See June 12, 2020 paper by Mikhail Blagosklonny: "From causes of aging to death from COVID-19"; Aging 2020.
An excellent analysis by the great Blagosklonny of why risk of death from biological age is so closely like to risk of death from Covid and why both reduced by rapamycin.
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I have not been advised that any of my patients have died from Corona or been seriously sick and hospitalized on respirator. Many patients have gotten Corona; but their illness has been mild.
I believe Rapamycin is very good to help maintain a healthy immune system.
Hydroxychloroquine + Zithromycin might be effective treatment in the early stage of COVID-19 disease; but to date this has not been confirmed by controlled study. All published studies have focused on late stage disease in hospitalized patients with respiratory distress. Hydroxychloroquine is not helpful in late disease and the increased risk of cardiac complications makes Hydroxychloroquine contraindicated. My current advice on Hydroxychloroquine is not recommended until proven to work in early disease.
There are no published clinical studies showing sirolimus protects against COVID-19. Therefore I must provide the following warning:
There is NOT sufficient medical evidence to establish with scientific certainty the efficacy of sirolimus in the prevention and treatment of COVID-19 or furthermore whether sirolimus is contraindicated.
I have been inundated by the question of whether one should stop or not stop rapamycin in response to COVID-19. In response to those questions, I have prepared this summary of what I consider the best evidence that sirolimus provides protection against COVID-19. I think most of this protection is having a healthy immune system prior to exposure.
"Reduction and Functional Exhaustion of T cells in Pateints with Coronavirus Disease 2019.
Diao, 2020; Hubei province, China.
Methods: We reviewed the counts of total T cells, CD4, CD8 T cell subsets and serum cytokine from 522 inpatients COVID-19 admitted two hospitals Wuhan, December 2019 to January 2020 and 40 healthy controls.
Also measure T cell exhaustion markers PD-1, Tim-3.
Results: Total T cells, CD4, CD8 T cells were dramatically reduced in COVID-19 patients, especially elderly patients (>60 years) and in patients requiring ICU care.
Severe cases: Total T. CD4, CD8 down.
Serum cytokines: IL-6, IL-10, TNF-a are UP.
Higher levels exhaustion marker PD-1.
Increasing PD-1 and Tim-3 increase as patients progress from prodromal to overtly symptomatic, further indicative of T cell exhaustion."
"An effective immune response against viral infections depends on activation of cytotoxic T cells than can clear infection by killing virus-infected cells...Our results provide a preliminary demonstration of T cell exhaustion during COVID-19 infection."
Results:
1. Decreasing numbers total T cells, CD4 CD8
2. Negative correlation between T cell numbers and cytokines.
Increased in ICU patients: TNF-a, IL-6, IL-10.
The above cytokines decreased as patients improved.
"The phenomena suggests that the decrease on T cells is likely the result of high serum concentrations of TNF-a, IL-6 and IL-10 negatively regulation T cell survival and proliferation."
3. Enhancing T cell exhaustion in COVID-19 patients.
Low levels of PD-1, Tim-3 in prodromal stage; increase in symptomatic stage, highest in ICU period.
Discussion:
T cells play a vital role in viral clearance, with CD8 cytotoxic T cells capable of secreting an array of molecules to eradicate viruses. CD4 helper T cells can assist cytotoxic T cells and B cells.
Persistent stimulation by the virus may induce T cell exhaustion.
In ICU group 95% decrease in total T cells and CD4 and 100% decrease in CD8 T cells.
Cytokine storm is a phenomenon of excessive inflammatory reaction in which cytokines are rapidly produced in large amount in response to microbial infection. This phenomenon is considered to be an important contributor to acute respiratory distresss syndrome (ARDS). It has been implicated in respiratory virus infections such as SARS in 2002, avian H5N1 influenza. Cytokines TNF-a, IL-6, IL-10 increased in COVID-19.
TNF-a is a pro-inflammatory cytokine which can promote T cell apoptosis via interacting with its receptor, TNFR1, which is increased in aged T cells.
Our work suggests monocytes and macrophages as source of pro-inflammatory cytokines IL-6, IL-10, TNF-a.
T-cell exhaustion is a state of T cell dysfunction that arises in many chronic infections and cancer...Blocking IL-10 has been shown to prevent T cell exhaustion in animal models of chronic infection. COVID-19 patients have high levels of serum IL-10 while showing PD-1 and Tim-3 markers of T cell exhaustion.
"Taken together, we conclude that T cells are decreased and exhausted in patients with COVID-19. Cytokines such as IL-10, IL-6, TNF-a might directly mediate T cell reduction.
[AG note: These same cytokines are the usual suspects in various age-related diseases.]
"mTOR inhibition improves immune function in the elderly", Mannick, Dec 2014.
AG: This is the paper on which weekly rapamycin therapy is based. If rapamycin patients know just one thing, they should know they are not kidney transplant patients in whom daily rapamycin is being used to cause immune suppression; but rather they are anti-aging patients in whom weekly rapamycin is being used to improve immune function in the elderly.
Abstract:
Rapalog was used to ameliorate immunosenescence (the decline in immune function during aging) in elderly volunteers. Rapalog enhanced response to influenza vaccine by about 20%.
Rapalog also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age.
Introduction:
Immunosenescence is the decline in immune function that occurs in the elderly, leading to an increased susceptibility to infection...Adults 65 years of age and older account for 90% of influenza related deaths in the United States compared to younger adults.
"The decline in immune function with age is due to an accumulation of immune defects, including a decrease in the ability of hematopoietic stem cells (HSCs) to generate naive lymphocytes and an increase in numbers of "exhausated programmed death (PD-1) positive T lymphocytes that have diminished responses to antigenic stimulation in elderly mice.
Results:
Decrease in percent PD-1 positive T cells
6 weeks 12 weeks
CD4 30% 33%
CD8 37% 41%
Patient were given rapalog for 6 weeks. Then tests for PD-1 cells compared to baseline. 2 weeks later given flu shot. 4 weeks later (12 weeks) tests for CD-1 cells. Note: There is a marked reduction from baseline in PD-1 cells.
Discusssion:
Rapalog treatment decreased the percentage of PD-1 positive CD4 and CD8 T cells compared to placebo. PD-1 positive CD4 and CD8 T cells accumulate with age and have diminished response to antigen stimulation because PD-1 inhibits T cell receptor-induced T cell proliferation, cytokine production, and cytolytic function. PD-1 expression is induced by T cell signaling and remains high in the setting of persistent antigen stimulation, including chronic viral infection.
"A rapalog associated decrease in the percentage of PD-1 positive CD4 and CD8 T cells may contribute to enhanced immune function and improve the quality of T cell responses to antigenic stimulation in the elderly."
AG note: The decrease in PD-1 T lymphocytes was directly on point to the finding in the above study from Wuhan China.
Wang, Chun-Hua, American Thoracic Conference, 2012.
This is 2012 study from Taipei, Taiwan involving the treatment of patients with ARDS (Acute Respiratory Distress Syndrome) due to H1N1, also known as Avian flu (Bird flu).
39 patients with confirmed H1N1 pneumonia and on mechanical ventilator support (respirator) were randomized to receive either 10 days of Oseltamir (Tamiflu) alone or Oseltamir with rapamycin 2 mg day.
Results:
Rapamycin +Tamiflu Tamiflu alone
Mortality 20% 42%
Days on Respirator 14 days 33 days
Improved PaO2/FiO2 106 to 164 at 3 days None (106-107)
Conclusion: "Early adjuvant rapamycin therapy was significantly associated with a greater improvement in lung injury and multiple organ dysfunction, and shortened the duration of ventilator support in survivors."
Same group did a similar study with Steroids with or without rapamycin 2 mg a day.
"Adjuvant Treatment with a Mammalian Target of Rapamycin Inhibitor, Sirolimus, and Steroids Improves Outcome in Patients with Severe HiN1 Pneumonia and Acute Respiratory Failure. Wang, Chun-Hua. Taiwan. 2014, Critical Care Medicine. (only abstract available).
"Severe H1N1 pneumonia with acute respiratory failure (ARDS) results in infiltration of lungs due to presence of hyperactive immune cells. Rapamycin and corticosteroids inhibit this immune response by blocking the activation of T and B cells.
Patients: Between 2009 and 2011, of 4,012 H1N1-infected patients, 38 patients with severe H1N1 pneumonia and acute respiratory failure enrolled.
38 patients with confirmed HIN1 pneumonia on respirator were randomized to receive treatment of corticosteroids with sirolimus (2 mg/day) or without sirolimus.
Results: Sirolimus group: 7 days respirator; vs non-sirolimus 15 days respirator.
After treatment PaO2/FIO2 values:
Day 3: Sirolimus group significantly better: 167.5 vs 106.8.
Day 7: Sirolimus group: 241.6 vs 147.0.
Sirolimus plus steroid group had rapid clearance of virus.
Conclusion:
"In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroid and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened ventilator days."
AG note: Tamiflu seems of minimal value while rapamycin reduced mortality from 42% to 20%.
Rapamycin was also much better than corticosteroids alone without rapamycin.
Tamiflu, A BRAND NAME DRUG, is now promoted as the standard of care for bird flu. Rapamycin, a generic drug, was totally ignored.
Although H1N1 and COVID-19 are different virus; this is not about killing the virus. Rapamycin works by modulating the human response side of the equation. The human side of COVID-19 and Avian flu as regards ARDS should be essentially the SAME.
This 2002 Taiwan study suggests that rapamycin should be the number one drug in the universe being studied for treatment of respiratory failure and ARDS due to COVID-19. The problem is rapamycin doesn't have a billion dollar price tag. Rapamycin as a generic drug has ZERO commercial value.
Svatek, 2018, Journal of immunology.
Toxins in our most common and most loved foods, called Advanced Glycation End Products, acronyn A.G.E.s, have emerged in the past 20 years as something of great importance. However, A.G.E.s and their dangers and origins remain unknown to most health care professionals and most people. These toxins are not directly related to mTOR or treatment with rapamycin. They are toxins that work downstream to action of mTOR and rapamycin. The connection is Preventive Medicine. For people taking rapamycin to try to maintain good health; it does not seem like a good idea to be simultaneously poisoned by high levels of toxins in our diet. Especially, since these toxins can be reduced to safe level with no cost, no risk, no caloric restriction, no medication. All that is required is information about the risk and a practical guide showing how to lower A.G.E.s. in our diet.
Dr. Helen Vlassara arrived at Rockerfeller University, a leading world center for medical research in NYC, in the summer of 1974 as a newly minted medical school graduate. Over the next 20 years her group studied diabetes. Over the next 20 years her group became more and more impressed with the role of A.G.E.s in the pathogenesis of all diabetic complications, including those involving the eye, brain, heart, kidney, nerves, circulatory system. They noted that diabetes resembled accelerated aging. They considered A.G.E.s a strictly endogenous problem, produced in the body.
A.G.E.s had been described by a French chemist Louis Maillard in 1912 as a complex chemical reaction between amino acids and sugars during cooking. They were then called "browning products" for the brown color they gave food as oven-baked bread. Everybody is very well acquainted with these brown substances as they impart the enticing aroma, flavor and taste to our favorite foods, including roast chicken, grilled steak, fried bacon, pizza from the oven and grilled burgers and fries.
Until 1995 it was assumed that there was no connection between the delicious A.G.E.s in foods and the very bad A.G.E.s causing havoc in the body of diabetics. One day in 1995, Dr. Vlassara was the guest speaker at an international diabetes conference and was attending a spectacular banquet reception. As she looked out at the stunning display of food she exclaimed, "Look at all those A.G.E.s at a diabetes event !". Her colleague responded, "Why not, We don't absorb A.G.E.s from food."
However, by this time, Dr. Vlassara's lab had the newly developed the technical ability to measure A.G.E.s in blood. The next day the colleague cooked up a delicious meringue of egg whites and table sugar, loaded with A.G.E.s. The colleague gave a blood sample before and after eating the meringue. The results showed the the A.G.E.s in his blood skyrocketed within minutes after he ate the meal. Two years later they published the ground breaking paper; "Orally absorbed reactive glycation products (glycotoxins): an enviornmental risk factor in diabetic nephropathy", Koschinsky...Vlassara, 1997.
The science of the toxic effect of A.G.E.s in foods was off and running.
Dr. Vlassara was at the center and leading researcher in the development of this story. She has published over a hundred scientific papers. In 2017, she published an excellent book on this subject; Dr. Vlassara A.G.E Less Diet. The book is highly authoritative and gives a first hand account of how field developed
Most of the A.G.E.s in the body come from our diet, in particular, a relatively small number of very high A.G.E. foods. The toxins are produced by exposing animal products, meat, fish, dairy, to high dry heat as in broiling, grilling, frying and baking. The average NYC diet has 16,000 KU quantity of A.G.E.s. The body can handle about 5000-8000 A.G.E.s. Most people consume 2-3 times more A.G.E.s than their body can handle. The kidneys remove the A.G.E.s and when kidney function decreases with age and disease, the ability to handle A.G.E.s becomes much less. Excess A.G.E. accumulate in the body and cause havoc. The following sections will discuss the havoc caused by an excess of these toxins.
Feeding mice 40% less standard mouse chow is called 40% caloric restriction. Standard mouse chow is commercially heat processed for longer shelf life and is very high in AGEs. Mouse chow provides mice with a higher relative AGE diet than typical standard Western diet. Therefore, feeding mice 40% less standard mouse chow is 40% less AGEs PLUS 40 percent less calories. As will see in later discussion, feeding mice same amount of chow with same calories; but with AGEs reduced 40% results in substantial improvement in lifespan and health span. In many studies, what is called 40% caloric restriction has superior results to oral rapamycin. In my opinion, the superior results of 40% caloric restriction over oral rapamycin is the combined synergistic effect of reduction in both AGEs and a separate effect from reduction in calories. It is also my opinion, that the combination of oral rapamycin combined with substantial reduction in AGEs can achieve all the benefits of caloric restriction.