Thread by @drkohilathas

Rapamycin

A drug with massive potential and anti-inflammation, anti-cancer, anti-ageing, anti-diabetic, immunomodulation, immune-enhancing, cardioprotection, neuroprotection, antiviral, and anti- prion effects.

A THREAD 🧵

Rapamycin was first isolated as an antibiotic in 1975 by researchers in the soil of the South Pacific island of Rapa Nui, where the islanders never wore shoes and were rarely infected with tetanus.

pubmed.ncbi.nlm.nih.gov/1102509/

It later became known as an antifungal agent, and in addition to its anti-inflammatory effects, it was found that rapamycin also suppressed the immune system. It was later approved as an oral immune inhibitor in 1999.

Rapamycin is now primarily used in clinical settings to suppress tissue rejection after organ transplantation and as an adjuvant in therapy for certain cancers.

pubmed.ncbi.nlm.nih.gov/30425336/

In 2009, though, it was found that rapamycin extended the maximal lifespan of both male and female mice by 9% and 14%, respectively.

nature.com/articles/natur…

Animal studies since 2009 have shown that rapamycin has powerful pharmacological effects on delaying ageing, extending healthspan, and attenuating age-related diseases by inducing autophagy (similar to what happens when fasting).

nature.com/articles/s4158…

More on the many benefits of fasting here 👇🏾

https://twitter.com/drkohilathas/status/1631571434504847360

More specifically, rapamycin increases the lifespan of multiple species by inhibiting the mammalian target of rapamycin (mTOR), a master regulator of cell growth, metabolism, and ageing.

sciencedirect.com/science/articl…

And it’s not just mice; evidence exists showing that rapamycin-induced mTOR inhibition prolongs the lifespan of many other species, ranging from yeast to flies.

oncotarget.com/article/1272/t…

The longest documented lifespan extension by rapamycin was 26%; this was in mice. Unfortunately, there has been no study of rapamycin in the lifespan extension of humans and primates so far.

onlinelibrary.wiley.com/doi/10.1111/ac…

As biological function declines with and also contributes to ageing, it has been put forward that rapamycin might not only result in longer lifespans but better overall health by delaying the ageing of multiple organs systematically.

With regards to the nervous system, rapamycin has shown great potential in targeting and reversing many aspects of ageing and disease progression found in age-related neurodegenerative disorders like dementia and Parkinson’s disease.

In animal models rapamycin has been shown to induce autophagy and activate various signalling pathways to reverse amyloid β-induced oxidative stress and synaptic dysfunction in areas of the brain linked to memory formation.

link.springer.com/article/10.100…

Rapamycin has also been shown to protect against age-related oxidative stress, cell death, and neuroinflammation, as well as improving mitochondrial function and acting as an anti-inflammatory agent within the brain.

ncbi.nlm.nih.gov/pmc/articles/P…

Rapamycin has also been shown to extend the survival of prion-infected mice when administered orally, starting at day 100 post-infection.

pubmed.ncbi.nlm.nih.gov/19183256/

Though related to an increased risk of menstrual disturbances in women, in animal models rapamycin has shown to improve ovarian reserve, as well as improve ovarian lifespan, increase egg cell quality, and improve the ovarian microenvironment.

link.springer.com/article/10.100…

Similarly, in male mice, rapamycin was shown to protect against age-caused testicular shrinking and improve markers of sperm production.

onlinelibrary.wiley.com/doi/10.1111/j.…

With regards to the cardiovascular system, rapamycin has shown to prevent age-related pathogenic heart muscle growth, whilst improving overall pump function.

onlinelibrary.wiley.com/doi/10.1111/ac…

It has also shown to attenuate cardiac scarring that is usually linked with myocardial dysfunction, increased stiffness, decreased cardiac compliance, decreased myocardial systolic function, and increased incidence of arrhythmia.

ahajournals.org/doi/full/10.11…

Importantly, rapamycin has also been shown to reduce myocarditis associated with Trypanosoma cruzi, the causative agent of Chagas disease, as well as experimental autoimmune myocarditis.

pubmed.ncbi.nlm.nih.gov/31801138/

pubmed.ncbi.nlm.nih.gov/16043946/

Before you carry on, if you'd like to learn more about rapamycin, vitamins, minerals, and medicinal mushrooms and how they may help a wide range of bodily issues, then you can find it all in one place.

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Usually, mTOR signalling activation leads to impaired endothelial function and foam cell formation, which is the initial process of atherosclerosis formation.

pubmed.ncbi.nlm.nih.gov/30259816/

And thus, rapamycin has been hypothesised to, and later shown to reduce vascular inflammation and alleviate atherosclerosis progression.

ahajournals.org/doi/10.1161/CI…

Rapamycin also exerts effects on venous disease. In aged mice (16 months old) with experimental deep vein thrombosis (DVT), 2-month rapamycin treatment resulted in a significant reduction in susceptibility to DVT as compared to the aged controls.

sciencedirect.com/science/articl…

This was thought to be done by rapamycin’s effect of significantly decreasing platelet size and activation.

SASP (senescence-associated secretory phenotype) are pro-inflammatory, tissue-destructive molecules that are expressed by senescent cells, having deleterious effects on the tissue microenvironment, as well as promoting tumour progression.

ncbi.nlm.nih.gov/pmc/articles/P…

Senescent cells are unique in that they eventually stop multiplying but don't die off when they should. They are thought to be a fundamental driver of chronic conditions and functional decline in late life.

One study noted that SARS-CoV-2 induced senescence in human non-senescent cells and exacerbated the SASP in human senescent cells.

aging-us.com/article/203560…

Another study noted that the spike protein amplifies SASP in senescent, cultured human cells.

ncbi.nlm.nih.gov/pmc/articles/P…

In a clinical trial involving older adults with coronary artery disease, 12-week daily oral low-dose rapamycin had some positive effects on alleviating SASP. This has also been demonstrated in mice.

sljch.sljol.info/articles/abstr…

Clinically, rapamycin is used as an immunosuppressant for preventing rejection in transplant patients, and there have been queries about whether it may have a potential negative effect on immunity.

However, rapamycin is now recognised as an optimal immunomodulator rather than an immunosuppressant.

nature.com/articles/natur…

In fact, rapamycin has immunostimulatory effects on the generation of memory CD8 T cells, and in one study, treatment of mice with rapamycin following a viral infection increased not only the quantity but also the quality of virus-specific CD8 T cells.

nature.com/articles/natur…

And in humans rapamycin has shown to enhance the ability of vaccine response in the elderly.

science.org/doi/abs/10.112…

Rapamycin has also been shown to inhibit the replication of the 1918 flu virus by 100-fold.

ncbi.nlm.nih.gov/pmc/articles/P…

Though no specific studies have been performed evaluating the effectiveness of rapamycin in treating COVID-19, one review did note that it may ....

“represent a better candidate for COVID-19 therapy than commonly tested antivirals” and also “that its efficiency will not be reduced by the high rate of viral RNA mutation."

ncbi.nlm.nih.gov/pmc/articles/P…

The beneficial effects of rapamycin do not stop there. This drug has shown anti-aging potential in nearly all biological areas, from helping with alopecia to helping with age-related frailty.

sciencedirect.com/science/articl…

But the use of rapamycin does not come without the risk of side effects.

Side effects reported using rapamycin in clinical studies include low white blood count levels, low platelets, raised triglycerides, hypercholesterolemia, aphthous ulcers, oedema, joint pain...

...pneumonia, acne, delayed wound healing, sinus tachycardia, decreased renal function, gastrointestinal toxicity, rash, menstrual cycle disturbance, ovarian cyst, and infection.

It must be noted that most of these side effects are not reported by healthy participants. And, an increasing amount of evidence continues to suggest that most of these adverse reactions are due to rapamycin-related dose dependence and are reversible after ending treatment.

pubmed.ncbi.nlm.nih.gov/34089901

Plus, other studies show more side effects in the placebo group than in the rapamycin group.

Take this study of healthy male participants given a single dose of rapamycin. Complaints about fatigue were reported by 23% in the rapamycin group and by 40% in the placebo group.

journals.lww.com/drug-monitorin…

The other commonly stated "side effect" of rapamycin, usually when taken for a prolonged period of time, is insulin resistance.

pubmed.ncbi.nlm.nih.gov/22461615/

Confusingly, rapamycin can actually induce insulin sensitivity as well as insulin resistance. This mirrors the effect of fasting which improves insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes.

One research paper noted that this was not to worry about as the raised blood sugar levels in some who take rapamycin are reversible and suggested that for anti-aging purposes, rapamycin...

nature.com/articles/s4141…

“can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.”

It has been said that “rapamycin is not much more dangerous than ordinary drugs”, and that “if used properly, rapamycin is not much more dangerous than ordinary aspirin.”

ncbi.nlm.nih.gov/pmc/articles/P…

This was no better demonstrated than in a case series of a failed suicide attempt involving an 18-year-old woman who ingested 103 rapamycin tablets (103 mg). The only detected effect was an elevation in total blood cholesterol.

pubmed.ncbi.nlm.nih.gov/26020944/

The benefits of rapamycin seem near endless, and given that rapamycin is a fasting- and ketogenic diet-mimicking medication, the benefits and potential side-effects of the three have considerable crossover.

More on keto here 👇🏾

https://twitter.com/drkohilathas/status/1635251870213230592

There is no official dosage of rapamycin for age prolongation. Anecdotally, one researcher is noted to take 20 mg once every two weeks (noting that high peak levels theoretically may cross the BBB, and should be given under doctor supervision).

rapamycin.news/t/what-is-the-…

Everyday treatment in the elderly (1 mg/day for several weeks) was not associated with side effects and has been shown to be safe.

pubmed.ncbi.nlm.nih.gov/29408453/

But, as one research paper puts it, “to avoid side effects and maximize anti-aging effects, a feasible approach would be to prolong intervals between rapamycin administrations while keeping the total dose constant....

...For example, instead of daily administration, a weekly administration of a higher dose can be suggested to achieve a high peak blood level, followed by drug-free period to avoid undesirable effects.”

ncbi.nlm.nih.gov/pmc/articles/P…

@Blagosklonny is an expert in this area