I’ve been saying for a very long time that the idea of cycling supplements/meds never made much sense to me. The whole “it’s good to give your body a break” rebuttal just doesn’t seem logical.
What are we giving our bodies a break from? Taking something that will improve our health? Might as well take a break from eating blueberries too.
I understand your point and sympathize. However, there’s a counterargument, and you brought up blueberries. The idea is that the healthiest eating pattern incorporates seasonality. People/animals ate seasonally. Blueberries and fruit in general don’t grow year round - that’s an artifact of modern supply chains. Fruit, and all food are incredibly complex chemically. They have some defensive chemicals, which in small amounts are beneficial through hormesis, but what if you eat them “unnaturally” long? Toxins might accumulate and be a net negative. Especially with modern growing methods and the use of pesticides and herbicides. Blueberries and strawberries are some of the most polluted fruit. Are you comfortable consuming these exact same poisons for prolonged periods? I’m uneasy, personally.
Instead, animals and people naturally cycle their food seasonally. You eat different fruit with a different mix of chemicals, and then switch again before they have a chance to become problematic from too long an exposure to the same chemical agents. That’s another reason why it’s recommended that you eat a variety of F&V, rather than honing in on a few.
With drugs it’s all about particular cases. Statins, no reason to stop ever, BP meds, glucose control etc. But bisphosphonates, you hit and run, build up the bone, take a drug holiday or stop altogether. The idea with rapa is that prolonged use might start impinging on mTORC2, which is likely a negative. So you hit the mTORC1 pathway, but stop before it becomes an issue with complex 2, let C2 build back up, then hit it again.
I personally am not sure I buy it in the case of rapa if you are already taking it in a pulsatile way, once a week, because that mode already incorporates that idea to begin with, it’s the whole reason you take it once a week and not daily. Adding a holiday on top seems unnecessary. A hat on a hat. But who knows, it’s all speculation. We don’t have firm data.
I could see an argument for cycling based on the cautionary principle. We know that beneficial effects of rapamycin persist for quite a while after stopping, based on mice data. If so for humans, then stopping every few months then resuming might not lose you much, but might provide an additional margin of safety in case there are negative effects of persistent exposure. This is highly speculative, but there you have it. Personally I’m not convinced, but YMMV.
I’m not really sure you can apply fruit seasonality changes to the topic of cycling supplements/medications since the later doesn’t undergo seasonal changes. I only used blueberries as an example since they’re generally considered a health food, seasonality changes aside.
I actually don’t think you said anything wrong in your post. I would never suggest staying on an antibiotic forever, for example, since that is only used to treat a specific condition we are trying to get rid of and we know there are tremendous downsides to antibiotics.
For Rapamycin, I think we can safely say that daily dosing is a pretty bad idea for anti aging so I meant taking it once every 1-2 weeks while the drug remains in the system before the next dose. I didn’t necessarily mean continuous use to be defined as daily dosing.
That being said, with respect to longevity interventions, I still can’t think of anything that would be better off cycled on and off. Unless I am proven wrong, I will continue to hold this opinion.
How about Fasting? (20 chars)
IMO: The effects of rapamycin are subjectively much more profound in the elderly.
I began taking rapamycin shortly after turning 80, and it has truly changed my life. Occasionally, I have taken breaks from rapamycin, mainly due to concerns that it might delay wound healing, which is something I’ve noticed myself with minor injuries like paper cuts and insect stings. However, whenever I stop taking rapamycin, I start to feel unwell within about a week. Looking back, those breaks don’t seem to make much sense given how much better I feel while on the medication.
Patients undergoing kidney transplants take rapamycin and recover well.
So now, I have decided not to cycle off rapamycin, even for medical procedures.
Oddly, and it may be in my mind, after taking rapamycin for years, I don’t notice any increase in healing time from insect bites (mosquitoes), minor injuries, etc.
It’s not so much “reversal of benefits” as it is what John Hemming has mentioned - the return of the harmful SASP levels once you stop rapamycin, so the resumption of damaging processes. During the time you are on rapamycin you are effectively pausing a lot of the damage (at lease the subset of damage that is caused by SASP), is what this research is suggesting.
I think like most things; it’s a balance. If you take too much rapamycin for too long you risk blocking mTORC2, and getting negative side effects like blood lipid or glucose disregulation. But of course “what is too much, for too long” is going to vary by person and situation… so its all very difficult to parse out right now due to individual differences and lack of robust clinical trials.
SASP has negative effects. I think it is through Il-10, but that is contrary to the conventional wisdom.
I was starting to get side effects from 6mg per week (not sleeping well, not feeling good in the days after a dose, worsening of existing chronic pain). I’ve tried a few different dose regimens now, so I decided to try 1mg daily for 1 month following the recent small studies on APOE4/4 participants, as I have APOE4/4 and that’s my main reason for taking Rapa.
Anyway, I’ve nearly completed the month and have had no sides other than the occasional painless tiny lump somewhere in my mouth. I’ll go back to 6mg weekly after this to see if the side effects come back. I did have a medical checkup after 3 weeks of daily Rapa and my LDL-C was 46 (Brillo EZ, Ator 20mg) and my HbA1c was 5.1% (Acarbose & Dapa), so I was happy about that. Unfortunately, routine NHS checkups in the UK are not very extensive and that’s all they tested for, which is a bit of a waste but better than nothing.
I’m doing well on 3 ng per week. Higher dose makes me sick. I think it’s weight dependent. I’m only 110 lbs.
Randox and medicheck both do reasonable broad blood panels. Randox has a lot of tests.
Yes. Dosing is definitely weight dependent. A lot of lighter folks here cannot handle normal weekly doses without severe side effects. The dosing amount is different from.person to person. You also need the goldilocks dose. Too little does nothing and too much is annoying due to side effects.
Rapamycin blood tests should help you find your sweet spot.
I’m 120lbs and had no problem taking 10mg/week for months. I backed off to 7mg to ensure clearance by the next dose.
Yes, probably backing down was a good choice… too high and MTOR2 is affected… and you age faster. I did much higher for 7 months and did not feel a problem (silent pathology)… but inflammation and methylation test said otherwise. Lost some of the rejuvenation I had gained.
For me 6 - 8 mg is my sweet spot for catabolic and anabolic balance. Now my biological tests show I regained those years back.
I forgot you had spoken about that here a while back. To be clear, your current dose is 6-8mg once every 7 days?
Exactly… pure pharmaceutical grade zydus.
2 mg pills… I take 3 pills … so 6 mg once a week. Mostly 6 mg past 7 months.
I will do a blood test in 2 weeks and test my blood absorption at 3 hours… C-max.
Average person get 3 ng/mL per 1 mg. So should be at 18 ng/mL at 6 mg dose.
I think the dosage is not only related to body weight, but also to gender.
Generally, the dosage for women is less than that for men. Perhaps because men have a higher tolerance level than women.
Yes! Most research says women get same bang at a lower dose than men at a higher dose.
Men processing… faster… metabolism… more cells than women…might require men to have a higher dose than women.
More for women does not show increased benefits in longevity.
Blueberries and fruit in general don’t grow year round - that’s an artifact of modern supply chains. Fruit, and all food are incredibly complex chemically. They have some defensive chemicals, which in small amounts are beneficial through hormesis, but what if you eat them “unnaturally” long? Toxins might accumulate and be a net negative. Especially with modern growing methods
I’m with you on pesticides, but I think it’s important to point out that modern growing techniques have led to a reduction in the levels of nutrients in our foods (see, for example, this news report Why modern food lost its nutrients).
I’m not at all concerned about consuming too many naturally occuring defensive chemicals year-round when modern farming practices have made our food less nutricious and full of chemicals whose effects we still don’t fully understand.
I think that was the core message of the PEARL study. Women saw benefits at the low dose while men did not.
Dr. Blagosklonny wrote in his later years that he use to cycle on and off rapa, but later became convienced that his cancer got a hold in his body when he was not on drug during on of these cycles. I started rapa at 71 and I am 79 now never stopped. Also, just started low dose Retatrutide to lose a few pounds, but to mainly reset my mitocondria balance. Unlocking longevity with GLP-1: A key to turn back the clock? Unlocking longevity with GLP-1: A key to turn back the clock? - PubMed