Sun Avoidance Is a Major Cause of Mortality

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With the coming of spring and summer, you don’t have to look very far to find “experts” insisting that if you plan to spend any time outdoors, you should limit your sun exposure as much as possible. Many doctors advise their patients to cover up or slather themselves with sunscreen.

The warnings aren’t just for perpetual sun worshipers, but for people who are just going about their daily activities, such as walking to and from their cars, mowing the lawn or hanging their elbows out the window while driving.

With all the cautions about it being the leading cause of skin cancer, not to mention wrinkles and premature aging, you might think fair-skinned people from Sweden would avoid the sun like the plague. But scientists in Sweden conducted a study revealing that it’s sun avoidance that’s statistically more liable to kill people, not the other way around.

The study, published in Journal of Internal Medicine,1 asserts that women, specifically, who make it a habit to expose themselves to sunlight for a limited amount of time per day have a lower mortality rate than those who avoid it.

A caveat is in order, however: Anyone who gets too much sun has a higher risk of developing skin problems, including cancer. Getting a serious sunburn is as unwise as it ever was, but the fact is, you need daily sun exposure to stay healthy.

To reflect this, scientists have recently asked public health entities to do an “about face” on their previous (and erroneous) stance that sun exposure is unhealthy and, further, to emphasize that moderate but consistent amounts of sun are healthy.

‘D’ Isn’t Really a Vitamin; They Gave It the Wrong Name

If you ever wondered why other vitamins are derived from the foods you eat, but what you know as vitamin D comes from the sun, you were on the right track. According to the Endocrine Society’s Hormone Health Network, the “vitamin D” designation is a misnomer:

“This often-misunderstood ‘vitamin’ is not a vitamin — it is a prohormone. Prohormones are substances that the body converts to a hormone. In fact, unlike other vitamins, only about 10 percent of the vitamin D the body needs comes from food (such as dairy products and oily fish), and the rest the body makes for itself.”2

Your body makes vitamin D in a chemical reaction when sunlight hits your skin. It works by binding to a protein called the vitamin D receptor, which is present in nearly every cell and affects many different body processes. It helps your body absorb calcium, which in turn enables your bones to gain strength by “mineralizing” them.

Research indicates that the best way to raise your vitamin D level is not through supplementation, but through sun exposure. It’s crucial for the public to understand that the latest science shows that the real risk is avoiding the sun. But perhaps understanding the problems associated with low vitamin D is a more effective way of communicating how important getting optimal sun exposure is. The top five signs are:

  • Constant aches and pains, which are frequently misdiagnosed
  • Frequent illnesses and infections due to a low immune system
  • Neurological symptoms from headaches to cognitive impairment
  • Fatigue, daytime sleepiness and low back pain
  • Sweaty head, often seen in infants, but can occur at any age

In 2018, the International Journal of Environmental Research and Public Health3 noted that the risk of heart problems and cancer aren’t the only potential problems. Lack of sun exposure is also linked specific cancers, diabetes, multiple sclerosis, autism, Alzheimer’s disease and age-related macular degeneration.

Contrary to the present narrative, ultraviolet (UV) light is the primary source of vitamin D, as well as other compounds crucial for your health. The authors concluded that “non-burning UV exposure is a health benefit and — in moderation — should be recommended as such.”4

The Risk Factor for Sun Exposure

Researchers wanted to explore the risk factor for all-cause mortality by comparing women, depending on the differences in their sun exposure as a 20-year follow-up of the Melanoma in Southern Sweden (MISS) cohort.5

Recruited between 1990 and 1992, 29,518 Swedish-born women between the ages of 25 and 64 years of age and with no history of cancer supplied detailed information regarding their sun exposure habits, as well as “potential confounders” such as marital status, education level, alcohol consumption, disposable income and number of births.

In 2000, physical exercise and individual body mass index (BMI) were added to the questionnaire. However, there may be a link between BMI and vitamin D levels, as one study noted that a higher BMI leads to lower vitamin D levels.6

People with a high BMI also don’t get the same increase in vitamin D levels by UV radiation as lean subjects do.7 Four questions supplied the basis for the study, with options for frequency, including “never”:

  • How often do you sunbathe during the summertime?
  • Do you sunbathe during the winter, such as on vacation to the mountains?
  • Do you use tanning beds?
  • Do you go abroad on vacation to swim and sunbathe?

Which Is Worse — Avoiding Sunlight or Vitamin D Deficiency?

Scientists and members of the health community call it an ongoing debate, the question of whether avoiding sunlight is worse for you than having a vitamin D deficiency. According to the featured study, they looked at two reviews in regard to the importance and impact of vitamin D, and they came to polar opposite conclusions.

One review asserted that the “highly convincing evidence of a clear role of vitamin D does not exist for any outcome,”8 while the second review showed the risk of death was comparable to the risks expected by people who were smokers.9

While studies on sun exposure are limited, a 2014 study in the Journal of Internal Medicine reported, “The mortality rate amongst avoiders of sun exposure was approximately twofold higher compared with the highest sun exposure group.”10

For every skin cancer death in northern Europe, 60 to 100 people die from stroke or heart disease related to high blood pressure, which is strongly associated with vitamin D deficiency, and a lack of sun exposure in particular.11 Further, a 2016 study observed:

“Epidemiological and observational data thus suggests that sunlight exposure can reduce all-cause mortality, and has particular benefits on hypertension and cardiovascular disease. These benefits are at the cost of increasing the risk of skin cancer incidence, although the overall benefits outweigh the risks as demonstrated by dose-dependent reductions in all-cause mortality with increased sun exposure.”12

How Does Lack of Sunlight Cause Cardiovascular Disease and/or Cancer?

The scientists noted that what causes the higher incidence of death among women who avoid sunlight — a relatively small subgroup of 5.8 percent — is unknown. They classified “mortality” into three categories: cardiovascular disease (CVD), cancer and noncancer/non‐CVD for the purpose of showing how sun exposure is related.

Interestingly, the researchers noted the women’s smoking habits, but also created a “dummy variable” called comorbidity to measure another condition to identify whether the women had been treated with specific diabetes medication (which can lower vitamin D levels) or anticoagulant drugs for CVD for more than one month. According to the study:

“Women with active sun exposure habits were mainly at a lower risk of cardiovascular disease (CVD) and noncancer/non‐CVD death as compared to those who avoided sun exposure. As a result of their increased survival, the relative contribution of cancer death increased in these women.

Nonsmokers who avoided sun exposure had a life expectancy similar to smokers in the highest sun exposure group, indicating that avoidance of sun exposure is a risk factor for death of a similar magnitude as smoking. Compared to the highest sun exposure group, life expectancy of avoiders of sun exposure was reduced by 0.6–2.1 years.”13

It’s important to note that exposure to sunlight also produces a number of other health benefits that are unrelated to vitamin D production. For instance, exposure to UV light increases T cell activity — white blood cells involved in immune function and fighting infections.14

The Relationship Between Sun Exposure and Skin Cancer

The researchers also noted that most studies analyzing the relationship between extreme sun exposure and skin cancer show an increased incidence, so it’s hard to examine the impacts of sun exposure without considering skin cancer, which is typically divided into three groups:

  • Basal cell carcinoma (BCC)
  • Squamous cell carcinoma (SCC)
  • Cutaneous melanoma MM

Basal cell and squamous cell carcinomas are generally grouped together and referred to as nonmelanoma skin cancer (NMSC) because of their similarity and because both are considered less threatening (nonfatal).

One study shows that squamous cell carcinoma usually relates to cumulative exposure to UV light, while UV light is the main risk factor of cutaneous melanoma due to excess exposure to sunlight and/or tanning beds. In addition, “Incidence of MM in Sweden has doubled during the last 15 years, whilst the mortality rate has been constant since (the) 1980s.”15

Putting Sunscreen on Your Kids Is Safe, Right?

For several decades, the chemical industry has been providing sunscreens that can be “safely” used by both adults and children, but are they really safe? Multiple studies indicate that hazardous ingredients exist in sunscreen and can cause a number of serious and potentially life-altering conditions.

Not only are people encouraged to use sunscreen whenever they go out, doctors also urge parents to use it on their children, which millions do as a matter of course, and to keep applying it throughout the day while they’re swimming, golfing or visiting amusement parks.

As of late 2018, the U.S. Food & Drug Administration’s list of chemicals used in sunscreens16 manufactured as “drugs for human use” still contain numerous hazardous active ingredients, including as much as 6% oxybenzone, linked to degraded sperm quality in men17 and endometriosis in women.18

But that’s not all. One study contends that oxybenzone may also cause Hirschsprung’s disease, a condition that “affects the large intestine (colon) and causes problems with passing stool. The condition is present at birth (congenital) as a result of missing nerve cells in the muscles of the baby’s colon.”19

“Researchers found that pregnant women with medium to high levels of oxybenzone in their urine had a higher chance of giving birth to a baby with Hirschsprung’s Disease. Later testing of the human cell lines demonstrated that very low levels of oxybenzone have the ability to disrupt cell migration in a similar fashion as Hirschsprung’s Disease.

The amount of oxybenzone to do this disruption would be easily found in the body after normal sunscreen use. This confirms that oxybenzone could very well be the hidden link behind this disease that has impacted so many lives in the United States.”20

Oxybenzone was referred to as an “ecologically threatening chemical” after it was found, along with octinoxate (up to 7.5% in some sunscreens21), another chemical, to damage coral reefs in places like Hawaii in amounts as small as the equivalent of one drop in 6.5 Olympic-sized swimming pools.”22 Hawaii banned its use in 2018.23

In lieu of sunscreen, limit your initial sun exposure to just a few minutes and slowly work your way up. The more tanned your skin gets, the longer you can stay in the sun without burning. In addition, the powerful antioxidant astaxanthin can be used both internally and topically to protect your skin from the sun. Whenever possible, wear a wide-brimmed hat to protect your skin and eyes.

The bottom line is that if avoiding sun exposure puts your health at similar risk as smoking does, it’s time to make a change. There’s ample evidence to indicate that “catching some rays,” as well as avoiding chemical concoctions to block sunlight, is not just good for you; it’s crucial for maintaining — or regaining — your health.

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SIRT6 in Longer Lived Mammals Produces More Efficient DNA Repair

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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.

Link: https://www.rochester.edu/newscenter/longevity-gene-responsible-for-more-efficient-dna-repair-375752/

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Injecting Self-Assembling Artificial Extracellular Matrix into a Damaged Heart

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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.”

Link: https://www.eurekalert.org/pub_releases/2019-04/nu-fab042319.php

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An Interview with Carolina Oliveira of OneSkin Technologies

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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.

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Chai Tea Muffins Recipe

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Recipe by Naturally Savvy

Teas are well-loved all over the world for their delicious flavors, fragrant aroma and health benefits. Chai tea possesses all  of these qualities. Its origins can be traced to India, , but it has become popular around the world,  with cafes and restaurants offering various chai beverages and companies producing premade tea bags and concentrates.

Chai tea tastes marvelous on its own, but it also pairs well with custards and baked goods. You can also incorporate it into a snack, just like in this recipe from Naturally Savvy. These muffins are infused with the goodness of chai and can be eaten as a tasty snack or a filling breakfast. If you’re looking for another way to consume chai or simply want to enjoy its flavor in a different form,   try making  these muffins and share them with your coworkers or friends.

Ingredients:

1 cup coconut milk
2 spiced chai tea bags
1 tablespoon apple cider vinegar
1/4 cup coconut oil
2 organic cage-free eggs
1 teaspoon vanilla
1 cup equivalent of monk fruit sweetener
2 teaspoons baking powder
1 1/2 teaspoons baking soda
1/2 teaspoon salt
1 cup spelt flour
3/4 cup brown rice flour
1/4 cup almond flour
2 1/2 teaspoons cinnamon
1 1/4 teaspoons ginger
1/4 to 1/2 teaspoon allspice

Procedure:

  • In a medium sauce pot bring coconut milk to a simmer. Add tea bags and simmer for five minutes. Remove from heat and steep for 15-plus minutes.
  • Heat oven to 350 degrees F.
  • Strain the coconut milk into a large mixing bowl. Add the remaining wet ingredients and whisk to combine.
  • Put all the dry ingredients in a separate mixing bowl and whisk to combine.
  • Combine the ingredients into the mixing bowl and mix until well-combined.
  • Divide the batter into a lined muffin pan and bake for 20 minutes, or until the muffins have set and a toothpick comes out clean.

What Are the Health Benefits of Chai?

The word “chai” translates to “tea” in Hindi, so chai tea actually translates to  “tea tea.” You can simply call this beverage “chai” or “masala chai,” as it’s known in India.

Chai is made by combining black tea with milk and spices like cardamom, cinnamon, ginger, star anise and cloves, although you can find varieties containing pepper, coriander, nutmeg and fennel. Some recipes add sugar, but I advise that you avoid using it or instead  add healthier sweeteners like raw honey, monk fruit (Luo Han) or stevia. ,

Black tea, which makes up the bulk of this drink, possesses antioxidant and anti-inflammatory abilities that may help reduce risk for coronary heart disease, lower blood pressure levels and assist in preventing weight gain. If you want to know more about how black tea is made and what it can do for your health, check out “Black Tea Is Great for Your Gut.”

The spices in this tea blend also increase the drink’s nutritional value, and various research has linked them to different health-boosting abilities:

  • Cinnamon may deliver antibacterial capabilities, help improve cardiovascular health by reducing blood pressure and bad cholesterol levels, , lower risk for insulin resistance and decrease fasting blood sugar levels. ,
  • Ginger, a well-loved spice, is known for its antinausea effects.
  • Cardamom may provide antioxidant and antibacterial abilities.
  • Cloves and black pepper both possess antibacterial properties, according to research. , ,

If you want to purchase black tea so you can make chai from scratch, only buy from a reputable seller or company that will  provide you with information regarding the tea’s processing and packaging methods. Don’t be misled by companies placing “quality” seals on their teas. Unfortunately, this could  just be a front to  cover up illegal and inhumane practices involved in tea production. For more on this topic, read my article, “The Dark Side of the Global Tea Industry.”

A Note if You Need to Lessen Your Grain or Lectin Intake

Take note that the recipe above uses grain-based flours. While I believe grains can be part of a healthy diet, they must not be consumed in excess  or they may trigger health-damaging issues. As much as possible, lessen your net carb intake below 15 to 20 grams daily until you have gained (or even regained) the ability to undergo ketosis or burn fat as your primary fuel. If this amount still isn’t enough for you to be in a state of ketosis, you may want to entirely avoid grain consumption, chai muffins included.

Another reason to be careful about consuming too many grains would be their lectin content. Lectins are a plant protein present in various foods that may provide some benefits, albeit in very small quantities.

However, most lectins act as “antinutrients” (especially in large amounts) since they can resist digestion, negatively affect the balance of your gut bacteria and cause problems within your gut microbiome. Lectins are abundant in wheat and other seeds belonging to the grass family like barley, corn, millet, oats and rye. In particular, wheat germ agglutinin (WGA),  found in wheat and in the other mentioned seeds, is considered one of the most detrimental lectins.

 If you have an autoimmune or inflammatory condition, exercise caution and be careful about consuming high amounts of lectin-rich foods like grains, beans, legumes and nightshade vegetables. Read my “Limit the Lectins” article to know more about what lectins are and how you can prevent some of the adverse effects that have been linked to them.

About Naturally Savvy

Founded by two holistic nutritionists and a trusted expert on healthy living, Naturally Savvy’s main focus is to make sure its readers eat organic and whole foods, while learning how to integrate nutrition into their daily lives. The website shares the latest news on heathy living, lessons about the harmful ingredients lurking in various food items available today and other tips to make you and your family live a happy and healthy life.

Find out more on Nitric Oxide Supplements and Cardiovascular health.

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Fight Aging! Newsletter, April 29th 2019

Top rated Supplements needed for Nitric Oxide Health


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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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Contents

  • Mesenchymal Stem Cells Derived via Reprogramming of Old Cells Exhibit a Transcriptomic Signature Closer to that of Younger Cells and Pluripotent Cells
  • Towards an Artificial Lymph Node
  • Physical Activity, mTOR Signaling, and Alzheimer’s Disease
  • Tackling Amyloid-β Oligomers by Interfering in Specific Interactions Necessary to Protein Aggregation
  • Dysfunctional and Senescent Immune Cells in Bone Marrow as a Cause of Age-Associated Lineage Skewing of Hematopoietic Stem Cells
  • STAT3, FAM3A, and Increased Muscle Stem Cell Activity
  • The NYC 2019 Ending Age-Related Disease Conference is Coming Up In July
  • A Demonstration of Amyloid-β Clearance via Affibodies in Mice
  • A New Approach to Targeting Tau Aggregation in Neurodegenerative Disease
  • Light Physical Activity Slows Brain Aging
  • Reviewing the Importance of the Blood-Brain Barrier in Brain Aging
  • The Influence of p53 on Aging is Far From Fully Understood
  • Amyloid-β is not Merely Molecular Waste
  • MicroRNAs Assist in Heart Regeneration
  • The Debate Continues over Sitting and Its Effects on Mortality

Mesenchymal Stem Cells Derived via Reprogramming of Old Cells Exhibit a Transcriptomic Signature Closer to that of Younger Cells and Pluripotent Cells

https://www.fightaging.org/archives/2019/04/mesenchymal-stem-cells-derived-via-reprogramming-of-old-cells-exhibit-a-transcriptomic-signature-closer-to-that-of-younger-cells-and-pluripotent-cells/

In today’s open access paper and publicity materials, researchers report on an assessment of induced mesenchymal stem cells (iMSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were produced via the usual approach of reprogramming from tissue samples taken from old adults. The researchers then compared the gene expression profiles of these iMSCs with similar MSCs taken from fetal and adult tissues. They declare the the profile to be rejuvenated in comparison to that of the adult MSCs, but I think one has to be careful when using that word. We might better call the profile reflective of reprogramming, in that while it has commonalities with the fetal MSCs, it also has has commonalities with the iPSCs, expression of proteins usually not found in adult cells.

The reason for attempting this experiment is that there are concerns regarding the safety and efficacy of MSCs derived from the tissues of old individuals, such as in the case of autologous stem cell therapies. These cells are damaged and in some ways notably dysfunctional, such as in the decline of mitochondrial function. If those cells could be derived instead from a skin sample and then via iPSCs, with many of their age-related defects corrected along the way, acquiring a more beneficial phenotype, then perhaps this would be a better option. The question is always whether or not this is just unsafe in a different direction, such as risk of cancer. A great deal of work is going into answer that question.

Reprogramming somatic cells into iPSCs clearly repairs a range of age-related phenotypes exhibited by cells in old tissues, most notably mitochondrial dysfunction. Moreover, these cells begin to secrete signals that on balance beneficial for regeneration, inflammation, and other aspects of cellular metabolism that become problematic in aging. Most stem cell transplants provided in clinics today work in this way, producing benefits due to the signals issues by the transplanted cells, which soon die rather than integrating into tissues. This signaling and damage repair are the basis for experimental work in inducing pluripotency in the tissues of living animals, and for advances on that work such as the epigenetic not-quite-reprogramming of Turn.bio.

Human iPSC-derived MSCs from aged individuals acquire a rejuvenation signature


The use of primary mesenchymal stem cells (MSCs) is fraught with ageing-related shortfalls such as limited expansion and early senescence. Human induced pluripotent stem cells (iPSCs) -derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these ageing-associated drawbacks. A collaborative study analysed the acquisition of rejuvenation-associated hallmarks in iMSCs. In their study, the team compared cellular features, transcriptomes and secretomes of iMSCs differentiated from embryonic stem cells (ESCs-H1) and iPSCs, emanating from MSCs isolated young and elderly individuals. The generated iMSCs (irrespective of source) met the criteria set out for MSCs and dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and distinct from pluripotent stem cells.

Irrespective of donor age and initial cell type, iMSCs acquired a rejuvenation-associated 50-gene comprising signature which is also expressed in pluripotent stem cells but not in the parental MSCs. Significantly, in terms of regenerative medicine, iMSCs acquired a secretome similar to that of primary MSCs, thus highlighting their ability to act via paracrine signalling. The iMSC concept has enabled circumventing the drawbacks associated with the use of adult MSCs and thus provide a promising tool for use in various clinical settings in the future.

Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature


Primary human bone marrow-derived stem cells (MSCs) contain a sub-population of multipotent stem cells. Due to highly proliferative, immune-modulatory properties, and paracrine orchestration, MSCs offer significant therapeutic potential for an increasing aging demographic. Although the bone marrow can be collected routinely to isolate MSCs, there are several drawbacks associated with the use of MSCs from aged individuals. The expansion possibilities and application potential of primary MSCs are limited, in part, by changes in the differentiation/response potential and function of MSCs isolated from aged donors. However, to date, it remains unclear whether there are any age-related differences in transcriptome and secretome signatures between human fetal MSCs and MSCs from elderly donors.

Recent studies have shown that the shortfalls associated with primary MSCs can be circumvented by reprogramming them to induced pluripotent stem cells (iPSCs). An iPSC-derived cell type that is of prime interest for circumventing shortfalls associated with primary MSCs are MSCs differentiated from iPSCs and ESCs (iMSCs). The similarity of iMSCs to primary MSCs and their regenerative potential in vivo has already been demonstrated. Moreover, the reflection of donor age in iMSCs was shown to be reverted into a younger state and at the same time reflected in iMSCs from patients with early onset aging syndromes. Although the paracrine effects of iMSCs have been indicated, relatively little is known about the potential to rejuvenate the paracrine features of MSCs from elderly patients via iMSC generation.

In view of this, there is a dire need to clarify in more detail whether age-related features inherent to primary MSCs isolated from elderly patients are retained in the corresponding iMSCs at the transcriptional, secretome, and functional level. In this study, we report the age-associated differences between fetal MSC (fMSC) populations and MSCs isolated from elderly donors with respect to their transcriptomes. We successfully reprogrammed fMSCs (55 days post conception) and adult MSC (aMSC; 60-74 years) to iPSCs and, subsequently, generated the corresponding iMSCs. In addition, iMSCs were also derived from ESCs. The iMSCs were similar although not identical to primary MSCs. We unraveled a putative rejuvenation and aging gene expression signature. We show that iMSCs irrespective of donor age and cell type re-acquired a similar secretome to that of their parental MSCs, thus re-enforcing their capabilities of context-dependent paracrine signaling relevant for tissue regeneration.

Towards an Artificial Lymph Node

https://www.fightaging.org/archives/2019/04/towards-an-artificial-lymph-node/

Artificial structures capable of replicating at least some of the functions of natural organs and tissues may turn out to be quite different in shape, structure, and content when compared to their natural counterparts. This is particularly true for chemical factory tissues, such as the liver, or tissues in which cells migrate and collaborate, such as lymph nodes. In today’s research, scientists demonstrate that a comparatively simple structure can perform some of the same useful functions of a lymph node, at least those related to training and replicating T cells to attack a particular pathogen or cancer cell population.

Natural lymph nodes act as a point of coordination for the immune system, allowing cells to recognize threats and marshal in numbers to fight it. Unfortunately lymph nodes deteriorate and become fibrotic with age, and this degrades the immune response by preventing the necessary coordination between cells. It is a major concern for the many groups attempting to produce rejuvenation of the aged immune system in one way or another. It is interesting to consider that there may be shortcuts towards useful implanted structures in the near future, artificial constructs that are far removed from an actual tissue engineered replacement lymph node, but that nonetheless alleviate a part of this problem. The work here is a very early proof of concept carried out with the goal of replicating T cells more efficiently outside the body, but it could nonetheless be carried forward to potential use in implants.

Scientists Advance Creation of ‘Artificial Lymph Node’ to Fight Cancer, Other Diseases


n the past few years, a wave of discoveries has advanced new techniques to use T-cells – a type of white blood cell – in cancer treatment. To be successful, the cells must be primed, or taught, to spot and react to molecular flags that dot the surfaces of cancer cells. The job of educating T-cells this way typically happens in lymph nodes, small, bean-shaped glands found all over the body that house T-cells. But in patients with cancer and immune system disorders, that learning process is faulty, or doesn’t happen.

CAR-T therapy generally takes about six to eight weeks to culture engineered T-cells in laboratories. To make the engineered T-cells’ environment more biologically realistic, researchers tried using a jelly-like polymer, or hydrogel, as a platform for the T-cells. On the hydrogel, the scientists added two types of signals that stimulate and “teach” T-cells to hone in on foreign targets to destroy. In their experiments, T-cells activated on hydrogels produced 50 percent more molecules called cytokines, a marker of activation, than T-cells kept on plastic culture dishes.

Because hydrogels can be made to order, scientists created and tested a range of hydrogels, from the very soft feel of a single cell to the more rigid quality of a cell-packed lymph node. One of the surprising findings was that T-cells prefer a very soft environment, similar to interactions with individual cells, as opposed to a densely packed tissue. More than 80 percent of T-cells on the soft surface multiplied themselves, compared with none of the T-cells on the most firm type of hydrogel. “As we perfect the hydrogel and replicate the essential feature of the natural environment, including chemical growth factors that attract cancer-fighting T-cells and other signals, we will ultimately be able to design artificial lymph nodes for regenerative immunology-based therapy.”

Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy


T cell therapies require the removal and culture of T cells ex vivo to expand several thousand-fold. However, these cells often lose the phenotype and cytotoxic functionality for mediating effective therapeutic responses. The extracellular matrix (ECM) has been used to preserve and augment cell phenotype; however, it has not been applied to cellular immunotherapies. Here, a hyaluronic acid (HA)-based hydrogel is engineered to present the two stimulatory signals required for T-cell activation – termed an artificial T-cell stimulating matrix (aTM).

It is found that biophysical properties of the aTM – stimulatory ligand density, stiffness, and ECM proteins – potentiate T cell signaling and skew phenotype of both murine and human T cells. Importantly, the combination of the ECM environment and mechanically sensitive TCR signaling from the aTM results in a rapid and robust expansion of rare, antigen-specific CD8+ T cells. Adoptive transfer of these tumor-specific cells significantly suppresses tumor growth and improves animal survival compared with T cells stimulated by traditional methods. Beyond immediate immunotherapeutic applications, demonstrating the environment influences the cellular therapeutic product delineates the importance of the ECM and provides a case study of how to engineer ECM-mimetic materials for therapeutic immune stimulation in the future.

Physical Activity, mTOR Signaling, and Alzheimer’s Disease

https://www.fightaging.org/archives/2019/04/physical-activity-mtor-signaling-and-alzheimers-disease/

Alzheimer’s disease is a condition that sits atop a mound of many contributing causes, layered in chains of cause and effect. Given that chronic inflammation and age-related impairment of the cellular housekeeping mechanisms of autophagy both appear to be significant, somewhere in the mix, it is perhaps to be expected that many of the usual healthy lifestyle choices have some modest impact on the progression of the condition. Exercise and calorie restriction both act to upregulate autophagy and it is thought that this accounts for a sizable fraction of the resulting benefits to health and life span. Unfortunately, the sort of stress response upregulation appears to scale down in impact on life span as species life span increases, though the effects on short term health and metabolism appear quite similar. Mice can live up to 40% longer when on a calorie restricted diet, but that is certainly not true for humans; we gain a few years at most.

Autophagy recycles damaged structures and broken proteins inside the cell. Neurodegenerative conditions such as Alzheimer’s disease involve the presence of toxic molecules, such as those associated with amyloid-β and tau, but even if not directly involved in clearing away disease-associated damage, increased autophagy is generally protective of cell function. Given that this includes everything from neurons to the microglia responsible for clearing away intracellular debris and protein aggregates, we should expect increased autophagy to modestly improve just about every issue in the aging brain. Sadly, doing better than modest improvement is probably not within the scope of what might be achieved via increased rates of autophagy, even when researchers directly influence regulatory genes such as mTOR.

Physical Activity Alleviates Cognitive Dysfunction of Alzheimer’s Disease through Regulating the mTOR Signaling Pathway


Autophagy as an evolutionary-conserved process can maintain normal physiological events or regulate the progression of a series of diseases through sequestering mis-folded/toxic proteins in autophagosomes, thus executing its cytoprotective role. Growing evidence demonstrates that autophagic capacity to degrade harmful proteins in cells declines with increasing age. Moreover, dysfunctional autophagy has also been linked to several aging-related neurodegenerative diseases including Alzheimer’s disease (AD). Previous studies have documented the critical role of autophagy in the pathogenesis of AD, including amyloid-β (Aβ) production or deposition, Aβ precursor protein (APP) metabolism, and neuronal death. Furthermore, insufficient or reduced autophagic activity can lead to the formation of harmful protein aggregates, which results in increased reactive oxygen species (ROS), cell death, and neurodegeneration. As a result, autophagy has a crucial role in the regulation of longevity.

Mammalian target of rapamycin (mTOR) regulates a series of physiological processes. On the one hand, mTOR plays an important role in different cellular processes including cell survival, protein synthesis, mitochondrial biogenesis, proliferation, and cell death. On the other hand, the mTOR signaling pathway can execute an important role in memory reconsolidation and maintaining synaptic plasticity for memory formation, due to its regulatory function for protein synthesis in neurons. Moreover, mTOR also can interact with upstream signal components, such as growth factors, insulin, PI3K/Akt, AMPK, and GSK-3. Currently, although the molecular mechanisms responsible for AD remain unclear, more and more studies have confirmed the involvement of dysregulated mTOR signaling in AD. Activated mTOR signaling is a contributor to the progression of AD and is coordinated with both the pathological and clinical manifestations of AD. Furthermore, there is a close relationship between mTOR signaling and the presence of Aβ plaques, neurofibrillary tangles, and cognitive impairment in clinical presentation. Therefore, the development of mTOR inhibitors may be useful for the prevention and treatment of AD.

It has been reported that regular physical activity can improve brain health and provide cognitive and psychological benefits. Mechanically, regular exercise training is related to the inhibition of oxidative stress and apoptotic signaling, thus effectively executing neuroprotection. Previous studies have demonstrated that treadmill or voluntary wheel running is beneficial for the improvement of behavioral capacity, and can promote the dynamic recycling of mitochondria, thereby improving the health status of mitochondria in brain tissues. Moreover, other studies have demonstrated that regular exercise has a beneficial effect on the structure, metabolism, and function of human and rodent brains. Interestingly, our recent study has also documented that the brain aging of d-gal-induced aging rats can be noticeably attenuated by eight-week swimming training, due to the rescuing of impaired autophagy and abnormal mitochondrial dynamics in the presence of miR-34a mediation. Therefore, physical activity is regarded as an effective approach against AD.

Tackling Amyloid-β Oligomers by Interfering in Specific Interactions Necessary to Protein Aggregation

https://www.fightaging.org/archives/2019/04/tackling-amyloid-%ce%b2-oligomers-by-interfering-in-specific-interactions-necessary-to-protein-aggregation/

The present consensus on the the development of Alzheimer’s disease is that it starts with the accumulation of amyloid-β, though there are many competing theories as to why only some people exhibit this problem to a great enough degree to produce pathology. The biochemistry of oligomers supporting amyloid-β causes sufficient disarray in brain metabolism to set the stage for neuroinflammation, malfunction of immune cells in the brain, and aggregation of altered forms of tau protein into neurofibrillary tangles that cause most of the damage and cell death in the later stages of the condition. The failure to improve outcomes via attempts to remove amyloid-β from the brains of Alzheimer’s patients may be a case of too little, too late, but there is still good reason to remove amyloid-β. Doing so early enough and efficiently enough should prevent the later stages of the condition from developing at all.

The most modern approach to drug development, built atop greatly improved capacities in computation and associated modeling of protein structures and interactions, is to find points of intervention through a greater understanding of how proteins interact with one another, in detail, and how those interactions pertain to disease processes. Researchers can then rationally design molecules that (a) interfere at a vulnerable and highly specific point in a desired interaction and (b) due to this specificity are safe enough for clinical use, as they cause only limited disruption elsewhere in the operation of cellular biochemistry. This is the ideal, in any case. The challenge, as ever, is finding a point of intervention that does in fact turn out to be both specific enough and good enough in practice, in patients.

The research noted here today is an example of this approach to development applied to preventing the aggregation of amyloid-β. In principle, sufficient disruption of the process of forming protein aggregates should allow existing systems of clearance to remove excess or damaged protein molecules before they causes issues. In practice, we shall see how it turns out as this work progresses.

Synthetic peptide can inhibit toxicity, aggregation of protein in Alzheimer’s disease


Alzheimer’s is a disease of aggregation. Neurons in the human brain make a protein called amyloid beta. Such proteins on their own, called monomers of amyloid beta, perform important tasks for neurons. But in the brains of people with Alzheimer’s disease, amyloid beta monomers have abandoned their jobs and joined together. First, they form oligomers – small clumps of up to a dozen proteins – then longer strands and finally large deposits called plaques. For years, scientists believed that the plaques triggered the cognitive impairments characteristic of Alzheimer’s disease. But newer research implicates the smaller aggregates of amyloid beta as the toxic elements of this disease.

Now, researchers have developed synthetic peptides that target and inhibit those small, toxic aggregates. Their synthetic peptides – which are designed to fold into a structure known as an alpha sheet – can block amyloid beta aggregation at the early and most toxic stage when oligomers form. The team showed that the synthetic alpha sheet’s blocking activity reduced amyloid beta-triggered toxicity in human neural cells grown in culture, and inhibited amyloid beta oligomers in two laboratory animal models for Alzheimer’s. These findings add evidence to the growing consensus that amyloid beta oligomers – not plaques – are the toxic agents behind Alzheimer’s disease. The results also indicate that synthetic alpha sheets could form the basis of therapeutics to clear toxic oligomers in people.

“This is about targeting a specific structure of amyloid beta formed by the toxic oligomers. What we’ve shown here is that we can design and build synthetic alpha sheets with complementary structures to inhibit aggregation and toxicity of amyloid beta, while leaving the biologically active monomers intact.”

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease


Alzheimer’s disease (AD) is characterized by the deposition of β-sheet-rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils.

De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

Dysfunctional and Senescent Immune Cells in Bone Marrow as a Cause of Age-Associated Lineage Skewing of Hematopoietic Stem Cells

https://www.fightaging.org/archives/2019/04/dysfunctional-and-senescent-immune-cells-in-bone-marrow-as-a-cause-of-age-associated-lineage-skewing-of-hematopoietic-stem-cells/

The immune system declines with age for a range of reasons. The thymus atrophies, reducing the supply of new T cells; persistent infection by cytomegalovirus causes cells to become uselessly specialized rather than ready to tackle new threats; and the hematopoietic stem cells responsible for generating immune cells become damaged, inactive, and dysfunctional. One of these forms of dysfunction is that hematopoietic stem cells begin to generate too many myeloid cells and too few lymphoid cells, the so-called myeloid skew.

The cause of this skewing in cell production is much debated, but researchers have found that chronic inflammation plays a role. Naturally, nowadays whenever inflammation appears to be an important aspect of any age-related dysfunction, attention turns towards senescent cells. Lingering senescent cells accumulate with age in all tissues, and secrete a potent mix of signals that rouses the immune system into an inflammatory state. It seems likely that they are an important part of the problem when it comes to the myloid skew in the hematopoietic stem cell population.

Why do senescent cells accumulate with age? Cells become senescent in great numbers throughout life, but only later do they linger to a significant degree. Near all are destroyed, either by their own programmed cell death processes, or by the immune system, called into action by the inflammatory signaling of the senescent cells. One reason for a greater number of lingering senescent cells in later life is that the immune system declines and falters in destroying errant cells. Thus, like many issues in aging, the relationship between cellular senescence and immune decline is a circular one; these two processes start off very slowly, but feed one other and accelerate as time passes and damage mounts.

Aged marrow macrophages expand platelet-biased hematopoietic stem cells via Interleukin1B


Dysfunction of the human hematopoietic system with age includes diminished immune response, marrow failure, and clonal selection. Aging is also associated with a general increase in tissue inflammation that remains largely unexplained. The mechanisms driving these characteristics of aged hematopoiesis have, to date, primarily been attributed to intrinsic hematopoietic stem cell (HSC) changes. With age, in both humans and mice, the phenotypic long-term HSC (LT-HSC) pool is expanded and globally LT-HSCs differentiate preferentially towards the myeloid lineage.

Multipotent HSCs with platelet bias were recently identified by a number of investigators describing their increased expression of von Willebrand Factor (vWF) and of the Integrin αIIb (CD41). Recent data demonstrate that aged murine HSCs also have increased cell-surface expression of CD41 and vWF. Notably, human aged HSCs display platelet (or megakaryocytic) bias, suggesting that insights in mechanisms determining murine HSC platelet bias will not only improve our understanding of diseases attributed to the aging hematopoietic system, but also provide novel therapeutic approaches to hematopoietic dysfunction associated with advanced age.

Since the bone marrow microenvironment (BMME) critically regulates HSCs, whether it be considered instructive or enabling distinct HSC fates, unique characteristics of the aged BMME could contribute to HSC changes associated with age. In fact, in the Drosophila gonad, extrinsic signals from the niche contribute to stem cell aging, and mathematical models have suggested that non-cell-autonomous changes could drive this process in mammalian HSCs. While data have suggested that aged endothelial and mesenchymal BMME populations are abnormal and may participate in HSC aging, microenvironmental signals governing the megakaryocytic bias of aged HSCs remain unclear. Thus, we hypothesized that defects in critical BMME populations caused by age could lead to the expansion of platelet-biased HSCs.

We found that macrophages (Mφs) within the aged BMME could impose the megakaryocytic bias characteristic of aging in HSCs. Aged human and murine marrow Mφs had distinct transcriptional profiles compared to young Mφs, including an increased inflammatory activation signature. We identified increased interleukin 1B (IL1B) mRNA in aged marrow Mφs and elevated caspase 1 activity in Mφs and neutrophils from aged bone marrow. Moreover, IL1B signaling was necessary and sufficient to induce HSC bias and drive young HSPCs to adopt an aged phenotype.

While investigating the cause of this increase, we made the novel observation that aged marrow Mφs had a defect in efferocytosis – their ability to clear apoptotic cells. Clearance of apoptotic cells is a critical function of Mφs that prevents necrosis of dead cells and associated local inflammation and also triggers anti-inflammatory responses in phagocytes. In young mice, removal of phagocytic cells or genetic loss of the efferocytic receptor Axl increased HSCs with megakaryocytic bias, suggesting that the efferocytic defect in aged marrow Mφs leads to the increase in IL1B activation and signaling. Together these data define a novel mechanism within the aged BMME that enables a specific HSC fate.

STAT3, FAM3A, and Increased Muscle Stem Cell Activity

https://www.fightaging.org/archives/2019/04/stat3-fam3a-and-increased-muscle-stem-cell-activity/

Expression of the STAT3 gene influences a number of vital cellular processes, such as mitochondrial activity, cellular differentiation, and cellular proliferation. Researchers have investigated its activity in the context of spurring greater regenerative activity in heart muscles, for example. Arguably this is a good example of a regulatory gene that is involved in too many processes to make it a good target for therapeutics, however. More specific, lower-level mechanisms for specific desired goals would be helpful. That requires slow and costly investigative work, however, picking apart the relationships between proteins and their roles.


Researchers have uncovered a molecular signaling pathway involving Stat3 and Fam3a proteins that regulates how muscle stem cells decide whether to self-renew or differentiate – an insight that could lead to muscle-boosting therapeutics for muscular dystrophies or age-related muscle decline. “Muscle stem cells can ‘burn out’ trying to regenerate tissue during the natural aging process or due to chronic muscle disease. We believe we have found promising drug targets that direct muscle stem cells to ‘make the right decision’ and stimulate muscle repair, potentially helping muscle tissue regeneration and maintaining tissue function in chronic conditions such as muscular dystrophy and aging.”

Muscle wasting occurs as part of the natural aging process, called sarcopenia, or due to genetic diseases such as muscular dystrophy. Sarcopenia affects nearly 10 percent of adults over the age of 50 and nearly half of individuals in their 80s. Muscle stem cells select between two fates over a person’s lifetime: Either differentiate to become adult muscle cells or self-renew to replenish the stem cell population. Accumulating evidence shows that mitochondrial respiration is a key switch that drives muscle stem cells to differentiate, an energy-intensive process, instead of self-renew.

In the study, the scientists used mouse models to demonstrate that Stat3 promotes mitochondrial respiration. Because Stat3 regulates many cellular processes, the scientists combed through genes expressed during muscle growth to find additional proteins regulated by Stat3 that might serve as more specific targets. These efforts uncovered the protein Fam3a. Further work conducted, including generating a mouse model and cell lines that lack Fam3a, demonstrated that the protein is required for muscle stem cell differentiation and muscle growth. The researchers also showed that Fam3a is secreted by muscle cells during muscle repair, and treatment with the protein restored mitochondrial respiration and stem cell differentiation in muscle stem cells that lacked Stat3 – all demonstrating the integral role of Fam3a in determining muscle stem cells’ fate.

The NYC 2019 Ending Age-Related Disease Conference is Coming Up In July

https://www.fightaging.org/archives/2019/04/the-nyc-2019-ending-age-related-disease-conference-is-coming-up-in-july/

It isn’t long now until the Life Extension Advocacy Foundation will be hosting their second Ending Age-Related Diseases conference in New York City. The event takes place on July 11th and 12th this year, and features a mix of noted researchers, investors, and entrepreneurs involved in the present development of means to treat aging as a medical condition. Last year’s conference was a great event for networking with new members of our growing longevity science and advocacy community, and video of the presentations can be found online.


Aging research is on the cusp of some major breakthroughs in the battle against age-related diseases, and we invite you to join us for an action-packed event filled with exciting talks and discussion panels featuring some of the leaders of aging research and the biotech business. We are still announcing more speakers for this exciting event and think that today is a great time to update everyone about what has been happening. We are delighted that Dr. Maria Blasco will be speaking at the conference this year. Dr. Blasco is a true pioneer in aging research, and her work with cancer and telomeres is well known.

Dr. João Pedro de Magalhães from Liverpool University has also just confirmed that he is going to be speaking at the event this year. Dr. Magalhães believes that the complexity and multi-dimensional nature of aging require that this biological problem be tackled using a combination of disciplines and approaches. He and his team have been conducting studies of the genetics, physiology, and cell biology of long-lived animals. He is perhaps best known for his genetic studies on long-lived species, such as the bowhead whale and the naked mole rat.

We will also be joined by Dr. Michael Lustgarten from Tufts University. Dr. Lustgarten is no stranger to us, as he has appeared in an episode of the Journal Club, a special microbiome webinar, and an interview with us. Dr. Lustgarten is a researcher at the Nutrition, Exercise Physiology, and Sarcopenia Laboratory (NEPS) at the Human Nutrition Research Center on Aging at Tufts. His research is focused on how the gut microbiome and serum metabolome affect muscle mass and function in older people. Dr. Lustgarten is an expert on the gut microbiome, exercise, biomarkers, and nutrition.

A Demonstration of Amyloid-β Clearance via Affibodies in Mice

https://www.fightaging.org/archives/2019/04/a-demonstration-of-amyloid-%ce%b2-clearance-via-affibodies-in-mice/

While clearing out amyloid-β from the brain has so far proven to be a matter of too little, too late in late stage Alzheimer’s disease patients, there is still a strong basis of evidence for the merits of removing amyloid-β. It is reasonable to say that it causes meaningful pathology; if people did not accumulate amyloid-β deposits, then there would be no consequent disarray in the function of neurons and immune cells in the brain. This particular foundation of the development of dementia would be removed. Even if the mechanisms of the later stages of Alzheimer’s, the chronic inflammation and tau protein aggregation, for example, were blocked, then amyloid-β accumulation would still cause at least mild cognitive impairment on its own. Thus despite the continued failure of clinical trials, even those in which amyloid-β was in fact cleared to a fair degree from the brains of Alzheimer’s patients, we should still be encouraged by new approaches and other signs of progress in this area of the field.


Present therapies for Alzheimer’s disease (AD) have either no or minimal disease-modifying effect, and thus, there is an urgent need for new effective treatments. Numerous therapeutic strategies are under investigation to delay the onset or slow progression of the disease. Active and passive immunotherapeutic approaches have been suggested to improve clinical progression and cognitive impairment through different mechanisms: (i) inhibition of amyloid-β (Aβ) production; (ii) interference with the formation of toxic aggregation intermediates; and (iii) accelerated clearance of Aβ from the central nervous system into the periphery.

Several anti-Aβ antibodies have demonstrated effective clearance of Aβ together with cognitive improvements in transgenic animal models and consequently progressed to clinical trials. However, translation to safe and efficacious therapies for humans has been challenging as AD clinical trials have failed to show sufficient clinical benefits. Recently, the monoclonal antibody (mAb) Solanezumab, that binds monomeric Aβ, was extensively evaluated in a phase III prevention trial in patients with mild AD. The study was however terminated due to failure in showing cognitive improvements.

It has been proposed that challenges related to the failure in showing overall clinical improvement or clear disease-modifying results of these mAbs could be addressed to some of the inherent properties of antibodies. Thus, new approaches based on engineered antibody domains or alternative scaffold-proteins that generally lack immunoglobulin-related effector functions are now investigated and moving into clinical development, as they might provide safer and more effective treatments. Antibody derivatives and non-immunoglobulin affinity proteins are in general smaller than full-length antibodies. Their smaller size could potentially result in a different in vivo biodistribution profile as well as simplified administration routes, which could be important in the treatment of e.g., AD.

Affibody molecules represent a class of promising alternative scaffold proteins that have been investigated for various applications. We have previously reported on the generation of an affibody molecule (denoted ZAb3) that binds to monomeric Aβ. This Aβ-sequestering affibody molecule has demonstrated efficient inhibition of formation of Aβ aggregates in an in vivo Drosophila AD model, and abolished the neurotoxic effects as well as restored the life span of the flies. The affibody molecule was further engineered into a truncated genetic dimer, ZSYM73-ABD.

Encouraged by these positive results, we here investigate the efficacy of ZSYM73-ABD as a therapeutic candidate to prevent the development of AD-related pathology in transgenic AD mice. The animals received three weekly injections of 100 μg therapeutic protein or negative control protein during 13 weeks, starting at the expected onset of pathology development. Extensive behavioral assessment together with histological evaluation demonstrated a significantly lower amyloid burden in both cortex and hippocampus, as well as rescued cognitive functions of the ZSYM73-ABD treated mice relative to controls.

A New Approach to Targeting Tau Aggregation in Neurodegenerative Disease

https://www.fightaging.org/archives/2019/04/a-new-approach-to-targeting-tau-aggregation-in-neurodegenerative-disease/

Researchers here report on discovering that an existing farnesyltransferase inhibitor drug reverses the accumulation of altered tau protein aggregates in a mouse model. The death and dysfunction of nerve cells in the neurodegenerative conditions known as tauopathies is driven by the formation of neurofibrillary tangles, made of tau protein. That in turn has deeper causes, such as the chronic inflammation produced by senescent cells and disruption of immune cell activity in the central nervous system, one of which is no doubt being adjusted in some way by the action of the drug in this case. As in all such quite indirect mechanisms, there is the question as to whether results in mice will translate to humans in any useful way. In the case of an existing drug, there is at least a shorter path to an answer.


Tau, a protein found primarily in neurons, is typically a somewhat innocuous, very soluble protein that stabilizes microtubules in the axon. However, when soluble, stable tau misfolds the resulting protein becomes insoluble and tangled, gumming up the works inside the neuron as a neurofibrillary tangle. In one of several neurodegenerative diseases caused by tau, frontotemporal dementia, the frontal and temporal lobes of the brain are impaired, resulting in problems with emotion, behavior and decision-making.

By taking skin cell samples from a few individuals who harbor tau mutations and converting them in vitro into stem cells, and then into neurons, researchers found that three genes were consistently disregulated in those with tau mutations, one of which was of particular interest: RASD2 – a gene expressed primarily in the brain that belongs in a family that catalyzes energy-producing molecules (GTPases) and which has been studied extensively. A GTPase called Rhes is encoded by the gene RASD2. Like its cousins in the Ras superfamily, Rhes is a signaling protein that does its work on the cell surface, where it is attached to the inner membrane by a small carbon chain – a farnesyl group – through a process called farnesylation.

This attachment has been the target of a couple decades of cancer research under the assumption that if the Ras protein connection to the cell membrane could be interrupted, so would the signals that cause unregulated growth of tumor cells and other cancer behaviors. The drugs in this category, called farnesyltransferase inhibitors, have been tested in humans. But, they did not work in cancer.

In mice models with frontotemporal dementia, however, it seems they do. And the results are dramatic. Using the drug Lonafarnib, the researchers treated mice who at 10 weeks were erratic – running around in circles or completely apathetic – and by 20 weeks they were sniffing around their cage or nest building and doing other normal mouse behaviors. Scans revealed the arrest of brain tissue deterioration and inflammation. Most dramatic: The once-insoluble neurofibrillary tangles were greatly reduced, and in some areas including the hippocampus – the memory part of the brain – were nearly completely gone. To prove the drug was targeting the farnsylated Rhes protein, the scientists introduced into the brains of other mouse models an inhibitory RNA gene that specifically suppresses the production of Rhes. And the results completely replicated the effects of the drug.

Light Physical Activity Slows Brain Aging

https://www.fightaging.org/archives/2019/04/light-physical-activity-slows-brain-aging/

In recent years, with the enthusiastic adoption of accelerometers by the designers of epidemiological studies, it has become clear that even quite modest levels of physical activity correlate strongly with improved health and a slower pace of age-related degeneration. In most human data there is no way to establish which of these is cause and which of these is consequence, but animal studies are quite definitive on the point that exercise produces improvements in health, even if it doesn’t appear to extend life span. Physical activity, like all interventions, has a dose-response curve, and there is a sizable difference between being sedentary and being even modestly active. It is still a better idea to be more than just modestly active, of course; research suggests that the recommended levels of exercise, 150 minutes per week, may well be too low.


Considerable evidence suggests that engaging in regular physical activity (PA) may prevent cognitive decline and dementia. Active individuals have lower metabolic and vascular risk factors, and these risk factors may explain these individuals’ propensity for healthy brain aging. Even short-term exercise interventions have been shown to prevent hippocampal atrophy in older adults11 and may also improve brain connectivity. Furthermore, cross-sectional epidemiologic studies have established an association of physical inactivity with brain aging. However, further work is needed to pinpoint the optimal dosage of PA needed to promote healthy brain aging.

A growing body of literature has established light-intensity PA as an important factor for improving health outcomes, but in our review of the literature, light-intensity PA has not often been considered separately from total PA for its association with brain structure. Previous studies have identified positive associations of self-reported PA with brain volume, but accelerometry studies often have smaller sample sizes and have focused on examining the association of total PA with brain volume. However, PA variables are associated with one another, so in our analyses, we went a step further and modeled them together to determine what type of PA intensity (low or high) is driving the association of PA with brain volume.

The simplification of PA as a predictor variable has potentially masked more nuanced associations of components of PA with brain health. Compared with previous research, our study provides multiple PA levels and intensities and uses accelerometry-determined intensity thresholds (ie, light-intensity PA and moderate to vigorous PA) in the same statistical models to provide a more sensitive measure of PA doses and examine what type of PA is driving the associations we observe.

The study sample of 2354 participants had a mean age of 53 years, 1276 were women, and 1099 met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging. Among individuals not meeting the PA guidelines, each hour of light-intensity PA and achieving 7500 steps or more per day were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume.

Reviewing the Importance of the Blood-Brain Barrier in Brain Aging

https://www.fightaging.org/archives/2019/04/reviewing-the-importance-of-the-blood-brain-barrier-in-brain-aging/

The blood-brain barrier is a specialized layer of cells that wrap blood vessels passing through the central nervous system, ensuring that only certain molecules can pass in either direction. Thus the biochemistry of the central nervous system is kept distinct from that of the rest of the body. This separation is necessary for correct function, as illustrated by the point that the blood-brain barrier begins to break down with advancing age. This produces damage and dysfunction in the brain, as unwanted cells and molecules leak through the faulty blood-brain barrier. As noted here, however, the relative scope and size of this contribution to neurodegeneration, in comparison to other contributing factors, is far from fully determined.


Changes in the immune system have long been recognized to occur with aging, and it is now appreciated that neuroinflammation likely contributes to age-associated neurological diseases. However, it is less well understood how specific changes in the immune system with aging may affect central nervous system (CNS) functions and contribute to neurological disease. We posit that brain barriers, especially the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are important interfaces between CNS and peripheral tissues that are affected by age-associated changes in the immune system. The BBB/BCSFB may, in turn, affect homeostatic functions of the CNS, and/or exhibit more detrimental responses to pathological stimuli.

One of the most-studied (and yet, poorly understood) aspects of BBB dysfunction is disruption, which is typically defined by the apparent leakage of normally BBB impenetrant molecules. Recent imaging results argue that BBB disruption does occur in healthy aging, and is worse in individuals with mild cognitive impairment, which is considered a prodrome of Alzheimer’s disease (AD). One common approach to proxy BBB disruption in living humans is to measure the ratio of abundant, BBB-impermeant proteins such as albumin or immunoglobulin G (IgG) in cerebrospinal fluid (CSF) versus serum. However, these measures may be confounded by other known CNS deficits with aging, such as altered production and reabsorption of CSF, and inflammatory changes in the serum and CSF levels of these proteins. Further, there may be leakage of the BCSFB and altered protein synthesis at this site with age. Recent studies have implemented advanced imaging technologies that can visualize leakage of intravenously injected tracers via dynamic contrast MRI, and these have indicated that vascular BBB disruption does occur in the aging human brain, albeit at low levels.

In healthy aged mice, leakage of IgG into the parenchymal space of the cerebral cortex and hippocampus occurs when compared with young mice, suggesting that there is BBB disruption in this model. Increased IgG leakage in aged mice was associated with astrogliosis, endoplasmic reticulum (ER) stress, and increased endothelial cell levels of TNF-α; the latter measure significantly correlated with circulating levels of IL-6. In the same study, a significant reduction in occludin expression per brain endothelial cell was also observed in aged mice. Other studies have corroborated findings of BBB disruption in aging mice. Molecular mechanisms of BBB disruption in aging have been identified, and include reduced expression of sirtuin-1, a de-acetylase enzyme which has been implicated in the regulation of lifespan, senescence, and inflammatory responses to environmental stress.

BBB disruption in the context of aging or disease could result in disease exacerbation through leakage of potentially harmful proteins into the brain. However, it is not entirely clear that BBB disruption under any circumstance will always lead to brain damage. For example, certain therapeutic strategies for delivery of chemotherapeutics to the brain have relied on transiently disrupting the BBB, and are generally well-tolerated when brain cancers are the target. Recent work has also indicated that repeated transient BBB disruption in humans with AD using focused ultrasound did not cause any serious clinical or radiological adverse events. In contrast, healthy rodents with no prior brain abnormalities showed symptoms of reactive gliosis and neurodegeneration when transiently perfused with mannitol to cause widespread disruption of the BBB, and also had increased deposition of harmful serum proteins like fibrinogen in the CNS. The apparent paradox in efforts to disrupt the BBB as a therapeutic strategy versus BBB disruption having known adverse consequences on the CNS and associations with many CNS diseases highlights the complexities of BEC barrier functions that are likely nuanced and context-specific. Why BBB disruption in and of itself is apparently innocuous under some conditions, but clearly detrimental in others remains to be understood in greater molecular detail.

The Influence of p53 on Aging is Far From Fully Understood

https://www.fightaging.org/archives/2019/04/the-influence-of-p53-on-aging-is-far-from-fully-understood/

The p53 protein sits at the intersection of aging and cancer. Too much p53 activity and cell is activity is shut down, cells are made senescent more aggressively, and this leads to accelerated aging. Too little p53 activity, and precancerous cells might survive to form an ultimately fatal tumor. This is a considerable oversimplification of a very complex set of systems, however. There are plenty of exceptions to the above rule, including examples of conditional upregulation of p53 in mice that both extends life and reduces cancer incidence. The open access paper here discusses some of the complexities and contractions in what is known of the role of p53 – a gene that is well studied, but not yet comprehensively understood.


To accelerate aging, p53 induces apoptosis or cell cycle arrest as a prerequisite to cellular senescence; both can impair the mobilization of stem and progenitor cell populations. To suppress aging, p53 inhibits unregulated proliferation pathways that could lead to cellular senescence and a senescence-associated secretory phenotype (SASP), which creates a pro-inflammatory and degenerative tissue milieu. A review of mouse models supports both possibilities, highlighting the complexity of the p53 influence over organismal aging. These models were originally designed to study cancer but some appear to impact aging and longevity as well. They range from complete p53 null mutations to truncations or point mutations that alter activity. A comparison of these models reveals the complex influence p53 has over organismal aging – which can be independent or a consequence of its tumor suppressor role.

The initial mouse models were simple knockouts that produced no p53 protein. Most p53-/- embryos developed into apparently healthy adults, almost all of which succumb to cancer in about half a year. Heterozygous (p53+/-) mice develop cancer at a later age. Since simple p53-deletion increases cancer, simple overexpression should reduce cancer. Indeed, mice harboring an extra p53 gene contained within a BAC (bacterial artificial chromosome) had a lower incidence of cancer with no obvious effect on aging. Furthermore, increased gene dosage of p53 together with Arf lowered the cancer incidence and improved overall survival. ARF elevates p53 levels by inhibiting MDM2. Similarly, mice with a hypomorphic MDM2 allele, which increased p53 levels, showed a reduced cancer incidence without deleterious side effects. Thus, enhanced p53-mediated cancer suppression was not toxic to adult mice. It is possible that the pro-aging side effects of p53 are manifest only when p53 overwhelms the many regulatory mechanisms that modulate its activity.

The p53-null and p53-elevated mouse models support a simple notion of function; that is, p53 suppresses cancer without toxic side effects. However, other p53-altered mouse models confound this notion. p53 levels influenced aging in mice defective for BRCA1. BRCA1 repairs DNA double strand breaks (DSBs) created during DNA replication as a part of the homologous recombination repair pathway. Deleting one copy of p53 rescued brca1-/- mice from embryonic lethality but these mice displayed an early aging phenotype. Moreover, decreased capacity to repair DSBs caused p53-dependent early cellular senescence in cells and early organismal aging. Another genetic alteration that implicates p53 in aging is REGγ. REGγ-deficient mice display early aging. Elevated p53 might contribute to this phenotype because REGγ is a proteasome activator that regulates p53. Finally, skin-specific MDM2 deficiency resulted in p53-induced senescence in epidermal stem cells and precocious skin aging. These examples are interesting contrasts to the MDM2 hypomorphic allele described above, which reduced cancer without side effects, and suggests that different aspects of p53 regulation, coupled with genetic and environmental variances, can drive distinct biological outcomes.

Further complicating the picture, there are multiple p53 isoforms and family members (p63 and p73) generated from variant promoter usage, alternative splicing, and alternative translation initiation. How these isoforms differ functionally is not fully understood. There is evidence that some of these isoforms could influence aging. For example, expression of the N-terminally truncated p53 isoform in mice lowered cancer risk at the expense of early aging. These mice showed poor tissue regeneration, implicating a defect in stem and progenitor cells. Supporting this possibility, old p53+/- mice exhibited increased levels of hematopoietic stem and progenitor cells, but not if N-terminally truncated p53 was present. The truncated p53 likely forms a tetramer with full-length p53 to improve stability and nuclear localization. Another isoform stabilized p53 in the presence of MDM2. Thus, p53 isoforms have the potential to influence p53 function in a manner that affects aging.

Amyloid-β is not Merely Molecular Waste

https://www.fightaging.org/archives/2019/04/amyloid-%ce%b2-is-not-merely-molecular-waste/

Alzheimer’s disease begins with the accumulation of amyloid-β in the brain, but this doesn’t mean that amyloid-β is purely molecular waste. Yes, it is harmful given the presence of too much of it in the central nervous system, but that is true of most of our biochemistry. There is good evidence for amyloid-β to act as an antimicrobial system, for example, which is the basis for considering persistent infection as a potential contributing cause of Alzheimer’s disease, in which infectious agents drive the generation of ever increasing amounts of amyloid-β. Even setting aside that and other evidence, however, it is quite possible to argue that amyloid-β must have some important function, based on evolutionary theory and the fact that the molecule exists at all.


The argument is frequently made that the amyloid-β protein (Aβ) persists in the human genome because Alzheimer’s disease (AD) primarily afflicts individuals over reproductive age and, therefore, there is low selective pressure for the peptide’s elimination or modification. This argument is an important premise for AD amyloidosis models and therapeutic strategies that characterize Aβ as a functionless and intrinsically pathological protein. Here, we review whether evolutionary theory and data on the genetics and biology of Aβ are consistent with low selective pressure for the peptide’s expression in senescence.

Aβ is an ancient neuropeptide expressed across vertebrates. Consistent with unusually high evolutionary selection constraint, the human Aβ sequence is shared by a majority of vertebrate species and has been conserved across at least 400 million years. Unlike humans, the overwhelming majority of vertebrate species do not cease reproduction in senescence and selection pressure is maintained into old age. Hence, low selective pressure in senescence does not explain the persistence of Aβ across the vertebrate genome.

The Grandmother hypothesis (GMH) is the prevailing model explaining the unusual extended postfertile period of humans. In the GMH, high risk associated with birthing in old age has lead to early cessation of reproduction and a shift to intergenerational care of descendants. The rechanneling of resources to grandchildren by postreproductive individuals increases reproductive success of descendants. In the GMH model, selection pressure does not end following menopause. Thus, evolutionary models and phylogenetic data are not consistent with the absence of reproductive selection pressure for Aβ among aged vertebrates, including humans.

Our analysis suggests an alternative evolutionary model for the persistence of Aβ in the vertebrate genome. Aβ has recently been identified as an antimicrobial effector molecule of innate immunity. High conservation across the Chordata phylum is consistent with strong positive selection pressure driving human Aβ’s remarkable evolutionary longevity. Ancient origins and widespread conservation suggest the human Aβ sequence is highly optimized for its immune role.

MicroRNAs Assist in Heart Regeneration

https://www.fightaging.org/archives/2019/04/micrornas-assist-in-heart-regeneration/

Many researchers are exploring the therapeutic utility of microRNAs involved in fundamental cellular processes such as replication. These molecules act to regulate the processes of gene expression, determining how much of specific proteins are produced from their genetic blueprints, and when. Protein amounts are the switches and dials of cellular operation, and delivering microRNAs into cells is one possible way to steer cells into useful behavior – through the sheer complexity of the cell makes identifying the right tools to use quite difficult, and any given microRNA may produce quite sweeping changes, only few of which are helpful in any given context. Nonetheless, as illustrated here, there are some possible paths forward towards near future applications of microRNA delivery in regenerative medicine.


Once the heart is fully formed, the cells that make up heart muscle, known as cardiomyocytes, have very limited ability to reproduce themselves. After a heart attack, cardiomyocytes die off; unable to make new ones, the heart instead forms scar tissue. Over time, this can set people up for heart failure. New work advances the possibility of reviving the heart’s regenerative capacities using microRNAs – small molecules that regulate gene function and are abundant in developing hearts. Researchers had earlier identified a family of microRNAs called miR-17-92 that regulates proliferation of cardiomyocytes. In the new work, they show two family members, miR-19a and miR-19b, to be particularly potent and potentially good candidates for treating heart attack.

Researchers tested the microRNAs delivered two different ways. One method gave them to mice directly, coated with lipids to help them slip inside cells. The other method put the microRNAs into a gene therapy vector designed to target the heart. Injected into mice after a heart attack – either directly into the heart or systemically – miR-19a/b provided both immediate and long-term protection. In the early phase, the first 10 days after heart attack, the microRNAs reduced the acute cell death and suppressed the inflammatory immune response that exacerbates cardiac damage. Tests showed that these microRNAs inhibited multiple genes involved in these processes. Longer-term, the treated hearts had more healthy tissue, less dead or scarred tissue and improved contractility, as evidenced by increased left-ventricular fractional shortening on echocardiography. Dilated cardiomyopathy – a stretching and thinning of the heart muscle that ultimately weakens the heart – was also reduced.

The Debate Continues over Sitting and Its Effects on Mortality

https://www.fightaging.org/archives/2019/04/the-debate-continues-over-sitting-and-its-effects-on-mortality/

Do periods of sedentary behavior, in particular sitting, increase the risk of mortality and age-related disease regardless of whether or not there are periods surrounding exercise? The epidemiological research community can take decades and dozens of studies to chew over questions like this. Most recently, evidence was presented to suggest that sitting for longer periods of time is an independent risk factor for mortality even for those who exercise. The study here presents evidence for a more nuanced conclusion, that exercise does compensate for periods of time spent sitting.

This sort of contradictory data is very much par for the course in this area of study: ignore any single set of results, and look for consensus across as many studies as possible. Meanwhile consider whether or not the arrow of causation might point from health and mortality risk to behavior such as sitting and activity; are less active people exhibiting higher mortality because unhealthy people tend to be less active, for all the obvious reasons, for example?


For less active adults, the amount of time spent sitting may be associated with an increased risk of death; however, increasing physical activity to recommended levels may eliminate this association in some. Recent studies have determined that high levels of sedentary behavior are associated with adverse health outcomes. However, the link between sedentary behavior, mortality, and heart disease are not always well understood.

In this study, researchers aimed to determine the association between sedentary behavior and physical activity on mortality and to estimate the effects of replacing sitting with standing, physical activity and sleep. Participants included 149,077 Australian men and women aged 45 years and older who were asked to complete a questionnaire that determined how many hours per day an individual spent sitting, standing and sleeping. They also were questioned about the total time spent walking or participating in moderate or vigorous physical activity.

After a median follow up time of 8.9 years for all-cause mortality and 7.4 years for cardiovascular disease mortality, higher sitting times (more than six hours) were associated with higher all-cause and cardiovascular disease mortality risks, but mostly in those did not meet physical activity recommendations. Meeting even the lowest requirements for physical activity eliminated the association with all-cause mortality risk, with the exception of those who sat the most (more than 8 hours a day). Compared to those who were highly active and sat for less than four hours per day, the risk remained substantially elevated even among physically inactive participants who sat for 4 hours per day only.

While replacing sitting with standing was associated with risk reduction in low sitters, replacing sitting with physical activity was more consistently associated with risk reduction in high sitters. The researchers found that moderate physical activity only reduced cardiovascular disease death risk among high sitters. The largest replacement effects were seen for vigorous physical activity, but this level of activity may not be possible for all adults.

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MicroRNAs Assist in Heart Regeneration

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Many researchers are exploring the therapeutic utility of microRNAs involved in fundamental cellular processes such as replication. These molecules act to regulate the processes of gene expression, determining how much of specific proteins are produced from their genetic blueprints, and when. Protein amounts are the switches and dials of cellular operation, and delivering microRNAs into cells is one possible way to steer cells into useful behavior – through the sheer complexity of the cell makes identifying the right tools to use quite difficult, and any given microRNA may produce quite sweeping changes, only few of which are helpful in any given context. Nonetheless, as illustrated here, there are some possible paths forward towards near future applications of microRNA delivery in regenerative medicine.


Once the heart is fully formed, the cells that make up heart muscle, known as cardiomyocytes, have very limited ability to reproduce themselves. After a heart attack, cardiomyocytes die off; unable to make new ones, the heart instead forms scar tissue. Over time, this can set people up for heart failure. New work advances the possibility of reviving the heart’s regenerative capacities using microRNAs – small molecules that regulate gene function and are abundant in developing hearts. Researchers had earlier identified a family of microRNAs called miR-17-92 that regulates proliferation of cardiomyocytes. In the new work, they show two family members, miR-19a and miR-19b, to be particularly potent and potentially good candidates for treating heart attack.

Researchers tested the microRNAs delivered two different ways. One method gave them to mice directly, coated with lipids to help them slip inside cells. The other method put the microRNAs into a gene therapy vector designed to target the heart. Injected into mice after a heart attack – either directly into the heart or systemically – miR-19a/b provided both immediate and long-term protection. In the early phase, the first 10 days after heart attack, the microRNAs reduced the acute cell death and suppressed the inflammatory immune response that exacerbates cardiac damage. Tests showed that these microRNAs inhibited multiple genes involved in these processes. Longer-term, the treated hearts had more healthy tissue, less dead or scarred tissue and improved contractility, as evidenced by increased left-ventricular fractional shortening on echocardiography. Dilated cardiomyopathy – a stretching and thinning of the heart muscle that ultimately weakens the heart – was also reduced.

Link: https://vector.childrenshospital.org/2019/04/micrornas-heart-attack/

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The Debate Continues over Sitting and Its Effects on Mortality

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Do periods of sedentary behavior, in particular sitting, increase the risk of mortality and age-related disease regardless of whether or not there are periods surrounding exercise? The epidemiological research community can take decades and dozens of studies to chew over questions like this. Most recently, evidence was presented to suggest that sitting for longer periods of time is an independent risk factor for mortality even for those who exercise. The study here presents evidence for a more nuanced conclusion, that exercise does compensate for periods of time spent sitting.

This sort of contradictory data is very much par for the course in this area of study: ignore any single set of results, and look for consensus across as many studies as possible. Meanwhile consider whether or not the arrow of causation might point from health and mortality risk to behavior such as sitting and activity; are less active people exhibiting higher mortality because unhealthy people tend to be less active, for all the obvious reasons, for example?


For less active adults, the amount of time spent sitting may be associated with an increased risk of death; however, increasing physical activity to recommended levels may eliminate this association in some. Recent studies have determined that high levels of sedentary behavior are associated with adverse health outcomes. However, the link between sedentary behavior, mortality, and heart disease are not always well understood.

In this study, researchers aimed to determine the association between sedentary behavior and physical activity on mortality and to estimate the effects of replacing sitting with standing, physical activity and sleep. Participants included 149,077 Australian men and women aged 45 years and older who were asked to complete a questionnaire that determined how many hours per day an individual spent sitting, standing and sleeping. They also were questioned about the total time spent walking or participating in moderate or vigorous physical activity.

After a median follow up time of 8.9 years for all-cause mortality and 7.4 years for cardiovascular disease mortality, higher sitting times (more than six hours) were associated with higher all-cause and cardiovascular disease mortality risks, but mostly in those did not meet physical activity recommendations. Meeting even the lowest requirements for physical activity eliminated the association with all-cause mortality risk, with the exception of those who sat the most (more than 8 hours a day). Compared to those who were highly active and sat for less than four hours per day, the risk remained substantially elevated even among physically inactive participants who sat for 4 hours per day only.

While replacing sitting with standing was associated with risk reduction in low sitters, replacing sitting with physical activity was more consistently associated with risk reduction in high sitters. The researchers found that moderate physical activity only reduced cardiovascular disease death risk among high sitters. The largest replacement effects were seen for vigorous physical activity, but this level of activity may not be possible for all adults.

Link: https://www.eurekalert.org/pub_releases/2019-04/acoc-pam041819.php

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Dysfunctional and Senescent Immune Cells in Bone Marrow as a Cause of Age-Associated Lineage Skewing of Hematopoietic Stem Cells

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The immune system declines with age for a range of reasons. The thymus atrophies, reducing the supply of new T cells; persistent infection by cytomegalovirus causes cells to become uselessly specialized rather than ready to tackle new threats; and the hematopoietic stem cells responsible for generating immune cells become damaged, inactive, and dysfunctional. One of these forms of dysfunction is that hematopoietic stem cells begin to generate too many myeloid cells and too few lymphoid cells, the so-called myeloid skew.

The cause of this skewing in cell production is much debated, but researchers have found that chronic inflammation plays a role. Naturally, nowadays whenever inflammation appears to be an important aspect of any age-related dysfunction, attention turns towards senescent cells. Lingering senescent cells accumulate with age in all tissues, and secrete a potent mix of signals that rouses the immune system into an inflammatory state. It seems likely that they are an important part of the problem when it comes to the myloid skew in the hematopoietic stem cell population.

Why do senescent cells accumulate with age? Cells become senescent in great numbers throughout life, but only later do they linger to a significant degree. Near all are destroyed, either by their own programmed cell death processes, or by the immune system, called into action by the inflammatory signaling of the senescent cells. One reason for a greater number of lingering senescent cells in later life is that the immune system declines and falters in destroying errant cells. Thus, like many issues in aging, the relationship between cellular senescence and immune decline is a circular one; these two processes start off very slowly, but feed one other and accelerate as time passes and damage mounts.

Aged marrow macrophages expand platelet-biased hematopoietic stem cells via Interleukin1B


Dysfunction of the human hematopoietic system with age includes diminished immune response, marrow failure, and clonal selection. Aging is also associated with a general increase in tissue inflammation that remains largely unexplained. The mechanisms driving these characteristics of aged hematopoiesis have, to date, primarily been attributed to intrinsic hematopoietic stem cell (HSC) changes. With age, in both humans and mice, the phenotypic long-term HSC (LT-HSC) pool is expanded and globally LT-HSCs differentiate preferentially towards the myeloid lineage.

Multipotent HSCs with platelet bias were recently identified by a number of investigators describing their increased expression of von Willebrand Factor (vWF) and of the Integrin αIIb (CD41). Recent data demonstrate that aged murine HSCs also have increased cell-surface expression of CD41 and vWF. Notably, human aged HSCs display platelet (or megakaryocytic) bias, suggesting that insights in mechanisms determining murine HSC platelet bias will not only improve our understanding of diseases attributed to the aging hematopoietic system, but also provide novel therapeutic approaches to hematopoietic dysfunction associated with advanced age.

Since the bone marrow microenvironment (BMME) critically regulates HSCs, whether it be considered instructive or enabling distinct HSC fates, unique characteristics of the aged BMME could contribute to HSC changes associated with age. In fact, in the Drosophila gonad, extrinsic signals from the niche contribute to stem cell aging, and mathematical models have suggested that non-cell-autonomous changes could drive this process in mammalian HSCs. While data have suggested that aged endothelial and mesenchymal BMME populations are abnormal and may participate in HSC aging, microenvironmental signals governing the megakaryocytic bias of aged HSCs remain unclear. Thus, we hypothesized that defects in critical BMME populations caused by age could lead to the expansion of platelet-biased HSCs.

We found that macrophages (Mφs) within the aged BMME could impose the megakaryocytic bias characteristic of aging in HSCs. Aged human and murine marrow Mφs had distinct transcriptional profiles compared to young Mφs, including an increased inflammatory activation signature. We identified increased interleukin 1B (IL1B) mRNA in aged marrow Mφs and elevated caspase 1 activity in Mφs and neutrophils from aged bone marrow. Moreover, IL1B signaling was necessary and sufficient to induce HSC bias and drive young HSPCs to adopt an aged phenotype.

While investigating the cause of this increase, we made the novel observation that aged marrow Mφs had a defect in efferocytosis – their ability to clear apoptotic cells. Clearance of apoptotic cells is a critical function of Mφs that prevents necrosis of dead cells and associated local inflammation and also triggers anti-inflammatory responses in phagocytes. In young mice, removal of phagocytic cells or genetic loss of the efferocytic receptor Axl increased HSCs with megakaryocytic bias, suggesting that the efferocytic defect in aged marrow Mφs leads to the increase in IL1B activation and signaling. Together these data define a novel mechanism within the aged BMME that enables a specific HSC fate.

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Eating Garlic Could Protect Brain Health

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Eating garlic may be good for your brain, particularly as you age. The pungent herb may protect brain health by fighting age-related changes in gut health linked to cognitive function, according to University of Louisville researchers.

The study, which was presented at the American Physiological Society’s 2019 annual meeting, adds more credence to garlic’s status as a superfood, and support for its powerful medicinal properties, which have been valued since ancient times.

A high diversity of gut bacteria tends to be associated with better health, but as you age, gut diversity may decline. At the same time, neurodegenerative diseases including Alzheimer’s and Parkinson’s tend to develop in later life, leading researchers to look into the association between changes in gut microbiota and cognitive decline associated with aging, and how garlic may help.

Garlic Compound Improves Gut Bacteria, Memory

The study involved 24-month-old mice, which is equivalent to between 56 and 69 years in humans. Some of the mice received allyl sulfide, a compound in garlic, which led to improved long- and short-term memory, as well as healthier gut bacteria,1 compared to mice that didn’t receive the supplement.

Mice taking the garlic compound also had higher gene expression of neuronal-derived natriuretic factor (NDNF), a gene required for memory consolidation. Reduced gene expression of NDNF may be linked to cognitive decline.

“Our findings suggest that dietary administration of garlic containing allyl sulfide could help maintain healthy gut microorganisms and improve cognitive health in the elderly,” study author Jyotirmaya Behera, Ph.D., said in a press release.2

The link between gut bacteria and neurological health is not new. People with dementia, for instance, have a different makeup of gut microbiota compared to those without.3 Researchers further explained in the journal Protein & Cell:4

“New researches indicate that gastrointestinal tract microbiota are directly linked to dementia pathogenesis through triggering metabolic diseases and low-grade inflammation progress.

A novel strategy is proposed for the management of these disorders and as an adjuvant for psychiatric treatment of dementia and other related diseases through modulation of the microbiota (e.g. with the use of probiotics).”

That garlic could act as a key modulator of gut microbiota is a more novel concept, although perhaps it shouldn’t be, as garlic is a source of inulin, a type of water-soluble prebiotic fiber. Inulin assists with digestion and absorption of your food and plays a significant role in your immune function.

Inulin is a fructan, which means it is made up of chains of fructose molecules. In your gut, inulin is converted into short-chain fatty acids (SCFAs) that are then converted to healthy ketones that feed your tissues.

Aged Garlic Extract May Benefit Your Brain

Previous research has also highlighted the benefits of a specific type of garlic — aged garlic extract (AGE) — for brain health. Known to have strong anti-inflammatory effects, AGE improved short-term recognition memory and relieved neuroinflammation in rats with an Alzheimer’s-like disease.5

The study used fresh garlic that was aged in order to create aged garlic extract, which produces beneficial organosulfur compounds including s-allyl cysteine (SAC), which is found in far greater quantities in aged garlic and black fermented garlic than it is in raw garlic.

AGE also contains thiosulfinates that have antioxidant effects, and more than 350 studies have demonstrated its safety and effectiveness in humans. AGE may protect the brain in a number of ways, including:6

  • Protect against neurodegenerative conditions
  • Prevent brain injury following ischemia
  • Protect neuronal cells against apoptosis
  • Preventing β-amyloid-induced oxidative death

“Moreover,” researchers explained in the journal Nutrients, “treatment with AGE or S-allyl cysteine has been shown to prevent the degeneration of the brain’s frontal lobe, improve learning and memory retention, and extend life span.”7

Aged garlic extract has also been found to improve gut microbiota, including increased microbial richness and diversity after three months of use.8 AGE and SAC have even been highlighted as potential preventative and therapeutic agents for Alzheimer’s disease.9 That being said, fresh garlic has also shown promise for memory function, including one study in which rats fed garlic had increased memory retention.10

Garlic Has Been Prized Since Ancient Times

The value of garlic has been recognized for centuries. There are references to garlic on Sumerian clay tablets dating back to 2600 B.C. In ancient Egypt, garlic was given to the working class to support heavy labor. And in the first Olympic games in Greece, the athletes ate garlic to increase stamina.11

In ancient Chinese medicine, garlic was used for digestion and to treat diarrhea and worm infestations, while in India, garlic was used for general healing as well as to treat fatigue, parasites, digestive issues, heart disease and arthritis.12

“It is fascinating to observe how cultures that never came into contact with one another came to the same conclusions about the role of garlic in health and disease. If folk wisdom is not ignored, it may teach us valuable lessons,” researchers wrote in Nutrition Journal, and many of these lessons are being backed by science today. They continued:13

“With the onset of Renaissance, increasing attention was paid in Europe to the medical use of garlic. A leading physician of the 16th century, Pietro Mattiali of Siena, prescribed garlic for digestive disorders, infestation with worms and renal disorders, as well as to help mother during difficult childbirth.

In England, garlic was used for toothache, constipation, dropsy and plague. In modern era scientists have been trying to validate many of these properties of garlic, specially in terms of the identity of the active components, their mechanisms of action and exploring the potential benefits as food supplements.”

Garlic Is Good for Your Heart

Garlic is known to prevent and treat a wide variety of cardiovascular and metabolic diseases, including atherosclerosis, thrombosis, high blood pressure and diabetes.14 Not only does it stimulate immune function, enhance detoxification and exert an antimicrobial effect, but it has strong antioxidant powers that support health.

In addition, taking garlic powder had a protective effect on the elastic properties of the aorta in elderly adults. The aorta is the largest of your body’s arteries with the job of transporting blood from your heart to the rest of your body. Not only is aortic stiffness often seen with aging but it’s associated with an increased risk of heart disease, heart attack, heart failure and stroke.15

However, among elderly adults who took garlic powder, the age-related increases in aortic stiffness were attenuated, with researchers concluding, “These data strongly support the hypothesis that garlic intake had a protective effect on the elastic properties of the aorta related to aging in humans.”16

In separate research, consuming 2 grams of fresh garlic increased plasma concentrations of nitric oxide (NO) in healthy adults,17 which is beneficial for your heart and more. Nitric oxide is a soluble gas continually produced from the amino acid L-arginine inside your cells.

While nitric oxide is a free radical, it’s also an important biological signaling molecule that supports normal endothelial function and protects your mitochondria — the little “power stations” in your cells that produce a majority of your body’s energy in the form of ATP.

It’s a potent vasodilator, helping relax and widen the diameter of your blood vessels, and healthy blood flow allows for efficient oxygenation of tissues and organs, and aids in the removal of waste and carbon dioxide. Further, NO improves brain neuroplasticity by improving oxygenation of the somatomotor cortex, a brain area that is often affected in the early stages of dementia.18

Garlic Fights Infections, Cancer

Garlic has immune stimulating properties and as such may be useful for fighting off a variety of infections. When 146 adults received either a placebo or garlic supplement for 12 weeks, those taking the garlic had significantly fewer colds and if they were infected they recovered faster.19

In another study involving AGE (aged garlic extract), those taking the garlic had reduced cold and flu severity, reduced symptoms and fewer days of suboptimal functioning or missed work or school. “Garlic contains numerous compounds that have the potential to influence immunity,” according to researchers in the Journal of Nutrition.20

“These results suggest that AGE supplementation may enhance immune cell function and may be partly responsible for the reduced severity of colds and flu reported. The results also suggest that the immune system functions well with AGE supplementation, perhaps with less accompanying inflammation.”21

Toward this end, the cancer-fighting effects of garlic are also well established. Garlic has been shown to kill cancer cells in laboratory studies, as well as shown promise when consumed via your diet.

Those who consume high amounts of raw garlic also appear to have a lower risk of stomach and colorectal cancers.22 Furthermore, among people with inoperable forms of colorectal, liver or pancreatic cancer, taking an extract of aged garlic for six months helped to improve immune function, which suggests it may be useful for helping your immune system during times of stress or illness.23

The Many Types of Healthy Garlic

You can’t go wrong when eating garlic, but if you’re not fond of the pungent flavor or are looking to boost the health effects even more, consider black garlic, which is produced by “fermenting” whole bulbs of fresh garlic in a humidity-controlled environment in temperatures of about 140 to 170 degrees F for 30 days.

Once out of the heat, the bulbs are then left to oxidize in a clean room for 45 days. This lengthy process causes the garlic cloves to turn black and develop a soft, chewy texture with flavors reminiscent of “balsamic vinegar” and “soy sauce,” with a sweet “prune-like” taste.24 Even garlic haters may love the taste of black garlic, and this superfood has been found to have more antioxidant activity compared to fresh.25

Writing in Molecules, researchers noted, “[S]ome people are reluctant to ingest raw garlic due to its unpleasant odor and taste. Therefore, many types of garlic preparations have been developed to reduce these attributes without losing biological functions. Aged black garlic (ABG) is a garlic preparation with a sweet and sour taste and no strong odor.”26

If you choose to eat fresh garlic, be aware that the fresh clove must be crushed or chopped in order to stimulate the release of an enzyme called alliinase, which in turn catalyzes the formation of allicin, which rapidly breaks down to form a number of different beneficial organosulfur compounds. So to “activate” garlic’s medicinal properties, compress a fresh clove with a spoon or chop it finely before to swallowing it.

If you’re worried about garlic breath, it’s a small price to pay for the many health benefits you’ll receive, but you can cut back on any resulting unpleasant odor by chewing raw apple, mint leaves or lettuce. All of these natural foods have been found to significantly reduce garlic breath,27 so you can eat garlic to your heart’s content without worrying about offending others.

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