Conclusions: Rapamycin inhibits the activation of mTOR pathway, which contributes to protect against the loss of dopaminergic neurons and provide behavioral improvements in mice with Parkinson's disease. These results are partially related to the ability of rapamycin in inducing autophagy and reducing oxidative stress.
Is there a natural alternative to rapamycin?
In particular, they identified allantoin and ginsenoside as strong mimetics of metformin, epigallocatechin gallate and isoliquiritigenin as strong mimetics of rapamycin, and withaferin A as a strong mimetic of both.
Withaferin A is in Ashwagandha, and I have some arriving today!
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Allantoin is a byproduct of uric acid that can be extracted from urea and is the result of metabolic processes that occur in most organisms – among them animals (including humans) and bacteria. It can also be extracted from comfrey (taken from the roots and leaves) and is proven safe and effective because it does not contain the potentially irritating alkaloid compounds that occur in the comfrey plant.
Why was comfrey banned?
The pyrrolizidine alkaloids in comfrey can cause severe liver damage, liver cancer, mutagenicity, and even death. [8,9] For this reason, the U.S. Food and Drug Administration has banned the sale of oral comfrey products in the United States.
Allantoin is available in some skin care products and can be absorbed from topical application. Have not tried it myself (yet).sciencedirect.com/science/a...
Treating mice with rapamycin has been shown to increase lifespan when started early in life [12], late in life [13], when provided intermittently [14], or when given transiently during middle-age [15]. Along with increased lifespan, improvements from rapamycin or rapalog treatment have been reported for age-related cancers [16,17] and age-related declines in cognitive function [18], kidney function [19], heart function [[20], [21], [22]], immune function [23], intestinal function and gut dysbiosis [[15], [25]], ovarian function [26], and oral health [27,28], among others. This large body of literature has suggested multiple potential indications for clinical evaluation of the geroscience hypothesis via treatment with rapamycin or other mTOR inhibitors.
This page is by a doctor who seems to specialize in Rapamycin to treat aging and age related disease. This is not an endorsement.
How good is Rapamycin
Rapamycin is a true miracle drug. For persons over 50, it it most the important drug in the world today. Rapamycin does not reverse aging. It does not make you 25 again; but it may buy you an extra decade or more of good health.
Rapamycin is a generic drug. For Big Pharma, Rapamycin is worthless. There is no money to be made from Rapamycin for the anti-aging industry. You can't sell Rapamycin on the internet. If want a prescription for Rapamycin you must go to a physicians office, become a medical patient etc. And since the medical world does not recognize Aging as a disease; no insurance coverage. For the patient, all out of pocket.
Small world. I was in contact with this doctor, Alan Green, back in 2017. I talked with him about giving me a prescription for it and he was open to the idea as long as I could get to his office in New York. I couldn't do it, so I dropped it.
Six or so years ago, I bought some sirolimus (brand of rapamycin) from someone in India over on reddit. I bought 100 pills for about $300 as I recall. There were a few of us on Longecity who tried it out. Everyone had a different idea of what dosage should be. I just found the last four I have. Tried looking up the seller a few years ago but no luck.
It looks like that Dr Green in the link I shared will prescribe it if you wanted to try again. It is generic.
Found a newer report:
More Mouse Trials - 2021 - Effects and potential mechanisms of rapamycin on MPTP-induced acute Parkinson’s disease in mice
Results: Rapamycin can effectively alleviate symptoms of PD. The levels of key protein p-4EBP1 in the striatum and substantia nigra were both significantly higher in PD group compared with control group (P<0.01), while being pretreated with rapamycin, the expression of p-4EBP1 in the striatum and substantia nigra were both decreased obviously (P<0.01).
Conclusions: p-4EBP1 protein may be involved in the pathogenesis of PD via mTOR signaling pathway. Inhibited mTOR-4EBP1 pathways could make a certain protective effect for the acute attack of PD induced by MPTP.
"However, rapamycin has some drawbacks, including an increase in insulin resistance that could set the stage for diabetes, observed in both humans and laboratory animals. The new findings, published in the Journals of Gerontology: Biological Sciences, help to explain why that happens, and what could be done to address it.
It found that both dietary restriction and rapamycin inhibited lipid synthesis, but only dietary restriction increased the oxidation of those lipids in order to produce energy. Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in insulin resistance, which in humans can lead to diabetes.
However, the drug metformin can address that concern and is already given to some diabetic patients to increase lipid oxidation. In lab tests, the combined use of rapamycin and metformin prevented the unwanted side effect.
“If proven true, then combined use of metformin and rapamycin for treating aging and age-associated diseases in humans may be possible,” the researchers wrote in their conclusion.
Yes, it is called melatonin and has a hugely better safety profile than rapamycin. The side effects list may be the longest I have ever seen and some are very serious. Look at the side effects for Sirolimus/rapamycin :
Side effects requiring immediate medical attention
Along with its needed effects, sirolimus may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking sirolimus:
More common
Abdominal or stomach cramps or pain
accumulation of pus
anxiousness, unexplained
backache
black or red, tarry stools
bleeding from the gums or nose
blurred vision
body aches or pain
bone pain
bruising
burning or stinging of the skin
burning while urinating
burning, dry, or itching eyes
burning, tingling, numbness, or pain in the hands, arms, feet, or legs
change in mental status
changes in skin color
chest pain
chills
confusion
convulsions (seizures)
cough
dark or bloody urine
deafness
decreased urine output
decreased vision
difficulty with breathing or swallowing
dilated neck veins
discharge from the eyes
dizziness
drowsiness
dry mouth
earache
excessive tearing
extreme fatigue
eye pain
facial hair growth in females
faintness or lightheadedness when getting up from lying or sitting position
fast, slow, or irregular heartbeat
fever
flushing or redness of the skin, especially on the face and neck
general feeling of discomfort or illness
increased hunger
increased menstrual flow or vaginal bleeding
itching, pain, redness, swelling, tenderness, or warmth on the skin
lack or loss of appetite
large, flat, blue, or purplish patches in the skin
loss of sexual ability, desire, drive, or performance
loss of voice
muscle pain
nasal congestion
nausea or vomiting
numbness or tingling around the lips, hands, or feet
pain in the chest, groin, or legs, especially the calves
painful cold sores or blisters on the lips, nose, eyes, or genitals
pale skin
prolonged bleeding from cuts
rapid heartbeat
rash
red or dark brown urine
redness or swelling in the ear
redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
ringing in the ears
runny nose
sensation of pins and needles
severe constipation
severe vomiting
severe, sudden headache
slurred speech
sore throat
sores or white spots on the lips or in the mouth
stomach pain or upset
sudden decrease in the amount of urine
sudden loss of coordination
sudden, severe weakness or numbness in the arm or leg
sudden, unexplained shortness of breath
sweating
swollen, painful, or tender lymph glands in the neck, armpit, or groin
tenderness, pain, swelling, warmth, skin discoloration, and prominent superficial veins over affected area
tremor
ulcers on the lips or in the mouth
unusual tiredness or weakness
vision changes
weakness or heaviness of the legs
white patches in the mouth or on the tongue
yellow skin and eyes
Less common
Bloating
change in size, shape, or color of existing mole
hoarseness
mole that leaks fluid or bleeds
new mole
pains in the stomach, side or abdomen, possibly radiating to the back
skin ulcer or sores
Incidence not known
Abnormal wound healing
headache
hives or itching
large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
nails loose or detached
puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
swelling of the arms or legs
yellow nails lacking a cuticle
Side effects not requiring immediate medical attention
Some side effects of sirolimus may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.
Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
More common
Abnormal vision
acne
belching
blistering, crusting, irritation, itching, or reddening of the skin
burning feeling in the chest or stomach
burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feeling
constipation
continuing ringing or buzzing or other unexplained noise in the ears
cracked, dry, or scaly skin
crying
decrease in frequency of urination
degenerative disease of the joint
depersonalization
diarrhea
difficulty with moving
difficulty with passing urine (dribbling)
dysphoria
ear pain
enlarged abdomen or stomach
euphoria
excess air or gas in the stomach or intestines
excessive muscle tone, muscle tension or tightness
fear
feeling sad or empty
hearing loss
heartburn
inability to have or keep an erection
increase in heart rate
increased hair growth, especially on the face
increased urge to urinate during the night
indigestion
irritation in the mouth
joint pain or swelling
leg cramps
loss of bladder control
loss of energy or weakness
loss of interest or pleasure
loss of strength
lower abdominal or stomach pain
muscle aches, pain, stiffness, or weakness
nervousness
pain in the back, ribs, arms, or legs
pain or burning in the throat
pain or tenderness around the eyes and cheekbones
paranoia
pelvic pain
quick to react or overreact emotionally
rapid breathing
rapidly changing moods
inflammation, redness, or swelling of the gums or mouth
shaking or trembling
shivering
sleepiness
sunken eyes
swelling
swelling of the scrotum
tender or enlarged gums
tenderness in the stomach area
thickening of the skin
trouble concentrating
trouble sleeping
waking to urinate at night
Managing side effects (general information)
For Healthcare Professionals
Applies to sirolimus: oral solution, oral tablet
Respiratory
Very common (10% or more): Dyspnea (up to 30%), upper respiratory infection (up to 26%), pharyngitis (up to 21%)
Common (1% to 10%): Pneumonia, epistaxis, pleural effusion, epistaxis
Uncommon (0.1% to 1%): Pulmonary hemorrhage
Rare (less than 0.1%): Alveolar proteinosis
Frequency not reported: Pleural effusion, alveolar proteinosis[Ref]
Metabolic
Very common (10% or more): Hypertriglyceridemia (up to 58%), hypercholesterolemia (up to 46%), hypokalemia, hypophosphatemia, hyperglycemia
Common (1% to 10%): Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes mellitus[Ref]
Cardiovascular
Very common (10% or more): Peripheral edema (up to 58%), hypertension (up to 49%), chest pain (up to 24%), edema (up to 18%), lymphocele
Common (1% to 10%): Venous thromboembolism (including pulmonary embolism, deep venous thrombosis), tachycardia
Uncommon (0.1% to 1%): Pericardial effusion (including hemodynamically significant effusions in children and adults), lymphedema
Rare (less than 0.1%): Pericardial effusion[Ref]
Gastrointestinal
Very common (10% or more): Constipation (up to 38%), abdominal pain (up to 36%), diarrhea (up to 35%), nausea (up to 31%), vomiting (up to 25%), dyspepsia (up to 25%)
Common (1% to 10%): Stomatitis[Ref]
General
The most common adverse reactions associated with this drug are peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.[Ref]
Hematologic
Very common (10% or more): Anemia (up to 33%), thrombocytopenia (up to 30%), blood lactate dehydrogenase increased, blood creatinine increased
Common (1% to 10%): Thrombocytopenic purpura/hemolytic uremic syndrome, leukopenia, neutropenia, aspartate aminotransferase increased, alanine aminotransferase increased
Uncommon (0.1% to 1%): Pancytopenia
Frequency not reported: Capillary leak syndrome[Ref]
Genitourinary
Very common (10% or more): Urinary tract infection (up to 33%)
Common (1% to 10%): Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with this drug, ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia), proteinuria
Postmarketing reports: Azoospermia[Ref]
Musculoskeletal
Very common (10% or more): Arthralgia (up to 31%)
Common (1% to 10%): Bone necrosis[Ref]
Nervous system
Very common (10% or more): Headache (up to 34%)
Common (1% to 10%): Osteonecrosis, tremor, insomnia[Ref]
Dermatologic
Very common (10% or more): Acne (up to 22%), rash (up to 20%)
Very common (10% or more): Creatinine increased (up to 40%)
Uncommon (0.1% to 1%): Nephrotic syndrome
Frequency not reported: Focal segmental glomerulo-sclerosis, BK virus associated nephropathy, nephrotic syndrome, higher serum creatinine levels, lower glomerular filtration rates[Ref]
Ocular
Frequency not reported: Eyelid edema[Ref]
Hepatic
Common (1% to 10%): Liver function tests abnormal
Frequency not reported: Hepatic failure, hepatic artery thrombosis[Ref]
Hypersensitivity
Rare (less than 0.1%): Hypersensitivity reactions, including anaphylactic/ anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis[Ref]
Other
Very common (10% or more): Fever (up to 34%), pain (up to 29%)
Common (1% to 10%): Impaired healing[Ref]
Oncologic
Common (1% to 10%): Skin cancer, lymphoma/post-transplant lymphoproliferative disorder
Frequency not reported: Hepatocellular adenoma and carcinoma, testicular adenoma[Ref]
Immunologic
Common (1% to 10%): Sepsis, pneumonia, pyelonephritis, herpes simplex, fungal, viral, and bacterial infections (such as mycobacterial infections, including tuberculosis, Epstein-Barr virus, CMV, and Herpes zoster), mycobacterial infections (including M tuberculosis), cytomegalovirus (CMV), Epstein-Barr virus
Frequency not reported: Clostridium difficile enterocolitis[Ref]
That is one heckava list! To add a little context, though, Sirolimus is used in very high dosages in order to suppress the patient's immune system, in order to keep them from rejecting their organ transplants. What drugs WOULDN'T have a long list of side effects if you increased the dosage 10x? When you're dealing with saving someone who is obviously very close to dying (or they wouldn't have had the organ transplant) I think you'd accept a lot of side effects. With that said, one good question would be: is there a safe dose that is effective at slowing aging?
That is a very good question, Jas and your point is well taken!
Another question would be what dose of melatonin would have a similar effect, since to date, melatonin has maintained an excellent safety profile at every dose that has been tested in studies in humans, animals and plants and melatonin also offers many other potential health benefits with limited side effects based on human and animal studies?
I'm not good with dog breeds, but Momo looks like a Westie to me and if Momo is 13 in that video, that is a high activity level since Westies have a life expectancy of 12~16 years. On the other hand, my sister had two Westies with one living to 16 1/2 years and the other to 17 1/4 years and they were both very active up to the 14~15 year area.
It would have been helpful if they had mentioned the dose they were using on Momo.
Melatonin is also thought to have antiaging effects, but I doubt they are as fast acting as they appeared to be in Momo. A before video of Momo would have been useful in the linked to video.
The pilot study used either 0.05 mg or 0.1 mg / kg 3x per week (Mon-Wed-Fri) ; this was for dogs weighing at least 18 kg (40 lbs) - so Momo was not part of the pilot study. It concluded that low-dose rapa was safe and effective, so I'm guessing Momo was on the low dose.
One potential issue with rapamycin is that it can shrink testicles, something Momo (most likely) and most of the other male dogs in the Dog Aging Project don't need to worry about. Don't know if this particular dosing regimen has that effect on intact males.
This gives a whole new meaning to the phrase, "traveling light"! That's a side effect I would definitely like to avoid!
The low dose for me would be approximately 7.5 mg each dose and the high dose would be 15 mg. It is a prescription med with very specific uses, so the uses being discussed would be off label usage. Not many, if any doctors are going to be willing to prescribe this drug for this off label use, so are we spinning our wheels with this discussion or is there a way forward for off label use?
What are they charging their patients for this service? Doesn't sound like anything insurance will be covering any time soon. Btw, it appears that melatonin is synergistic with rapamycin as an mTOR inhibitor.
I'm afraid to ask ... There needs to be regular blood work, so that expense is a necessary part of treatment. There are doctors who are well-known in big urban centers (e.g., Alan Green, NY) and presumably it costs a lot just to see them, but there are probably concierge medicine doctors who charge less, but still a lot for someone on a budget. Good Rx says the rapa itself costs around $150 per 30 x 1 mg - so $75 or $150 / month at the PEARL trial dosing levels.
When I looked at Alan Green's web pages I noticed another drawback - the instructions for fever - stop taking rapa (okay) and take z-pack (not good) - I guess to reduce risk of bacterial pneumonia? Overall the treatment should improve immune function but I suppose even at low dose they are assuming some immunosuppression. Hopefully the PEARL trial will find this is not necessary.
Constant and potent inhibition of mTOR may increase life span, but mTOR has a useful purpose at times and activation of that pathway may actually have beneficial effects in specific instances that may be critical. The "smart molecule", melatonin, seems to have the dual ability to activate or suppress mTOR as the situation dictates.
Here is a study that shows the usefulness of melatonin in activating the mTOR pathway when needed as one step to offset high glucose induced apoptosis of Schwann cells.
In this study, melatonin shows synergy with Rapamycin to inhibit the mTOR pathway and melatonin also protected healthy cells from the damaging effects of mTOR.
If Rapamycin inhibits activation of the mTOR pathway, and according to what you just wrote the mTOR pathway contributes to protect against loss of dopaminergic neurons, why in the world would you want to take Rapamycin?
Quote:”We observed that niacin pretreatment enhances UV induced activation of AKT (Ser473 phosphorylation) as well as that of the downstream signal mTOR (S6 and 4E-BP1 phosphorylation). The PI3K/AKT inhibitor, LY294002, and the mTOR inhibitor, rapamycin, largely neutralized the protective effects of niacin, suggesting that AKT and downstream signaling mTOR/S6 activation are necessary for the niacin-induced protective effects against UV-induced cell death and cell apoptosis.”
Neurons are not subject to UV damage, like keratinocytes. The damage in neurons in PD comes from accumulation of protein aggregates. Inhibiting mTOR increases autophagy which clears protein aggregates.
Another potential mechanism of action for rapamycin in PD could be increase in Treg function. There was an SoP blog post on immune function and PD and the potential for treatments based on ex vivo expansion of Tregs using rapamycin and IL-10. It seems possible that rapamycin might do so in vivo also (i.e. , mouse or human takes rapamycin orally and their Treg function increases), but I have not found any studies reporting this.
Below is link to my comment on the blog post (scroll up for the post, which explains in detail about Tregs, etc.) : scienceofparkinsons.com/202...
From what I understand, you don't want to have mTOR activated all the time, as is the case with most people especially as we get older. You want to switch between the two states periodically. So, I think the best application of rapamycin would be, maybe a week on and then a week off. That way, you get the digest/repair state AND the remove-garbage/grow- new-cells state (these "programs" can't run at the same time). If you don't periodically turn off mTOR you end up with damaged cells that are full of garbage and malfunctioning mitochondria, which is where we are right now. If you don't clear out the damaged cells, more inflammation builds up as the body keeps signaling that something's wrong, protein plaque builds up, and our stem cells never get a chance to be new neurons.
This mimics the way our ancestors lived; sometimes they had plenty of food, so they spent energy digesting and storing as much fat as possible. But sometimes food was scarce, so their bodies used that stored fat, cleaned up their damaged cells, and used them for fuel too. That's autophagy ("self eating") for you.
This phaze 1/2 clinical trial on RAPA in healthy elderly subjects showed no significant changes in cognitive or physical function. ncbi.nlm.nih.gov/pmc/articl.... But a larger PHASE 2 clinical trial is in progress. clinicaltrials.gov/ct2/show...
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