The authors of today’s open access research offer an interesting viewpoint on cellular senescence in the context of cancer, presenting it as an aspect of the innate immune response to the signs of cancer-inducing mutational damage, or to the signs of cancer suppression programs operating in cells. The objective of the body’s numerous, layered defenses against cancer is to destroy all cells that show the signs of becoming cancerous. The first line of defense is the state of cellular senescence, in which cells shut down their ability to replicate, prime themselves to self-destruct via the programmed cell death path of apoptosis, and alert the immune system via a mix of inflammatory secretions known as the senescence-associated secretory phenotype (SASP). These secretions also raise the odds of other surrounding cells becoming senescent, which in theory helps to stay ahead of the replication of an early cancer.
Cellular senescence in this context of cancer is likely an adaptation of an existing tool. Transient cellular senescence occurs during embryonic growth and wound healing, a way to help guide structure and regeneration. That it can also help to shut down early stage cancer has the look of a later development. Unfortunately cellular senescence is an imperfect tool: senescent cells are not reliably removed by the immune system, and they do not reliably self-destruct. Some tiny fraction linger, and their continued inflammatory secretions are an important contributing cause of aging and age-related disease.
We describe here an essential innate immune signaling pathway in oncogene-induced senescence (OIS) established between TLR2 and acute-phase serum amyloid A1 and serum amyloid A2 (A-SAAs) that initiates the senescence-associated secretory phenotype (SASP) and reinforce cellular senescence in vitro and in vivo. We also identify new important SASP components, A-SAAs, which are the senescence-associated damage-associated molecular patterns (DAMPs) sensed by TLR2 after oncogenic stress. Therefore, we are reporting that innate immune sensing is critical in senescence. We propose that cellular senescence shares mechanistic features with the activation of innate immune cells and could be considered a program of the innate immune response by which somatic cells switch their regular role to acquire an immune function under certain conditions of stress and danger, for instance, upon oncogene activation.
Besides revealing a role for TLR2 in SASP induction and cell cycle regulation, we identified the DAMP that activates TLR2 in OIS. Acute-phase proteins SAA1 and SAA2 act to prime the TLR2-mediated inflammasome, and in turn, their full induction depends on TLR2 function. Hence, they establish a foundational feedback loop that controls the SASP. A-SAAs are systemically produced in the liver and released into the bloodstream during an acute inflammatory response. Our identification of these molecules as mediators of senescence suggests that systemic elevation of A-SAAs might have an impact on the accumulation of senescent cells and the activation of their proinflammatory program at the organismal level.
We found activation of TLR2 expression in parallel to A-SAAs in models of OIS in mice, in inflammation-induced senescence, in aging, and in different in vitro systems of senescence. Also, we have shown that TLR2 controls the activation of the SASP and OIS in vivo. Moreover, we have observed a dose-dependent effect for TLR2 in A-SAA sensing and a role for TLR2 in SASP activation during paracrine senescence. Together, these data suggest that systemic A-SAA elevation during acute inflammation could affect cells expressing TLR2, thereby promoting aging and other pathological roles of senescence. Further investigation may reveal additional physiological circumstances under which senescence is induced or reinforced by the interaction of TLR2 with A-SAAs or indeed with other endogenous DAMPs or exogenous pathogen-associated molecular patterns (PAMPs) from the microbiome. These circumstances could have implications for organismal well-being, in particular, the development of aging and cancer.
In recent years, several strategies have been implemented to eliminate senescent cells or to modulate the activation of the SASP in anti-aging and cancer therapies (senotherapies). For example, genetic targeting for the elimination of senescent cells can delay organismal aging and aging-associated disorders. Furthermore, the pharmacological suppression of the SASP has been shown to improve homeostasis in tissue damage and aging. However, most of these manipulations are directed to essential homeostatic regulators such as mTOR or crucial proinflammatory mediators such as IL-1 signaling. Here, we propose the alternative of manipulating A-SAA-TLR2 as a new rationale for senotherapies aiming to manipulate nonessential and senescence-specific signaling pathways.
Read more about N . O . and Cardio physical health.
Sugar is one of the most harmful and addictive substances that you can consume, as it’s associated with various metabolic diseases.1 Nowadays, it’s found in almost everything you eat.
In fact, the average American consumes around 17.4 teaspoons of sugar per day — that’s more than 5 teaspoons higher than the average sugar intake recommended by the U.S. Dietary Guidelines for Americans, 2015-2020.2 A 2015 article from The Washington Post states that the U.S. even ranks first in the countries that consume the highest amount of sugar.3
According to a study published in the Journal of the Academy of Nutrition and Dietetics, around 75% of packaged foods sold in supermarkets contain added sugar. This includes processed foods like sweet snacks, cereals, energy drinks, fruit juices and baked goods. It’s even present in infant food and baby formula, exposing children to numerous health issues at a very young age.4
But avoiding sugar is not as simple as skipping sweet foods, as savory foods, like salad dressing and pizza, contain this ingredient as well. Sugar hides behind 61 different names in food labels, the most common of which include sucrose, high-fructose corn syrup, molasses, maple syrup, glucose, maltose, lactose and fruit juice concentrate, among others.5,6
What makes sugar so addicting?
When you eat sugary foods, the reward center of your brain, known as the nucleus accumbens, is stimulated through increased signals of dopamine, a neurotransmitter that plays a role in your perception of pleasure.7
Because eating sugar makes you feel good, you’re likely to eat it often. As you consume excessive amounts of sugar on a regular basis, your body’s dopamine signals become weaker and you develop tolerance, so you have to eat more sugar to get the same level of reward, eventually resulting in sugar addiction. This is why manufacturers use sugar to drive your behavior.8
There have been many studies regarding the addictive potential of sugar.9,10 For instance, a 2018 review published in the British Journal of Sports Medicine states that “sugar has been found to produce more symptoms than is required to be considered an addictive substance.”
It exhibits drug-like effects such as bingeing, craving, tolerance, withdrawal, cross-sensitization, cross-tolerance and cross-dependence.11 Another study published in the journal Neuroscience states that intermittent bingeing on sucrose and abusing drugs can both increase extracellular dopamine in the nucleus accumbens.12
60 ways sugar can ruin your health
Excessive sugar consumption is associated with chronic metabolic problems, such as Type 2 diabetes, obesity and heart disease.13 Aside from these, there have been numerous studies spanning decades that demonstrate the other ways in which eating too much sugar can lead to detrimental effects to your health. I counted 60 of these health risks, divided into four categories:
Affects carbon dioxide production when given to infants82
How to manage sugar addiction
It’s never too late to kick your sugar-loading habits to the curb. Here are some of my recommendations to help manage or limit your sugar consumption:
1. Limit your sugar intake — Sugar in its natural form is not bad provided that it’s consumed in moderation. Generally, your total sugar consumption should be below 25 grams per day from all sources, including sugar that you get from whole fruits. However, if you have insulin or leptin resistance, it’s ideal to limit your fructose intake to as little as 15 grams per day until you’ve normalized your insulin and leptin levels.
2. Avoid high-fructose corn syrup (HFCS) — This sweetener is made from corn and found in many of the food items that you eat and drink today. It’s considered to be dangerous not only because of the amount of sugar that it contains, but also because of the health risks that it can cause, most of which are mentioned above.83
Discover the fructose content of common foods, beverages, sauces, and even sugar substitutes in our infographic “Fructose Overload.” Use the embed code to share it on your website or visit our infographic page for the high-res version.
<img src="https://media.mercola.com/assets/images/infographic/fructose-overload-infographic.jpg" alt="fructose overload infographic" border="0" style="max-width:100%; min-width:300px; margin: 0 auto 20px auto; display:block;"><p style="max-width:800px; min-width:300px; margin:0 auto; text-align:center;">Discover the fructose content of common foods, beverages, sauces, and even sugar substitutes in our infographic "<a href="https://www.mercola.com/infographics/fructose-overload.htm">Fructose Overload</a>." Visit our infographic page for the high-res version.</p>
Click on the code area and press CTRL + C (for Windows) / CMD + C (for Macintosh) to copy the code.
3. Increase your consumption of healthy fats — Healthy fats, such as omega-3 fatty acids, saturated fats and monounsaturated fats, are your body’s preferred source of fuel. The best sources of these include grass fed butter, coconut oil, free-range eggs, wild-caught Alaskan salmon, avocado and raw nuts like pecans and macadamia.
4. Add fermented foods into your diet — Eating fermented foods like kimchi, natto, organic yogurt and kefir may help reduce the negative effects of excessive sugar on your liver by supporting your digestive function and detoxification.
5. Drink pure water — Instead of drinking sweetened beverages like soda and fruit juices, I recommend that you rehydrate your body with pure, clean water.
6. Try the Emotional Freedom Techniques (EFT) — Food cravings are sometimes triggered by an emotional need, such as wanting to relieve stress or feel a little happier after a tiring day.84 EFT is a simple and effective psychological acupressure technique that could help you manage the emotional components of your cravings.
It has been proven to help relieve emotional traumas, ease phobias and post-traumatic stresses, break down food cravings and lessen physical pain and discomfort. What EFT entails in its practitioners is to have the right mindset when going on a diet or just taking steps to improve on their health. If you’re already curious, you can browse through the basics of EFT here.
Aside from the recommendations mentioned above, I recommend exercising every day, along with optimizing your vitamin D levels, getting enough sleep and managing your stress levels. These strategies may help minimize the effects of excessive sugar intake. Exercise in particular is known to improve insulin sensitivity,85 reduce stress levels,86 suppress ghrelin (the appetite hormone),87 speed up metabolism,88 strengthen bones89 and boost your mood.90
It can be quite difficult to say no to sweets, especially if you have been consuming them on a daily basis, but once you feel the effects that lowering your sugar intake has on your body, it will all be worth it.
Tissues are supported by dense and intricate networks of capillaries, hundreds passing through any square millimeter cross-section. Many studies have shown that capillary density decreases with age, which is perhaps another of the many results of faltering tissue maintenance due to the decline in stem cell activity, or alternatively, a specific dysregulation of the processes of angiogenesis at the small scale, resulting from inappropriate cellular reactions to rising levels of damage and chronic inflammation. Fewer capillaries means a lesser delivery of nutrients and oxygen, and we might well wonder to what degree this contributes to atrophy and dysfunction in energy hungry tissues such as muscles and the brain.
In this context, consider of the loss of muscle mass and strength that occurs with aging, known as sarcopenia. While sarcopenia is associated with a long, long list of potential contributing mechanisms, arguably the best evidence suggests that this loss of muscle capacity is caused by the declining activity of muscle stem cell populations. This connects well with a decline in capillary density, in that we can theorize either side as cause or consequence of the other. Another possible contributing factor is age-related mitochondrial dysfunction. Given that mitochondria are the power plants of the cell, responsible for transforming energy from nutrients into a form that cells can use, here too the possible connections to declining capillary density are obvious.
The two different approaches to this challenge are quite different. On the one hand, the first and more mainstream approach would be to attempt to override changes in the regulation of angiogenesis, forcing different expression levels in various regulatory proteins in order to generate greater generation of blood vessels. This strategy can produce benefits, but because it fails to address the underlying causes, the benefits are necessarily limited. The damage of aging marches on, causing all of its other consequences. One might look at past efforts to control raised blood pressure or chronic inflammation to see the plausible beneficial outcomes that can emerge from tackling important facets of aging in ways that do not repair the causes. The second, and as yet less popular – but better! – approach is to repair the damage that causes aging, and thus remove the dysregulation in angiogenesis and tissue maintenance that way. Sadly, this path forward is nowhere near as popular and well funded as it should be.
The term “microcirculation” in contrast with macrocirculation (which is the flow of blood to and from organs), refers to a network of terminal vessels comprising arterioles, capillaries and venules that are less than 100 μm in diameter. In other words, the microcirculation is defined as the blood flow through the smallest vessels in the vasculature and are embedded within organs and tissues, which facilitate the exchange of biological material between the blood and tissue via its large surface area and low blood velocity in these regions. For organs to function well, there must be sufficient perfusion throughout the tissue in the form of intact and appropriate microcirculatory vascularization.
There is a substantial number of studies presenting strong evidence of decreased vessel density with age, indicating an age-associated failure of vascular recovery in organs such as the brain in animals and humans alike. In studies involving aged rodents: healthy senescent rats (29 months) experienced a loss of about 40% of arteriolar density on the cortical surface compared with young adult rats (13 months). In the hippocampus of aged rats, there was a 20% decrease in capillary number, 3% decrease in capillary length, and 24% increase in intercapillary distance. Comparable reductions could also be found in other brain regions including the brain stem, cortex, and white matter. In studies involving aged humans: Capillary density decreased by 16% in the calcarine cortex while vascular density decreased by 50% in the paraventricular nucleus, frontal cortex, and putamen. Importantly, angiogenesis has been found to be impaired in aged tissues, which could contribute to the significant decreases in vascular density and number that has been reported.
Factors of vascular aging are reported to be closely associated with chronological age. Indeed, alterations in vascular mechanics and structure are related with vascular aging, resulting in less elastic arteries and diminished arterial compliance. Furthermore, the increased diffusion distance for oxygen caused by reduced capillary numbers and density, gives rise to heterogeneous perfusion, where the close proximity of perfused capillaries and non-perfused capillaries triggers alterations to oxygen extraction even when blood flow to the tissue is conserved.
Under normal physiological conditions, the microcirculatory blood flow is adapted to the metabolic levels of human tissues and organs, so the physiological functions of various organs in the human body can function as they should. Once the microcirculation of the human body is impaired, cells would not be able to get enough nutrition and oxygen, and meanwhile, CO2 and metabolic products, including those that are toxic, cannot be removed and will accumulate. Consequently, deterioration of physiological functions of cells and then organs that are necessary for survival and reproduction will occur. Microcirculatory impairment arises in adulthood and becomes progressively impaired with aging; the corresponding tissue system or internal organs are affected and unable to function normally, which eventually lead to aging. Therefore, aging is the process of continuous impairment of microcirculation in the body.
Minoxidil is, of course, the well known basis for certain popular hair growth products. That outcome was an accident, however, as the compound originally entered clinical trials – some 30 years ago – as a possible treatment for hypertension, or chronic raised blood pressure. The primary mechanism of interest is that minoxidil spurs greater deposition of elastin in blood vessel walls and other tissues, thereby reversing a fraction of the progressive loss of elastin that takes place over the course of aging.
It is interesting to see researchers still working on minoxidil. The original clinical trials for hypertension, while leading to an approved drug, showed that minoxidil causes edema around the heart at useful doses for the elastin deposition effect, a potentially severe consequence. For me, that is more than enough to reconsider its use in this way. During the early studies and trials, hair growth in the patients was noted, and the rest of the development program thereafter is history. It is possible that now, with a far greater ability to take a small molecule as a starting point and build different versions with different characteristics, it is plausible to build a minoxidil analog that doesn’t have the serious side-effects at usefully high doses, where that was simply not possible in earlier decades. We shall see.
Arterial wall elastic fibers, made of 90% elastin, are arranged into elastic lamellae which are responsible for the resilience and elastic properties of the large arteries (aorta and its proximal branches). Elastin is synthesized only in early life and adolescence mainly by the vascular smooth muscle cells (VSMC) through the cross-linking of its soluble precursor, tropoelastin. In normal aging, the elastic fibers become fragmented and the mechanical load is transferred to collagen fibers, which are 100-1000 times stiffer than elastic fibers.
Minoxidil, an ATP-dependent K+ channel opener, has been shown to stimulate elastin expression in vitro and in vivo in the aorta of young adult hypertensive rats. Here, we have studied the effect of a 3-month chronic oral treatment with minoxidil (120 mg/L in drinking water) on the abdominal aorta structure and function in adult (6-month-old) and aged (24-month-old) male and female mice. Our results show that minoxidil treatment preserves elastic lamellae integrity, which is accompanied by the formation of newly synthesized elastic fibers in aged mice. This led to a generally decreased pulse pressure and a significant improvement of the arterial biomechanical properties in female mice, which present an increased distensibility and a decreased rigidity of the aorta. Our studies show that minoxidil treatment reversed some of the major adverse effects of arterial aging in mice and could be an interesting anti-arterial aging agent, also potentially usable for young female-targeted therapies.
Laura Deming is one of the people influential in the sweeping shift of the past few years in research and development of therapies to treat aging, in which rejuvenation biotechnologies such as senolytic therapies finally started the move from the laboratory into startup companies, on the way to the clinic. She founded the first venture fund to specialize in what people are now calling the longevity sector of the biotech industry, somewhat before that longevity sector actually existed in any meaningful way. Now, of course, funding is pouring into this area of development; the years ahead will be interesting. Now is very much the time for entrepreneurs to step up, find viable projects in aging and longevity, raise the funds, and carry them forward into clinical development.
At 25, Laura Deming has already achieved more in her chosen field – anti-ageing – than many people twice her age. At 12 she was researching the biology of ageing in the laboratory of one of the world’s leading scientists; at 14 she went to study physics at MIT, only to drop out at 17 and start a venture capital fund under the guidance of Silicon Valley entrepreneur Peter Thiel. Aubrey de Grey, the English gerontologist who has suggested that humans might live to be 1,000, calls Deming an “utter genius” for her scientific and investment “brilliance”.
There is a long history of charlatans selling the cure to getting old. However, Deming is no biohacker; she isn’t fiddling with diet, exercise, or pills to add an extra year or two to her life. Her ambition is far greater: to accelerate anti-ageing science so that everyone can live healthier lives for longer. To that end, she founded the Longevity Fund in 2011, when she was still a teenager, to invest in biotech companies making treatments for age-related diseases.
When Deming decided to start raising money to get anti-ageing research out of the lab, she was still too young to sign the paperwork – her father had to do it on her behalf. She received some advice from Peter Thiel but confesses that she really did not know what she was doing. “You’d google ‘How to start a venture capital fund’ and there were just no articles,” she says, amazed. For the first two years of the fund, Deming tried to sell investors on the “science and the humanitarian issues at stake”. “Honestly, for two years I gave the same pitch of, here’s a $20 billion market and here’s all the people who are dying, can someone help them? And everyone was like, ‘That’s amazing, you’re such a good person’, and nobody invested,” she laughs. She learned she needed to link her passion for the cause to a “very concrete business case”.
The fund’s first investment, in Unity Biotechnology, helped her to do that. Unity is developing a drug that targets senescent cells – decrepit cells that refuse to die. If it works, the drug could be used to treat age-related diseases such as osteoarthritis, eye diseases, and pulmonary diseases. Unity went public last year and now has a valuation of more than $350 million. “Having a concrete case to show potential investors … that was what brought it together.” Deming’s biggest fear is the hype cycle: what if a few early anti-ageing trials flop, and the money goes away? “That gives me a lot of fear, because it’s a field that is still very early. There’s a lot of stuff that’s still being figured out, and I think a lot of things will fail.”
“Preventative strategies for fracture should not focus on older patients at the expense of younger women and of men. And focusing on bone health and bone strength isn’t just for women.” – Dr. Mike Smith
“Around the age of 30, you start losing bone and I knew this when I was a personal trainer [when and I was younger] and I used to think, oh man – I’ve got to get my bones as strong as I possibly can because I know when I hit 30 I’m going to start losing bone density!” – Dr. Crystal Gossard
In this episode:
The role of minerals like boron and vitamins such as D and K
The role of hormones in bone health
What tests to take to evaluate your bone density
What the research says
About Live Foreverish: Join Dr. Mike and Dr. Crystal as they sit down with some of today’s leading medical, health and wellness experts to discuss a variety of health-related topics. From whole-body health to anti-aging and disease prevention, you’ll get the latest information and helpful advice to help you live your life to the fullest. If you like what you hear, please take a moment to give Live Foreverish a 5-star rating on iTunes!
When present for a limited period of time, senescent cells are helpful, a necessary part of wound healing, embryonic development, and suppression of cancer. Cells become senescent in response to the circumstance, the SASP assists in calling in the immune system to help, or in spurring growth, or in instructing nearby cells to also become senescent. Then the senescent cells self-destruct or are destroyed by the immune system once their contribution to the task at hand is complete. It is only when senescent cells linger for the long term that the SASP becomes dangerous, corrosive to tissue function.
Why do some senescent cells fail to self-destruct? Further, while we know that the immune system declines with age, becoming less effective in all of its tasks, why specifically do immune cells fail to identify and destroy some senescent cells? Progress towards more complete and detailed answers these questions may open the door to new classes of senolytic therapy, capable of purging senescent cells from old tissues. While a variety of senolytic treatments are either available or under development, none are capable of destroying more than about half at best of these cells, and then only in some tissues. Combinations of different therapies, and more efficient therapies will be needed in the years ahead.
Cellular senescence is an evolutionarily conserved mechanism with beneficial effects on tumour suppression, wound healing and tissue regeneration. During ageing, however, senescent cells accumulate in tissues and manifest deleterious effects, as they secrete numerous pro-inflammatory mediators as part of a senescence-associated secretory phenotype (SASP). The elimination of senescent cells in mouse models was shown sufficient to delay the onset or severity of several age-related phenotypes. This has prompted the development of senolytic drugs that selectively target senescent cells. Despite successful reversal of age-related pathologies in animal models, the use of senolytic drugs in humans may be hampered by their lack of specificity for senescent cells, leading to the risk of toxicity. Therefore, alternative approaches that can be used in isolation or in combination with senolytic drugs to improve the elimination of senescent cells in humans should be explored.
Senescent cells can be recognised and eliminated by the immune system. Different immune cell types including macrophages, neutrophils, natural killer (NK) cells and CD4+ T cells have been implicated in the surveillance of senescent cells, depending on the pathophysiological contex. Senescent cells become immunogenic by expressing stimulatory ligands like MICA/MICB that bind to NKG2D and activate their killing by NK cells. Moreover, by secreting chemokines and cytokines, senescent cells can recruit immune cells into tissues that enable senescent cell clearance. However, this secretory process may perpetuate a low-level chronic inflammatory state that underlies many age-related diseases.
Despite the evidence for senescent cell clearance by the immune system, it is not yet clear why senescent cells accumulate during ageing and persist at sites of age-related pathologies. A decline in immune function may contribute to incomplete elimination of senescent cells with age. Ageing has a great impact in both innate and adaptive immune systems, a process known as immunosenescence. Alternatively, changes in major histocompatibility complex (MHC) expression can lead to escape from recognition by the immune system as previously described in cancer and virally infected cells in vivo. Nevertheless, the effects of senescence on MHC expression are not fully understood.
Here, we show that senescent primary human dermalfibroblasts express increased levels of the non-classical MHC-class Ib molecule HLA-E. HLA-E inhibits immune responses against senescent cells by interacting with the inhibitory receptor NKG2A expressed on NK and highly differentiatedCD8+ T cells. Accordingly, we find an increased frequency of HLA-E expressing senescent cells in the skin of old compared with young subjects. HLA-E expression is induced by SASP-related pro-inflammatory cytokines, in particular IL-6 and regulated by p38 signalling in vitro. Lastly, we show that that blocking HLA-E/NKG2A interactions in cell culture enhances NK and CD8+ T cell-mediated cytotoxicity against senescent cells. Taken together, these findings suggest that HLA-E expression contributes to the persistence of senescent cells in tissues. HLA-E may therefore represent a novel target for the therapeutic elimination of senescent cells in age-related diseases.
Known as a multipurpose herb and “rejuvenator” used in ancient Ayurvedic1 and Chinese medicine for thousands of years, ashwagandha2 (Withania somnifera) is a plant native to India with a host of bioactive functions.
Ashwagandha is one of the few true adaptogenic herbs that helps your body adapt to stress3 by balancing your immune system,4 metabolism and hormonal systems.5 As noted in the medical review, “Scientific Basis for the Therapeutic Use of Withania Somnifera (Ashwagandha)”:6
“Studies indicate ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoietic, and rejuvenating properties. It also appears to exert a positive influence on the endocrine, cardiopulmonary, and central nervous systems … Toxicity studies reveal that ashwagandha appears to be a safe compound.”
While some adaptogens are stimulants in disguise, this is not the case with ashwagandha. It can give your morning exercise a boost, yet when taken before bed it can help you get a good night’s sleep as well. It’s also capable of “intelligently” upregulating or downregulating your adrenal cortisol as needed, which makes it a valuable adjunct against stress and anxiety.
Ashwagandha shown to reduce stress, depression and anxiety
In one placebo-controlled clinical trial,7 published in 2012, volunteers with a history of chronic stress who took 300 milligrams (mg) of a highly concentrated full-spectrum ashwagandha extract twice a day for 60 days reported significant reductions in stress, compared to controls who received a placebo.
While perceived stress scale (PSS) scores in the control group declined by a modest 5.5% over the 60 days, the treatment group receiving ashwagandha had a 44% reduction in PSS scores. And, as reported by the authors:8
“Furthermore, the decrease in the stress measure over the study period of 60 days was considerably higher in the Ashwagandha group than in the placebo group … In the Ashwagandha group, by Day 60 there was a significant reduction in scores corresponding to all of the item-subsets:
76.1% for the ‘Somatic’ item-subset, 69.7% for the ‘Anxiety and Insomnia’ item-subset, 68.1% for the ‘Social Dysfunction’ item-subset, 79.2% for the ‘Severe Depression’ item-subset.
In contrast, in the placebo control group, the corresponding reductions in scores were much smaller: 4.9%, 11.6%, –3.7% and –10.6%, respectively. As can be readily seen, the difference is at least 58 percentage points and as high as 89 percentage points.”
Blood testing also revealed the cortisol levels of the treatment group decreased by an average of 27.9% after 60 days of supplementation, while the placebo group had a reduction of just 7.9%. In conclusion, the researchers stated:9
“The findings suggest that high-concentration full-spectrum Ashwagandha root extract improves an individual’s resistance towards stress and thereby improves self-assessed quality of life. High-concentration full-spectrum Ashwagandha root extract can be used safely as an adaptogen in adults who are under stress.”
Other studies showing antianxiety benefits of ashwagandha
Similar results were found in a 2009 study,10 in which patients diagnosed with moderate to severe anxiety lasting longer than six weeks who were treated with 300 mg of ashwagandha root for three months reported “significantly decreased” symptoms compared to those undergoing standard psychotherapy.
Beck anxiety inventory (BAI) scores decreased by 56.5% in the ashwagandha group after 12 weeks of treatment, compared to 30.5% in the psychotherapy group. According to the researchers:
“Significant differences between groups were also observed in mental health, concentration, fatigue, social functioning, vitality, and overall quality of life with the [naturopathic care] group exhibiting greater clinical benefit.”
A systematic review11 of five human trials published in 2014 also concluded that treatment with ashwagandha “resulted in greater score improvements (significantly in most cases) than placebo in outcomes on anxiety or stress scales.”
However, while all five studies supported this conclusion, the authors noted that “Current evidence should be received with caution because of an assortment of study methods and cases of potential bias.”
A fourth study,12 this one published in 2015, found “empirical evidence to support the traditional use of [ashwagandha] to aid in mental process engaging GABAergic signaling.” According to the authors:
“Our results provide evidence indicating that key constituents in [ashwagandha] may have an important role in the development of pharmacological treatments for neurological disorders associated with GABAergic signaling dysfunction such as general anxiety disorders, sleep disturbances, muscle spasms and seizures.”
Main bioactive compounds in ashwagandha
Flavonoids and other compounds are the active ingredients that give ashwagandha its many powerful properties. These include but are not limited to:
• Withanolides — naturally occurring steroids — have been shown13 to suppress pathways responsible for several inflammation-based illnesses, including arthritis, asthma, hypertension, osteoporosis14 and cancer.
Withanolides in ashwagandha also have immunomodulating properties,15 described as substances that can either stimulate or suppress your immune system to help fight infections, cancer and other diseases.
• Somniferin — One of the alkaloids in ashwagandha, helps promote relaxation and sound sleep. A study16 at the University of Tsukuba in Japan also found it relieves related problems such as insomnia and restless leg syndrome.
• Triethylene glycol — Found in the leaves of the ashwagandha plant, this compound has also been shown to induce sleep and combat insomnia.17
• Ashwagandholide — a dimeric withanolide found in ashwagandha root — has been shown18 to inhibit growth of several types of cancer (including gastric, breast, central nervous system, colon and lung). It also inhibits inflammation by inhibiting activity and lipid peroxidation of cyclooxygenase-2,19 an enzyme that speeds up production of inflammatory prostaglandins.20
The many health benefits of ashwagandha
If you suspect ashwagandha might be beneficial for other ailments beside anxiety and stress, you’d be absolutely correct. It’s not considered one of the most important herbs in Ayurvedic medicine for nothing. Importantly, a number of studies have shown it can treat several diseases and disorders better than medications, without all the side effects.
For example, studies show ashwagandha has antitumor and blood production (hemopoietic) capabilities, and benefits the cardiopulmonary, endocrine and central nervous systems, all “with little or no associated toxicity.”21Ashwagandha has also been shown to:22,23,24,25,26,27,28
Support healthy levels of total lipids, cholesterol and triglycerides that are already in the normal range
Enhance radiation therapy effects29 by reducing tumor GSH levels.30 It also reversed paclitaxel-induced neutropenia (low neutrophil count, a type of white blood cell) in mice31
Counteract osteoporosis32 (reduced bone density)
Protect your brain from oxidative stress,33 and lower your risk of Alzheimer’s 34,35
Stimulate proper thyroid function36 and treat subclinical hypothyroid — In one double-blind, placebo-controlled study,37 ashwagandha was pitted against some of the most popular drugs targeted for hypothyroid patients. The study involved 50 participants with elevated serum thyroid hormone (TSH), all between the ages of 18 and 50.
Divided into two groups, each was given either ashwagandha treatments or starch as a placebo for eight weeks. According to the researchers, ashwagandha effectively and significantly normalized serum thyroid stimulating hormone (TSH), T3 and T4 levels, compared to placebo, stating such treatment may be beneficial for hypothyroid patients.
As explained by Thyroid Advisor,38 ashwagandha “directs THS hormone to travel to the pituitary. TSH triggers the thyroid gland to produce sufficient amounts of T4 and T3.” Improved thyroid function will also help stabilize mood39
Reduce blood pressure40
Inhibit inflammation — In animal studies, ashwagandha was found to be more effective against inflammation than phenylbutazone41 or hydrocortisone42
Protect nerve function and oxidation43
Provide natural pain relief44
Nourish and protect your liver
Increase red blood cell production
Improve adrenal function45
Increase energy and endurance
Promote healthy immune function
Treatment aid for ADHD
Treatment aid for Type 2 diabetes as it helps restore insulin sensitivity
Treatment aid for vitiligo
Ease symptoms of Parkinson’s disease
Improve cardiovascular health — Ashwagandha helps maintain your heart health through its regulation of blood circulation. It helps prevent blood clots, and helps keep blood pressure levels within the normal range, which prevents the stress from burdening your heart47
Maintain youthful appearance of skin — Ashwagandha increases your estrogen levels, which in turn triggers the production of collagen. This allows the skin to keep its youthful appearance and helps in the production of natural oils. It also fights off free radicals that cause wrinkles, dark spots and blemishes48
Aid wound healing — Ashwagandha root powder can be used topically as a poultice to help treat wounds. Mix the powder with water to make a smooth paste, and apply to the wound. It will help fight off bacteria, alleviate pain and speed up the healing process
Treat arthritis — Ashwagandha has been noted in Ayurvedic manuscripts as well as modern medicine as being an effective remedy for rheumatoid arthritis (Amavata) and osteoarthritis (Sandhi-gata Vata).49
According to one study,50 “Patients of rheumatoid arthritis receiving Ashwagandha root powder showed excellent response. Their pain and swelling completely disappeared. A double-blind placebo controlled study, combining Ashwagandha, turmeric and zinc showed significant improvement in pain and inflammation”
Support sexual and reproductive health in men and women — In men struggling with infertility, ashwagandha has been shown to balance their luteinizing hormone,51 which controls reproductive organ function in both men and women. Ashwagandha can also help boost testosterone levels in men,52,53 which can have a beneficial effect on libido and sexual performance.
In one placebo-controlled trial,54 men between the ages of 18 and 50 were given either a placebo or 300 mg of ashwagandha root extract twice a day in addition to participating in a strength training program. After eight weeks, those taking ashwagandha had greater increases in testosterone, muscle size and strength, compared to those taking a placebo.
It’s also been shown to improve the quality of semen in infertile men,55 in part by inhibiting reactive oxygen species and improving essential metal concentrations, including zinc, iron and copper levels. Other research56 suggests ashwagandha improves semen quality by regulating important reproductive hormones.
In otherwise healthy women, ashwagandha has been shown to improve arousal, lubrication, orgasm and overall sexual satisfaction.57 In addition, ashwagandha’s ability to rebalance hormones (including thyroid hormone, estrogen and progesterone) has been shown to improve polycystic ovary syndrome58 and relieve symptoms associated with menopause.59
Possible side effects and contraindications of ashwagandha
While generally safe, well-tolerated and nontoxic, side effects can still occur. Memorial Sloan Kettering Cancer Center cites case reports showing side effects from ashwagandha may include:
Nausea, headache, stomach irritation and loose stools
Burning, itching and discoloration of skin/mucous membrane
Irregular heartbeat, dizziness
While ashwagandha appears to be beneficial for thyroid problems, if you have a thyroid disorder, use caution and consult with your doctor, as you may need to tweak any medications you’re taking for it. Ashwagandha is also contraindicated60 for, and should not be used by:
Pregnant women, as it may induce abortion
Breastfeeding women, as it may have an effect on your child
People taking sedatives, as ashwagandha may augment the sedative effects
Beware of adulterated ashwagandha products
Needless to say, making sure you’re getting a high-quality product is of utmost importance. To ensure effectiveness, I recommend using 100% organic ashwagandha root, free of fillers, additives and excipients.
Ashwagandha oil61 is another form of ashwagandha that offers a wide variety of medicinal and practical uses. It’s usually mixed with other essential oils (or diluted in a safe carrier oil). Ashwagandha oil has antioxidant properties, and may be used for topical pain relief for those with arthritis and rheumatism.
Unfortunately, adulterated ashwagandha products have been found on the market, so buyer beware. A bulletin62 by the Botanical Adulterants Prevention Program reveals many ashwagandha root powders and root extracts manufactured in India are being adulterated by adding leaves, stems and aerial parts of the plant, without declaring this on the label.
In some tests, up to 80% of products were found to be adulterated in this manner. The fraudulent addition on undeclared plant material is a cost-saving strategy that results in an inferior product with questionable efficacy. The take-home message is, when buying ashwagandha, it’s worth doing your homework to make sure you’re getting a quality product.
Addressing anxiety without drugs
Getting back to anxiety, it’s important to realize there are many ways to address this now pervasive problem.63 Ideally, drugs would be your last resort, not your first, as many can cause other severe problems.
While genetics, brain chemistry, personality and life events play a role in the development of anxiety disorders, stress is a common trigger. Anxiety is a normal response to stress, but in some people the anxiety becomes overwhelming and difficult to cope with, to the point that it affects their day-to-day living.64
A number of other situations and underlying issues can also trigger or exacerbate anxiety. This includes but is not limited to the following, and addressing these issues may be what’s needed to resolve your anxiety disorder. For more information about each, please follow the links provided:
Traumatic life events — Research published in 2015 concluded traumatic life experiences were the single largest determinant of anxiety and depression, followed to a lesser extent by family history of mental illness and other social factors. In the link provided, you’ll find guidance on how to reprogram your body’s reactions to traumatic events using a simple tapping technique
Exposure to microwave radiation — Common sources include devices like cellphones, Wi-Fi routers, portable phones, smart meters, baby monitors and cellphone towers. Lowering your exposure to electromagnetic fields and microwaves is an important step if you’re struggling with anxiety or depression as it has been shown to have a direct impact
Food additives and food dyes — Food dyes of particular concern include Blue #1 and #2 food coloring; Green #3; Orange B; Red #3 and #40; Yellow #5 and #6; and the preservative sodium benzoate
GMOs and glyphosate exposure through your diet — Most nonorganic foods are contaminated with glyphosate these days, and glyphosate has been shown to produce anxiety and depression-like behaviors in mice by affecting gut microbiota65
Lack of animal-based omega-3 — Research has shown a 20% reduction in anxiety among medical students taking omega-3s67
Lack of magnesium — Anxiety is one of a myriad symptoms of low magnesium, and as noted in the 2018 paper,68 “The Role of Magnesium in Neurological Disorders”:
“Magnesium is involved in several physiological processes in the psychoneuroendrocrine system and modulates the hypothalamic pituitary adrenal (HPA) axis, along with blocking the calcium influx of NMDA glutamatergic receptors, all of which help prevent feelings of stress and anxiety.”
While no tissues can be said to be simple, some are simpler than others. In the past decade, tissue engineers have made considerable progress towards the manufacture of these simpler tissues, from the starting point of cells and scaffold materials. Bioprinting, a form of rapid prototyping, has proven to be an important class of approach. The research noted here is a representative example of progress towards the production of corneas to replace those that are damaged by accident or age, and thus eliminate the need for donor tissue.
When a person has a severely damaged cornea, a corneal transplant is required. For this reason, many scientists have put their efforts in developing an artificial cornea. The existing artificial cornea uses recombinantcollagen or is made of chemical substances such as synthetic polymer. Therefore, it does not incorporate well with the eye or is not transparent after the cornea implant. Now, researchers have 3D printed an artificial cornea using the bioink which is made of decellularized corneal stroma and stem cells. Because this cornea is made of corneal tissue-derived bioink, it is biocompatible, and 3D cell printing technology recapitulates the corneal microenvironment, therefore, its transparency is similar to the human cornea.
The human cornea is organized in a lattice pattern of collagen fibrils. The lattice pattern in the cornea is directly associated with the transparency of cornea, and many researches have tried to replicate the human cornea. However, there was a limitation in applying to corneal transplantation due to the use of cytotoxic substances in the body, their insufficient corneal features including low transparency, and so on. To solve this problem, the research team used shear stress generated in the 3D printing to manufacture the corneal lattice pattern and demonstrated that the cornea by using a corneal stroma-derived decellularized extracellular matrix bioink was biocompatible.
In the 3D printing process, when ink in the printer comes out through a nozzle and passes through the nozzle, frictional force produces shear stress. The research team successfully produced transparent artificial cornea with the lattice pattern of human cornea by regulating the shear stress to control the pattern of collagen fibrils. The research team also observed that the collagen fibrils remodeled along with the printing path create a lattice pattern similar to the structure of native human cornea after 4 weeks in vivo.
Neurodegenerative diseases have a strong inflammatory component, the dysregulation of the immune system in the brain, with consequences to tissue function. In the process of astrogliosis, the supporting cells known as astrocytes react to damaging or inflammatory circumstances, and radically change their behavior. This can help in the short term for some forms of injury to the central nervous system, but is harmful when it continues for the long term. Like microglia, another supporting cell type, astrocytes can adopt different packages of behaviors, or phenotypes, and switch back and forth between them in response to circumstances. The primary distinction of interest in these is between (a) a supportive, regenerative phenotype, and (b) an aggressive, inflammatory phenotype. The latter tends to show up ever more often as aging progresses, and this imbalance is the cause of further harms.
Astrocytes are the most abundant cells with various structures and functions and are ubiquitous in all regions of the central nervous system (CNS). Astrocytes are associated with various aspects of physiological functions, including secretion of nutrients, maintenance of neuronal microenvironment, regulation of the permeability of the blood-brain barrier and the development of pathological processes in the brain. Studies on mouse models have shown that astrocytes play a complex role in the pathogenesis of neurodegenerative diseases, and the dysfunction of astrocytes may contribute to either neuronal death or the process of neural disturbances. It has been found that reactive astrocytes always lose their supportive role and gain toxic function in the progression of neurodegenerative diseases.
During brain insult or neurodegeneration process, astrocytes can respond to pathological changes by releasing extracellular molecules, such as neurotrophic factors (for example BDNF, VEGF, and bFGF), inflammatory factors (including IL-1β, TNF-α, and NO, etc.) and cytotoxins (such as Lcn2) through reactive astrogliosis. As a result, they play either a neuroprotective or neurotoxic role (such as provoking inflammation or increasing damages) in the CNS. It has been shown that the specific deletion of STAT3 in astrocytes can cause reactive gliosis, which leads to increased level of inflammation, tissue damage as well as compromised motor recovery after spinal cord injury. Interestingly, some studies have shown that the activation of NF-κB in astrocytes contributes to the pathogenesis of CNS, and inhibition of this signaling pathway can limit tissue damage.
These findings suggest that astrocytes may play a protective role through STAT3 signaling pathways in some neurodegenerative lesions, while NF-κB signals may mediate neurotoxicity. In analogy to the “M1” and “M2” phenotype categories for macrophages, recent studies have reported that neural inflammation and ischemia can induce two types of reactive astrocytes, termed “A1” and “A2”, respectively. Gene transcriptome analysis of reactive astrocytes shows that A1 reactive astrocytes (A1s) can upregulate many classical complement cascade genes that are destructive to synapses, and secret neurotoxins that have not yet been well identified. In contrast, A2 reactive astrocytes (A2s) can upregulate many neurotrophic factors, which can promote either the survival and growth of neurons or the synaptic repair. Thus, A1s may have “harmful” features, while A2s may carry “useful” or repair functions. So far, it remains unclear what the possible signaling pathways have been involved in inducing the phenotypes of A1s and A2s in the process of different initiating CNS injuries.