as many of us are diligently following various longevity strategies, informed by numerous studies, a crucial question arises: How do we effectively combine these strategies? In longevity, sometimes 1+1 may not equal 2, and in some cases, it might even result in zero benefit or adverse interactions.
A key component in our longevity toolkit is exercise. Workouts also divide our week into training/resting days. Therefore: I’m keen to discuss with you the combination strategies that revolve around exercise as a central pillar, which might be a possibility for everyone to organize his weekly routine.
Here is my current routine, which I would discuss with you:
Training days (days with dedicated aerobic / anaerobic workout session) – 2-4 times a week:
slow carbohydrate as pre-training meal: fuel for training
GlyNAC (regulates glutathione homeostasis, possibly not directly interfering with natural body response to training)
Microbiome Optimization (Inulin, complex fiber): not part of pre/after-training meals, as interfere with digestion
Resting days (days without training) – 2-4 times a week:
Blood sugar optimization (Alphaglucosidase inhibitors / GLT-2 inhibitors): according to individual regime
as was discussed many times in forum, overactivation or constant activation of the Nrf2 antioxidant system can potentially contribute to various diseases, including certain types of cancer, autoimmune, neurodegenerative, and cardiovascular diseases – so I am cycling corresponding block of supplements between training and resting days;
besides that, antioxidant supplements interfere with skeletal muscle adaptation to exercise training - so → only on resting days
Resting days with intermittent mTOR inhibition – once weekly/biweekly:
Intermittent mTOR inhibition: rapamycin according to individual dosage
Blood sugar optimization (Alphaglucosidase inhibitors, GLT-2 inhibitors, metformin): acts synergistically to rapamycin, but interferes with workout (so → resting day)
I’m reaching out to the community for feedback on this approach. I would greatly appreciate if you could comment on or particularly critique specific points, or add your insights on your combinational strategy.
I am trying to integrate rapamycin and metformin therapy with training, but I have found that I need to think in terms of weeks rather than days. When I take rapa and met my lifts plateau or go backward. If I abstain from r and m for two weeks I get a growth spurt. Weight training remains my primary exercise during the winter, but I will be back on the bicycle in late February. Hard intervals on the bike also make my lifts go backwards, but vo2 max is more important to overall health. I am hoping to get a new personal record squat this coming weekend. (only 230 lbs but it is still an accomplishment) If that occurs I will resume rapa and met, lose weight, and get weaker for a few weeks. Rinse and repeat. I seriously doubt that these cycles are best for longevity.
This is how it is supposed to work. That is why i go for infrequent rapamycin use. To really have an effective synergy you need a mechanistic hypothesis to start. I think people know mine now. I continue searching for metrics to use to identify what works.
@SilentWatcher I like how your mind works. I am also pursuing a cyclic schedule for my interventions.
Fortnight— rapa and metformin
Weekly — chemical fasts and food fast
24 hours — hard training / growth stimulus AMPK down/ mTOR up) and then moderate cardio, low protein, calorie restriction (AMPK up / mTOR down)
Circadian— follow the sunshine. Use bright lights, HRV biofeedback, etc to get good sleep and be energetic during day.
Thank you, @Joseph_Lavelle for your detailed response. It’s really clarified for me the need to alternate between cardio and weight training, especially when considering the AMPK and mTOR pathways. This insight has gotten me thinking more about adjusting micro/macro-nutrients on workout days:
On days with weights lifting: supplementation of creatine and beta-alanine, with “increased” protein intake for leveraging mTOR activation?
For cardio days: “normal” protein intake with something to boost AMPK activation (running at fasted state?)?
This is turning into a fascinating topic all on its own .
Also, loved your point about the circadian rhythm. Makes total sense to align workouts and eating with our body clock.
It’s discussions like these that make our community such a valuable resource for learning and growth.
@SilentWatcher It’s a work in process. Just to be clear, I shift the BCAA / full EAA / calorie surplus to the post weight training 24 hours rather than the same “day”. This is particularly important since I lift in the afternoon or evening.
I also go light on protein on the AMPK “days”, just to cycle the other effects of protein such as IGF-1. I also emphasize mTOR inhibitors here as well, such as Circuman and berberine.
Is anyone using acarbose and rapamycin in combination rather than metformin / berberine? Good evidence in the ITP at least for acarbose and often better tolerated…
Yes, many of us here use Rapamycin + Acarbose. Some utilize Rapamycin + Metformin. Others, like myself, use all 3 and yet I still have decent blood sugar levels. If you overdose metformin, it can induce hypoglycemia. I know from personal experience.
Personally, I really like supplementing the amino acids - Glycine, Cysteine (NAC), Taurine and Citrulline. They have a very safe profile and they improve my mood and sleep dramatically. They are also quite inexpensive. Considering we also run a deficit in these amino acids as we age, supplementing them seems like a no brainer. However, if you have an allergic reaction to one, you should discontinue it. For instance, I am allergic to beta-alanine.
This is a very sensible approach. I think the underlying issue is that longevity and health-span can in some degree conflict with increasing muscle mass which might benefit from unbridled high levels of IGF1.
A cyclical approach, individualized where there is mTORC1 inhibition and only a bit of mTORC2 inhibition with a good period of no inhibition seems to improve muscular development to an extent. I however doubt that if building muscle mass is your goal (with no consideration of life-health-span) that this would be the strategy.
Incidentally, we have switched to acarbose from metformin and will need to track our c-peptide, fasting insulin levels and HbA1C in 3 months. I suspect this is a kinder agent and may have some advantages for athletes.
Interested in other opinions.
Cycling between anaerobic regime AMPK down / mTOR up (alongside with hGH, pushed naturally) and aerobic regime AMPK up / mTOR down seems very interesting (respect to @Joseph_Lavelle for bringing food for thoughts here).
Regarding acarbose, I find it particularly promising but tend to use it selectively. On workout days, I prefer to rely on slow carbohydrates to fuel my muscles without causing significant glucose spikes. This approach allows me to maintain energy levels during exercise without the potential drawbacks of acarbose, which I believe could negatively impact my workouts. Therefore, I reserve acarbose for my resting days.
On the other hand, while metformin has its own set of considerations, I still find it interesting, especially when used in conjunction with rapamycin. The synergistic effect of metformin-rapamycin combination could be beneficial, yet as you’ve pointed out, metformin might have a negative impact on workout performance (hence, I prefer to take this combination only on resting days without workout). Besides that: after introducing metformin at rapamycin day, I have mitigated side effect of “destabilizing fasting glucose”, which I have personally experienced after rapamycin administration (@DeStrider, thank you for inspiration here).
This strategy appears to effectively harmonize the pursuit of longevity with the goals of muscle development and maintaining optimal VO2max, ultimately contributing to enhanced overall longevity.
Excellent points and approach.
I’m wondering in regard to timing on increasing HGH which should activate MTORC2 I believe - and please correct me if I’ve got this wrong - but I’ve wondered what experiences people have with inhibition of MTORC1 (e.g. use of Rapamycin) while simultaneously stimulating MTORC2 with HGH. This situation could never occur in nature generally, but I’m sure there are a number of people doing this.
What is everyone’s assessment of logic for doing this or avoiding this, and the timing of the 2 agents if you are going to use them.
For example, during the 72 hours after taking Rapamycin, hold doses of HGH to allow a true unopposed MTOR1 affect, and then until next dose of Rapamycin take HGH (or other secretagogue) to build back stronger with activation of MTORC2.
I’d love to hear some thoughts and logic behind approach on this issue?
MTORC1/MTORC2: subjective opinion: while MTORC1 and MTORC2 have distinct roles, there is a level of interplay between these pathways. MTORC1 primarily regulates protein synthesis and autophagy, while MTORC2 is involved in cell survival, cytoskeletal organization, and metabolism. There is significant cross-talk between MTORC1 and MTORC2. Inhibition of MTORC1 can lead to a compensatory activation of MTORC2 and vice versa. This interplay is part of the body’s mechanism to maintain cellular and metabolic homeostasis. When you disrupt this balance, such as by inhibiting MTORC1 with rapamycin, it could potentially lead to a compensatory or exaggerated response in MTORC2 activity, especially when further stimulated by exercises like HIIT.
Context of hGH, mentioned above: It’s important to note that the hGH discussed above is the natural surge post-exercise, not synthetic injections. This distinction is crucial because the natural release of hGH due to anaerobic exercises like resistance training is a physiological response with potentially different effects and implications than exogenous hGH administration.
Food for thoughts in terms of practical advice: The idea of postponing anaerobic training until rapamycin levels have sufficiently decreased (48 hours? 76 hours?) is a sound one in light of consideration above (activating MTORC2 and inhibiting MTORC1 might send conflicting signals within the cells, leading to unpredictable or less understood cellular responses). This approach allows for a period where MTORC1 activity is inhibited without overlapping with the activation of MTORC2, which is stimulated by anaerobic exercises.
You somewhat mirror my thoughts on this. The issue remains a lack of evidence, and acting on theory. Unfortunately, we often make errors when we think we understand mechanism and activity as to how things actually play out.
As someone who advises patients and prescribes, it is a real challenge, and there is obviously “shared decision making” that occurs. There is no option.
So we (my wife and I) took our Rapamycin on the 20th, and from my perspective, I think things that stimulate MTORC2 should not be pursued vigorously until at least 72 hours there after. We’ve opted for an 8 day cycle, and might go to a 9 day cycle.
So for folks who inject HGH or something that stimulates secretion of HGH, I’d say likewise, hold the dose of those items for 72 hours post Rapamycin - but this is my theoretic approach to this issue.
There is marginal evidence from the TRIIM trial that maybe a year or more of HGH with other agents might be good and regenerate the Thymus and T cells. Impressive MRI’s on that paper. However, HGH seems to also have a lot of risks (including the wallet biopsy for payment) and it might create risk of other health issues.
But can you get an even better outcome with cyclic MTORC1 inhibition then activation of MTORC2?
This is the question in my mind and a question in how we personally manage our longevity regimen, which often times has to be separate from how I advise patients, as I must be more conservative - but flexible.
I am in the land of melatonin hectodoses (not really megadoses and perhaps more so decidoses). Melatonin is thought to stimulate the production of HGH.
I am probably one of the least frequent users of Rapamycin at a maximum frequency so far of 21 days, but I have not thought to vary melatonin usage around Rapamycin dosing.
Several months later, I’m still contemplating what you wrote, @Joseph_Lavelle
I’ve been experimenting with berberine on days when I focus on cardio and AMPK activation. This leads me to wonder about the necessary duration for berberine to start influencing AMPK. Given that the half-life of berberine is approximately 5 hours, but its effect on glucose levels only becomes apparent after a month of supplementing, what does this imply for its timing for AMPK pathway? Should we begin taking berberine a day (or days) before our cardio-focused days to amplify effect on AMPK? Any thoughts on that in absence of any in-vivo evidence?
@SilentWatcher it is clear you have moved beyond me in your thinking about this. I will watch for your findings. I’ll say that I doubt the berberine and curcumin supplements have a large effect on mTOR. The big mTOR levers for me are the rapamycin, exercise and type, staying below or above the mTOR threshold of leucine (volume and quality of protein), and insulin (volume and type of food plus good sleep and stress management). The rest is on the other side of the 80/20 equation, but I’m always interested in learning more about easy to implement tactics.
A new element for me is I’ve started lifting in the early AM, and the next morning I fast until an early dinner, after which I do easy cardio. This is designed to increase the variation of diet based stimulus of mTOR.
@Joseph_Lavelle, thank you for your comment(s). I don’t believe I am much further ahead. However, after considering your feedback and that of @DrFraser, the following strategy came to my mind, which I am now pursuing.
GlyNAC supplementation: Aims to regulate glutathione homeostasis, potentially without disrupting the body’s natural response to training.
Training Days with Anaerobic Sessions (weight lifting):
Elevated protein intake on the day of and the day after training: This strategy is key for activating mechanistic target of rapamycin complex 2 (mTORC2), amplifying effect of strength exercise, leading to an automatic increase in IGF-1, which is crucial for muscle building.
GlyNAC supplementation: As above, it helps in managing glutathione levels without negatively impacting the training response.
Rest Days (days without training) – 2-4 times a week:
NRF-2 activators: Including Sulforaphane, Moringa, Astaxanthin, Lutein, Zeaxanthin, and Ashwagandha, these compounds are known for their role in oxidative stress management and overall cellular defense mechanisms.
Rest Days with mTORC1 Inhibition – once every two to three weeks:
Intermittent mTORC1 inhibition: Utilizing rapamycin in individually tailored dosages to intermittently inhibit mTORC1.
Training pause: Avoid training 1-2 days after dosing to prevent interaction between mTORC1 and mTORC2 pathways.
Blood sugar optimization/AMPK activation: administer Metformin 1-2 days before and after the rapamycin dose. The glucose-regulating effects of Metformin become significant only after three days of administration.
My current schedule: aerobic session day / rest day / anaerobic session day / rest day …
Looks great. Perhaps consider that easy (zone 0-1) aerobic workouts do not require recovery or a rest day. They ARE the rest day (active recovery). They also help lower blood glucose after a meal, and get you out of sympathetic activation (stress mgmt). I try not to have any days with no movement; it means I have to be careful not to beat myself up too much in any workout (HIIT workouts are short). I even when I feel very sore, and long warmup can bring me around to get a nice and easy spin. Good luck.
On your anaerobic training days I would add 5g creatine pre workout and 6g taurine + 2g AKG intra-workout. All relatively inexpensive and with proven health benefits. Here 's an article about taurine;
Good point, @Joseph_Lavelle .That supports a point, that the regulation of metabolic pathways, such as mTOR (mechanistic target of rapamycin), AMPK (AMP-activated protein kinase), IGF (Insulin-like Growth Factor), NRF2 (Nuclear Factor Erythroid 2–Related Factor 2), and several others pivotal for longevity, relies more significantly on appropriate physical stimuli rather than solely on pharmacological interventions and magic pill.
This doesn’t imply that more physical activity is necessarily better. But, for instance, for my personal observation (n=1), a 30-minute walk after lunch (slow carb meal) can reduce the postprandial glucose peak comparably to the administration of 50mg of acarbose, highlighting the potent physiological impact of moderate exercise.
Interesting article about taurine, thank you, @Ludovic .
Unfortunately, I am the one experiencing insomnia after creatine supplementation, and currently, I have no definitive explanation. My understanding is that supplementing with creatine spares the body’s production of S-adenosylmethionine (SAMe), a crucial methyl group donor involved in various bodily functions, including the synthesis of creatine. Since over 40% of SAMe is used to synthesize 1-2g of creatine daily, supplementation can lead to elevated levels of SAMe, which is associated with insomnia in some individuals. Additionally, creatine acts as an adenosine agonist. Adenosine plays a vital role in sleep regulation, and its signaling pathways can influence sleep patterns. Unfortunately, I have not been successful in mitigating these effects with glycine and niacin.
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