Garlic Supports Healthy Blood Sugar

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Although the exact origin of garlic (Allium sativum) is not known, it’s believed to be a native of middle Asia, likely from West China.1 As a medical remedy it’s been used since 2700 B.C. to treat numerous afflictions, from depression to rheumatism to coughs and more, and the journey it’s taken has touched nearly every major civilization.

For example, the Egyptians fed it to slaves to give them strength and endurance; Hippocrates used it as for breathing problems and tumors;2 Pliny the Elder liked it for joint diseases and seizures; Easterners used it to treat diarrhea — and that’s just a short list.

In folk medicine, ancients believed garlic could ward off all kinds of evils including vampires and witches, as well as the black plague.3 On the other hand, as food and medicine, it was so valued that it even was used as a form of payment for slaves while the pyramids were being built. And, when the tomb of King Tutankhamun was opened, they found well preserved garlic cloves dating back to 1325 B.C.4

Garlic is a member of the onion family and one of the oldest known flavorings used on food. Currently, China is the world’s largest producer of garlic; 90% grown in the U.S. comes from California. Scientifically, in addition to the multiple other benefits associated with garlic, researchers have found raw garlic improves your body’s sensitivity to insulin and may help in the management of Type 2 diabetes.5

Garlic May Increase Insulin Availability

According to the Centers for Disease Control and Prevention,6 more than 30 million people living in the U.S. have diabetes. This is nearly 10% of the population. For the most part, Type 2 diabetes develops more frequently in those over 45 and often presents with few symptoms.

Insulin plays a significant role in how your body utilizes glucose. As you are exposed to higher amounts of glucose, your cells may become insulin resistant, which requires higher levels of insulin to move glucose from your blood into your cells.7 Insulin is produced in your pancreas in response to levels of glucose in your blood,8 and is inactivated in your liver.9

One way of helping to control blood sugar levels is to retain more insulin in your bloodstream to be used by the cells. However, 50% is removed on the first pass through the liver, reducing the amount of insulin for use. Research has demonstrated compounds found in garlic prevent this metabolism of insulin, freeing up more for your body.10

The compounds found in garlic include allicin, allyl propyl disulfide and S-allyl cysteine sulfoxide (alliin). The last is a bioactive compound researchers11 have evaluated for its effect on blood sugar. In one animal study mice were treated with drinking water with and without alliin for eight weeks. 

While the animals had no change in body weight, energy or fat deposits, those drinking alliin infused water demonstrated increased insulin sensitivity and a better lipid profile. The researchers believe this may also be attributed to the compounds ability to modulate intestinal gut microbiota.12

Raw Is Better

Researchers have found the effects on blood glucose are much more significant when the garlic is administered in a raw form, rather than cooked. Raw garlic had a “profound effect” in animal studies to reduce glucose and lipid levels, while boiled garlic did not.13

In another animal study,14 researchers sought to evaluate the effect of raw garlic on plasma glucose, metabolic syndrome and oxidative stress in animals suffering from Type 2 diabetes. At the end of an eight-week trial, researchers concluded that “raw garlic homogenate is effective in improving insulin sensitivity while attenuating metabolic syndrome and oxidative stress.”

While researchers have found the use of raw garlic demonstrates a greater effect on glucose control, other studies have found garlic supplements will also demonstrate a decrease in glycated hemoglobin (HbA1c) and lipid profiles without complications.15 The first was a meta-analysis of randomized controlled trials using garlic and individuals with Type 2 diabetes.

In another, researchers16 undertook a single-blind, placebo-controlled, 24-week study with individuals who had fasting blood sugar above 126 mg/dl. They divided 210 individuals into seven groups.

One received the oral hypoglycemic drug metformin; another received a placebo; and the final five were given garlic tablets at doses of 300, 600, 900, 1,200 and 1,500 mg each day. The results showed garlic was “more effective than placebo and comparable to metformin in reducing fasting blood glucose.” There was a dose and duration dependent reduction in fasting blood sugar and improvement in HbA1c.17

Diabetes Is a Metabolic Condition

Metabolic syndrome is defined by a number of conditions occurring at the same time to increase your risk of Type 2 diabetes, heart disease and stroke.18 While having one does not mean you have a greater risk of disease, when they develop together, it raises your risk. The conditions are glucose intolerance, high blood pressure, dyslipidemia and central obesity.19

While the addition of garlic may help improve blood glucose control by affecting insulin metabolism and the action of your gut microbiota, the foods you eat exert an even stronger effect on your blood glucose.20 I recommend using intermittent fasting and a ketogenic diet to help control your blood sugar and reduce your risk of metabolic syndrome.

Currently, many are recognizing the power of eating a ketogenic diet to reduce both the glucose load in the body and the need for medication. While you may still find some who recommend strategies that raise blood sugar by eating certain carbohydrates,21 and adding beans and whole grain items to your shopping list,22 I urge you to read my article on lectins and their role in inflammation and chronic disease before you elect to follow such a diet.

One note: While garlic has had a significant impact on blood sugar control and insulin availability, it is important you add this into your regimen slowly, and under the supervision of your physician. Your blood sugar will need to be closely monitored, as will any hypoglycemic medications you may be taking, to avoid dangerous low blood sugar events.

Garlic Power: Organosulfur Compounds

Researchers have found frequent consumption of garlic has been associated with specific health benefits, namely the influence over toxicity and carcinogenicity of environmental toxins.23 Epidemiological studies have found phytochemicals, namely organ sulfites, present in garlic and onion, have an anticarcinogenic effect in experimental models.24

These organosulfur compounds are a subclass of sulfur found throughout the environment and are necessary components of enzymes, proteins and vitamins.25 The exact mechanism organosulfur compounds use in protecting cells against cancer is not clear.

It is known the compounds modulate activity using enzymes and inhibit the formation of DNA adducts,26 or segments of DNA bound to potentially cancer-causing chemicals.27 Organosulfur compounds have also demonstrated activity against cellular proliferation in tumors potentially mediated by starting apoptosis.28

In addition to anticarcinogenic effects, the sulfur compounds commonly found in garlic have antioxidant, anti-inflammatory and antimicrobial properties.29 In a meta-analysis of 39 trials of the effect of garlic on cholesterol and lipid levels, researchers found garlic to be effective in reducing total serum cholesterol when garlic was used for more than two months.30

Another animal study31 presented at the 2019 Experimental Biology conference held in Florida, evaluated the effect of garlic compounds on long- and short-term memory, as well as gut bacteria. The researchers believe their findings suggest daily administration of garlic could achieve improved results in the elderly.32

Organosulfur compounds found in garlic are also linked to a decrease in the synthesis of cholesterol in the liver,33 reducing total cholesterol level. In a test tube, they inhibit platelet aggregation,34 potentially reducing the risk of thrombotic events including stroke and pulmonary embolism and protecting your cardiovascular system.

Black Garlic Packed With More Benefits

One of the powerful organosulfur compounds in garlic is allicin, which is not technically part of a garlic clove, but is produced when the plant is crushed or chopped. Allicin is part of the plants defense system against insects and fungi. It is produced in a reaction between alliin and allicinase found in garlic.35

However, processing such as cooking, aging, dicing or crushing garlic triggers a breakdown in the allicin. To receive these benefits at higher levels consider purchasing aged black garlic. This product was originally developed in Korea and is achieved by processing the garlic in humidity-controlled environments with no additives and no preservatives.

Although some call the process fermenting, it does not involve microbial changes. Garlic cloves transition from the pearly white you are accustomed to seeing, to a black appearance containing a new range of compounds and taste some describe as a “sweet, earthy” flavor.36

In addition to greater health benefits, black aged garlic is also odorless and not as pungent as raw garlic. The product is higher in S-allyl cysteine (SAC), which has demonstrated preventive and protective properties against oxidative stress.37

One of the benefits of SAC found in natural garlic is how well it is absorbed, and it is 100% bioavailable.38 Researchers are confident of the role it plays in the overall health benefits of garlic.39 However, while some benefits may be more effective than fresh garlic, levels of allicin in aged black garlic is low.

How to Make Garlic Part of Your Diet

Although some research has had positive results using garlic supplements, their performance is variable as it depends upon your digestive conditions. Many supplements are enteric-coated to keep them from being destroyed in stomach acid. For this reason, I believe it’s much better to get your organosulfur compounds from real food rather than relying on a supplement.

Since allicin is not formed until a raw garlic clove is either crushed or diced, you may want to also consider using aged black garlic. But, whether you choose to use raw or black, you can’t go wrong with garlic. Add garlic to your salad dressing, run it through your juicer or put the cloves directly into your pasture-raised organic beef before cooking to add a rich infused flavor to the beef.

Another way to enjoy your garlic is after it’s sprouted. While you may toss garlic cloves that bright green shoots, researchers40 have found extracts from garlic cloves that have sprouted for five days have higher antioxidant activity than fresh bulbs.

You may easily grow garlic at home in the garden or your house, from cloves you purchase at the store or from seed. This gives you an ample supply of fresh grown, pesticide free garlic for your recipes.

If you’d like to try eating a raw clove of garlic, you’ll want to dice it before swallowing since taking a whole clove doesn’t activate the allicin. Raw garlic may be added to guacamole or salsa or diced into a teaspoon of locally sourced honey before going down the hatch.41

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Tea Is Great for Your Brain

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Tea is an ancient beverage recognized for millennia as having a dramatic and positive impact on health, as well as playing an important part in cultures around the world. For example, tea has been an integral part of British life for nearly two centuries, having started in England in 1840 when the Duchess of Bedford needed sustenance between lunch and dinner. As such, teatime began as a small snack with tea, but soon became a social gathering in the wealthy class.1

Today, teatime is an honored tradition in Great Britain for all classes, with protocols on not only how to “take tea” but when to take it and what to eat — or not eat — with it. In a fun article on British teatime, NPR2 warns: Don’t eat everything you’re offered (you don’t want to appear too hungry) and whatever you do, don’t put out your pinky when holding your cup. “It makes you look pretentious,” a British teatime expert explains.

In contrast, teatime in the West often focuses on the food — generally sandwiches and cakes — in a setting where tea appears to be more of an afterthought than the center of the event.3 Eastern culture, on the other hand, has elevated tea drinking to an art form, if for no other reason than this is where tea originated as a “pillar” of life. In China, tea has been the drink of choice for 5,000 years.4

Today, tea is one of the most popular beverages around the world, second only to water. According to the Tea Association of the U.S.A.,5 nearly 80% of all U.S. households have tea and it’s the only beverage commonly served hot or cold; 84% of the tea consumed in the U.S. is black tea and 15% is green (more about the types of tea later in this article).

In 2018, 84 billion servings of tea equaling 3.8 billion gallons were served to Americans. However, despite those large numbers, the U.S. does not rank in the top 10 tea consuming countries of the world.6 That honor goes to, in order, Turkey, Ireland, United Kingdom, Iran, Russia, Morocco, New Zealand, Egypt, Poland and Japan.

Drinking Tea May Help Develop Better Brain Connections

A recent study from the National University of Singapore has found those who regularly drink tea may experience healthier cognitive functioning.7,8 Past research already indicated that drinking tea is healthy for your brain. However, this recent study using data from neuroimaging taken of 36 older adults has a twist.

Interested in the effect tea may have on brain structure and organization, scientists gave participants a questionnaire about what they could remember about their drinking habits from age 45 into the present. Participants then underwent an MRI.

From the imaging, the researchers found that tea not only has a positive effect on brain structure, function and organization, but that those who drank the most tea — at least four times a week for about 25 years — also had greater functional connectivity strength. They did not find tea had any effect on a symmetry between hemispheres, though.

As assistant professor Feng Lei from the National University of Singapore explained in a EurekAlert press release, connectivity is very important:9

“Take the analogy of road traffic as an example — consider brain regions as destinations, while the connections between brain regions are roads. When a road system is better organised, the movement of vehicles and passengers is more efficient and uses less resources. Similarly, when the connections between brain regions are more structured, information processing can be performed more efficiently.

We have shown in our previous studies that tea drinkers had better cognitive function as compared to non-tea drinkers. Our current results relating to brain network indirectly support our previous findings by showing that the positive effects of regular tea drinking are the result of improved brain organisation brought about by preventing disruption to interregional connections.”

Catechins Protect Your Heart and Brain

The results from this study offer a better understanding of brain organization and its intricate relationship with cognitive performance. The team said they plan to continue examining the effects of tea and its bioactive compounds on cognitive decline.10

While this study demonstrated long-term effects, a different one11 found evidence of short-term benefits linking consumption of black tea after fasting overnight with improved executive functioning, simple reaction time and reduced errors in cognitive tasks.

A key property found in green tea is epigallocatechin-3 gallate (EGCG), a type of catechin or flavonoid that works with antioxidants in the brain to improve cognition.12 In a clinical study to test how this works, 12 elderly nursing home residents with diagnosed cognitive dysfunction took 2 grams of green tea powder each day for three months. At the conclusion of the study, data demonstrated they had significantly improved scores on cognitive function tests.13

EGCG has also been shown14 to improve learning and reduce memory loss in subjects who consume a high-fat, high fructose diet (HFFD). In this study, EGCG also appeared to significantly modulate insulin resistance, which is another factor associated with cognitive decline.

Another study showed drinking green tea is associated with a lower risk of cognitive impairment,15 and a literature review of in vitro and in vivo administration of EGCG in participants suffering from Alzheimer’s disease found a reduction in beta-amyloid accumulation.16

Catechins Are a Strong Key to Good Health

The ability to break up beta-amyloid plaques may also be the basis for an association with EGCG and reduction of atherosclerotic plaques.17 The researchers believe the results demonstrate EGCG may be effective against the types of plaques that cause heart attack and stroke.18

In an extensive review of the literature,19 one team found epidemiological data and results from clinical and experimental studies demonstrating the benefit EGCG has on cardiovascular health. These benefits include reducing vascular inflammation, thrombogenesis and oxidation, as well as modulating lipid profiles and inhibiting lipid peroxidation.

In addition to brain health and heart health, EGCG is an effective chemopreventive. One review of the literature found delayed cancer onset, prevention of colorectal adenoma and inhibition of melanoma metastasis in an animal model.20 Another found EGCG may synergistically inhibit cancer both in vitro and in vivo.21

Health Benefits and Warnings — Green Tea Extract

If drinking green tea is not something you enjoy and yet you still want the benefits, it may be worth your effort to investigate green tea extract. As defined by the National Cancer Institute,22 this is a polyphenol mixture isolated from the Camellia sinensis plant from which green tea is derived. It contains flavonoids, vitamins and polyphenols, including EGCG.

As with any chemical you put into your body, there may be side effects. According to the University of Rochester Medical Center, green tea extract’s side effects may include anxiety, tremors, irritability and sleep problems related to the amount of caffeine.23

There have also been reports of liver damage with green tea extract when you consume higher amounts of EGCG in supplement form than you would get from simply drinking your tea.

Health Canada24 strengthened their warnings on green tea extract products, as did the Norwegian food safety authority and European Food Safety Authority25 after reviewing earlier papers26 linking dozens of cases of liver damage to the consumption of high amounts of EGCG. That said, supplementation with green tea extract in concentrations no greater than you would get from drinking green tea has several possible advantages, including:

  • Help with heart, liver and brain health and support for blood pressure, bone mineral density and weight control27
  • Reduction of oxidative stress28
  • Support for exercise recovery and enhancement of antioxidant protection and exercise performance29
  • Reduction of inflammation from nonalcoholic fatty liver disease30
  • Enhancement of insulin sensitivity and help in regulating blood sugar production31

Different Teas and How They Taste

According to TeaClass.com, all tea leaves come from the Camellia senensis plant, and they’re categorized in five types, all distinguished by how they’re processed and oxidized or fermented:32

  • Black
  • Oolong
  • Green
  • White
  • Pu’erh

Black tea is fully oxidized while oolong teas are partially oxidized. Green and white teas are not oxidized after the leaf harvesting. Pu’erh is a fermented, aged tea compressed into cakes.

When preparing them according to Chinese custom, each of the different teas is prepared in different vessels. For instance, oolong is traditionally brewed in a clay pot while green tea is prepared in a glass pot. In addition, the traditional ceremony involves an entire set of utensils including scoops, tray, decanter, fragrance cup and tea cup.33

One cup of black tea contains approximately 25 to 48 mg of caffeine depending on the type and how it’s brewed, as opposed to a typical 8-ounce cup of brewed, black coffee, which contains 95 to 165 mg of caffeine.34

White tea is the least processed of all teas, with a delicate taste and natural sweetness. When this tea is brewed at a low temperature and short steeping time, you’ll enjoy low amounts of caffeine than when hotter temperatures are used.35 All white teas are produced in China and only young, tender leaves are used.36

Green tea leaves are harvested in the morning and bypass oxidation, allowing the tea to retain much of the natural color, tannins, chlorophyll and minerals.37 Oxidation is stopped by rapidly heating the leaves. When it’s brewed at lower temperatures it has less caffeine.38 Most are a light green in color. The finely powdered matcha tea has a more vibrant green hue with “a grassy flavor and sweet aftertaste.”39

According to The Tea Spot, oolong teas have body and complexity compared to black tea, but a greater freshness of green tea related to the oxidation level.40 Oolong isn’t as robust as a black tea, but the fragrance and taste have been compared to fresh flowers or fresh fruit, TeaSource says41 Oolong is a deep amber or light green color with a smooth finish and malty flavor, according to Cup and Leaf.42

Black tea is fully oxidized,43 during which water is evaporated from the leaf, allowing the plant to absorb oxygen, resulting in a dark brown or black color and a more robust flavor.44

How to Store Your Tea

You’ll want to take care as you store, brew and drink your tea to enjoy the greatest health benefits and best flavor. Like most fresh foods, good storage extends the shelf life, quality and flavor.45 Light and UV rays will degrade your tea quickly, so avoid purchasing from vendors who store their product in clear containers.

Heat and moisture will degrade your tea and reduce shelf life. Interestingly, your tea will also absorb odor easily so avoid storing it near your spice cabinet or anywhere else there is a source of strong odors.46 Your tea should be sealed in an airtight container.

Additionally, you should keep your delicately flavored tea separate from your strongly scented teas. Using an opaque, nonreactive container — preferably glass or ceramic — with a double lid and tight seal will help to protect the shelf life of your product.47

Brew the Perfect Pot

In this short video a representative from Ahmad Tea demonstrates one way to brew loose leaf tea. While he recommends brewing for five minutes, shorter times will produce lighter flavor with less caffeine. Always use clean filtered water and fresh tea leaves.

Start with the instructions that come with your loose tea leaves, but don’t be afraid to experiment with the process you’re using until you find one you enjoy the most. Warming the brewing tea pot is a must as it helps keep the water at a steadier temperature as the tea is brewing.

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FGF23, Klotho, and Vascular Calcification

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Klotho and FGF23 interact with one another in a number of mechanisms that might explain the effects of klotho on longevity in mice: more klotho slows aging, while loss of klotho accelerates it. Vascular function is fairly high on that list, given the importance of the cardiovascular system in aging. The mechanism of interest in the research here is calcification of blood vessels, the dysfunction in cell populations in blood vessel walls that leads to mineralization akin to that involved in generation of bone tissue. Some of this is clearly the result of rising levels of cellular senescence and the harmful signaling that is produced by senescent cells. Investigations of the sort noted here are more concerned with proximate causes, however, in the sense of altered levels and interactions of various proteins.


Vascular calcification (VC) constitutes a major risk factor for cardiovascular (CV) morbidity and mortality and involves a complex regulated process of biomineralization that resembles osteogenesis. This process is mainly driven by the vascular smooth muscle cells (VSMCs), and includes the transformation of these cells into an osteoblastic phenotype.

Chronic kidney disease (CKD) is a major risk factor for CV disease (CVD) and is a clinical scenario closely related to the development of VC. In addition to the traditional CV risk factors, subjects with CKD are also exposed to other non-traditional factors predisposing for this pathology. Fibroblast growth factor (FGF) 23 is the most potent phosphatonin. This is an osteocyte-derived hormone produced in response to phosphate levels which, in combination with its cofactor Klotho, reduces the reabsorption of phosphate and the synthesis of active vitamin D in the kidneys. In patients with CKD, FGF23 concentrations increase with declining renal function and reach extremely high levels in end-stage renal disease. Clinical epidemiological studies have shown that FGF23 strongly predicts mortality in patients with CKD independently of other risk factors. These results suggest that FGF23 may causally be related to the high mortality observed in CKD patients and, importantly, that may exert direct effects on CV system besides its function as a phosphaturic hormone.

FGF23 binds to its cognate receptors (FGFRs), which are activated in the presence of the co-receptor Klotho. Our group and others described the expression of FGFR and Klotho in the human vascular wall, allowing to speculate that vascular tissue may be an objective for the actions of FGF23. Moreover, the synthesis of FGF23 by calcified vascular tissues and its contribution to CVD is an intriguing question not adequately studied. Only two previous works have explored the expression of FGF23 in calcified tissues, although solely coronary arteries and carotid atheroma plaques were analyzed. Moreover, the relationships of vascular FGF23 gene and protein expression levels with soluble FGF23 concentration and with the expression of Klotho and FGFRs in the vessels have not been previously established.

In this work, we determined the levels of both intact and fragmentary circulating FGF23 in 133 patients with established cardiovascular disease, the expression of FGF23, its receptors, and its co-receptor Klotho in vascular fragments of aorta, carotid, and femoral in 43 out of this group of patients, and in a control group of 20 organ donors. Patients with atherosclerosis and vascular calcification presented increased levels of FGF23 respect to the control group. Vascular immunoreactivity for FGF23 was also significantly increased in patients with vascular calcification as compared to patients without calcification and to controls. Finally, gene expression of FGF23 and RUNX2 were also higher and directly related in vascular samples with calcification. Conversely, expression of Klotho was reduced in patients with cardiovascular disease when comparing to controls. In conclusion, our findings link the calcification of the vascular tissue with the expression of FGF23 in the vessels and with the elevation of circulating levels this hormone.

Link: https://doi.org/10.18632/aging.102297

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Permanently Boosting Levels of Natural Killer Cells in Mice to Increase Cancer Resistance

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Researchers here demonstrate a very interesting approach to immunotherapy: they introduce engineered stem cells in mice that will give rise to additional natural killer T cells, boosting the capability of the immune system for the entire life span of the mouse. Even if this class of treatment is not actually permanent in the same way in humans, and merely long-lasting, it still seems a promising step towards enhancing the immune system at any age, not just trying to repair it when it fails in later life.


They’ve been called the “special forces” of the immune system: invariant natural killer T cells. Although there are relatively few of them in the body, they are more powerful than many other immune cells. Scientists have hypothesized that iNKT cells could be a useful weapon against cancer because it has been shown that they are capable of targeting many types of cancer at once – a difference from most immune cells, which recognize and attack only one particular type of cancer cell at a time. But most people have very low quantities of iNKT cells; less than 0.1% of blood cells are iNKT cells in most cases. Still, previous clinical studies have shown that cancer patients with naturally higher levels of iNKT cells generally live longer than those with lower levels of cells.

The researchers’ goal was to create a therapy that would permanently boost the body’s ability to naturally produce more iNKT cells. They started with hematopoietic stem cells – cells found in the bone marrow that can duplicate themselves and can become all types of blood and immune cells, including iNKT cells. The researchers genetically engineered the stem cells so that they were programmed to develop into iNKT cells.

They tested the resulting cells, called hematopoietic stem cell-engineered invariant natural killer T cells, or HSC-iNKT cells, on mice with both human bone marrow and human cancers – either multiple myeloma (a blood cancer) or melanoma (a solid tumor cancer) – and studied what happened to the mice’s immune systems, the cancers and the HSC-iNKT cells after they had integrated into the bone marrow. They found that the stem cells differentiated normally into iNKT cells and continued to produce iNKT cells for the rest of the animals’ lives, which was generally about a year.

While mice without the engineered stem cell transplants had nearly undetectable levels of iNKT cells, in those that received engineered stem cell transplants, iNKT cells made up as much as 60% of the immune systems’ total T cell count. Plus, researchers found they could control those numbers by how they engineered the original hematopoietic stem cells. Finally, the team found that in both multiple myeloma and melanoma, HSC-iNKT cells effectively suppressed tumor growth.

Link: https://www.uclahealth.org/engineered-killer-t-cells-could-provide-longlasting-immunity-against-cancer

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Your Favorite Episodes of The Live Foreverish Podcast – International Podcast Day

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Your Favorite Episodes of The Live Foreverish Podcast – International Podcast Day

September 30th is International Podcast Day! To celebrate, we’ve rounded up our top 5 podcast episodes of Live Foreverish, as determined by your downloads!

Here are the fan favorites:

1.The Truth Behind Varicose Veins – Targeting the underlying problem with nutrition

Spider and varicose veins…nobody wants them. But venous insufficiency is more than just a cosmetic problem – it can be a sign of overt cardiovascular risk. Drs. Mike and Gossard discuss what’s really going on inside your veins and how to fix it with targeted nutrition.

2. All Eyes on Astaxanthin – Astaxanthin is a wellness powerhouse that deserves attention.

Nature’s cellular protector, astaxanthin, provides numerous health benefits. Dr. Mike discusses the research with author Bob Capelli and why you should add it to your daily routine.

3. Getting Under Your Skin(care) – Build and protect your skin’s structure

Rebuilding and protecting your skin’s scaffolding is key to less wrinkles and fine lines. Mike and Dr. Gossard discuss research-proven techniques to increase collagen and prevent its degradation.

4. Why am I Always so Tired? The human energy crisis and chronic fatigue

Dr. Jacob Teitelbaum, author of From Fatigued to Fantastic, joins Dr. Mike and Dr. Gossard to discuss the human energy crisis and how it’s driving a near epidemic of fatigue. And there’s good news…there are ways to reverse the crisis.

5. Maintaining Muscle Mass for Longevity – Exercises for increasing muscle and best times to work out

Did you know that men can lose up to 8% of muscle mass per decade starting in their 40’s? Dr. Mike discusses the best strategies for maintaining and building muscle mass with exercise physiologist and registered dietitian, Dr. Chris Mohr. Learn more about the Men’s Health Series.

Which is your favorite episode? What topic would you like us to cover next? Tell us in the comments!

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

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Slow Cooker Pumpkin Barbecue Pulled Pork

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Slow Cooker Pumpkin Barbecue Pulled Pork
Recipe by Megan Olson
Halloween is just around the corner and, for many, this means getting ready to do fun activities like carving jack-o-lanterns, which is a highly popular pastime for kids, as well as adults who are  kids at heart. After creating your pumpkin masterpiece, you’ll be left with the “pumpkin guts,”  —the goopy insides that you scoop out from the fresh pumpkin. 
The good news is there are a lot of creative and delicious ways to save and recycle pumpkin guts. One trick is by transforming them into pumpkin puree. All you need to do is remove the seeds from the guts, then blend in a food processor until you have a smooth mixture.   
This puree can be used for plenty of recipes, like this slow cooker pumpkin barbecue pulled pork recipe by Megan Olson. If you have a slow cooker at home, this is the perfect dish to make for fall, or anytime you have a fresh pumpkin on hand. 

Slow Cooker Pumpkin Barbecue Pulled Pork

Cook Time: 3 hours
Prep Time: 15 minutes
Serves: 6

Ingredients:
1 tablespoon coconut oil
1 pound pasture-raised organic pork roast
2 1/2 cups barbecue sauce
1/2 cup pumpkin purée
1/8 cup monk fruit sweetener
1 tablespoon apple cider vinegar
1 tablespoon garlic powder
1/2 teaspoon onion powder
1/2 teaspoon paprika
Salt and pepper to taste

Procedure: 
1. Add the coconut oil into the slow cooker and turn it on high.
2. While the slow cooker heats, sprinkle the pork roast with salt and pepper. Rub the salt and pepper into the roast with your hands, then place in the slow cooker.
3. Make the pumpkin barbecue sauce by mixing barbecue sauce, pumpkin purée, monk fruit sweetener, apple cider vinegar, garlic powder, onion powder and paprika together in a bowl.
4. Pour the sauce over the pork roast.
5. Cook on high for 2 1/2 hours.
6. Once the pork is cooked, remove  from the slow cooker and shred using two forks.
7. Place the pork back in the slow cooker and cook for another 30 minutes.
8. Serve immediately or store in an airtight container in the refrigerator for up to five days.

Why Slow Cookers Are Becoming a Big Hit
Using a slow cooker is now becoming a popular trend, as people look for ways to elevate their dishes without spending too much time in front of a hot stove. Using a slow cooker may seem like a lot of work, but if done correctly, it’s actually quite economical and brings about a number of benefits. Here are a few examples, according to the Spruce Eats: 
It gives a better distribution of flavors, thanks to the extended cooking time.
Slow cooking reduces the risk of having scorched foods, due to the low temperatures used.
This cooking method gives cheap but tough meats like chuck steaks and venison a more tender texture.  
This handy appliance uses less electricity than a standard oven. Many units are portable as well.
Remember that slow cookers rely on moist heat to cook food properly, so don’t be tempted to keep taking off the lid to check if your food is done. Doing so will allow the steam and heat to escape, meaning you have to increase the cooking time. 
Pumpkins Are a Great Fall Food
Did you know that in the early days, jack-o-lanterns were carved out of potatoes and turnips? It was only upon the arrival of Irish immigrants in the U.S. when people decided to use pumpkins as an ideal material for jack-o-lanterns, paving the way for this new Halloween tradition. 
Typically harvested in October,  pumpkins are botanically classified as berries, although they are more popularly referred to as a vegetable. Despite having a hard outer shell, their inside is actually spongy, with a yellow-orange flesh. When you slice one open, you’ll see hundreds of oval seeds inside, which appear as green, light brown or white.   
Pumpkins are well-loved by many because of their versatile sweet flavor, which can be used for desserts like pies and cookies. It also goes well in savory dishes like stews and soups.  
Plus, pumpkins are chockfull of nutrients. They’re one of the most popular sources of the powerful antioxidant beta-carotene. Pumpkins also contain fiber, vitamin C and potassium. According to Medical News Today, the combination of these nutrients may help maintain cardiovascular health.  You can read “What Are Pumpkins Good For?” to learn more about the many benefits of pumpkins.
Make Sure You Choose the Right Kind of Pork
The main ingredient of this recipe is pork. But despite being the most widely consumed meat in the world — accounting for more than 36% of the global meat intake, according to the Food and Agricultural Organization of the United Nations (FAO)  — you must buy pork with caution, mainly because of the many issues surrounding it. 
Most of the pork consumed today comes from concentrated animal feeding operations (CAFOs), which are connected with pollution and disease. For example, a study conducted in North Carolina University found that exposure to pig CAFO emissions led to symptoms such as headache, runny nose, sore throat, coughing, diarrhea and burning eyes. 
So, if you choose to eat pork, stay away from CAFO meats and purchase it from a trustworthy farmer who raises grass fed heritage breeds. Look for the American Grassfed Association (AGA) logo as well, which ensures that the pork meets the grass fed standards of this organization. 
The standards of the AGA pastured pork require the animals to have a forage-based diet that comes from pasture. It also puts a premium on animal health and welfare, ensuring that the pigs are not fed antibiotics or given growth hormones.   
One Final Reminder When Cooking This Dish
It is never recommended to cook frozen meat in a slow cooker, so make sure the pork is completely thawed before putting it in. This rule is applicable not just for pork, but for any type of meat. Cooking frozen meat in a slow cooker will lead to uneven cooking.  

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Contents

  • Conversion of Glial Cells into Neurons as an Approach to Regeneration in the Brain
  • RAGE and Chronic Inflammation in Aging
  • Senescent Cells Implicated in Age-Related Changes in Blood Clotting
  • ApoE Levels Rise with Age and Degrade the Ability to Regenerate Bone
  • Alzheimer’s Disease as a Condition of Many Subtypes and Contributing Causes
  • ADRB1 Mutation Grants a Lesser Need for Sleep, and thus a Longer Subjective Life
  • Aging Biotech Info is a Curated List of Companies in the Longevity Industry
  • Exosomes Improve Collagen Production in Aged Skin
  • Fitter, Thinner Older Adults Have a Measurably Different Gut Microbiome
  • Risk Factors versus Lifestyle Choices in the Mortality of Old Age
  • An Interview with Tristan Edwards of Life Biosciences
  • The Boost to the Unfolded Protein Response Achieved via Exercise Declines with Age
  • Altered Calcium Transport in Aging Mitochondria is Maladaptive
  • A Skeptical Review of the Evidence for Metformin
  • A Non-Invasive Approach to Measuring Cellular Senescence in the Kidney

Conversion of Glial Cells into Neurons as an Approach to Regeneration in the Brain

https://www.fightaging.org/archives/2019/09/conversion-of-glial-cells-into-neurons-as-an-approach-to-regeneration-in-the-brain/

The authors of today’s research report on success in use of a gene therapy to convert glial cells into neurons in a living mouse brain, and thereby improve the normally limited recovery that takes place following brain injury, such as that caused by a stroke. A number of research groups are investigating this class of approach to enhance regeneration in the brain, an organ that has little capacity to repair itself. The capacity that does exist is generated by neural stem cells that, arguably, continue to produce new neurons at some pace throughout life. As for all stem cell populations, activity declines with age, however. An increased supply of new neurons, provided that they are capable of correctly maturing and integrating into neural circuits, should prove beneficial.

Interestingly, increasing the supply of neurons is not just relevant to regeneration in the brain. Functions such as memory rely on changes in neural networks, and in turn on a supply of new neurons. It is possible that increasing the pace at which new neurons emerge could improve cognitive function even in younger people. We are a long way removed from that sort of application of new biotechnology, however – the focus today is very much on addressing age-related conditions.

Gene therapy helps functional recovery after stroke


Researchers have pioneered a new approach to regenerate functional neurons using glial cells, a group of cells surrounding every single neuron in the brain that provide essential support to neurons. Unlike neurons, glial cells can divide and regenerate themselves, especially after brain injury. Researchers previously reported that a single genetic neural factor, NeuroD1, could directly convert glial cells into functional neurons inside mouse brains with Alzheimer’s disease, but the total number of neurons generated was limited. The research team believed that this limited regeneration was due to the retroviral system used to deliver NeuroD1 to the brain. In the current study, the research team used the AAV viral system, which is now the first choice for gene therapy in the nervous system, to deliver NeuroD1 into mouse motor cortex that had suffered from stroke.

Many neurons die after stroke but surviving glial cells can proliferate and form a glial scar in the stroke areas. The AAV system was designed to express NeuroD1 preferentially in the glial cells that form these scars, turning them directly into neuronal cells. Such direct glia-to-neuron conversion technology not only increased neuronal density in the stroke areas, but also significantly reduced brain tissue loss caused by the stroke.

“The most exciting finding of this study is to see the newly converted neurons being fully functional in firing repetitive action potentials and forming synaptic networks with other preexisting neurons. They also send out long-range axonal projections to the right targets and facilitate motor functional recovery. “Because glial cells are everywhere in the brain and can divide to regenerate themselves, our study provides the proof-of-concept that glial cells in the brain can be tapped as a fountain of youth to regenerate functional new neurons for brain repair not only for stroke but also for many other neurological disorders that result in neuronal loss.”

A NeuroD1 AAV-Based Gene Therapy For Functional Brain Repair After Ischemic Injury Through In Vivo Astrocyte-To-Neuron Conversion


Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 AAV-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA-sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level.

Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.

RAGE and Chronic Inflammation in Aging

https://www.fightaging.org/archives/2019/09/rage-and-chronic-inflammation-in-aging/

Chronic inflammation is a very important downstream consequence of molecular damage in the progression of aging, arising from numerous causes. The past decade of work on the presence of lingering senescent cells in old tissues indicates that their signaling is significant cause. In animal studies, removing senescent cells can reverse the course of many age-related and other conditions that are primarily inflammatory in nature. Visceral fat tissue in excess amounts can accelerate the production of senescent cells, but it also generates inflammation through other mechanisms, such as debris from dead cells, signaling by non-senescent fat cells that resembles the signaling of infected cells, and so forth.

There are also numerous other contributing factors relating to the growing dysfunction of the immune system, or some of the metabolic issues that accompany excess fat tissue. The one examined in today’s open access paper is the interaction of advanced glycation end-products (AGEs) with the receptor for AGEs (RAGE). There are a couple of different issues in aging, type 2 diabetes, and obesity relating to AGEs. The more interesting one for the SENS rejuvenation research community is the accumulation of persistent cross-links in the extracellular matrix formed from glucosepane; these cross-links degrade tissue elasticity, which in turn contributes to hypertension via arterial stiffening, among many other issues. However, there are many other short-lived AGEs that arise from the diet and from cellular metabolism, and which are particularly prevalent in the distorted metabolism of obese and diabetic patients.

These short-lived AGEs produce inflammation by overactivating RAGE; this mechanism has been fairly well studied in past years, particularly in diabetic patients. As the authors of this paper note, however, even well studied parts of human biochemistry have plenty of unanswered questions left for researchers to work on. As for a number of processes that may operate to a significant degree in both diabetes and aging, it is an open question as to the degree to which RAGE is important in purely age-related dysfunction, versus other mechanisms such as the accumulation of senescent cells. Older people tend to have more fat tissue, which obscures the matter.

Is RAGE the receptor for inflammaging?


In its full-length form the receptor for advanced glycation end products, RAGE, is a multi-ligand, transmembrane receptor promoting activation of key pro-inflammatory and pro-oxidative pathways. The deleterious effects of its activation via the binding of AGEs (the advanced glycation end products after which it is named) are widely reported, especially in diabetes mellitus. Indeed, our current understanding of RAGE relies heavily upon research on this metabolic disorder, but it is simplistic to apprehend this receptor solely within a diabetic context or through its interactions with AGEs. RAGE is more broadly implicated in both immunity and inflammation: more than 28 RAGE ligands are known, many of which are damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs).

RAGE can thus be more accurately considered a pattern recognition receptor (PRR), and has been labelled a “noncanonical Toll-like receptor (TLR)” by some authors. This wider involvement of RAGE signalling nevertheless remains poorly-studied relative to research involving diabetes and AGEs, but evidence is accumulating of its role in what has come to be known as “inflammaging”. RAGE deletion has been shown to be protective against both cardiovascular disease and Alzheimer’s disease in RAGE-/- mice, and while the impact of anti-RAGE therapeutics remains to be demonstrated in humans, laboratory results highlight the potential of targeting this receptor to address multiple public health issues.

RAGE has obvious similarities with other PRRs and there are acknowledged pro-aging mechanisms such as oxidative stress, mitochondrial dysfunction or inflammasome activation resulting from its interaction with several of its ligands. The concomitant, age-related increase of circulating DAMPs, and the expression of RAGE on many cell membranes, even in the absence of a pathological event, could favour low-grade, persistent, pro-inflammatory processes which in turn could drive increased production of DAMPs and expression of RAGE. This pro-aging vicious circle of events places RAGE firmly in the spotlight as a key-actor in inflammaging, not least because senescent cells also produce RAGE ligands like HMGB1 and S100s.

This hypothesis is attractive and opens up significant possibilities in the development of anti-RAGE therapeutics, but many questions remain. To what extent do the different RAGE ligands compete for binding, and how does this competition modulate its activation? Are the activated signalling pathways ligand-specific, or perhaps specific to the configuration of RAGE in its various forms? Are there negative effects to RAGE inhibition?

Senescent Cells Implicated in Age-Related Changes in Blood Clotting

https://www.fightaging.org/archives/2019/09/senescent-cells-implicated-in-age-related-changes-in-blood-clotting/

Senescent cells are created constantly in the body as the result of a number of processes: the Hayflick limit, wound healing, a toxic local environment, DNA damage, and so forth. Near all are destroyed quite quickly, either via programmed cell death or by the immune system. Some few linger, however, and secrete a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). The SASP produces wide-ranging damage and dysfunction in tissues, causing issues such as chronic inflammation, fibrosis, and harmful behavior or increased senescence in nearby cells. Thus senescent cell burden is one of the important causes of aging, and efforts to produce senolytic therapies capable of selectively destroying these cells are a very important new branch of medicine.

As noted in today’s scientific materials, researchers have recently provided data to associate the burden of senescent cells in older individuals with detrimental changes in blood clotting. This adds one more item to a very long list of harmful effects resulting the SASP. With age, blood clots form more readily, and in inappropriate circumstances, such as inside major blood vessels. This can cause serious issues such as thrombosis, the blocking of blood vessels and consequent ischemia, or worse, such as a stroke or heart attack should a sizable clot fragment and the fragments block a more vital blood vessel elsewhere.

The data here associating components of the SASP with increased susceptibility to blood clotting is interesting to compare with a recent review paper on changes in platelet function with age. The biochemistry of the age-related hyperactivity of platelets, leading to increased clotting, has been examined in a proximate sense, but reaching backwards to root causes is something that the research community has never been all that good at following through on. The work here is a good example of starting with a known cause of aging and working forwards, a much more efficient approach, and one that must become more widespread in the research community if we are to see meaningful progress in treatments for age-related conditions in the years ahead.

Cellular senescence is associated with age-related blood clots


Cells that become senescent irrevocably stop dividing under stress, spewing out a mix of inflammatory proteins that lead to chronic inflammation as more and more of the cells accumulate over time. Researchers have identified 44 specific senescence-associated proteins that are involved in blood clotting, marking the first time that cellular senescence has been associated with age-related blood clots. “The incidence of venous thrombosis, which includes deep vein thrombosis and pulmonary embolism is extremely low until the age of 45, when it begins to rise rapidly. Over time it becomes a major risk factor for death. By 80, the condition affects five to six people per thousand individuals. Blood clots are also a serious side effect of chemotherapy, which sets off a cascade of senescence in those undergoing treatment. That’s why blood thinners, which carry their own risks, are often included in treatment protocols.”

In this study, researchers validated the expression of some of the specific factors in cultured cells and in mice, which were treated with doxorubicin, a widely-used chemotherapy drug which induces widespread senescence. Those mice showed increased blood clotting, similar to what happens in humans who undergo chemotherapy. “Conversely, when we selectively removed senescent cells in specially bred transgenic mice, the increased clotting caused by doxorubicin went away.”

SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells


Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids (SILACs) and cultured cells, we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared with quiescent cell counterparts. Bioinformatic analysis reveals that 44 of these proteins participate in hemostasis, a process not previously linked with cellular senescence.

We validated the expression of some of these SASP factors in cultured cells and in vivo. Mice treated with the chemotherapeutic agent doxorubicin, which induces widespread cellular senescence in vivo, show increased blood clotting. Conversely, selective removal of senescent cells using transgenic p16-3MR mice showed that clearing senescent cells attenuates the increased clotting caused by doxorubicin. Our study provides an in-depth, unbiased analysis of the SASP and unveils a function for cellular senescence in hemostasis.

ApoE Levels Rise with Age and Degrade the Ability to Regenerate Bone

https://www.fightaging.org/archives/2019/09/apoe-levels-rise-with-age-and-degrade-the-ability-to-regenerate-bone/

ApoE is a important protein in lipid metabolism, one of those responsible for transporting cholesterols and other lipids around the body. In today’s open access research, the authors present evidence for rising levels of ApoE with aging to degrade the ability of bone to regenerate. This is unfortunate, because it will not be straightforward to just reduce ApoE levels. The protein is vital; a number of serious inherited conditions involve ApoE mutation that leads to greatly increased lipid levels on the bloodstream and organs.

Bone regeneration, and normal tissue maintenance of bone for that matter, is a balance between constant creation and destruction of extracellular matrix structures. Osteoblast cells build bone, and osteoclasts tear it down. Age-related loss of bone density and strength is the result of a growing imbalance that favors osteoclast activity. There is good evidence for numerous mechanisms to be important here, including the usual suspects such as the inflammatory signaling produced by senescent cells. The data here for reversal of loss of regenerative capacity via reduced ApoE levels is quite compelling as an argument for this to be an important proximate mechanism, however.

Protein prevalent in older people could be key to healing bones


Researchers confirmed that older people have more Apolipoprotein E, ApoE for short, than younger people. (If that protein name rings a bell, it’s because ApoE is also implicated in Alzheimer’s and heart disease). The team found that 75-85 year olds had twice as much ApoE in their bloodstreams as 35-45 year olds, then found the same was true for 24-month-old mice versus 4-month-old mice, which approximate the same human age ranges. Next, they wanted to figure out if and how ApoE affects the multi-step process of bone healing. When you break a bone, your body sends signals through the bloodstream to recruit cells to fix it. Some of those recruits, specifically skeletal stem cells, build up cartilage as a temporary scaffolding to hold the fracture together.

In the next step, more recruited cells mature into osteoblasts, bone-building cells, which lay strong, dense bone cells on top of the cartilage scaffolding. Finally, a different kind of cell eats up the cartilage scaffolds and osteoblasts fill those holes with bone. That’s if the bone healing process works perfectly. But the researchers found that if they added ApoE to a petri dish with skeletal stem cells, fewer cells developed into osteoblasts and the osteoblasts were worse at building bones. Next, the researchers created an intervention by injecting a virus which keeps mice from making ApoE protein. Circulating ApoE levels dropped by 75 percent and the healed bones contained one and a half-times more strong, hard bone tissue than bones of untreated mice.

Lowering circulating apolipoprotein E levels improves aged bone fracture healing


In our previous work investigating aged bone regeneration, we identified apolipoprotein E (ApoE) to be one of many candidates potentially involved in aged bone fracture healing. ApoE is a widely expressed lipoprotein classically associated with lipid metabolism and fatty acid transport. ApoE polymorphisms are present in 20% of the population and are associated with hypercholesterolemia, atherosclerosis, and Alzheimer’s disease. More recently, clinical evidence has revealed that these ApoE polymorphisms are also associated with decreased bone mineral density and increased risk of hip and vertebral fracture. Mouse models lacking ApoE expression display increased cortical thickness, trabecular number, and bone mineral density. However, a role for ApoE in fracture healing and musculoskeletal aging remains to be investigated.

Here, we sought to understand the role of ApoE in age-associated deficiencies in bone fracture healing. Our previous work has established the importance of circulating factors in the age-associated impairment of bone regeneration. Here, we use our established tibial fracture model coupled with μCT and histological analysis as well as our parabiosis models to identify a role for circulating ApoE in bone fracture healing. We identify ApoE as a negative regulator of osteoblast differentiation and combine this work with functional metabolic assessment and transcript analysis to identify the mechanism by which ApoE influences osteoblast differentiation. Finally, we identify that lowering circulating ApoE levels, using siRNA strategies, in aged mouse models leads to improved bone fracture healing. Collectively, our findings demonstrate that ApoE impairs bone fracture healing in an age-dependent manner by decreasing osteoblast differentiation.

Alzheimer’s Disease as a Condition of Many Subtypes and Contributing Causes

https://www.fightaging.org/archives/2019/09/alzheimers-disease-as-a-condition-of-many-subtypes-and-contributing-causes/

Neurodegeneration in late life is a very complex phenomenon, and its complexity strains against the nice neat clinical definitions of disease found in the textbooks. Different patients with Alzheimer’s disease can exhibit quite different mixes of various forms of pathology, developing at different paces and times: aggregates of amyloid-β, tau, and α-synuclein; vascular degeneration; markers of neuroinflammation; metabolic disruption similar to that of diabetes, and so forth. One case of Alzheimer’s might be different enough from another to require a different designation. Thus researchers talk about defining subtypes of Alzheimer’s disease, or that individual patients have Alzheimer’s that is exacerbated by a comorbidity arising from other neurodegenerative processes.

Another way of looking at this is to categorize mechanisms that contribute to Alzheimer’s. To what degree is a given set of mechanisms important in a given patient? A sizable amount of work has gone into investigation of processes and feedback loops other than the primary amyloid cascade hypothesis of the condition. It is an open question as to where all of these contributing aspects of the condition fit into a chain of cause and consequence, or whether the ordering of that chain is similar from patient to patient. Alzheimer’s disease may well be a collection of distinct conditions that all happen to wind up in a similar end state.

The authors of this paper draw the gloomy conclusion that this complexity, and continued failures in the development of therapies based on the amyloid cascade hypothesis, imply that there are no silver bullets. I would argue otherwise, and say that instead comparatively simple points of intervention have not yet been developed fully. Senolytic therapies that clear senescent glial cells from the brain seem quite effective in animal models, for example. The approach of restoring lost drainage of cerebrospinal fluid, to clear out aggregates from the brain, also looks promising. There will be others. The complexity of aging emerges from simpler root causes, and there will always be some clever way to intervene at a point of maximum leverage.

Multi-Loop Model of Alzheimer Disease: An Integrated Perspective on the Wnt/GSK3β, α-Synuclein, and Type 3 Diabetes Hypotheses


Alzheimer’s disease (AD) is among the most ominous of modern health epidemics. AD is not alone in its ascent. Other chronic diseases, particularly Parkinson’s disease (PD), a neurodegenerative disorder associated with the build-up of α-synuclein protein and death of dopaminergic neurons, and type 2 diabetes mellitus (T2DM) are increasing in prevalence at similarly alarming rates. Although AD, PD, and T2DM share common risk factors, chief among these being age, there is more to their relationship. Evidence suggests that the pathophysiological mechanisms underlying AD, PD, and T2DM interact synergistically.

In addition to the well-known amyloid cascade hypothesis of AD, other hypotheses have been proposed that include: (1) the Wnt/Glycogen Synthase Kinase 3β (GSK3β) hypothesis, (2) the α-synuclein hypothesis, and (3) the type 3 diabetes hypothesis. Dsfunctional Wnt-signaling can contribute to the development of AD and its two pathological hallmarks, Aβ plaques and p-tau tangles. The canonical PD-associated protein α-synuclein may be locked in pathological positive feedback loops with Aβ and tau. Finally, insulin resistance in the brain, “type 3 diabetes,” may contribute to development and exacerbation of AD. Each model interacts with the others. These interrelationships, make it clear that the pathology of AD is not a linear cascade, nor a simple feedback loop, but rather a network of cross-talking models and overlapping vicious cycles.

Given the cooperative and reinforced nature of this complex network, it is no surprise that the prototypical monotherapeutic approach to AD has reliably failed. Certainly, drugs that target key nodes within the network, such as GSK3β inhibitors or AKT activators, have shown promise in animal models, and this important work affords us valuable mechanistic insights. However, these pre-clinical successes generally have not translated into clinical success, at least not with the same degree of efficacy. This is likely because animal models harboring distinct AD-causing mutations and dysfunctions in particular linear pathways do not accurately recapitulate the complex pathologies underlying sporadic human AD. In brief, we are proposing that the single-target silver-bullet approach to AD drug discovery is doomed to fail and that we may only be able to treat or prevent AD by developing new multifaceted treatment options.

ADRB1 Mutation Grants a Lesser Need for Sleep, and thus a Longer Subjective Life

https://www.fightaging.org/archives/2019/09/adrb1-mutation-grants-a-lesser-need-for-sleep-and-thus-a-longer-subjective-life/

We lose a third of our life to sleep. If we didn’t need to sleep at all, then we would have the experience of living 50% longer, considered subjectively. We would accomplish much more, experience much more. There are, unfortunately, few useful ways to safely reduce the amount of time spent asleep, without reductions in the quality of life while awake. Here, researchers report on a rare human genetic variant that manifests itself in a family whose members with the mutation need comparatively little sleep to be fully rested, and who appear to be otherwise unaffected by this genetic difference.

This discovery may well prove to be the basis for enhancement treatments to reduce required sleep time in the years ahead. We should consider the caveats, however: sleep appears to be important in clearance of some aggregates from the brain, and it could be the case that individuals who sleep less have raised rates of neurodegenerative disease in late life, but these possible risks and associations have not yet been evaluated.


An understanding of the regulatory mechanism for sleep lays at the foundation for healthy living and aging. Sleep behavior has long been thought to be regulated by the interactions of circadian clock and sleep homeostasis pathways. In humans, variations of genetically inherited sleep features in the population have been recognized for a long time. Importantly, human sleep has unique features that are different from that of animal models. For example, human sleep is usually consolidated, whereas mice sleep throughout the 24 hour day. Drosophila sleep-like behavior is consolidated into one long period, but the level of similarity between the Drosophila and human molecular regulatory mechanisms remains unclear.

Previously, we identified a series of genetic variations that influence the timing of sleep in humans, and mouse models of these mutations mostly recapitulate the phenotypes. Timing of sleep is heavily influenced by the circadian clock, which has been intensely studied, and we now have a large and growing body of knowledge on how the clock is regulated at the molecular level. On the other hand, our understanding of sleep homeostasis regulation for human lags behind. We reported a mutation in the human DEC2 gene that causes mutation carriers to sleep 6 hours nightly for their entire lives without apparent negative effects. Another mutation in DEC2 was later reported in a single individual who is a short sleeper and resistant to sleep deprivation. Identification of additional genes participating in modulation of human sleep duration provides a unique way to expand our knowledge of genes and pathways critical for human sleep homeostasis regulation.

Noradrenergic signaling in the central nervous system (CNS) has long been known to regulate sleep. The network involving the noradrenergic neurons has been extensively studied, and most of the receptor subtypes have been genetically defined. In contrast to α1 and α2 adrenergic receptors (ARs), relatively little is known about the function of β receptors in the CNS. βARs within the brain were previously suggested to mediate the effect of norepinephrine (NE) for alert waking and rapid eye movement (REM) sleep. Clinically, β-blockers are widely used and can be associated with difficulty falling asleep and staying asleep, possibly due to reduced production and release of melatonin.

We report here a rare mutation in the β1AR gene (ADRB1) found in humans with natural short sleep. Engineering the human mutation into mice resulted in a sleep phenotype similar to that seen in familial natural short sleepers. We show that β1AR is expressed at high levels in the dorsal pons (DP). Neuronal activity measured by calcium imaging in this region demonstrated that ADRB1+ neurons in DP are wake and REM sleep active. Manipulating the activity of these ADRB1+ neurons changes sleep/wake patterns. Also, the activity of these neurons was altered in mice harboring the mutation. Together, these results not only support the causative role of this ADRB1 mutation in the human subjects but also provide a mechanism for investigating noradrenaline and β1AR in sleep regulation at the circuit level.

Aging Biotech Info is a Curated List of Companies in the Longevity Industry

https://www.fightaging.org/archives/2019/09/aging-biotech-info-is-a-curated-list-of-companies-in-the-longevity-industry/

Karl Pfleger is one of the small community of angel investors and philanthropists who collectively initially supported the first rejuvenation biotechnology companies to emerge in this present generation of the longevity industry. Here he is performing the public service of publishing a curated list of biotechnology companies in the industry, startups that are either definitively or at least arguably working on a means to intervene in important mechanisms of aging, along with their targets and progress to date. That there are still fewer than 100 such companies indicates that this is very much an industry in its initial growth phase – but growth is certainly happening. The sizable pools of venture funding dedicated to the longevity industry, such as Juvenescence and Life Biosciences are attracting new entrepreneurs, and the scientific community is starting to realize that the prospects for advancing their research programs into clinical translation have greatly improved these past few years.


Chronic diseases of aging have over the past century taken over from infectious diseases as the predominant causes of death and suffering. The science of aging has shown over the past few decades that certain slow biological changes collectively underlie most (if not all) chronic diseases. The aging and longevity field, the understanding of these slow changes and how to interfere with them, is currently a small part of the overall medical, healthcare, and biotech spaces, but the efficiency of targeting the underlying causes of multiple diseases will rapidly cause aging to grow to become a much larger portion.

The aging and longevity field has recently grown to the point where it is difficult to follow important developments, even for insiders. There are books, journals, and blogs, but few sources of structured information to refer to for broader context or to consult for targeted inquiries, particularly few focused narrowly on aging defined as the underlying molecular causes of multiple age-related diseases.

As an especially important example, the internet previously had no reasonably comprehensive and precise list of companies with therapies or diagnostics for underlying aging in the above sense. Some argue that aging will be a scientific, commercial, and cultural revolution to rival any others. What is even more certain is that the field is important and of interest to many, so concise ways to pay attention will be useful. This will be a living site with ongoing updates. Focus will be on content, not flashiness, with the goal being utility for the community, those interacting with it, and the wider interested public.

Exosomes Improve Collagen Production in Aged Skin

https://www.fightaging.org/archives/2019/09/exosomes-improve-collagen-production-in-aged-skin/

Loss of collagen in the extracellular matrix is one of the manifestations of aging in skin. There are any number of very marginal approaches intended to improve matters presently available in clinics and stores, very few of which in any way address the underlying causes, or in only very minor ways if they do. Delivery of signals generated by healthy skin cells is an approach that might be more effective, but again this doesn’t address the underlying causes of skin aging – it is an attempt to override cellular reactions to the aged environment. In this vein, researchers here demonstrate the harvesting of exosomes, small membrane bound packages that carry signals between cells, from cell cultures, and their delivery to aged skin as a possible therapy.


Researchers have shown that exosomes harvested from human skin cells are more effective at repairing sun-damaged skin cells in mice than popular retinol or stem cell-based treatments currently in use. Additionally, the nanometer-sized exosomes can be delivered to the target cells via needle-free injections. Exosomes are tiny sacs (30 – 150 nanometers across) that are excreted and taken up by cells. They can transfer DNA, RNA, or proteins from cell to cell, affecting the function of the recipient cell. In the regenerative medicine field, exosomes are being tested as carriers of stem cell-based treatments for diseases ranging from heart disease to respiratory disorders.

To test whether exosomes could be effective for skin repair, researchers first grew and harvested exosomes from skin cells. They used commercially available human dermal fibroblast cells, expanding them in a suspension culture that allowed the cells to adhere to one another, forming spheroids. The spheroids then excreted exosomes into the media. “These 3D structures generate more procollagen – more potent exosomes – than you get with 2D cell expansion.”

In a photoaged, nude mouse model, the researches tested the 3D spheroid-grown exosomes against three other treatments: retinoid cream; 2D-grown exosomes; and bone marrow derived mesenchymal stem cells (MSCs) exosomes, a popular stem cell-based anti-aging treatment currently in use. The team compared improvements in skin thickness and collagen production after treatment. They found that skin thickness in 3D exosome treated mice was 20% better than in the untreated and 5% better than in the MSC-treated mouse. Additionally, they found 30% more collagen production in skin treated with the 3D exosomes than in the MSC treated skin, which was the second most effective treatment.

Fitter, Thinner Older Adults Have a Measurably Different Gut Microbiome

https://www.fightaging.org/archives/2019/09/fitter-thinner-older-adults-have-a-measurably-different-gut-microbiome/

In recent years, researchers have demonstrated that the microbiome of the gut is influential over the pace of aging. Dietary changes, immune system changes, tissue changes, and microbiome population changes all take place and interact with one another with advancing age. There is evidence for changes in the microbiome to aggravate the immune system into chronic inflammation, and evidence for declining immune function to lead to unhelpful changes in the balance of microbes. Some people have better microbiomes, such as athletes tending to have microbes that secrete compounds such as proprionate that can incrementally improve health. In animal models, transplanting gut microbes from young to old animals improves the health and longevity of the older animals.

In this broader context, we should probably expect fitter adults to have a measurably different gut microbiome in comparison to their less fit and overweight peers. Are those different bacteria helping to maintain fitness? The evidence here suggests that they are, but questions of causation remain: is it diet, weight, and inflammation that determines whether or not helpful bacteria are present, or do natural variations in bacterial populations between individuals make it easier or harder to maintain fitness?


The gut-muscle axis, or the relationship between gut microbiota and muscle mass and physical function, has gained momentum as a research topic in the last few years as studies have established that gut microbiota influences many aspects of health. While researchers have begun exploring the connection between the gut microbiome, muscle, and physical function in mice and younger adults, few studies have been conducted with older adults. To gain insight into this population, the researchers compared bacteria from the gut microbiomes of 18 older adults with high-physical function and a favorable body composition (higher percentage of lean mass, lower percentage of fat mass) with 11 older adults with low-physical function and a less favorable body composition. The small study identified differences in the bacterial profiles between the two groups.

Similar bacterial differences were present when mice were colonized with fecal samples from the two human groups, and grip strength was increased in mice colonized with samples from the high-functioning older adults, suggesting a role for the gut microbiome in mechanisms related to muscle strength in older adults. Specifically, when compared to the low-functioning older adult group, the researchers found higher levels of Prevotellaceae, Prevotella, Barnesiella, and Barnesiella intestinihominis – all potentially good bacteria – in the high-functioning older adults and in the mice that were colonized with fecal samples from the high-functioning older adults.

“While we were surprised that we didn’t identify a role for the gut microbiome on the maintenance of body composition, with these results we now start to understand the role of gut bacteria in the maintenance of muscle strength in older adults. For example, if we were to conduct an intervention to increase Prevotella levels in the gut microbiome, we would expect to see an increase in muscle strength if these bacteria are involved. Prevotella’s role in the maintenance of muscle strength in older adults is one area we expect to continue to explore.”

Risk Factors versus Lifestyle Choices in the Mortality of Old Age

https://www.fightaging.org/archives/2019/09/risk-factors-versus-lifestyle-choices-in-the-mortality-of-old-age/

Environmental and lifestyle choices, as numerous epidemiological studies have demonstrated, have considerable influence over health and mortality in late life. This open access paper balances lifestyle choices against a range of environmental factors and measures of the progression of aging. The authors find that a healthy lifestyle can only partially offset the effects of having a greater burden of age-related damage and its consequences, or, separately, the impact of low socioeconomic status. The former makes a great deal of sense, given the inevitability of aging as matters currently stand, with even the healthiest succumbing, while the latter is an interesting finding. It remains unclear as to the mechanisms linking socioeconomic status to aging: wealth, education, intelligence, stress, access to medical services, and other factors are closely tied and hard to pick apart in the human data.


Annual mortality among oldest-old individuals was reduced by somewhere between 0.2% and 1.3% from 1998 to 2008 in China. Impaired cognitive functions were independent predictors of all-cause mortality in very old people. Moreover, the risk of mortality is very high for the oldest-old with disabilities. Additionally, socioeconomic inequalities, obesity, cardiovascular factors, and chronic diseases are associated with mortality in the oldest-old. Conversely, healthy lifestyle practices, such as consumption of fruits and vegetables, social participation, and maintaining a normal weight, are associated with lower mortality. The question remains as to whether a healthy lifestyle and behavioral factors (e.g., never smoking and physical training) can somehow compensate for the harmful effects of the risk factors on mortality.

In this large, nationwide cohort study of Chinese oldest-old (80 years of age and older), we found that rural residence, not in marriage, lower economic level, physical disability, impaired cognitive function, and comorbidity are independent risk factors for mortality. Using these factors, we computed a weighted “risk score.” Because never smoking, never drinking, doing physical exercise, having an ideal diet, and a normal weight were independently associated with lower mortality, we also combined them to compute a weighted “protection score.” Both scores were divided into lowest, middle, and highest groups using their tertiles.

In joint effect analyses, participants with the combined highest-risk score and lowest-protection score profile had a nearly threefold higher joint death risk. These analyses show that adherence to a healthy lifestyle counteracts the negative effect of risk factors on all-cause mortality in the oldest-old by more than 20%.

An Interview with Tristan Edwards of Life Biosciences

https://www.fightaging.org/archives/2019/09/an-interview-with-tristan-edwards-of-life-biosciences/

Alongside Juvenescence, Life Biosciences is one of the first large investment concerns wholly dedicated to the growing longevity industry. The Life Biosciences principals take the approach of providing the extensive supporting infrastructure needed to wrap a company around a senior scientist in the field of aging research, and then guide their work towards commercialization. Most scientists have very little interest in founding a company, and in any case lack the skills needed to do so. This approach of providing an environment that operates in much the same way as academia from the perspective of the researcher, in which the business side of things is handled, is a good way to accelerate progress in a field that presently lacks a sufficiently large population of entrepreneurs for companies to emerge naturally at a good pace.


How far along is longevity in becoming a defined category for investors? Put it on a scale of 0-10 for us. If fintech has developed to a nine or a ten, where would you score longevity?

From an investment perspective I would say it’s a one or a two. But I believe that will change very quickly. I think the scale will go from a two to an eight in the next four to five years. Like the Internet of Things, or Artificial Intelligence before it, in the next few years I can’t imagine a single person on the planet not being aware of the ability to extend lifespan and healthspan, both as an industry and as a benefit to humankind.

So, a major shift in our thinking is on the way?

In 1903, the Wright brothers defied expectation and took their first flight. We have the photo of this on our office wall, to remind us of who we are. The idea of humans being able to fly back then was crazy; most people were saying it couldn’t be done. Yet after they left the earth’s gravity, it didn’t take mankind years to accept it. We immediately forgot that it was crazy. All we needed was proof that it could be done, and we never looked back. That’s exactly where we are with longevity sciences. Longevity research has been evolving as a legitimate science for many years. But I think we are at the cusp of dramatic change. We’ll see more and more bright young minds focusing on longevity, and we will soon treat aging. Eventually, we’re talking about adding another 20 – 30 years to the average lifespan with none of the diseases of aging: Parkinson’s, Alzheimer’s, type 2 diabetes, etc. In other words, not only expanding lifespan but what we call “healthspan,” the period during which the individual can live a healthy, productive life.

Does all this development mean big institutional investors will soon be paying attention?

Plenty already are. The science, however, has to build to a point where the rounds are large enough for them to get involved. Once you start raising $100m to $200m rounds, they’ll start paying real attention and investing. The rounds must be large enough for the mandates to allow and value checks must be in place in new areas; this can be tough to do. As the science progresses, we see the investment interest ramping up, with bigger contributors stepping in. A lot also depends on how quickly some institutions learn to adapt. By “adapt” I mean simply this: There’s a long-held understanding that Big Pharma relies on illness for profits. But if they reframe their mission as being in the healthspan business, then the longevity revolution is valuable for them. It’s my hope that Pharma embraces this change as a wonderful and necessary way for them to evolve their business in a much more effective way.

The Boost to the Unfolded Protein Response Achieved via Exercise Declines with Age

https://www.fightaging.org/archives/2019/09/the-boost-to-the-unfolded-protein-response-achieved-via-exercise-declines-with-age/

Exercise achieves benefits to health in large part through upregulation of cellular maintenance processes. In this way it is similar to the practice of calorie restriction, but the outcome is of a lesser degree – exercise does not extend life span in laboratory species, while calorie restriction does. Nonetheless, exercise is certainly beneficial. One of the cellular maintenance processes involved is the unfolded protein response, which, as the name might suggest, clears out proteins that are improperly folded, or have otherwise become stuck at the folding stage of protein manufacture, in the endoplasmic reticulum structure of the cell. Like other maintenance processes, the unfolded protein response becomes less effective with age, for reasons that are far from fully explored. Here, researchers demonstrate this diminished effectiveness in the context of the response to exercise.


Aging is associated with the loss of skeletal muscle mass, quality, and function; decrements that have a negative influence on health span. Resistance exercise improves muscle mass and function, but there is emerging evidence that the molecular and cellular responses to anabolic stimuli (e.g., exercise and nutrition) are attenuated in older adults; a phenomenon termed anabolic resistance. The unfolded protein response (UPR) has emerged as a key regulatory pathway in skeletal muscle protein quality control and adaptations to exercise. Early evidence points to altered UPR as an explanation for age and disease related changes in protein folding and accumulation and aggregation of proteins within the endoplasmic reticulum (ER).

The influence of age on skeletal muscle adaptive UPR in response to exercise, and the relationship to other key exercise-responsive regulatory pathways is not well-understood. We evaluated age-related changes in transcriptional markers of UPR activation following a single bout of resistance exercise in 12 young (27 ± 5yrs) and 12 older (75 ± 5yrs) healthy men and women. At baseline, there were modest differences in expression of UPR-related genes in young and older adults. Following exercise, transcriptional markers of UPR pathway activation were attenuated in older adults compared to young based on specific salient UPR-related genes and gene set enrichment analysis. The coordination of post-exercise transcriptional patterns between the UPR pathway, p53/p21 axis of autophagy, and satellite cell (SC) differentiation were less evident in older compared to young adults.

In conclusion, older adults exhibited decreased markers of UPR activation and reduced coordination with autophagy and SC-associated gene transcripts following a single bout of unaccustomed resistance exercise. In contrast, young adults demonstrated strong coordination between UPR genes and key regulatory gene transcripts associated with autophagy and SC differentiation in skeletal muscle post-exercise. Taken together, the present findings suggest a potential age-related impairment in the post-exercise transcriptional response that supports activation of the UPR and coordination with other exercise responsive pathways (i.e., autophagy, SC differentiation) in skeletal muscle that is likely to contribute to sarcopenia and age-related attenuation of adaptive responses to exercise.

Altered Calcium Transport in Aging Mitochondria is Maladaptive

https://www.fightaging.org/archives/2019/09/altered-calcium-transport-in-aging-mitochondria-is-maladaptive/

Mitochondria are the power plants of the cell, responsible for packaging energy store molecules used to power cellular processes. There are hundreds of them in any given cell, the descendants of ancient symbiotic bacteria. They replicate by fission, like bacteria, and carry a remnant of their original DNA. Mitochondrial function declines with age, a problem that appears to stem from an imbalance in mitochondrial fission that in turn impairs the ability of the cell to clear out worn and malfunctioning mitochondria via the process of autophagy. Exactly why this imbalance arises is poorly understood, but it can be added to the long, long list of maladaptive processes that emerge in response to the underlying molecular damage of aging.

Researchers here focus on another maladaptive aspect of mitochondrial function in aging cells: they exhibit altered calcium transport, which may initially compensate for other shortfalls, but then ultimately further contributes to the faltering of mitochondrial function. This is very much a downstream consequence of deeper problems.


Sometimes the more a person tries to fix a seemingly minor problem, the worse things become. Cells are no different, it turns out, though attempting to compensate for what begins as a minor deficiency or dysfunction can be dire. In the case of Alzheimer’s disease, researchers now show that mitochondrial calcium transport remodeling – what appears to be an attempt by cells to compensate for flagging energy production and metabolic dysfunction – while initially beneficial, ultimately becomes maladaptive, fueling declines in mitochondrial function, memory, and learning.

Altered calcium regulation and metabolic dysfunction have been suspected of contributing to neuronal dysfunction and Alzheimer’s development. Calcium transport into mitochondria plays an important part in many cellular functions and requires the involvement of multiple proteins to be carried out effectively. Among the key regulators of this process is a protein known as NCLX, which previously was discovered to mediate calcium efflux from heart cells. NCLX expression is also important in mitochondrial calcium efflux in neurons.

In a new study, researchers examined the role of mitochondrial calcium uptake by neurons in Alzheimer’s disease. To do so, the team used a mouse model of familial Alzheimer’s disease in which animals harbored three gene mutations that give rise to age-progressive pathology comparable to Alzheimer’s progression in human patients. As mice carrying the three mutations aged, the researchers observed a steady reduction in NCLX expression. This reduction was accompanied by decreases in the expression of proteins that limit mitochondrial calcium uptake, resulting in damaging calcium overload. NCLX loss was further linked to increases in the production of cell-damaging oxidants. When NCLX expression was restored, levels of harmful protein aggregates declined, neuronal mitochondrial calcium homeostasis was reestablished, and mice were rescued from cognitive decline.

“Our findings indicate that maladaptive remodeling of pathways to compensate for abnormalities in calcium regulation, which perhaps are meant to maintain energy production in cells, lead to neuronal dysfunction and Alzheimer’s pathology. Moreover, our data suggest that amyloid beta and tau pathology actually lie downstream of mitochondrial dysfunction in the progression of Alzheimer’s disease, which opens up a new therapeutic angle.”

A Skeptical Review of the Evidence for Metformin

https://www.fightaging.org/archives/2019/09/a-skeptical-review-of-the-evidence-for-metformin/

This review paper more or less leans towards my thoughts on metformin as a treatment to slow aging: the animal data is not great, the human data is a single study, the effect size on life span is far too small to care about, and the detrimental side effects are large in comparison to that effect size. The strategy of upregulating stress response mechanisms via drugs such as metformin is a poor strategy for long-lived species, as we clearly don’t exhibit the sizable gains in life span that occur in short lived species such as mice under these circumstances. Metformin, in turn, is a low performance example of this strategy, much worse than, say, the practice of calorie restriction or mTOR inhibitors.


Metformin is sometimes proposed to be an “anti-aging” drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage, or running, to find a new use (or indication) for an aging population. In 2015, Nir Barzilai met with regulators from the FDA to discuss the now famous phase III multi-site TAME (Targeting Aging with Metformin) trial. The acronym chosen and the intention behind it – namely, that aging is a “disorder” that can be treated like any other disease – was a clear provocation. The FDA’s mandate is to regulate medications and devices to cure diseases or aid in their diagnosis, but aging is not (yet) an indication. Interestingly, frailty is missing from the proposed composite outcome. Other ongoing trials (e.g., NCT02570672) with metformin provide arguments that frailty may be an important endpoint. It will be interesting to compare the results with the ongoing fisetin trial (NCT03675724).

Although widely cited as evidence for the small effects of 0.1% metformin in the diet on the lifespan of older male inbred mice, earlier results obtained by researchers should be dismissed: the National Institute on Aging Interventions Testing Program could not replicate the findings regarding an extension of the lifespan with 0.1% metformin. The negative results were obtained at three different locations using genetically heterogeneous female and male mice.

The rationale for the ongoing or planned metformin trials is almost exclusively based on observations (associations) of potential benefits in a diabetic (or prediabetic) population. Its efficacy even in an at-risk cohort of aged people has not yet been proven. Metformin is associated with a higher risk of vitamin B12 and vitamin B6 deficiency, which may result in an increased risk of cognitive dysfunction. Supplementation is strongly recommended to metformin users.

Of greater concern are the results of small trials in which the effects of metformin on metabolic responses to exercise or on cardiorespiratory fitness were tested. In a placebo-controlled, double-blind, crossover trial with healthy young subjects, metformin caused a small but significant decline in maximal aerobic capacity. A double-blind, placebo-controlled landmark trial with older adults with one risk factor for type 2 diabetes investigated the effects of metformin and 12 weeks of aerobic exercise. Contrary to expectations – namely, that the effects of exercise and the drug would be additive – “metformin attenuated the increase in whole-body insulin sensitivity and abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration.”

A Non-Invasive Approach to Measuring Cellular Senescence in the Kidney

https://www.fightaging.org/archives/2019/09/a-non-invasive-approach-to-measuring-cellular-senescence-in-the-kidney/

Researchers here provide evidence that the presence in the urine of extracellular vesicles carrying p16 as a part of their cargo might be used as a way to assess cellular senescence levels in the kidney. The presence of lingering senescent cells increases with age, and these cells cause chronic inflammation and tissue dysfunction in proportion to their numbers. With rapid growth in the clinical development of senolytic drugs capable of clearing senescent cells from aged tissues, and the present availability of a few proven and potential senolytic treatments such as the dasatinib and quercetin combination, there is a strong need for ways to quantify the burden of senescent cells in humans. Simple, low-cost tests that can run before and after a senolytic treatment would go a long way towards quantifying the degree to which the presently available approaches actually work.


Hypertension may be associated with renal cellular injury. Cells in distress release extracellular vesicles (EVs), and their numbers in urine may reflect renal injury. Cellular senescence, an irreversible growth arrest in response to a noxious milieu, is characterized by release of proinflammatory cytokines. We hypothesized that EVs released by senescent nephron cells can be identified in urine of patients with hypertension.

We recruited patients with essential hypertension (EH) or renovascular hypertension and healthy volunteers. Renal oxygenation was assessed using magnetic resonance imaging and blood samples collected from both renal veins for cytokine-level measurements. EVs isolated from urine samples were characterized by imaging flow cytometry based on specific markers, including p16 (senescence marker), calyxin (podocytes), urate transporter 1 (proximal tubules), uromodulin (ascending limb of Henle’s loop), and prominin-2 (distal tubules).

Overall percentage of urinary p16+ EVs was elevated in EH and renovascular hypertension patients compared with healthy volunteers and correlated inversely with renal function and directly with renal vein cytokine levels. Urinary levels of p16+/urate transporter 1+ were elevated in all hypertensive subjects compared with healthy volunteers, whereas p16+/prominin-2+ levels were elevated only in EH versus healthy volunteers and p16+/uromodulin+ in renovascular hypertension versus EH.

In conclusion, levels of p16+ EVs are elevated in urine of hypertensive patients and may reflect increased proximal tubular cellular senescence. In EH, EVs originate also from distal tubules and in renovascular hypertension from Henle’s loop. Hence, urinary EVs levels may be useful to identify intrarenal sites of cellular senescence.

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Alzheimer's Disease as a Condition of Many Subtypes and Contributing Causes

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Neurodegeneration in late life is a very complex phenomenon, and its complexity strains against the nice neat clinical definitions of disease found in the textbooks. Different patients with Alzheimer’s disease can exhibit quite different mixes of various forms of pathology, developing at different paces and times: aggregates of amyloid-β, tau, and α-synuclein; vascular degeneration; markers of neuroinflammation; metabolic disruption similar to that of diabetes, and so forth. One case of Alzheimer’s might be different enough from another to require a different designation. Thus researchers talk about defining subtypes of Alzheimer’s disease, or that individual patients have Alzheimer’s that is exacerbated by a comorbidity arising from other neurodegenerative processes.

Another way of looking at this is to categorize mechanisms that contribute to Alzheimer’s. To what degree is a given set of mechanisms important in a given patient? A sizable amount of work has gone into investigation of processes and feedback loops other than the primary amyloid cascade hypothesis of the condition. It is an open question as to where all of these contributing aspects of the condition fit into a chain of cause and consequence, or whether the ordering of that chain is similar from patient to patient. Alzheimer’s disease may well be a collection of distinct conditions that all happen to wind up in a similar end state.

The authors of this paper draw the gloomy conclusion that this complexity, and continued failures in the development of therapies based on the amyloid cascade hypothesis, imply that there are no silver bullets. I would argue otherwise, and say that instead comparatively simple points of intervention have not yet been developed fully. Senolytic therapies that clear senescent glial cells from the brain seem quite effective in animal models, for example. The approach of restoring lost drainage of cerebrospinal fluid, to clear out aggregates from the brain, also looks promising. There will be others. The complexity of aging emerges from simpler root causes, and there will always be some clever way to intervene at a point of maximum leverage.

Multi-Loop Model of Alzheimer Disease: An Integrated Perspective on the Wnt/GSK3β, α-Synuclein, and Type 3 Diabetes Hypotheses


Alzheimer’s disease (AD) is among the most ominous of modern health epidemics. AD is not alone in its ascent. Other chronic diseases, particularly Parkinson’s disease (PD), a neurodegenerative disorder associated with the build-up of α-synuclein protein and death of dopaminergic neurons, and type 2 diabetes mellitus (T2DM) are increasing in prevalence at similarly alarming rates. Although AD, PD, and T2DM share common risk factors, chief among these being age, there is more to their relationship. Evidence suggests that the pathophysiological mechanisms underlying AD, PD, and T2DM interact synergistically.

In addition to the well-known amyloid cascade hypothesis of AD, other hypotheses have been proposed that include: (1) the Wnt/Glycogen Synthase Kinase 3β (GSK3β) hypothesis, (2) the α-synuclein hypothesis, and (3) the type 3 diabetes hypothesis. Dsfunctional Wnt-signaling can contribute to the development of AD and its two pathological hallmarks, plaques and p-tau tangles. The canonical PD-associated protein α-synuclein may be locked in pathological positive feedback loops with Aβ and tau. Finally, insulin resistance in the brain, “type 3 diabetes,” may contribute to development and exacerbation of AD. Each model interacts with the others. These interrelationships, make it clear that the pathology of AD is not a linear cascade, nor a simple feedback loop, but rather a network of cross-talking models and overlapping vicious cycles.

Given the cooperative and reinforced nature of this complex network, it is no surprise that the prototypical monotherapeutic approach to AD has reliably failed. Certainly, drugs that target key nodes within the network, such as GSK3β inhibitors or AKT activators, have shown promise in animal models, and this important work affords us valuable mechanistic insights. However, these pre-clinical successes generally have not translated into clinical success, at least not with the same degree of efficacy. This is likely because animal models harboring distinct AD-causing mutations and dysfunctions in particular linear pathways do not accurately recapitulate the complex pathologies underlying sporadic human AD. In brief, we are proposing that the single-target silver-bullet approach to AD drug discovery is doomed to fail and that we may only be able to treat or prevent AD by developing new multifaceted treatment options.

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ApoE Levels Rise with Age and Degrade the Ability to Regenerate Bone

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ApoE is a important protein in lipid metabolism, one of those responsible for transporting cholesterols and other lipids around the body. In today’s open access research, the authors present evidence for rising levels of ApoE with aging to degrade the ability of bone to regenerate. This is unfortunate, because it will not be straightforward to just reduce ApoE levels. The protein is vital; a number of serious inherited conditions involve ApoE mutation that leads to greatly increased lipid levels on the bloodstream and organs.

Bone regeneration, and normal tissue maintenance of bone for that matter, is a balance between constant creation and destruction of extracellular matrix structures. Osteoblast cells build bone, and osteoclasts tear it down. Age-related loss of bone density and strength is the result of a growing imbalance that favors osteoclast activity. There is good evidence for numerous mechanisms to be important here, including the usual suspects such as the inflammatory signaling produced by senescent cells. The data here for reversal of loss of regenerative capacity via reduced ApoE levels is quite compelling as an argument for this to be an important proximate mechanism, however.

Protein prevalent in older people could be key to healing bones


Researchers confirmed that older people have more Apolipoprotein E, ApoE for short, than younger people. (If that protein name rings a bell, it’s because ApoE is also implicated in Alzheimer’s and heart disease). The team found that 75-85 year olds had twice as much ApoE in their bloodstreams as 35-45 year olds, then found the same was true for 24-month-old mice versus 4-month-old mice, which approximate the same human age ranges. Next, they wanted to figure out if and how ApoE affects the multi-step process of bone healing. When you break a bone, your body sends signals through the bloodstream to recruit cells to fix it. Some of those recruits, specifically skeletal stem cells, build up cartilage as a temporary scaffolding to hold the fracture together.

In the next step, more recruited cells mature into osteoblasts, bone-building cells, which lay strong, dense bone cells on top of the cartilage scaffolding. Finally, a different kind of cell eats up the cartilage scaffolds and osteoblasts fill those holes with bone. That’s if the bone healing process works perfectly. But the researchers found that if they added ApoE to a petri dish with skeletal stem cells, fewer cells developed into osteoblasts and the osteoblasts were worse at building bones. Next, the researchers created an intervention by injecting a virus which keeps mice from making ApoE protein. Circulating ApoE levels dropped by 75 percent and the healed bones contained one and a half-times more strong, hard bone tissue than bones of untreated mice.

Lowering circulating apolipoprotein E levels improves aged bone fracture healing


In our previous work investigating aged bone regeneration, we identified apolipoprotein E (ApoE) to be one of many candidates potentially involved in aged bone fracture healing. ApoE is a widely expressed lipoprotein classically associated with lipid metabolism and fatty acid transport. ApoE polymorphisms are present in 20% of the population and are associated with hypercholesterolemia, atherosclerosis, and Alzheimer’s disease. More recently, clinical evidence has revealed that these ApoE polymorphisms are also associated with decreased bone mineral density and increased risk of hip and vertebral fracture. Mouse models lacking ApoE expression display increased cortical thickness, trabecular number, and bone mineral density. However, a role for ApoE in fracture healing and musculoskeletal aging remains to be investigated.

Here, we sought to understand the role of ApoE in age-associated deficiencies in bone fracture healing. Our previous work has established the importance of circulating factors in the age-associated impairment of bone regeneration. Here, we use our established tibial fracture model coupled with μCT and histological analysis as well as our parabiosis models to identify a role for circulating ApoE in bone fracture healing. We identify ApoE as a negative regulator of osteoblast differentiation and combine this work with functional metabolic assessment and transcript analysis to identify the mechanism by which ApoE influences osteoblast differentiation. Finally, we identify that lowering circulating ApoE levels, using siRNA strategies, in aged mouse models leads to improved bone fracture healing. Collectively, our findings demonstrate that ApoE impairs bone fracture healing in an age-dependent manner by decreasing osteoblast differentiation.

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What's the Best Way to Use a Standing Desk?

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Standing desks have become popular with computer users and office workers interested in avoiding risks from sitting for prolonged periods of time. There is a long list of people who may have used a standing desk throughout history, such as Leonardo DaVinci, Lewis Carroll, Ernest Hemingway, Philip Roth and Virginia Woolf.1,2

Reports also claim Oscar Hammerstein II may have written most of the music for “Oklahoma,” “The Sound of Music” and “South Pacific” standing up.3 Additionally, Winston Churchill was well-known for his use of a standing desk, and U.S. Supreme Court Justice Oliver Wendell Holmes Jr. credited his standing desk for his writing style.

As standing desks emerged into modern times, some embraced them at work in hopes it would help fight obesity, but research4 debunked this theory, finding the best way to burn more calories is to move. However, the reason to use a standing desk is not about burning calories but, rather, about improving your health.

From Heart to Brain: The Dangers of Prolonged Sitting

Sitting for prolonged periods of time has been linked to a number of health conditions, including weight gain, heart disease and cognitive decline. But, if you find yourself parked behind a desk for the majority of your workday, you’re not alone. According to the American Heart Association,5 the percentage of sedentary job positions has increased by 83% since 1950.

In a study6 evaluating the trends of occupation-related physical activity over the past five decades, researchers found a shift away from jobs requiring moderate-intensity activity to those largely composed of sitting. The researchers qualified moderate-intensity activity as construction, manufacturing and mining.7

They found a 48% reduction in the prevalence of moderate activity jobs in 1960 to 20% of jobs in 2008.8 This rise in sedentary behavior has also correlated with an increased risk of heart disease, diabetes and premature death.9 In a meta-analysis of 47 studies,10 researchers found “prolonged sedentary time activity was independently associated with deleterious health outcomes regardless of physical activity.”

Another study also links sedentary behavior with changes in brain function crucial to memory formation. The results suggested those who had more sedentary activity experienced a reduction in medial temporal lobe thickness.11 On the flip side, aerobic fitness has shown to improve this area of the brain.12

Not All Sitting Is Created Equally

The World Health Organization13 states physical inactivity is a leading risk for death and noncommunicable disease worldwide. They warn the terms “exercise” and “physical activity” should not be confused since exercise is really a subcategory of planned, repetitive physical activity done with an aim to improve fitness.

Failure to employ an adequate level of activity increases the risk of diabetes by up to 30% and shortens life span by three to five years.14 To that end, many early adopters of standing desks bought into the idea that standing while working would help them burn more calories, lose weight and stem the tide of obesity.

But as further research demonstrated,15 standing versus sitting doesn’t burn many more calories and certainly doesn’t encourage more joint movement. The amount of sedentary time you spend includes not only the time you spend behind your desk at work, but also time commuting and enjoying leisure activities, such as watching television or using electronics.

Research data16 from an examination of 17,013 Canadians found a “dose-response association between sitting time and mortality from all causes and cardiovascular disease, Independent of leisure time physical activity.” In other words, the longer people sat, the higher their risk of mortality from any cause.

TV Time May Be an Independent Sedentary Risk Factor

In 2010 when television viewing time was evaluated independently in relation to cardiovascular disease and all-cause mortality, researchers found an increased risk.17 A June 2019 study18 followed up with 3,592 participants, using self-reported data over 8.4 years. In this study, researchers found those watching more than four hours per day of TV had a greater risk of CVD events or all-cause mortality, compared to those watching less than two hours per day.

By comparison, the researchers found sitting at work did not have an association with these endpoints, suggesting minimizing leisure television viewing could be more effective in reducing negative health effects then reducing sedentary behaviors at work.

The researchers acknowledged there were some limitations to the study, but in spite of those, they believe the analysis was one of the first prospective data gathering analyses showing sedentary behavior may vary between leisure and nonleisure types.

Another study seeking to determine whether physical activity could modulate or eliminate the effects of prolonged sitting used a meta-analysis of 16 studies. In total there were 1,005,791 participants in all studies. The data showed getting 60 to 75 minutes of moderate-intensity physical activity each day seem to significantly reduce or eliminate an increased risk of death associated with prolonged sitting, but did not eliminate the risk associated with watching television.19

Avoid Prolonged Stationary Standing

Sit-to-stand desks offer significant health benefits to the user, but like most things, more is not always better. In other words, stationary standing for long periods of time may be nearly as challenging to your body as sitting for hours at a time.

In one study published in Applied Ergonomics on these desks,20 researchers found participants were standing more and sitting less. However, but the results were not enough to achieve benefits associated with reduction in obesity. The study said:21

“In order to achieve positive outcomes with sit-stand desks, we need a better understanding of how to properly use them; like any other tool, you have to use it correctly to get the full benefits out of it.

There are basic ergonomic concepts that seem to be overlooked. Many workers receive sit-stand desks and start using them without direction. I think proper usage will differ from person to person, and as we gather more research, we will be better able to suggest dosage for a variety of workers.”

For example, one study found standing in one position for long periods of time leads to muscle fatigue and other types of occupational injuries such as chronic venous insufficiency, carotid atherosclerosis, musculoskeletal disorders and preterm birth.22

In fact, prolonged standing can lead to chronic venous insufficiency, carotid atherosclerosis, musculoskeletal disorders and preterm birth. Other studies23 have identified prolonged standing as a trigger for low back pain, cardiovascular problems and chronic fatigue and discomfort.

The Point: Stand Up, Sit Less, Move More

Research data still haven’t proven standing desks alone improve your overall health, likely because it’s movement that reduces your risk of heart disease, stroke, obesity and back pain. For instance, a Cochrane review of 20 studies24 from high-income nations found using a sit-to-stand desk reduced sitting time, but showed no long-term positive effects from the change.

Interestingly, one study with individuals employed in sedentary jobs found a reduction in sitting time not only was associated with reduction in upper back and neck pain, but with improved mood status.25

However, the point behind the sit-to-stand movement is not simply to move from sitting to standing but, rather, to include movement. Since your mind and body are connected, your movement has an effect on the way that you feel and think. So, adding movement while you stand may also help with depression and anxiety, as well as help you think more creatively.26

People Move More at Home When They Move at Work

Physical activity helps to lower your blood pressure, improve your blood flow and prevent bone loss, all of which contribute to a longer life span.27 In a study28 led by the University of Minnesota,29 one company provided treadmill desks for 40 of their 400 employees to measure their productivity when they were standing and walking.

After the employees became experienced at working on the treadmill their performance improved above when they were sitting.30 There was some concern that the treadmill workstations would reduce the amount of activity day enjoyed outside of work, but researchers found the participants’ activity actually increased both during and after work.31

According to the Society for Human Resource Management,32 wellness specialists are working with employers to help get workers more active. They’re finding this improves concentration, reduces sick days and improves their ability to recruit quality employees. Employers are also enjoying a reduction in health care costs related to neck, elbow and back injuries.

Alan Hedge,33 director of the Human Factors and Ergonomics Research Laboratory at Cornell University, believes the addition of sit-stand desks to the office is cost-effective, and Dr. James Levine, an endocrinologist at Mayo Clinic, believes the return on investment maybe from $3 to $7 for every $1invested.

Posture Important While Sitting and Standing

Both excessive sitting and stationary standing contribute to lower back pain and muscle fatigue. One important method to reduce pain and discomfort is to use proper posture. When using a standing desk, it’s important that your computer monitor and keyboard are functional for your height.34

When it comes to a standing desk, one size does not fit all, since not everyone is the same height. It’s important to set the locations of your keyboard and computer screen to reduce slouching or constantly looking up. Both should be set at comfortable angles to reduce neck and head strain as well as shoulder and upper back problems.

Fletcher Zumbusch is a physical therapist from Santa Monica, California, who believes it’s not the number of hours we spend sitting at a desk or standing on a desk, but the position in which it’s done. An additional benefit to a standing desk is it reduces the potential for hip tightness, which increases with excessive sitting and creates stress on your adjacent joints.35

Zumbusch recommends36 that you consider asking a health care professional to help you set up your sit-stand desk, so you can make sure it’s positioned in a such a way that it will reduce strain on your muscles. In addition, you should ease into a standing and moving routine until you’re standing — and moving — as much as possible and sitting for shorter intervals.

It’s crucial to practice good posture while sitting, standing and walking as this places the least amount of strain on muscles and ligaments that support your core, back and neck. Slouching also affects your mood and emotional health. To discover tips to improve your posture see my past article, “Slouching Makes You Sad.”

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