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How the world got lost on
the road to an anti-aging pill
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March 29, 2016: by Bill Sardi
According to a compilation of recently published science the red wine molecule resveratrol (res-vair-ah-trol) is poised to open an era of regenerative medicine that could profoundly add many years to the healthspan and lifespan of Americans.
Why? Because, as researchers recently pointed out, any technology that delays the age-related decline in the human immune system could result in a generation of senior Americans who live 120 healthy years or more. [Ebiomedicine 2016]
While American medicine has stumbled around for the past decade or two debating how to do this [Immunology Reviews 2005], resveratrol has now been found to counter virtually all of the genetic pathways that lead to the age-related decline in the human immune system, a fate that affects virtually all senior adults over age 60 and results in otherwise avoidable cases of pneumonia and cancer as well as chronic inflammation and autoimmune disorders.
The age-related decline in the human immune system centers around the diminished production of what are called naïve white blood cells (T-cells) that create antibodies against all new incoming biological threats (bacteria, viruses, fungi, cancer cells) that the body has not made antibodies for.
The population of naïve T-cells emanates from the thymus gland. You are not going to live any longer than your thymus gland.
Babies born without a thymus gland rapidly succumb to infection if a thymus gland transplant is not performed.
The primary job of your thymus gland is to process white blood cells known as immature T-lymphocytes (or T-stem cells) to become mature T-cells (aka T-helper cells or T-cells with a surface protein called CD4 T-cells).
A class of T-cells stimulates the production of antibodies that becomes part of your immune memory. [International Journal Clinical Lab Research 1991; Clinical Infectious Diseases 2001]
The thymus gland shrinks with advancing age, a human health problem of enormous proportion. In advanced countries where human populations are living longer, people will face the greatest health challenges of their life with a decimated thymus gland.
With advancing age the progressive shrinkage (involution) of this gland will ultimately lead to the demise of all human beings if nothing else does.
The active young double-lobed thymus is about 5 centimeters long (2 inches), 4 cm (1.5 inches) wide, and just 6 mm (1-quarter inch) thick. A 90-year old thymus gland will be 1/10th of its size compared to childhood. It is about the size of a walnut in youth and about the size of a pea in old age.
By age 50 maybe 15 percent of the thymus remains. [Gerontologist 1964] The capacity of the human immune system to mount an immune response decreases with advancing age starting around age 60, though there are individual differences based upon dietary factors and obesity. [Lancet 1974] The incidence of cancer, infection, inflammation and autoimmune problems among the elderly is attributed to the decline in the immune system. [Critical Review Oncology Hematology 2010] Centenarians have been found to have an extremely low number of naïve T-cells. [Aging Cell 2006]
Fortunately thymus cells have a capacity to regenerate. It is this capacity that modern medicine currently ignores. Even an aged shrinking thymus gland still has capacity to maintain the immune system, albeit marginally, by producing a small amount of mature “naïve” T cells and thymus proteins.
The age-related decline in human immunity is called immunosenescence and directly related to thymus gland atrophy. It involves a diminished ability to recognize new a threat (bacteria, virus, fungus, tumor, etc.). [Organogenesis 2015] A normal immune response “depends heavily upon the presence of thymus-activated T-cells. [Advances Experimental Medicine Biology 1976]
It has been said: “of all the changes of the ageing immune system, regression (shrinkage) of the thymus gland is the most dramatic, ubiquitous and recognizable process, having been first recognized 70 years ago, however still little is known about mechanisms that contribute to this event.” [Aging & Disease 2011] That statement was made five years ago and recent scientific discoveries now reveal how to regenerate the thymus gland.
While it has been said that the study of immunosenescence is well timed given the expanding lifespan of Americans, this field of study is actually decades late. [Organogenesis 2015]
Thymic involution is characterized by fat accumulation and loss of normal thymus anatomy with reduction of T-cell production. Efforts to counter immunosenescence by counteracting the effects of obesity on the thymus gland are of paramount importance, particularly in societies where obesity is rampant.
Obesity accelerates thymic aging. Obesity reduces thymus gland function independent of diabetes. By age 40 maybe 80% of the space taken up by the thymus gland is dysfunctional and composed of fatty tissue. [Blood 2009]
Obesity, or engorgement of fat cells in the thymus gland, leads to impaired thymus function and a compromised immune system, which is characteristic of obese individuals who commonly experience acute and chronic infections. [Age 2014]
Some inroads are being made to address premature immunosenescence induced by high-fat diets. The thymus gland of laboratory mice fed a high-fat diet is engorged with fat which results in a decrease in mature T-cells. When the red wine molecule resveratrol is added to the diet of these mice many deleterious changes in the thymus gland are reversed and cellular immunity is normalized. [Journal Nutritional Biochemistry 2013]
Most humans will age at the rate of decline of their active T-cells.
The most important change in the immune system with advancing age involves T-cells. [Critical Review Oncogenesis 2013] In fact, shrinkage of the thymus gland in its earliest stages may “act as the triggering event that characterizes the aging process.” [Gerontology 1999]
Thymus cells die off at the rate of 3-5% per year until middle age when this process slows to 1% per year. The progressive and total loss of ability of the thymus gland to facilitate the maturity of T-cells is estimated at a 120-year theoretical limit in humans, which is the theoretical maximum lifespan. [In Vivo 1997]
Recently researchers used an array of blood tests to distinguish epigenetic from chronological (calendar) age. Epigenetics is explained as the protein-making property of genes. They found when epigenetic age is older than one’s calendar age that there is a greater likelihood of developing cancer and dying from it. These researchers correlated increasing epigenetic age with the loss of naïve T-cells. This novel data clinches the link between thymic aging and human aging. [Ebiomedicine 2016]
Thymus gland regeneration is on the horizon.
An understanding of the genetic origins of thymus gland atrophy is now at hand. Here is what is known genetically:
The FOXN1 gene protein stimulates the thymus gland to regrow.
FOXN1 is the key gene derived protein that regulates thymus gland function and development. [Journal Immunology 2015] A mutation in FOXN1 gene is correlated with T-cell immunodeficiency. [Gene Cards] The genetic transcription factor FOXN1 rejuvenates thymuses from old mice almost completely. [Rejuvenation Research 2016]
The deregulation of WNT4 gene is involved in the shrinkage of the thymus gland with advancing age. [Journal Gerontology Biological Sciences 2014] The provision of a protein from the Wnt4 gene to laboratory animals results in T-lymphocytes that are 3-4 times larger. [Fight Aging 2008]
The red wine molecule resveratrol, known to be a molecular mimic of calorie restriction, activates the Sirtuin1 survival gene whose activity declines with progressive atrophy of the thymus gland. [Cell Transplantation 2014]
The human body has marvelous compensatory mechanisms to withstand exposure to mild toxins. The most prominent and well-studied mechanism is the activation of internal antioxidant enzymes (glutathione, catalase, superoxide dismutase) via the Nrf2 gene transcription factor. In a laboratory dish experiment, exposure to a toxic metal (arsenic) activated Nrf2 and protected the thymus gland from damage. [International Immunopharmacology 2015] The red wine molecule resveratrol activates Nrf2 and protects T-cells from potentially toxic oxidation. [Food & Function 2014]
So the key genes have been identified.
A hormone and longevity factor known as fibroblast growth factor 21 is reported to maintain thymus gland size and function in aging laboratory animals. [Rejuvenation Research 2016] Biologists now know a calorie restricted diet or activation of fibroblast growth factor 21 (FGF-21) are reported to maintain thymus function in aging mice.
In recently published research, it was found that FGF-21 protein is produced in the thymus gland and declines with advancing age of laboratory animals that correlates with thymus involution (shrinkage). Calorie restriction or over-production of FGF-21 protein reduces lipids (fats) in the thymus gland, increases surrounding brown adipose (fatty) tissue and elevates the naïve number of T-cells. The decline of FGF-21 with advancing age correlates with the demise of lab animals.
The maintenance of FGF-21 extends the lifespan of mice by a striking 40% via its ability to maintain thymus gland function. This approximates the same increase in lifespan accomplished with a calorie-restricted diet. [Proceedings National Academy Science 2016]
It is also instructive to learn that another gene protein known as KLOTHO that is known as an aging suppressor is a co-factor for FGF-21. [Molecular Cellular Endocrinology 2009] Vitamin D3, the natural form of this sunshine vitamin, activates KLOTHO. [Advances Experimental Medicine Biology 2012]
The red wine molecule resveratrol exerts broad biological action to rescue the aging thymus gland.
Only recently has it been demonstrated that resveratrol increases FGF-21 activity via its regulation of the Sirtuin1 survival gene. [Gastroenterology 2014] Resveratrol has been shown to increase the number of mature T-cells (aka T-lymphocytes) in the thymus gland and elevate the number of naïve T-cells (CD4, CD8 T-cells). Resveratrol also activates the Nrf2 controller of internal antioxidant enzymes such as catalase, known to protect the thymus gland from attrition and aging. [Food & Function 2014]
Resveratrol counters the deleterious effects of diet-induced obesity upon thymus gland function and anatomy. [Journal Nutritional Biochemistry 2013]
Fortification of animal feed with resveratrol increased the weight of the thymus gland and increased the T-cell count and improved antibody production after vaccination in chickens. [American Journal Veterinary Research 2014]
The accumulation of fat in the body accelerates the attrition of thymus gland volume and function and reduces T-cell production. These negative effects can be reversed with resveratrol supplementation. [Journal Nutritional Biochemistry 2013] It is now possible to address ways to avert obesity-related decline in immunity.
A subset of T-cells called regulatory T-cells (aka TREGS) suppress other T–cells to limit and normalize the immune response. Resveratrol prolongs the life of TREGS and helps overcome the deleterious effects of a high-fat diet. [Journal Food Science 2014]
A molecule similar to resveratrol, quercetin, has been shown to act as an antioxidant to protect the thymus gland. [Experimental Cell Research 2003] Quercetin is found in red apple peel and grapes and is available as a dietary supplement.
The enzymatic antioxidant catalase is produced internally in the body in response to biological stress.
It is not surprising to learn that thymus shrinkage results from an increase in destructive hydrogen peroxide combined with a decline in catalase activity. One molecule of catalase can break 40 million molecules of hydrogen peroxide each second. [Enzymes]
As catalase declines the thymus gland shrinks and this results in a compensatory response where existing “memory” T-cells (T-cells that have already developed antibodies to specific antigens like bacteria and viruses) predominate over so-called “naïve” T-cells that address new biological threats. [Cell Reports 2015]
A genetically altered breed of mice that generates 50-fold more catalase activity produced a 17-21% increase in median and maximum lifespan. [Rejuvenation Research 2005]
Resveratrol raises catalase in aged mice. [Journal Gerontology A 2010] A modest dose of resveratrol and vitamin D3 increases catalase activity. [International Journal Vitamin Nutrition Research 2015]
While there are catalase dietary supplements, they may only exert activity in the digestive tract as there is no transport system to carry catalase to remote organs and tissues in the body and stomach acid breaks down catalase. Every cell in the body can activate catalase. Its precursors are zinc, manganese and copper.
The thymus gland is of such critical importance throughout life it is hidden deep within the body behind a protective bony plate.
Modern medicine is treating a lot of disease that is related to immune dysfunction while ignoring exhaustion of the thymus gland. Humanity is on the cusp of solving this problem, at least to some extent, with nutraceuticals.
In an era of pharmacologic medicine will these nutraceutical breakthroughs be adopted into the daily practice of medicine?
It should be noted that resveratrol addresses the genes involved in thymus gland maintenance, raises catalase, binds to copper thus restoring zinc/copper balance, and works synergistically with quercetin and vitamin D. Resveratrol molecularly mimics a calorie-restricted diet, helps overcome the adverse effects of a high-fat diet and rescues the aging thymus gland.
We now know that thymus shrinkage is regarded as one of the leading regulators of aging, not just disease. Will humans achieve unprecedented longevity, doubling their healthspan and lifespan by putting this knowledge into practice that as has already been demonstrated in the animal laboratory and limitedly in humans?
With some degree of certainty it can now be said that humanity can achieve superlongevity via maintenance of the human immune system. Older adults need not experience a decline in their immune response to the point where they succumb to some pathogen or cancer.
For those readers who have been taking resveratrol pills for the past decade, the latest science says you didn’t waste you money and that may have been a life-extending decision. – ©2016 Bill Sardi, ResveratrolNews.com
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