinical and neurocognitive features of LATE affect multiple areas of cognition, ultimately impairing activities of daily life. Additionally, based on existing research, the authors suggested that LATE progresses more gradually than Alzheimer’s. However, LATE combined with Alzheimer’s – which is common for these two highly prevalent brain diseases – appears to cause a more rapid decline than either would alone.


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Are Standard Lipid Profile Tests Enough? Advanced Cholesterol Testing

Are Standard Lipid Profile Tests Enough? Advanced Cholesterol Testing

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Are Standard Lipid Profile Tests Enough? Advanced Cholesterol Testing
With heart disease being a leading cause of death among Americans, you may be wondering: How healthy is my heart?

You eat right, exercise and know how to manage stress. Your annual physical includes the standard blood tests, including a lipid (cholesterol) profile to evaluate heart disease risk, cholesterol (HDL and LDL) and triglycerides. Your blood pressure and electrocardiogram (ECG) results may be normal. Everything looks OK, so there’s nothing to worry about . . . right?

A standard lipid panel that tests for serum total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) and triglycerides is a necessary part of regular blood work and a way to screen for factors that contribute to heart disease. But there are other blood tests available that provide a much clearer picture of where you stand heart-health-wise.

Listen to Life Extension’s Michael A. Smith, MD, and Crystal Gossard, DCN, CNS®, LDN, as they bring their audience up-to-date on the latest tests for cholesterol and more on the Live Foreverish Podcast.

Advanced heart tests

There’s more to cholesterol than HDL and LDL.

Cholesterol, an important fat-like substance found in all cells, is needed to produce steroid hormones and forms a part of cell membranes, among other functions. Although some cholesterol is provided by the diet, most is made by the liver. Cholesterol is transported by low-density lipoprotein to tissues, while high-density lipoprotein delivers excess cholesterol back to the liver, where it is broken down and eventually excreted. Having an HDL level of 50 mg/dL or higher, an LDL level of less than 80 mg/dL and fasting triglycerides that are lower than 100 mg/dL is optimal for most individuals without other risk factors.

What are the best blood tests for predicting heart problems?

One of the best tests you can take is the NMR Lipoprofile® test, which measures the standard lipid levels in addition to LDL particle size and number. Low-density lipoprotein should be large, fluffy and buoyant (described as pattern A) as opposed to small and dense (described as pattern B). Small, dense LDL particles are likelier to infiltrate the arterial wall, leading to plaque formation. They are therefore a good marker for predicting cardiovascular disease.1 The NMR Lipoprofile® test also provides an assessment of insulin resistance that can help detect the risk of type 2 diabetes, a disease that increases the risk of cardiovascular disease.2

Apolipoproteins bind fat and cholesterol to form lipoproteins. While there are a number of apolipoprotein classes, the ones we’re going to look at are apolipoprotein A and apolipoprotein B. Apolipoprotein B (ApoB) is a component of some of the “unhealthier” lipoproteins, including low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) particles. Apolipoprotein A1 (ApoA1) is a component of high-density lipoprotein (HDL) particles and is potentially helpful in reducing build-up of arterial plaque. The Apolipoprotein Assessment, which measures apolipoprotein B and apolipoprotein A1, is important because the ApoB-to-ApoA1 ratio has a stronger association with cardiovascular disease risk than better-known lipoprotein cholesterol fractions.3

Best Blood Tests for Heart Disease Detection: Does LDL Matter?

Yes, knowing one’s LDL level is of vital importance in assessing one’s risk of cardiovascular disease. Testing for oxidized lipoproteins is also important. Oxidized LDL can be compared to rancid fat that is likelier to trigger inflammation and plaque formation than LDL that is not oxidized. Increased serum or plasma oxidized LDL is a marker for coronary artery disease.4

Tests for inflammation are valuable in the assessment of cardiovascular disease risk. While C-reactive protein (CRP) is a better-known test for systemic inflammation, myeloperoxidase (an immune system enzyme that is a biomarker of oxidative stress) testing can assess inflammation specific to the arterial wall. Testing for CRP and myeloperoxidase may be as important as cholesterol levels to evaluate the risk of cardiovascular disease.5

Another advanced heart test is the PLAC® test for lipoprotein-associated phospholipase A2 protein (Lp-PLA2) activity. Lp-PLA2 is a vascular inflammatory marker that plays an important role in the formation of arterial plaque that is vulnerable to rupture.6 This test measures the function of Lp-PLA2 in the walls of the arteries to help predict the risk of coronary heart disease events.

Heart tests for chest pain

Chest pain should be immediately evaluated. Although it may not always be caused by a heart attack, it’s better not to take chances. An ECG is usually the first test that is administered to people complaining of chest pain. This test measures the heart’s electrical activity and can reveal damage that has occurred.

Troponin is a protein that increases in the blood in response to damage to the heart muscle. This is measured in the emergency department following an ECG assessment of suspected heart attack. Troponin testing confirms acute heart attack diagnosis but does not indicate the mechanism of damage inflicted upon the heart.7

Chest x-rays and CT scans are other tests that may be employed to evaluate individuals who report chest pain. They may be repeated at follow-up, along with ECG stress tests and/or an angiogram, which enables visualization of the heart’s arteries.

Chest pain that comes and goes

Chest pain that comes and goes over an extended period of time may not be due to a heart attack but should still be evaluated by a physician. There are a number of tests and procedures that can help identify the cause of chest pain.

Availing yourself of some of these advanced tests can provide a more complete picture of heart health than standard blood tests. If an increased risk of cardiovascular disease is identified, preventive measures can be taken. By proactively assessing your risk factors, you can act immediately to reduce the risk of becoming one of the casualties of the world’s leading cause of death.

About Live Foreverish: Join Dr. Mike as he sits 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 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!


  1. Ivanova EA et al. Oxid Med Cell Longev. 2017;2017:1273042.
  2. Balakumar P et al. Pharmacol Res. 2016 Nov;113(Pt A):600-609.
  3. Walldius G et al. J Intern Med. 2006 May;259(5):493-519.
  4. Holvoet P et al. Arterioscler Thromb Vasc Biol. 2001 May;21(5):844-8.
  5. Heslop CL et al. J Am Coli Cardiol. 2010; 55: 1102-1109.
  6. Kolodgie FD et al. Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2523-9.
  7. Foy AJ et al. Med Clin North Am. 2015 Jul;99(4):835-47.

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Rejuvenation Therapies Will Also Have Cycles of Hope and Disillusionment

Rejuvenation Therapies Will Also Have Cycles of Hope and Disillusionment

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Every new class of rejuvenation therapy, and there will be many of them in the decades ahead, will follow a cycle consisting of a few years of rapidly growing hype, followed by a sharp crash of disappointment, and then, ultimately, long years of slow and steady success. People attach great hopes to the early stages of every new technology, unrealistic expectations for sweeping, immediate change and benefit. Those expectations are usually possible to realize in the long term, but they can only be met in the later stages of development, perhaps several decades after the advent of the new approach to rejuvenation. Producing a mature product that meets the early visions needs the participation of an entire industry, much of which typically does not exist at the start of the process.

Every new technology goes through this cycle, lasting decades from start to finish. The life span of a technology is perhaps fifty years, depending on where one wants to draw the line between a given technology and its next generation, and the first decade can be quite the wild ride when it comes to raised expectations and sudden disillusionment. Human beings are just built this way, the incentives operating at every step of the development process produce this outcome regardless of the fact that we’ve all seen it before.

Nothing happens quickly, even when the course of action is obvious, even when proof of principle exists for a new medical technology. This is the result of the way in which investment and commercial development works in practice, as it is based on a great deal of happenstance in the percolation of new information through communities, as well as the process of finding, organizing, and persuading groups of people. It takes a few years for a potential entrepreneur to move from exposure to concept to launching a startup company. It takes a few years for a company to succeed or fail. It takes a few years for those lessons to percolate through the research and development communities. Similar cycles play out in the grant writing and publish or perish world of research. Several of these cycles may be needed for any new technology to launch in a useful form. This is why even comparatively straightforward advances can take a decade to make their way out of the labs. Nothing is really all that simple in practice, and regulation slows down these cycles of progress in medicine in comparison to other industries.

Why do the early years of development, those leading in to the first clinical therapies for a new medical technology, inevitably involve an excess of hype? Well, firstly it is sufficiently challenging to raise funds for research in the early stages that advocates tend to sell the vision of the complete industry, the end product rather than the first versions. Further, in the world of biotech startups and venture capital, near all investors are looking for the seeds of enormous, industry-changing companies, the big wins that will provide enormous returns on investment. All venture funds provide their investors with returns that are largely derived a couple of big wins amidst the failures and the mere successes, and the financial model for such funds is predicated on finding those few big wins. This cultivates, directly and indirectly, a culture of public relations and industry commentary that is prone to hype, to emphasizing the facts in ways that are attractive to investors. Lastly, the people who would benefit from rejuvenation therapies, or indeed any radical new advance the capabilities of medical science, rarely have a good understanding of the realities of and the underlying science, and can muster an enormous degree of hope on that basis.

It is worth considering that the development of therapies is in fact a difficult and challenging process in its details. It involves a great deal of discovery as matters move from cells to mice to human trials. The early stem cell therapies of fifteen to twenty years ago were an example of the type, in that the simple transplantation of stem cells did not led to the reliable regenerative therapies that were hoped for at the outset, cures that would reverse heart disease and numerous other age-related conditions. These hope led to the establishment of countless clinics and a sizable medical tourism industry. Obstacles were discovered, in the form of the sizable logistical costs, the difficulties in standardizing cells for therapy, the unreliably benefits when it comes to regeneration. Transplanted stem cells do not survive for long, and it is their temporary signaling that produces benefits, changing for a time the behavior of native cells and tissues. After the initial years of work, the results consist of a few standardized approaches that fairly reliably reduce chronic inflammation for a time, a considerably benefit, but that fail to reliably improve tissue function and structure. This is a lesser outcome by far than the goals aimed at by the early advocates and developers.

The development catches up to the early hype, however. It just takes time. Presently the field of stem cell research and development is well on the way towards approaches that are in principle capable of reliably producing regeneration. Some of those are quite similar to the early visions, the transplantation of cells that survive in large numbers to integrate with tissues and improve their function. They result from incremental, steady advances in capabilities, rather than any profound new approach to the problem. Others are indeed entirely novel lines of work that didn’t exist, even in concept, at the turn of the century, such as the use of full or partial reprogramming to produce patient-specific or universal cell lines, or even to alter cells in vivo.

The world turns, and we live in an age of change, a revolution in progress in the capabilities of biotechnology and its application to medicine. It just doesn’t happen quite as rapidly as everyone would like it to.

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Why You Should Embrace Healthful Sun Exposure

Why You Should Embrace Healthful Sun Exposure

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Marc Sorenson, who has a doctorate in education, and who is the founder of the Sunlight Institute,1 has written an excellent book, “Embrace the Sun,” in which he reveals why sunlight is foundational for optimal health and longevity.2 While vitamin D supplements clearly have their place, you cannot obtain all the benefits you get from the sun when you swallow it.

For example, many of the benefits of sunlight, such as a decreased risk of heart disease, have to do with its ability to increase nitric oxide (NO) production in your body.3 Ultraviolet A (UVA) and the near-infrared light spectrum both increase NO, so you’re getting that benefit from both ends of the light spectrum. Fifty percent of sunlight is near-infrared.4

Near-infrared also increases cytochrome c oxidase (COO),5 the fourth cytochrome in the mitochondria, and neither of these benefits can be had from swallowing a pill. It’s really important to realize that your body is designed to benefit from sun exposure, and if you’re diabetic or have heart disease, it may well be one of the missing factors. As noted by Sorenson:

“When we get out in the sun, the research is incredible. The risk of heart disease and the risk of myocardial infarction drop dramatically in the summertime, and go up dramatically in the wintertime.

Meaning, there’s something there that has to be beyond vitamin D, because the vitamin D supplement studies with heart disease haven’t worked out well. What we know now is the main mover to prevent heart disease is probably NO, which is a potent vasodilator. It opens them up.

Blood pressure can go down dramatically with regular sun exposure, which it does. Among people who are getting sunlight on a regular basis, the risk of dropping dead of a heart attack goes down rather dramatically …

You can produce 20,000 international units (IU) in 20 minutes of ideal unobstructed sun exposure on both sides of the body …  

How the Sun Avoidance Conspiracy Was Born

Importantly, for every death caused by diseases related to excessive sun exposure — such as common skin cancers (basal cell and squamous cell carcinomas) as well as some other uncommon diseases — there are 328 deaths caused by diseases related to sunlight deprivation,6 according to Sorenson’s data.

According to a 2013 study,7 for every skin cancer death in northern Europe, between 60 and 100 people die from stroke or heart disease related to hypertension alone. Knowing your risk of dying from heart disease or stroke is 80 times greater on average than from skin cancer should really put things into perspective.8 Clearly, sun avoidance is hardly the lifesaving strategy dermatologists make it out to be.

I’d always wondered why there was such an avid aversion of sun exposure within the dermatology community. It just doesn’t make any sense — until I read Sorensen’s book, in which he dissects the motivation behind this illogical stance. He explains:

“The powers of darkness, as I call them, are very highly invested in the sunscreen industry. About 70 percent of the funding comes from the sunscreen industry. Of course, with a dermatological society, they back those who produce sunscreens.

We’ve got a vast conspiracy with the sunscreen industry. That’s one of the main things. Besides … medicine in general is not that interested in keeping people well, because if they do get people well — and sunlight will do that to a great extent — they’re out of business. There is a conspiracy out there. I’ve written a very large chapter about that and how they used their anti-sun [propaganda] to keep people sick.”

On Skin Cancer

There are two basic types of skin cancer: melanoma and nonmelanoma. Importantly, 75 percent of all melanoma occurs on areas of the body that never see the sun, Sorenson notes, and indoor workers have double the rate of lethal melanoma skin cancer than outdoor workers.9 A primary risk factor for melanoma appears to be intermittent sun exposure and sunburn, especially when you’re young.

According to data presented in his book, in 1935 about 1 in 1,500 people contracted melanoma. As of 2002/2003, that rate was 1 in 50. Between 2006 and 2015, melanoma rates increased 3 percent per year,10 so rates just keep going up.

“The more we use sunscreen, the more melanoma we get. Australia’s proven that for many, many years,” Sorenson says. “They use more sunscreen than any people on Earth, yet they have the highest prevalence of melanoma …

Melanoma increased by 3,000 percent between 1935 and, let’s say, 2002 to 2003. That’s a tremendous increase. Sun exposure during that time, by my government figures, has gone down by over 90 percent. We have a 90-percent decrease in sun exposure and a 3,000-percent increase in melanoma.

How does that add up for their theory? It doesn’t add up at all. They’re now beginning to realize that, I think, little by little. But still, they’re in that hip pocket of the medical schools that promote sunscreens and such.”

As noted by Sorenson, the sun actually protects you from melanoma. It does not protect again the more common skin cancers, though. However, protection from those can be had from a diet high in antioxidants.

Sun Avoidance Kills Far More People Than Sun-Related Diseases

Nonmelanoma skin cancers are primarily divided into basal cell and squamous cell cancer, and sun exposure does increase your risk of those cancers. The thing to remember is that these are typically nonlethal. The relative safety of skin cancer is craftily hidden, however, by combining statistics for nonfatal and fatal skin cancers.

Most of the deaths attributed to nonmelanoma skin cancers (basal and squamous cell), which number around 4,420 per year, according to,11 are in those who have severely compromised immune systems. Melanoma, meanwhile, kills an estimated 7,230 people per year in the U.S.12,13 It’s also important to realize that common skin cancer does not turn into the deadlier melanoma.

When you consider the statistics, it seems clear that sun avoidance is actually increasing your risk of deadly skin cancer, and that by exposing your skin to the sun, you will decrease your risk of melanoma.

What’s more, sun avoidance will also raise your risk of internal cancers, along with a long list of chronic diseases, the mortality rates of which are far more alarming than melanoma. As mentioned earlier, for every sun-related death there are 328 deaths from sun-deficiency-related diseases.

Sorenson’s book also cites Iranian research showing women who cover themselves completely have a 10-times higher risk of breast cancer compared to women who don’t cover themselves completely. That’s a 1,000-percent greater risk of breast cancer. Yet women are being told to avoid sun exposure at all costs to protect their health.

You Can Benefit From Sun Exposure Year-Round

During wintertime at latitudes above 22 degrees you’re not going to be able to get enough ultraviolet B (UVB) exposure on your skin to significantly raise your vitamin D level, unless you are at high altitudes in the mountains.

However, you’re still getting other photoproducts such as brain-derived neurotrophic factor (BDNF), NO and others. They will be produced even in the winter when the sunlight is too weak to trigger vitamin D production.

“I tan every day in St. George, Utah,” Sorenson says. “It may be 40 degrees F. outside; I step into the garage, so I’m protected from the breezes. I get out in the sun every day. It’s not doing me a bit of good for vitamin D, but I do have my own tanning bed. I can go into that tanning bed and it produces a dramatic amount of vitamin D.

So will a good vitamin D sunlamp … Sometimes I fudge and take a vitamin D pill, but I would rather [use my tanning bed] because it’s a lot more natural than taking a vitamin D pill, in my opinion. That’s the way that I do it …

Of course, tanning beds have been much maligned, [yet it] dramatically increases bone strength. It dramatically increases vitamin D levels. It reduces the risk of psoriasis and eczema. It does many other things that they never give any credit for …

I was just thinking about the new study on Parkinson’s disease, [which] showed people who are out in the bright sun daily, regularly have 1/50th the risk of ever getting Parkinson’s. That’s fairly new research. I was stunned by that research.”

Avoid Sunburn at All Costs

Naturally, regardless of the season, you want to make sure you do not get sunburn. Once your skin turns the lightest shade of pink, move into the shade or put on clothing and a hat to cover up your skin. Beyond that point, there’s no benefit, only the risk of skin damage. As noted by Sorenson:

“Your body shuts it down at that point. In fact, your body will shut down your vitamin D production, along with anything else, that it doesn’t want. There is a very interesting piece of research … that shows people who use sunscreen have anywhere from three to six times the risk of sunburn.

Another one was a big meta-analysis, which showed there was no benefit whatsoever in using sunscreens. None at all. In fact, there was a slight increase in the risk of all skin cancers together.”

Sun Exposure Decreases Risk of Autoimmune Disease

Aside from lowering your risk for a variety of cancers, including melanoma, sun exposure also radically decreases your risk of autoimmune diseases. (Diseases in which your body identifies proteins and other structures made by the body as foreign and destroys them.) Two classic examples are multiple sclerosis (MS) and Type 1 diabetes.

Sorenson cites research from Finland showing vitamin D supplementation decreased the risk of Type 1 diabetes by five- to sixfold. When compared to Venezuelan children, who get ample sun exposure, Finnish children had 400 times the risk of Type 1 diabetes.

Researchers have also found an inverse risk between vitamin D status and MS risk,14 and studies have confirmed MS is far less prevalent in areas near the equator, such as Ecuador, where prevalence ranges from a low of 0.75 per 100,000 inhabitants in the South, to a high of 5.05 per 100,000 in the capital city of Quito.15

What’s a Healthy Vitamin D Level?

Science has shown 20 ng/mL (50 nmol/L), which is typically considered the cutoff for vitamin D sufficiency, is still grossly inadequate and dangerous to health. For optimal disease protection, you need a vitamin D blood level between 60 and 80 ng/mL16 (150 to 200 nmol/L).

Once you get above 60 ng/mL, the risk for cancer and other chronic illness declines dramatically — in the case of breast cancer by more than 80 percent.17

There appears to be variations in the ideal level, however, depending on the condition in question. Sorenson cites research showing that athletic performance, and the risk of injury due to falling among nonathletes, improved until they reached a level of about 63 ng/mL (158 nmol/L), at which point performance and risk of falling started to slightly decline again.

On the other hand, in the case of breast cancer, which is a major concern for women, levels upward of 80 ng/mL (200 nmol/L) appear to be the most protective. When aiming for those higher levels, though, I believe getting your vitamin D from sunlight becomes all the more important, especially if you’re seeking protection from diseases such as heart disease.

Because, remember, swallowing a vitamin D pill will not trigger NO production like sun exposure does, and increasing NO appears to be a significant way by which sun exposure lowers your heart disease risk. Sunlight also boosts your serotonin level, a neurotransmitter thought to play an important role in depression.

In his book, Sorenson cites research showing that spending the entire day in bright sunlight increases your serotonin level by 800 percent. A precursor to serotonin — melatonin — is also crucial for sleep and cancer prevention.

Sunlight and Visual Acuity

Myopia, with people needing glasses at an early age, and presbyopia, which is when you need reading glasses, are also on the rise, and this too may be a side effect of insufficient sun exposure. Sorenson explains:

“One of the studies was done comparing people in Singapore to people who grew up in Australia. They had the same ethnic background, basically Oriental-Asian background. Those who were playing in the sun in Australia had about one-sixth the risk of getting myopia.

It is so important. If we don’t get out and we don’t focus [our eyes] in the sun, [if] we don’t look into the distance — that may be one of the reasons we don’t get enough vitamin D, we don’t get enough serotonin, NO and any of the other photoproducts produced by the sun.

There is a pandemic of myopia. We’re seeing it here in the United States with the Asian kids. In many cases, as they get older, it will lead to blindness. Of course, they always talk about macular degeneration and so forth, but there’s a dichotomy here, because if you have macular degeneration, they tell you to totally stay out of the sun.

It does tend to relate to sun exposure. At the same time, vitamin D levels that are high tend to reduce the risk. So, what do you do? Stop getting your sun and take a vitamin D pill? I don’t think so. I think if we’re in the sun the way we ought to be and eat the polyphenols and so forth … that’s probably the way to prevent most of the older-age diseases.

Now, as far as presbyopia … I’ve had it since I was about 40. I just take some reading glasses and I can get along with reading my fine print. I wasn’t able to escape it. It runs in my family. I think there must be some genetic component there, because I was out in the sun and I never had any myopia.”

As for age-related macular degeneration (ARMD), which is the leading cause of blindness among the elderly, research by Dr. Chris Knobbe, an ophthalmologist who wrote a book on the risk factors of ARMD, whom I’ll be interviewing on this topic, has compiled massive amounts of data showing that ARMD did not exist before 1930 and this appears largely due to the consumption of processed foods, especially processed vegetable oils.

Sugar, of course, does not help either. That combination causes massive degeneration of your vision, which is very difficult to reverse in its advanced stages. But if you catch it at an early stage, you can reverse it using dietary changes.

For presbyopia, I recommend not wearing sunglasses and avoiding reading glasses. As you age, there’s a tendency to want to make that font bigger to see text better, but I recommend resisting that temptation, as it’s only going to make matters worse.

Also, avoid squinting and simply blink instead. Blink multiple times until the text becomes clear, then relax your eyes to refocus. Brighter light may also help you read without increasing the font size on your tablet or computer, or using reading glasses.

Sunlight for Bone Health

Sorenson also recounts some of the historical data supporting the idea that sun exposure benefits health in important ways and boosts athletic performance. Aside from breast health, research shows sun exposure also helps prevent osteoporosis, which is yet another significant concern for women in particular. Sorenson says:

“In Spain, women who were sun seekers, those who were always outside, trying to tan … as much as possible, those women had 1/11th the risk of ever having a hip fracture as women who were avoiding the sun. That one point alone should get every woman out in the sun, because all women are afraid not only of breast cancer but also of osteoporosis.

Women need sunlight to prevent it. Whether vitamin D pills will work, I am not convinced. They don’t give them enough vitamin D so they can’t really tell in the research. But we know that sunlight works to prevent hip fractures. Boy, that’s a big one to me …

[Higher] vitamin D levels also dramatically help your brain … People think better … You are 3.5 times more likely to end up in a rest home [assisted care facility] if you do not have a good vitamin D level … [If] you’ve got a mom, dad, uncle or whoever is in danger of going there, I think it can be prevented … They can stay at home, maybe with a son or daughter, and they wouldn’t need to worry about them injuring themselves every other second.”

More Information

To learn more, I strongly recommend picking up a copy of Sorenson’s book, “Embrace the Sun.” Strongly emphasized in the book is the importance of sunlight for the prevention of cardiovascular disease — again, by way of boosting NO, which lowers your blood pressure and increases blood flow, more so than raising your vitamin D.

Sorenson believes erectile dysfunction (ED), for men, may be a related problem that could be addressed through improved sun exposure, as one of the major reasons for ED is lack of NO. Cialis or Viagra is not the answer. Sunlight is.

“I think … we have to have holistic sun [exposure] again,” Sorenson says. “We need to have every single photoproduct produced. I have written down about five more photoproducts I haven’t even had the time to study. We don’t know what they do yet.

But why would you go for a vitamin D pill when you could get out in the sun and get all of the available [photoproducts] that we don’t even know [the benefits of] yet? For optimal human health, we need to be in the sunlight.”

Discover more about Nitric Oxide Supplements and Cardiovascular physical health.

Fight Aging! Newsletter, May 6th 2019

Fight Aging! Newsletter, May 6th 2019

Proven Vitamin supplements for Nitric Oxide Health

Searching for superior recognized quality health supplements?  Learn about  these important Medically Approved Vitamins.

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn’t work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • An Interview with Carolina Oliveira of OneSkin Technologies
  • Assessing Socioeconomic Correlations with Rate of Aging using the Epigenetic Clock
  • A Potential Approach to Tackling CEL and CML Advanced Glycation End Products
  • Presenting the SASP Atlas for the Senescence-Associated Secretory Phenotype
  • Increased Levels of Progerin Observed in Overweight Individuals
  • SIRT6 in Longer Lived Mammals Produces More Efficient DNA Repair
  • Injecting Self-Assembling Artificial Extracellular Matrix into a Damaged Heart
  • Opening a New Approach to Targeting LDL Cholesterol to Slow Atherosclerosis
  • Chronic Inflammation as Proximate Cause of a Large Fraction of Age-Related Disease
  • Pericyte Cell Therapy Promotes Muscle Regrowth Following Atrophy in Mice
  • Exercise Rapidly Improves Memory Function in Older Adults
  • On Alzheimer’s Disease Research, Both Appropriate and Inappropriate Pessimism
  • GATA3 Macrophages as a Contributing Cause of Cardiac Fibrosis
  • Senoinflammation: an Expanded View of Age-Related Chronic Inflammation
  • Fibrosis as a Consequence of Processes of Aging

An Interview with Carolina Oliveira of OneSkin Technologies

OneSkin Technologies is one of the few companies in the present community of startups focused on rejuvenation and slowing aging to adopt a serious cosmetics focus on development. Here “cosmetics” is a regulatory term, not an indication of something used for the purposes of looks: it is perfectly possible for a topically applied product that is regulated as a cosmetic to have therapeutic effects, just like a drug. Nonetheless, cosmetics and drugs have entirely distinct paths of regulation, very different from one another, and each with their own costs and challenges. In regulated cosmetics development there is no animal testing at all, everything proceeds to human trials on the basis of tissue models of skin. The trials themselves are quite different. It is arguably easier to run a rejuvenation therapy through the cosmetics regulatory pathway than to try to introduce it as a drug, provided that has a significant effect on skin aging.

This is the direction taken by OneSkin, where the staff are working on a line of senolytic compounds to selectively destroy senescent cells in aged tissues, and that will be developed as cosmetic products at the outset. I met the OneSkin founder earlier this year, and had a chance to pose a few questions about the work being carried out at the company. I think that this approach to the challenge of medical development is worth watching, particularly given that the next major area of rejuvenation research to take off may be cross-link breaking. Cross-links are influential in the age-related loss of elasticity in tissues such as skin and blood vessels. I imagine that companies analogous to OneSkin will emerge quite quickly in that space, once it has reached the same level of maturity as presently exists for senolytics research and development.

How did OneSkin Technologies come about? What led you into cosmetic senolytics?

OneSkin’s initial proposal was to validate the effectiveness of “anti-aging” skincare products available in the market, in order to meet the needs of consumers for science-validated products as well for the companies that are looking to differentiate their products from competitors. Our approach for this validation was to test a given molecule in 3D human skin equivalents and analyze changes in the methylation pattern by running age-predictor algorithms, such as the Molecular Clock developed by Steve Horvath in 2013. Since this and other algorithms used at the time largely failed to predict skin age accurately, we decided to develop our own skin-specific molecular clock, in which the average difference between predicted age and chronological age is lower (approximately 4.6 years) than the currently available molecular clocks. Later on, we realized that we could create more value and offer a scalable solution by developing new and more effective products for skin rejuvenation, instead of limiting ourselves to validating third party products. We also realized that there wasn’t any initiative for targeting senescent cells focused on our body’s largest organ, the skin.

We believe the skin will be the first tissue to benefit from a senotherapeutic approach since it allows for topical application, virtually no contact with the bloodstream, and possibly a faster route to the market, if categorized as a cosmetic. We also love the proposal to develop senotherapeutics for skin because their effects will be visually perceived by consumers. Finally, the International League of Dermatological Societies (ILDS), a global, not-for-profit organization representing 157 dermatological societies worldwide, has identified the consequences of skin aging as one of the most important grand challenges in global skin health. Reduced functional capacity and increased susceptibility of the skin with development of dermatoses such as dry skin, itching, ulcers, dyspigmentation, wrinkles, fungal infections, as well as benign and malignant tumors are the most common skin conditions in aged populations worldwide and may be prevented with the use of technologies that have been designed to promote skin age reversal, like ours.

The audience here is more familiar with the FDA process for new drugs. How does cosmetics development differ from that?

Here in the US, the law does not require cosmetic products to have FDA approval before they go on the market, but there are laws and regulations that apply to cosmetics on the market, including the voluntary cosmetic registration program. Despite the general feeling that cosmetics are hardly regulated by FDA, safety is the number one rule, accompanied by the important observation that cosmetic products must be properly labeled. This means that any cosmetic product in the market should do no harm to the skin. For this purpose, there are guidelines to be followed when introducing a new molecule in a cosmetic product.

Basically, the company should provide data regarding mutagenesis and chromosomal changes by performing tests such as the Ames test (which uses bacteria to analyze the potential of a given compound to cause DNA mutations), cytotoxicity (using human cells) and karyotyping analysis (using human cells). Since OneSkin does not use animals to develop products, additional safety studies using the complete formulation to assess skin irritation, corrosion, and sensitization are performed in human skin equivalents (in vitro) and also in human subjects. Additional tests, such as ocular toxicity are desirable and even mandatory according to the cosmetic product. At OneSkin, we performed most of the cited tests, including cytotoxicity in human fibroblasts and keratinocytes derived from different donors, mutagenesis (Ames) and chromosomal aberration (karyotyping), toxicity through human skin equivalents, and, finally, we have already performed the Repeated Insult Patch Testing (RIPT) in 54 human subjects, provided by an independent contract organization. All of them came out clear and in accordance with the parameters required, guaranteeing safety for our future clients.

Tell us something about your development. What is your candidate molecule, and how far along are you in the process of validation leading to human use?

Our lead candidate molecule is a new synthetic peptide, which was initially screened in a synthetic library for antimicrobial peptides (AMP). AMPs have multifunctional behavior and accumulate several interesting properties for skin applications, including tissue repair, antioxidant activity, collagen synthesis, anti-inflammatory activity and we decided to evaluate their senotherapeutic potential. From our initial 200 library, we selected 4 hits – the 4 compounds which were most effective in decreasing senescent cells in human skin. Then, we used an algorithm to create variations of such sequences, leading to hundreds of possible leads. Among those leads, we selected the two best peptides, deemed OS-1 and OS-2, which have consistently shown the ability to decrease human cellular senescence caused by aging, ultraviolet light, and other types of genotoxic stress by 25-50%.

It is worthy of mention that we chose to build a human cell-based platform in order to close the gap between preclinical and clinical scenarios and to mimic skin aging as closely as possible. Indeed, our valuable technological platform is proprietary and has been patented. To briefly outline our pipeline, first, we evaluate the ability of new compounds to decrease cellular senescence through two markers. The classical senescence associated-β-galactosidase (SA-β-Gal) marker is analyzed, as it has been consistently used in the aging field for a least 30 years and is considered an easily identifiable marker of cellular senescence. Nevertheless, since SA-β-Gal also has important limitations, we complement our analysis with a more recent and sensitive marker of cellular senescence, ATRX foci formation.

For each compound, we test both markers in cells obtained from at least three different healthy and aged donors. As positive controls, we have used senolytic and senomorphic molecules, such as fisetin and rapamycin. We also have tested most of senolytics described in the literature and most have failed to induce apoptosis in senescent cells in those cell types or show nonspecific effects, causing a significant toxicity to non-senescent cells. To date, our peptides are the molecules that have performed the best, considering safety and efficacy endpoints. We have been able to replicate human skin aging in vitro by growing skins with cell donors of diverse ages, ranging from a neonatal (0Y), to young (approximately 30Y) to aged (over 50Y). We have characterized these models according to skin equivalent structural organization, gene expression, and accumulation of senescent cells. Using aged skin equivalents, we test compounds by adding them into the culture media for 5 days. At this time, histological, SA-β-gal staining and qPCR analysis are performed to evaluate the skin health and the senotherapeutic and age reversal potential of such molecules. Additionally, we have formulated our main peptide in a topical cream and have applied onto skin biopsies of aged donors, and we could observe an improvement in epidermal thickness after 5 days of treatment.

Importantly, OS-1 is performing better than retinoic acid, currently considered the gold standard molecule for anti-aging skincare products. It is also worth mentioning that we have consistently seen an increased expression of p16 and inflammatory cytokines like IL-6 and IL-8, along with the “peeling effect” of retinoic acid, which is usually perceived in human use.

Finally, after performing these in vitro studies and clearing the safety (including an IRB approval) of our lead candidate, we have improved our own topical OS-1 formulation and began testing it on a group of 23 healthy volunteers, ranging from 32 to 84 years old. This experiment was initially focused on safety assessment only, but we already consider it a first validation of OS-1 effectiveness in humans, since our preliminary data is extremely promising, with 100% safety and a significant visual improvement observed in most patients within the first month of continuous use. Later this year, we will proceed to a randomized, placebo-controlled clinical study provided by an independent contractor organization.

Why can’t one just use dasatinib, or other established senolytics, in some form and spread it on skin? Why something new?

Despite major proofs of concepts generated in the longevity field recently, the clinical use of senolytics must be carefully evaluated. We initially tested several senolytics like dasatinib and unfortunately, the majority that we tested on our platform were either very toxic even to non-senescent cells, or are not effective in decreasing the relative percentage of cellular senescence. Initially, we were disappointed by the lack of reproducibility in our hands, but since we have tested such compounds consistently, we believe that the discrepancies observed may result from different experimental settings, since most papers are based on animal models or genetically-modified cell lines, while we work with healthy and normal aged human cells.

Furthermore, when tested in skin equivalent models, senolytics continued to be highly toxic, compromising skin equivalent general structure, and decreasing the thickness of the epidermis. ABT-263, A1331852 and Dasatinib + Quercetin are but a few senolytics we have already tested. We have tested other molecules which are safer and effective like fisetin, but this molecule has the limitation of requiring high concentration to be effective (i.e. 20 μM), due to its low bioavailability. Fisetin’s natural color (yellow to orange) also impairs its use in a topical product.

If your product works topically on skin, why not administer it systemically to clear out senescent cells throughout the body?

As mentioned before, we believe skin health is an important and highly overlooked target to rapidly promote drastic improvement of wellness, self-confidence, and prevention of aging-related skin disorders. Therefore, we have chosen skin as a starting point to validate our lead molecule and start bringing its benefits earlier to consumers. Once OS-1 ́is proven to be well-tolerated and effective at reducing skin senescence when applied topically, it will then open several avenues to explore other indications of the peptide throughout the body, which would fall in the regular FDA pathway for drug development. In this regard, one basic assay we performed in order to assess the potential application of OS-1 for longevity purposes was the evaluation of healthspan improvement and lifespan extension in C. elegans worms. In this experiment, parameters of healthspan (thrashing and esophageal pumping – which basically indicates how well the worm moves and eats) were improved, and the treated worms lived longer (median life extension increased approximately 12%).

This is comparable to other age reversal strategies published in the literature, and reflects the potential of OS-1 to be used for other therapeutic applications in the future. The positive result surprised us, because we have not yet optimized our candidates by applying any medicinal chemistry. However, this will soon be performed once the mechanism of action is elucidated. On this subject, we have shown that OS-1 promotes a decrease of cellular senescence levels of cells and tissues by promoting apoptosis (decrease in phosphorylated Akt on Ser473), increasing DNA repair capacity (induction of BLM and SIRT6 gene expression) and preventing DNA-damage induced senescence (UVB exposure induction model).

What other areas of rejuvenation research do you think would benefit from a cosmetics approach, to speed adoption?

Most strategies targeting one of the hallmarks of aging could be useful for a cosmetic approach. The main limitation we see is the delivery of whatever rejuvenation technology through the stratum corneum, the outermost layer of the skin, which is very well designed to work as a barrier to protect the skin from potential harm or infections. Our peptide, as a reference, is considered small (10 amino acids) and we were fortunate to validate its ability to penetrate through the stratum corneum barrier and into the dermal layer. Larger molecules may face additional challenges in penetratration and to promote their effects in deeper skin layers.

Importantly, to be able to validate any technology to promote skin rejuvenation it is not a trivial process. Previous experience has shown that skin aging is a little bit different from aging in other tissues. Therefore, it will be important to validate other strategies while considering the important drivers for skin aging by testing on aged models that replicate chronological aging such as UV exposure, oxidative stress, and pollution, and not on less important drivers such as oncogene-induced and chemically-induced senescence. The ability to replicate these models required years of optimization and it is an ongoing process when you start considering not only the influence of age, but also how the diverse genetic background plays a significant role in this matter.

What is the future of OneSkin Technologies beyond your first senolytic product?

OneSkin’s main goal is to build the first skincare line targeting cellular senescence and bring its own products to the market. We believe there is no proposal out there, focusing on skin, that tackles aging from its cause as we do. This makes us confident in the value our products will bring to consumers. After the first validation for aesthetic skin rejuvenation, we are going after other age-related skin disorders and eventually, age-related disorders beyond the skin. An oral application of our peptide is another avenue to be explored. As we intend to keep our focus mainly towards skin applications, we envision to explore these additional indications through partnerships with pharma or other longevity companies. Finally, OneSkin’s main asset is our screening and validation platform, which will constantly screen and identify new leads, be them small molecules, peptides, natural compounds or combinations thereof, to target cellular senescence and senescence-associated diseases. We are determined to work to position our technologies in the forefront of the future therapies for aging and longevity.

Assessing Socioeconomic Correlations with Rate of Aging using the Epigenetic Clock

Life expectancy, mortality, and risk of age-related disease are well known to correlate with a complicated web of socioeconomic factors. Educational attainment correlates with life expectancy, but so does intelligence. The relationship with intelligence might have underlying genetic causes, in that more intelligent people may be more physically robust. Or it may be that intelligence and education are inextricably linked – smarter people are better educated or better educated people do well on tests of intelligence – and the effect on life expectancy has little to do with genetics.

Further, educational attainment correlates with wealth, both of the region, and of the individual. Is it thus a proxy for greater access to medical technology purely due to greater wealth? What about the education and intelligence needed to use that access well? Or perhaps it has little to do with medical technology for most of the life span, and education and intelligence tend to lead to better lifestyle choices? Trying to peel apart these relationships is a complex task, and one that has not yet succeeded in any meaningful way, I would say.

The various epigenetic clocks are measures of age based on an algorithmic weighting of patterns of DNA methylation on the genome that appear to be a characteristic reaction to the damage and dysfunction of aging, occurring in very similar ways in every individual. The underlying molecular damage that causes aging is, after all, the same for everyone. It is as yet unknown as to exactly which underlying processes correspond to which DNA methylation sites on the genome, but the correlation is quite good overall. People in groups with higher risk of mortality or exhibiting age-related diseases tend to have higher assessed DNA methylation age than their healthier peers, which provides a way to determine pace of aging to some degree. Can this be useful as a tool to start dissecting the complicated relationships between aging, lifestyle, and socioeconomic status in populations? Perhaps.

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis

Aging is characterized by a gradual and constant increase in health inequalities across socioeconomic groups, an association based on strong epidemiological evidence known as the social gradient in health. On average, individuals with lower socioeconomic position (SEP) have lower life expectancy, higher risk of age-related diseases, and poorer quality of life at older ages compared with less disadvantaged groups. Although lifestyles differ by SEP, unhealthy habits only partially explain this association.

The role of epigenetic mechanisms in response to trauma, and evidence for their involvement in intergenerational transmission of biological impacts of traumatic stress have been proposed to explain how social adversity gets biologically embedded, leading to differences in biological functionalities among individuals in different social conditions, especially at older ages. Epigenetics, specifically DNA methylation (DNAm) has been proposed as one of the most powerful biomarkers of biological aging and as one of the plausible biological mechanisms by which social adversities get ‘under the skin’ and affect physiological and cellular pathways leading to disease susceptibility.

Two measures of epigenetic clocks have gained considerable popularity, and the concept of epigenetic aging acceleration (EAA) has been introduced as the difference between predicted DNAm age and chronological age. EAA has been associated with all-cause mortality, cancer incidence and neurodegenerative disorders, as well as non-communicable disease risk factors such as obesity, poor physical activity, unhealthy diet, cumulative lifetime stress and infections.

Given the above, it can be assumed that the various epigenetic clocks describe different aspects of the biological (epigenetic) aging process. We previously showed a dose-response relationship between SEP and EAA. Further, our results suggest that the effect could be partially reversible by improving social conditions during life. In addition, ours and two more recent studies indicate that childhood SEP might have a stronger effect on EAA than adulthood SEP.

Despite extensive research in the field, to date no studies have compared the effect of SEP on epigenetic aging biomarkers with those of other lifestyle-related risk factors for age-related diseases. We aimed to systematically investigate the association of education level, as a proxy for SEP, with the total number of SEMs and ‘accelerated aging’ as assessed using the three epigenetic clocks, and to compare the independent effect of low education with those of the main modifiable risk factors for premature aging: smoking, obesity, alcohol intake, and physical inactivity, by conducting a meta-analysis including data for more than 16,000 individuals belonging to 18 cohort studies from 12 different countries worldwide.

Epigenetic aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.

A Potential Approach to Tackling CEL and CML Advanced Glycation End Products

Advanced glycation end-products (AGEs) form in tissues as a side-effect of the normal operation of cellular metabolism where it touches on the processing of sugars. There are many types of AGEs, most short-lived, but some persistent and challenging for our biochemistry to break down. These persistent AGEs lead to cross-links, binding together molecules in the extracellular matrix and thereby altering the structural properties of tissues. This is perhaps most harmful where it reduces tissue elasticity, and is thus an important contributing cause of skin and vascular aging.

While sugars are involved, it is much debated as to whether the contents of diet, either fully formed AGEs from certain cooked and processed foods, or precursors in the form of excessive amounts of sugar, has much influence at all over the generation of the types of AGE involved in aging. As mentioned, there are many types of AGE. One of the big questions in the small research community focused on AGEs is whether or not glucosepane AGEs are the only target worthy of attention in the matter of aging. There is certainly good evidence for cross-links in humans to be overwhelmingly made of glucosepane, but equally there is a faction who argue that the research community does not yet have sufficiently robust data to be able to ignore AGEs such as carboxymethyl-lysine (CML).

The challenge inherent to all work on AGEs, and why this part of the larger field has been a comparative backwater for decades despite its great importance to aging, is that the usual tools for cell, tissue, and molecular biochemistry work just don’t exist. AGEs are hard to work with. The usual recipes for making the molecule of interest, the standardized tests for assessing its presence, and so forth, just don’t exist or didn’t exist until comparatively recently. Most research groups take a look at this desert of tooling and move on to something easier – it is a self-reinforcing problem. This was the case until the SENS Research Foundation and allied philanthropists turned up to try to solve the missing tools problem. Those efforts have led to significant progress in the past five years or so, but there is still a fair way to go yet. Today’s paper is of interest for showing progress towards tooling for CML, rather than for glucosepane. It is not open access, but sufficiently interesting to note nonetheless.

Biocatalytic Reversal of Advanced Glycation End Product Modification

Advanced glycation end products (AGEs) are non-enzymatic post-translational modifications of proteins derived from the condensation of reducing sugars and nucleophilic amino acid residues, such as lysine and arginine. Although AGEs are formed in the body as a part of normal metabolism, they can accumulate to high concentrations and contribute to the progressive decline of multiple organ systems. This process is accelerated in diabetics, owing to their hyperglycemic conditions. In addition to causing spontaneous damage by altering protein structure and function, AGEs also interact with the receptor for AGEs (RAGE), eliciting oxidative stress and activating the transcription factor NF-κB thought to be a major contributor of AGE-associated chronic inflammation and cellular damage.

Elevated levels of AGEs are linked to the pathology of many metabolic and degenerative diseases of aging, such as diabetic complications, atherosclerosis, and Alzheimer’s disease. This association is manifested by age-dependent increases in cross-linking, browning, fluorescence, and AGE content in long-lived proteins such as collagens and lens crystallins. Structural characterization and synthesis of some of the more prevalent AGEs (e.g., glucosepane) have allowed more focused investigations into their individual chemical properties and formation. Indeed, chemical studies have shown strong correlations between specific AGEs and the development of age-related illnesses; however, it has been difficult to unequivocally demonstrate that any AGEs are direct causal factors largely due to the lack of tools for investigating the reversal of mature AGE modifications at the molecular level.

Here, we show that MnmC, an enzyme involved in a bacterial tRNA-modification pathway, is capable of reversing the AGEs carboxyethyl-lysine (CEL) and carboxymethyl-lysine (CML) back to their native lysine structure. Combining structural homology analysis, site-directed mutagenesis, and protein domain dissection studies, we generated a variant of MnmC with improved catalytic properties against CEL in free amino acid form. We show that this enzyme variant is also active on a CEL-modified peptidomimetic and an AGE-containing peptide that has been established as an authentic ligand of the receptor for AGEs (RAGE).

To the best of our knowledge, this is the first biochemical demonstration of an enzyme that can reverse a mature AGE-functionalized peptide. While the kinetic parameters, which are similar to known Amadoriases, could be substantially improved, C-MnmC variants represent lead catalysts for further directed evolution and development. As MnmC natively acts on nucleic acids, glycated DNA (e.g., carboxyethyl/carboxymethyl-deoxyguanosine) may also be suitable substrates to test in future studies. Such improved AGE-reversal tools could in principle enable a better understanding of the biology of AGEs at the molecular level, elucidate their direct roles in the pathogenesis of age-related diseases, and serve as leads for recombinant enzyme therapies.

Presenting the SASP Atlas for the Senescence-Associated Secretory Phenotype

The presence of growing numbers of lingering senescent cells is one of the root causes of aging. Vast numbers of cells become senescent every day, but near all are quickly removed, either via programmed cell death or the actions of the immune system. A tiny number survive, however, and that alone would eventually be enough to cause age-related disease and death. While senescent cells never rise to very large fractions of all of the cells in a given tissue, they cause considerable harm via a potent mix of secreted signals known as the senescence-associated secretory phenotype, or SASP. The SASP causes chronic inflammation and destructive remodeling of the nearby extracellular matrix. Further, it changes the behavior of other cells for the worse, including increasing their chances of becoming senescent.

In today’s open access paper, researchers present the start of a new database that will categorize the many molecules making up the SASP for various cell types. Since nothing is simple in biochemistry, the SASP is undoubtedly meaningfully different from tissue to tissue and cell type to cell type. Why does the SASP exist? Senescent cells have important transient roles in wound healing and in regulating the growth of embryonic tissues. Here the signals are beneficial, involved in growth and regeneration, and senescent cells are cleared from the site after they have served their purpose. Further, senescence in response to DNA damage or a toxic environment is a defense against cancer, in that senescent cells cease to replicate, encourage nearby cells to do the same, and rouse the immune system into greater activity – exactly the sort of strategy that should put a halt to cancer in its earliest stages.

Unfortunately, that the clearance of senescent cells is imperfect, and some always linger, ensures that the SASP becomes a cause of aging. Signals that are beneficial in specific contexts in the short term become harmful when continually present. In old tissues, the secretions of senescent cells actively maintain a degraded, dysfunction state of cellular metabolism and tissue function. This is why senolytic treatments capable of selectively removing some fraction of senescent cells are proving to be so very effective for a very wide range of age-related diseases in animal studies. Fortunately, no great understanding of the SASP is needed to make progress in this form of treatment; we know that removing chronic SASP is beneficial, and that should be the primary focus of development.

SASP Atlas

The senescence-associated secretory phenotype (SASP) has recently emerged as both a driver of, and promising therapeutic target for, multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically monitored by a few dozen secreted proteins, has been greatly underappreciated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present ‘SASP Atlas’, a comprehensive proteomic database of soluble and exosome SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins, but also includes a subset of proteins elevated in all SASPs. Based on our analyses, we propose several candidate biomarkers of cellular senescence, including GDF15, STC1, and SERPINs. This resource will facilitate identification of proteins that drive specific senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus and tissue of senescent cells in vivo.

A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development

Cellular senescence is a complex stress response that causes an essentially irreversible arrest of cell proliferation and development of a multi-component senescence-associated secretory phenotype (SASP). The SASP consists of myriad cytokines, chemokines, growth factors, and proteases that initiate inflammation, wound healing, and growth responses in nearby cells and tissues. In young and healthy tissues, the SASP is typically transient and tends to contribute to the preservation or restoration of tissue homeostasis. However, the increase in senescent cells with age and a chronic SASP are now known to be key drivers of many pathological hallmarks of aging, including chronic inflammation, tumorigenesis, impaired stem cell renewal, and others.

Using either or both of two transgenic mouse models that allow the selective elimination of senescent cells, or compounds that mimic the effect of these transgenes, data from several laboratories strongly support the idea that the presence of senescent cells drives multiple age-related phenotypes and pathologies, including age-related atherosclerosis, osteoarthritis, cancer metastasis and cardiac dysfunction, myeloid skewing in the bone marrow, kidney dysfunction, and overall decrements in healthspan.

Several types of stress elicit a senescence and secretory response, which in turn can drive multiple phenotypes and pathologies associated with aging in mammals. Some of these stressors have shared effects. For example, telomere attrition resulting from repeated cell division (replicative senescence), elevated reactive oxygen species, chromatin disruption, and even the activation of certain oncogenes all can cause genotoxic stress, as can a number of therapeutic drug treatments, such as anti-cancer chemotherapies and certain highly active antiretroviral therapies for HIV treatment or prevention. However, whether these stressors produce similar or distinct SASPs is at present poorly characterized. Therefore, a comprehensive characterization of SASP components is critical to understanding how senescent response can drive such diverse pathological phenotypes in vivo. It is also a critical step in clarifying how various stimuli, all acting through senescence, differentially affect health.

Increased Levels of Progerin Observed in Overweight Individuals

Progerin is the malformed version of LMNA, a protein vital to the structure of the cell nucleus. It is the cause of progeria, a rare condition that has the superficial appearance of greatly accelerated aging. It isn’t aging, however, but rather an enormous burden of cellular damage and dysfunction resulting from structural issues in the cell nucleus that affect near all forms of function. In normal aging, there is also an enormous burden of damage and dysfunction, but this arises from a completely different mix of issues. Some of the end results, such as cardiovascular disease, are somewhat similar, but one can’t compare the two if interested in first causes.

In the case of patients with progeria, the LMNA gene is mutated, resulting in large amounts of progerin. One of the interesting observations made over the past decade is that some tiny fraction of LMNA is malformed in older people without progeria, however, and it has been suggested that this may contribute to the aging progress. As for many such mechanisms, the question is whether or not its contribution is significant in comparison to that resulting from the various other forms of disarray in aging tissues. That question has not been resolved. The easiest way to do so would be to find an efficient way to remove or block the activity of all progerin and observe the results, but that has yet to take place.

In the open access paper noted here, researchers report on the interesting observation that overweight individuals have higher levels of progerin. Being overweight does in fact accelerate most of the processes of aging. Visceral fat tissue is metabolically active, and generates chronic inflammation through a range of different mechanisms, from increased numbers of senescent cells through to inappropriate signaling on the part of normal fat cells. Inflammation drives the progression of many forms of age-related disease. Again we might ask the question: given this sizable contribution, is the presence of progerin in the observed amounts significant? Answers will remain speculative until such time as the progerin can be removed.

High Body Mass Index is Associated with Elevated Blood Levels of Progerin mRNA

Excess weight is growing in frequency globally. Obesity is associated with morbidity and premature mortality and represents a major risk factor for many diseases especially cardiovascular disease. It is linked to a significant decrease in life expectancy of 5-10 years in comparison to persons with Body-Mass-Index (BMI) between 22.5 to 24.9. An elevated BMI, adipose tissue and muscular fat depositions, respectively, have been associated with aging. Aging is defined as deterioration of cellular and organ function with time related to many physiologic and phenotypical changes and represents the strongest risk factor for myocardial infarction, stroke, diabetes, and cancer. Therefore, premature aging-like syndromes such as Hutchinson-Gilford progeria syndrome (HGPS) are of particular interest in exploring pathophysiological changes of aging processes related to cardiovascular disease.

HGPS is based on mutations influencing the precise encoding and processing of lamin A (LMNA) an important filament protein in the nucleus of eukaryotic cells. LMNA is involved in the correct forming of a filamentous meshwork between chromatin and the nuclear membrane, keeping the nuclear envelope upright, which is essential to regulate processes like DNA replication, DNA repair, and RNA transcription. Individuals suffering from HGPS exhibit early cardiovascular atherosclerosis and often die due to heart attack and stroke as teenagers. Toward the end of life, HGPS patients also suffer from heart failure due to cardiac fibrosis and cardiomegaly.

In most HGPS cases, a single point mutation activates a cryptic splicing site causing the production of 50 amino acids truncated prelamin A called progerin. Progerin lacks the cleavage site for zinc-metalloproteinase (ZMPSTE24) resulting in accumulation in the nucleus, leading to disturbed lamina, telomere and DNA damages, apoptosis, early cellular senescence, and finally to deterioration of organ function. Astonishingly, it was shown that low amounts of progerin mRNA derived by alternative splicing are also expressed in healthy individuals leading to the discussion of the role of progerin in normal aging by various groups. Since obesity and premature aging are both accompanied with an increased cardiovascular morbidity and mortality, we aimed to investigate the association of BMI with respect to progerin mRNA expression in the blood of individuals with known cardiovascular disease.

This study shows that mRNA levels of the aging related lamin A splice variant progerin, associated with premature aging in HGPS, were significantly upregulated in subjects with BMI ≥ 25 kg/m2. Moreover, our data revealed a significantly positive correlation of BMI with progerin mRNA. These data provide to our knowledge for the first-time evidence for a possible involvement of progerin in previously observed accelerated aging of overweight and obese individuals potentially limiting their longevity. Our results also showed that progerin mRNA was positively correlated with C-reactive protein (CRP). This might suggest an association of progerin with an inflammatory response triggering accelerated aging. Moreover, we found an increase of the acute phase protein CRP in patients with BMI ≥ 25, indicating a higher systemic inflammatory status in the overweight group. This is consistent with prior findings where obesity was considered to predispose to local and systemic inflammation with ongoing activation of immune cells.

SIRT6 in Longer Lived Mammals Produces More Efficient DNA Repair

The sirtuin gene SIRT6 is involved in DNA repair, among many other processes. Researchers here report that differences in SIRT6 between shorter and longer lived mammals give rise to more efficient DNA repair in the longer-lived species. This might be taken as evidence for nuclear DNA damage to be significant in aging, but the challenge is always in isolating just the one effect. So while altering fly SIRT6 to look more like that of mammals results in extended life spans, proving that this is all due to DNA repair is a challenging project yet to be accomplished.

SIRT6 is often called the “longevity gene” because of its important role in organizing proteins and recruiting enzymes that repair broken DNA; additionally, mice without the gene age prematurely, while mice with extra copies live longer. The researchers hypothesized that if more efficient DNA repair is required for a longer lifespan, organisms with longer lifespans may have evolved more efficient DNA repair regulators. Is SIRT6 activity therefore enhanced in longer-lived species?

To test this theory, the researchers analyzed DNA repair in 18 rodent species with lifespans ranging from 3 years (mice) to 32 years (naked mole rats and beavers). They found that the rodents with longer lifespans also experience more efficient DNA repair because the products of their SIRT6 genes – the SIRT6 proteins – are more potent. That is, SIRT6 is not the same in every species. Instead, the gene has co-evolved with longevity, becoming more efficient so that species with a stronger SIRT6 live longer.

The researchers then analyzed the molecular differences between the weaker SIRT6 protein found in mice versus the stronger SIRT6 found in beavers. They identified five amino acids responsible for making the stronger SIRT6 protein more active in repairing DNA and better at enzyme functions. When the researchers inserted beaver and mouse SIRT6 into human cells, the beaver SIRT6 better reduced stress-induced DNA damage compared to when researchers inserted the mouse SIRT6. The beaver SIRT6 also better increased the lifespan of fruit flies versus fruit flies with mouse SIRT6. Next steps in the research involve analyzing whether species that have longer lifespans than humans – like the bowhead whale, which can live more than 200 years – have evolved even more robust SIRT6 genes.

Injecting Self-Assembling Artificial Extracellular Matrix into a Damaged Heart

A number of approaches to tissue engineering and regenerative medicine have focused on providing a supporting structure for native cells, to steer their behavior towards regrowth rather than scarring or inactivity. The results here are an example of one class of minimally invasive approach, in which an artificial extracellular matrix material can be injected rather than implanted. In addition to providing a structure that cells favor, this sort of material can be laden with a mix of signal molecules that will aid cell survival and activity. Better repair following damage such as that of a heart attack is a poor second best to preventing the heart attack from occurring in the first place, but it is an incremental improvement over the present state of affairs.

Tissue engineering strategies to replace or supplement the extracellular matrix that degrades following a heart attack are not new, but most promising hydrogels cannot be delivered to the heart using minimally invasive catheter delivery because they clog the tube. Researchers have now demonstrated a novel way to deliver a bioactivated, biodegradable, regenerative substance through a noninvasive catheter without clogging.

When a person has a heart attack, the extracellular matrix is stripped away and scar tissue forms in its place, decreasing the heart’s functionality. Because of this, most heart attack survivors have some degree of heart disease, the leading cause of death in America. “We sought to create a peptide-based approach because the compounds form nanofibers that look and mechanically act very similar to native extracellular matrix. The compounds also are biodegradable and biocompatible. Most preclinical strategies have relied on direct injections into the heart, but because this is not a feasible option for humans, we sought to develop a platform that could be delivered via intracoronary or transendocardial catheter.”

Peptides are short chains of amino acids instrumental for healing. The team’s approach relies on a catheter to deliver self-assembling peptides – and eventually a therapeutic – to the heart following myocardial infarction, or heart attack. The team’s preclinical research was conducted in rats and segmented into two proof-of-concept tests. The first test established that the material could be fed through a catheter without clogging and without interacting with human blood. The second determined whether the self-assembling peptides could find their way to the damaged tissue, bypassing healthy heart tissue. Researchers created and attached a fluorescent tag to the self-assembling peptides and then imaged the heart to see where the peptides eventually settled. “In previous work with responsive nanoparticles, we produced speckled fluorescence in the heart attack region, but in this case, we were able to see large continuous hydrogel assemblies throughout the tissue.”

Opening a New Approach to Targeting LDL Cholesterol to Slow Atherosclerosis

In atherosclerosis, fatty deposits form in blood vessel walls, narrowing and eventually rupturing or blocking them. It is one of the largest causes of death. The majority of efforts to treat atherosclerosis are focused on reducing the input of LDL cholesterol. This means statins and other, more recent approaches to lower levels of LDL cholesterol in the bloodstream, such as PCSK9 inhibitors. It is possible to reduce blood cholesterol to very low levels indeed, far below normal, and this actually has comparatively little effect on existing atherosclerotic lesions. Patients still die. The disease still progresses, just more slowly.

Atherosclerosis isn’t a condition of cholesterol, for all that this is how it largely discussed in the medical profession, but rather a condition in which the macrophages responsible for clearing cholesterol from blood vessel walls become dysfunctional. The focus should be on the macrophages. Nonetheless, the research community remains largely focused on LDL. The work here is illustrative of attempts to find yet more ways to reduce LDL cholesterol in blood vessel walls, this time somewhat more specifically than by simply lowering levels everywhere. Still, I suspect it will be unlikely to produce benefits significantly greater than those of PCSK9 inhibitors and their general reduction in LDL cholesterol in the bloodstream.

Since low-density lipoprotein, or LDL, cholesterol entry into the artery wall drives the development of atherosclerosis, or hardening of the arteries, and atherosclerosis leads to heart attacks and strokes, future treatments preventing the process may help decrease the occurrence of these life-threatening conditions. A new study reveals for the first time how a protein called SR-B1 (short for scavenger receptor class B, type 1) ferries LDL particles into and then across the endothelial cells that line arteries. The study also found that a second protein called dedicator of cytokinesis 4, or DOCK4, partners with SR-B1 and is necessary for the process.

In the early stages of atherosclerosis, LDL that has entered the artery wall attracts and is engulfed by important immune system cells called macrophages that ingest, or “eat,” LDL particles. LDL-laden macrophages become foam cells that promote inflammation and further the development of atherosclerotic plaques. The plaques narrow the artery and can become unstable. Plaques that rupture can activate blood clotting and block blood flow to the brain or heart, resulting in a stroke or heart attack. In studies of mice with elevated cholesterol, the investigators determined that deleting SR-B1 from the endothelial cells lining blood vessels resulted in far less LDL entering the artery wall, fewer foam cells formed, and atherosclerotic plaques that were considerably smaller.

In their studies, the researchers compared SR-B1 and DOCK4 abundance in areas of the mouse aorta that are prone to plaque formation compared with regions less likely to become atherosclerotic. They found higher levels of SR-B1 and DOCK4 in the disease-prone regions long before atherosclerotic plaques formed. This finding suggests that atherosclerotic lesions may be more common in particular artery sites because of more SR-B1 and DOCK4 present there. To determine if these findings might apply to people, the researchers reviewed data on atherosclerotic and normal arteries from humans in three independent databases maintained by the National Institutes of Health (NIH). In all three databases, SR-B1 and DOCK4 were more abundant in atherosclerotic arteries compared with normal arteries. The researchers are now exploring the possibility of using gene therapy to turn off or reduce the function of SR-B1 or DOCK4 in the endothelial cells that line arteries in order to prevent atherosclerosis.

Chronic Inflammation as Proximate Cause of a Large Fraction of Age-Related Disease

This popular science article discusses at length the chronic inflammation that is characteristic of the old, and its role as a proximate cause of age-related disease. Inflammation is a necessary part of the immune response to injury and pathogens, and when present in the short term it is vital to the proper operation of bodily systems. But when the immune system runs awry in later life, and inflammatory processes are constantly running, then this inflammation corrodes metabolism, tissue function, and health.

The causes of excess, constant inflammation are both internal and external to the immune system. Internally, the supply of new immune cells falls off with age as the thymus atrophies and hematopoietic stem cell populations decline; this leads to an immune system made up of increasingly damaged, malfunctioning cells. Externally, much of the inflammation of aging is the result of signals secreted by lingering senescent cells, and removal of this inflammation is a primary reason why senolytic therapies produce rejuvenation and longevity when tested in animal models. Addressing these causes of inflammation will be an important aspect of rejuvenation therapies in the years ahead.

In 2007, researchers already knew that exercise reduces the risk of cardiovascular disease as much as cholesterol-lowering statin drugs do. By analyzing biomarkers in the blood of 27,055 women participating in a long-term study, and other objective measures, they hoped to tease out how much of the benefit was attributable to improved blood pressure, to lower body weight, or to something else. “We were actually surprised that reduced inflammation was the biggest explainer, the biggest contributor to the benefit of activity, because we hadn’t hypothesized that. We knew that regular exercise does reduce inflammation over the long term, but we also knew that acute exercise transiently increases inflammatory biomarkers during and immediately after exertion.” About a third of the benefit of regular exercise, they found, is attributable to reduced inflammation. The anti-inflammatory effect of exercise was much greater than most people had expected. That raised another question: whether inflammation might also play a dominant role in other lifestyle illnesses that have been linked to cardiovascular disease, such as diabetes and dementia.

In 2017, two cardiologists, who suspected such a link, published the results of a human clinical trial which involved more than 10,000 patients in 39 countries, and was primarily designed to determine whether an anti-inflammatory drug, by itself, could lower rates of cardiovascular disease in a large population, without simultaneously lowering levels of cholesterol, as statin drugs do. The answer was yes. But the researchers went a step further, building into the trial additional tests seeking to clarify what effect the same anti-inflammatory drug, canakinumab, might have on illnesses seemingly unrelated to cardiovascular disease: arthritis, gout, and cancer. Only the researchers themselves, and their scientific colleagues, were unsurprised by the outcome. Lung cancer mortality dropped by as much as 77 percent. Reports of arthritis and gout also fell significantly.

In medicine, believing something is true is not the same as being able to prove it. Because the idea that inflammation – constant, low-level, immune-system activation – could be at the root of many noncommunicable diseases is a startling claim, it requires extraordinary proof. Can seemingly unconnected illnesses of the brain, the vasculature, lungs, liver, and joints really share a deep biological link? Evidence has been mounting that these common chronic conditions – including Alzheimer’s, cancer, arthritis, asthma, gout, psoriasis, anemia, Parkinson’s disease, multiple sclerosis, diabetes, and depression among them – are indeed triggered by low-grade, long-term inflammation. But it took that large-scale human clinical trial to dispel any lingering doubt: the immune system’s inflammatory response is killing people by degrees.

Now the pertinent question is why, and what can be done about it. The pharmaceutical industry is deeply interested in finding ways to stop inflammation with medicines like canakinumab, an orphan drug that blocks a specific pro-inflammatory pathway called IL-1beta. But some researchers suggest that the inflammatory process – a normal and necessary part of the natural immune response – has itself has been misunderstood. Scientists know that the process can be turned on and off, but have only recently understood that this doesn’t mean normal physiology will resume once the inflammation caused by infection, injury, or irritant has been shut down. Instead, the restoration of health is an active phase of the inflammatory process itself, facilitated by a little-known class of molecules called pro-resolving mediators – the protectins, resolvins, maresins, and lipoxins – brimming with marvelous, untapped, regenerative capacities.

Pericyte Cell Therapy Promotes Muscle Regrowth Following Atrophy in Mice

Researchers here show that boosting the numbers of the pericyte cell population involved in vascular system growth and activity improves restoration of muscle mass following atrophy. This is particularly interesting in the context of the fact that capillary vessel networks decline in density in tissues with age, the processes of maintenance and blood vessel construction becoming disarrayed, and that this decline is thought to contribute to age-related loss of muscle mass and strength. Muscle is an energy-hungry tissue, and we might thus expect that factors relating to delivery of nutrients and oxygen via the vascular network have some impact on its maintenance and growth. That point is demonstrated here.

By injecting cells that support blood vessel growth into muscles depleted by inactivity, researchers say they are able to help restore muscle mass lost as a result of immobility. The research, conducted in adult mice, involved injections of cells called pericytes, which are known to promote blood vessel growth and dilation in tissues throughout the body. The injections occurred at the end of a two-week period during which the mice were prevented from contracting the muscles in one of their hind legs. “Just as the mice were becoming mobile again, we transplanted the pericytes and we found that there was full recovery of both muscle mass and the vasculature, too.”

The team also observed that muscle immobility itself led to a significant decline in the abundance of pericytes in the affected muscle tissues. “We know that if you are under a condition of disuse – for example, as a result of long-term bed rest, or the immobilization of a body part in a cast – you lose muscle mass. And even when you come out of that state of immobility and you start moving your muscles again, there’s this really long, slow process of recovery. Older adults might never fully rebuild the lost muscle mass after a period of immobility. They can’t recover, they become disabled, and there’s this downward spiral. They may become institutionalized and experience early mortality. To my knowledge, no one has demonstrated that anything has been effective in improving the recovery process. We’re excited by the new findings because we hope to one day use these cells or biomaterials derived from these cells to help restore lost muscle mass.”

Exercise Rapidly Improves Memory Function in Older Adults

Over the long term, regular exercise is correlated with improved cognitive function in later life, a slower decline of that function with aging. This is well established. The work here is interesting for showing that even in the very short term, exercise produces improvements in specific aspects of cognitive function, such as memory. One might add these results to the very long list of good reasons to avoid a sedentary lifestyle. Exercise cannot add a large number of years to life span, and indeed in mice it has no effect on overall life span, but given that it is essentially free and produces highly reliable benefits to health and resilience, slowing and postponing age-related disease, it would be foolish to ignore it.

How quickly do we experience the benefits of exercise? A new study of healthy older adults shows that just one session of exercise increased activation in the brain circuits associated with memory – including the hippocampus – which shrinks with age and is the brain region attacked first in Alzheimer’s disease. “While it has been shown that regular exercise can increase the volume of the hippocampus, our study provides new information that acute exercise has the ability to impact this important brain region.”

The research team measured the brain activity (using fMRI) of healthy participants ages 55-85 who were asked to perform a memory task that involves identifying famous names and non famous ones. The action of remembering famous names activates a neural network related to semantic memory, which is known to deteriorate over time with memory loss.

This test was conducted 30 minutes after a session of moderately intense exercise (70% of max effort) on an exercise bike and on a separate day after a period of rest. Participants’ brain activation while correctly remembering names was significantly greater in four brain cortical regions (including the middle frontal gyrus, inferior temporal gryus, middle temporal gyrus, and fusiform gyrus) after exercise compared to after rest. The increased activation of the hippocampus was also seen on both sides of the brain. “Just like a muscle adapts to repeated use, single sessions of exercise may flex cognitive neural networks in ways that promote adaptations over time and lend to increased network integrity and function and allow more efficient access to memories.”

On Alzheimer’s Disease Research, Both Appropriate and Inappropriate Pessimism

This is a pessimistic popular science article on the state of Alzheimer’s disease research. I think the tone appropriately pessimistic where it examines the present dominant approach to building therapies, which is to say clearing amyloid-β from the brain via immunotherapy. I think it inappropriately pessimistic for the near future, however, given the various projects currently under development. Take, for example, the brace of approaches based on restored drainage of molecular wastes in cerebrospinal fluid, or filtration of cerebrospinal fluid to achieve much the same outcome. Further, and closer to widespread availability in the clinic, senolytic therapies to clear senescent cells have been used to demonstrate that senescent immune cells in the brain, and the neuroinflammation that they cause, are a significant contribution to both Alzheimer’s disease and other neurodegenerative conditions. Removing these cells may well do more for Alzheimer’s patients in the near term than any other approach attempted to date.

Not only have there been more than 200 failed trials for Alzheimer’s, it’s been clear for some time that researchers are likely decades away from being able to treat this dreaded disease. Which leads me to a prediction: There will be no effective therapy for Alzheimer’s disease in my lifetime. Alzheimer’s sits right at the confluence of a number unfortunate circumstances. If you understand why there won’t be much headway on Alzheimer’s, you’ll also understand a bit more why modern medicine has been having fewer breakthroughs on major diseases.

For decades it was widely believed that the cause of Alzheimer’s was the build-up of abnormal proteins called amyloid and tau. These theories dominated the field and led some to believe we were on the verge of effective treatments – through preventing or removing these abnormal proteins. But had the theories been correct we would likely have had at least one or two positive clinical trials. In retrospect, the multi-decade amyloid fixation looks like a mistake that could have been avoided. It was always possible that the classic plaques and tangles were epiphenomena of aging and not the cause of the disease. Epiphenomena are characteristics that are associated with the disease but are not its cause.

But even more convincing that researchers are closer to the beginning than the end in understanding the cause of Alzheimer’s is the long list of alternative theories. This now includes but is not limited to: infection, disordered inflammation, abnormal diabetes-like metabolism, and numerous environmental toxins. And the past few years have seen more evidence for viral, bacterial, and fungal infections. These viral and bacterial hypotheses were portrayed as eureka moments. But this begs the question: How did powerful tools of epidemiology miss associations with things like cold sores and gum disease?

Here’s the thing – regardless of type, Alzheimer’s has a powerful age-related association. This is true even for patients with early-onset inherited form of Alzheimer’s. Give someone the worst possible genome for Alzheimer’s – including the dreaded APOE e4 gene that may be associated with a 10-fold increase in risk – and that person still needs to age a bit before developing the disease. If correct, this conception of the disease means we’re even further away from an effective treatment. Aging is not disease. It is the normal arc of life and an ineluctable part of being human (“dust unto dust”). As such, the biology of aging didn’t get the attention that was bestowed on organ systems and diseases during the golden years of research funding. In retrospect, I think this may have been a grave mistake. If you list the risk factors for the major diseases of modern life – heart disease, diabetes, dementia – the most powerful is almost always age. Bottom line: We also lack an understanding of the basic science of Alzheimer’s most important risk factor.

GATA3 Macrophages as a Contributing Cause of Cardiac Fibrosis

The innate immune cells called macrophages are deeply involved in both inflammation and regeneration. They adopt different phenotypes, or polarizations, depending on circumstances, such as the M1 polarization (inflammatory, aggressive in pursuit of pathogens) and M2 polarization (pro-regenerative, anti-inflammatory). The simple view of macrophage polarization in aging tissues is that problems arise with an excess of M1 macrophages, and this is a part of the chronic inflammation that is characteristic of aging. It is well known that inflammation, when maintained over the long term, is highly disruptive of tissue function, and contributes to the progression of all of the common age-related disease.

The open access commentary here makes the point that this model of polarization and inflammation is overly simplistic, and the reality is much more complex. The researchers illustrate this with data on M2 macrophages expressing GATA3, suggesting that it is these cells, rather than pro-inflammatory M1 macrophages, that are contributing to the fibrosis that appears in cardiac tissue with age. Fibrosis is a disarray of tissue maintenance and regeneration, involving the deposition of scar-like collagen structures that degrade tissue function. The usual view of fibrosis is that it is a consequence of inflammation, very connected to the inflammatory presence of senescent cells, for example. Given that, it is quite interesting to see this sort of contradictory data.

Chronic inflammation is believed to contribute to the pathogenesis of many age-related diseases including cardiovascular disease. Chronic inflammation, particularly from activation of innate immunity, is highly sensitive to changes in the tissue environment that is associated with aging. The immune cell type that is particularly influenced by changes in its microenvironment is the monocyte/macrophage. These cells display a high level of plasticity and heterogeneity in response to their environmental cues. For example, based on the response of cultured macrophages to treatment with IL-4 or interferon γ, cells have been proposed to polarize to either M2 or M1 phenotypes, respectively. Although the M1-M2 polarization concept is useful in describing the two extremes of macrophage phenotypes, the concept does not accurately recapitulate the complex response of cells to their driving tissue microenvironment in vivo.

The plasticity of monocytes/macrophages are determined by the constellation of transcription factors that are activated and expressed in response to environmental cues. To understand the role of GATA3 transcription factor in the pathogenesis of cardiac diseases, we generated myeloid-specific GATA3 knockout mice and found that their cardiac function is significantly improved in response to ischemia or pressure overload compared with the GATA3 sufficient control group. Analysis of the profile of monocytes/macrophages in vivo revealed that GATA3-positive macrophages are not found in the healthy adult tissue. In the setting of a myocardial infarction, however, the deficiency of GATA3-positive macrophages led to a significant improvement of cardiac function compared with the GATA3 sufficient control group.

This improvement was found to be associated with the presence of many pro-inflammatory macrophages, but, few “anti-inflammatory/reparative” macrophages. This was unexpected because the prevailing hypothesis is that controlling the pro-inflammatory pathways may improve cardiac function. Our data suggest that exuberant repair, rather than unrestrained inflammation, may contribute to the excessive and maladaptive remodeling of the myocardium in the post myocardial infarction setting. Extensive evidence suggests that the aging heart undergoes fibrotic remodeling. Although targeting of pro-inflammatory pathways is thought to be an important strategy to control excessive tissue fibrosis, numerous anti-inflammatory drugs have been found to have little or no therapeutic benefit in fibrotic diseases. Our data suggest that GATA3-positive macrophages, which presumably display an M2 phenotype, are highly fibrogenic. It is therefore possible that targeting a subset of inflammatory cells, rather than global inflammation, may be a useful therapeutic strategy to control fibrotic diseases associated with aging.

Senoinflammation: an Expanded View of Age-Related Chronic Inflammation

The ability to selectively destroy a sizable fraction of senescent cells in many tissues in old animals has led to the understanding that these errant cells and their secretions are an important cause of the chronic inflammation characteristic of old age. The accumulation of senescent cells is far from the only mechanism involved, but the contribution is sizable. Removing senescent cells can turn back numerous inflammatory age-related conditions in animal models. The open access paper here proposes a view of age-related chronic inflammation that pulls together this and all of the other discoveries of the past decade related to aging and inflammation into what they term “senoinflammation”.

Age-associated chronic inflammation is characterized by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the aging process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the aging process: molecular inflammation of aging and inflammaging. However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required.

Based on the available findings from biochemical, molecular, and systems analyses, we propose the senoinflammation concept. It provides not only a broader scope, but also creates an intricate network among many inflammatory mediators that can lead to systemic chronic inflammation. When gene regulation is impaired because of constant damage to the genomic DNA by augmented oxidative susceptibility during the aging progresses, several key inflammatory transcription factors, including p53, AP-1, STAT, and NF-κB, that are important in cell survival become over-activated.

The resulting aberrant gene regulation in senescent cells leads them into a proinflammatory state, thereby altering systemic chemokine or cytokine activities. The proinflammatory senescent cell secretome imposes further stresses on the intracellular organelles, as well as tissues, organs, and systems, thus influencing metabolic disorders such as insulin resistance. It seems plausible that a vicious cycle takes place between senescent cell secretome induction and metabolic dysregulation, as proposed in the senoinflammation concept, and this may well be the underpinning of the aging process and age-associated diseases.

It is hoped that a better understanding of the molecular mechanisms involved in senoinflammation will provide a basic platform for the identification of potential targets that can suppress age-related chronic inflammation and thereby lead to the development of effective interventions to delay aging and suppress age-associated diseases.

Fibrosis as a Consequence of Processes of Aging

Fibrosis is a malfunction of tissue maintenance and regeneration in which scar-like collagen deposits form, disrupting tissue structure and function. It almost always occurs in later life, even in fibrotic conditions clearly caused by environmental factors, such as smoking in the case of chronic obstructive pulmonary disease. Why is this? The authors of the open access paper noted here consider the mechanistic reasons as to why fibrosis is age-related, enumerating the processes associated with aging that are thought to have the greatest influence over fibrosis.

There is presently little that can be done to turn back fibrosis in established medical practice. That said, clearance of senescent cells has produced promising results in animal studies and an initial human study. That removal of senescent cells appears to reliably produce benefits ties in with the connection of fibrosis to chronic inflammation and its effects on regenerative processes. Senescent cells generate inflammation, and this appears to drive, to a sizable degree, many of the diseases and dysfunctions of aging.

Aging is a predisposing factor for cardiac and pulmonary fibrosis, with the prevalence of heart failure and fibrotic respiratory diseases such as idiopathic pulmonary fibrosis (IPF) increasing dramatically with advancing age. The aging of cardiac and lung tissue ultimately results in structural remodeling of the extracellular matrix (ECM) caused by alterations in the concentration and organization of ECM components such as collagen and elastin. Biological aging is accelerated by the cumulative damage and stress that occurs during a lifetime. This premature aging is particularly pertinent to the pulmonary system, which is subjected to lifelong challenges by airborne pollutants, particulates, and pathogens. Similarly, due to the high metabolic demand of the heart, large mitochondrial population and infrequent cardiomyocyte turnover, the heart is also highly susceptible to cumulative oxidative damage and stress with age. Cellular and immunological changes occur concomitantly with age-related tissue remodeling.

There are a great many hallmarks that represent common denominators of aging, such as stem cell exhaustion, genomic instability, telomere attrition, epigenetic alteration, and loss of proteostasis; in this review we focus on four processes of aging which play an integral role in fibrosis. Senescence, inflammaging, compromised autophagy and mitochondrial dysfunction are interrelated processes, which reduce the regenerative capacity of the aged heart and lung, and have been shown to be involved in cardiac fibrosis and IPF. As a consequence, challenges to an aging heart or lung are more likely to lead to pathological tissue remodeling rather than wound resolution and tissue restitution. This is exemplified in experimental models that show cardiac fibrosis in mice post-myocardial infarction increases with age. Similarly, pulmonary fibrosis in experimental lung injury is exacerbated by aging.

Age-related processes such as senescence and inflammaging diminish the regenerative capacity of damaged cardiac and pulmonary tissue, increasing the likelihood of pathological fibrosis following injury or challenge. What is interesting about these two processes is that at low levels, they mediate beneficial effects, but as you age and the level increases, they become deleterious. This is most evident with senescence, which protects the organism from cancer but which, in excess, can promote aging and the hallmark features of fibrosis. Furthermore, inflammaging and its sustained increase of inflammatory markers, which at normal levels regulate the immune response, contributes to the acquired resistance of myofibroblasts to apoptosis, and the low grade chronic inflammation which sustains the persistent fibrosis of cardiovascular disease and IPF. Given the similarities between cardiac and pulmonary fibrosis, investigating targets and testing future treatments in both organs with a focus on these key age-related processes seems justifiable and may lead to better treatment opportunities.

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