Well, I think the evidence is that IGF-1 is downstream of mTOR so when we take rapamycin we are also inhibiting IGF-1. So I think even with current rapamycin protocols we are getting some of this benefit of lower IGF-1/GH on a pulsatile basis.
It would be interesting to test IGF-1 levels over the rapamycin dosing cycle to see what the exact impact is… if anyone tries this, please report back. IGF-1 testing is pretty cheap - I think about $35 from some of our regular blood testing sites mentioned frequently here.
I wonder why you recall the evidence that IGF-1 is downstream of mTOR. It surely is one of the upstream signals, the insulin/IGF-1 signal, through the PI3K/Akt pathway.
We might envisage however some downstream signal resulting in an inhibitory effect on the production of IGF-1 in the liver, but according to interrogations to a couple of AIs, it seems not the case, on the contrary, it would seem that there may be an opposite effect. Here, Deepseek was very detailed.
Please tell me if mTOR inhibition by rapamycin can have some effects on circulating plasma IGF-1
Yes, rapamycin-mediated mTOR inhibition can increase circulating plasma IGF-1 levels, despite mTOR being a downstream effector of IGF-1 signaling. This counterintuitive effect is well-documented in both preclinical and clinical studies. Here’s a breakdown of the mechanisms, evidence, and implications:
1. Key Evidence
Animal Studies:
In mice/rats, rapamycin consistently elevates plasma IGF-1 by 20–50% after acute or chronic treatment.
Example: A 2020 study (Aging Cell) showed a 36% IGF-1 increase in aged mice after 3 months of rapamycin.
Human Data:
Renal transplant patients on rapamycin (sirolimus) exhibit higher serum IGF-1 vs. those on other immunosuppressants.
Healthy adults in trials (e.g., Science Translational Medicine, 2014) show similar trends, though effects vary by dose/duration.
2. Mechanisms Behind the Increase
The rise in IGF-1 occurs despite mTORC1 inhibition, primarily due to compensatory feedback loops:
Mechanism
Description
Growth Hormone (GH) Surge
Rapamycin disrupts mTORC1-mediated negative feedback on the hypothalamus/pituitary, leading to increased GH secretion → stimulates hepatic IGF-1 production.
Reduced IGF-1 Utilization
Tissues (e.g., muscle, liver) may develop transient resistance to IGF-1, reducing its clearance from circulation.
Hepatic Adaptation
Liver cells increase IGF-1 synthesis to counter perceived “insufficiency” from blocked mTOR signaling.
3. Paradox: IGF-1 Elevation vs. mTOR Blockade
While IGF-1 levels rise, rapamycin still inhibits IGF-1’s downstream actions:
Tissue-Specific Effects:
mTORC1 inhibition blocks IGF-1 signaling in peripheral tissues (e.g., muscle, fat), even with elevated plasma IGF-1.
Functional Decoupling:
The bioactivity of IGF-1 may be reduced due to altered binding proteins (e.g., IGFBP-1/2 upregulation).
4. Implications for Longevity & Disease
Aging Research:
Rapamycin extends lifespan in model organisms despite raising IGF-1. This challenges the dogma that low IGF-1 is universally pro-longevity.
Elevated IGF-1 may support maintenance of metabolic/immune functions in specific contexts.
Cancer Risk Concerns:
High IGF-1 is linked to tumor progression, but rapamycin’s direct anti-tumor effects (e.g., angiogenesis inhibition) likely offset this risk.
Metabolic Effects:
Increased IGF-1 could theoretically aid glucose regulation, though rapamycin often induces insulin resistance.
5. Final Comment
Rapamycin reliably increases circulating IGF-1 due to disrupted feedback loops, but this does not negate its therapeutic benefits. The dissociation between IGF-1 levels and signaling highlights the complexity of hormone-mTOR crosstalk. In aging or disease contexts, mTOR inhibition’s net effects (e.g., reduced inflammation, enhanced autophagy) appear to outweigh theoretical risks from elevated IGF-1. However, long-term human data are still evolving, and individualized risk assessment remains crucial.
Sources:
Cell Metabolism (2014): Feedback loop between mTOR/S6K1 and GH/IGF-1.
I don’t know if there is a camp that specifically suggests targeting IGF-1 reduction, maybe proponents of Caloric Restriction, maybe some vegan doctors like Dr. Greger or others. But apparently the issue is more complicated, since reduction in systemic IGF-1 may not be coupled to reduction in tissues, and the above providing that total IGF-1 is sufficient as a parameter or it is necessary to evaluate its binding proteins as well.
In my n=1 case, I have chronic (probably epigenetically induced) lowish IGF-1, in the range of 90-100 ng/mL, but muscle mass is not low, on the contrary it takes little exercise to me to induce hypertrophy. Evidently, there are more mechanisms in action, like the local IGF-1 release in muscle tissues induced by resistance exercise (paracrine regulation).
Again, I’m posting the outlook provided on the specific aspect by Deepseek R1, that seems pretty reasonable.
can you please detail the relationship among circulating IGF-1 and local IGF-1 in muscle, bone and nervous tissues
The relationship between circulating (endocrine) IGF-1 and locally produced (autocrine/paracrine) IGF-1 in tissues is complex and tissue-specific, involving distinct regulatory mechanisms and functions. Below is a detailed breakdown for muscle, bone, and nervous tissues:
1. Muscle Tissue
Circulating IGF-1
Source: Primarily liver-derived (endocrine).
Role:
Maintains basal muscle mass and metabolic homeostasis.
Activates systemic growth via PI3K/Akt and mTOR pathways.
Actually, although I do not suffer from myopenia, Presently my tendons, ligaments and joints tend to ache after exercise. It seems though that the subset of connective tissues is maybe the least influenced by systemic IGF-1, being governed by the expression of local IGF-1 analogs. Apparently, this local expression starts to fail with age and inflamamtory states.
Deepseek again.
The relationship between systemic (circulating) and local IGF-1 in connective tissues—including tendons, ligaments, fascia, cartilage, and extracellular matrix (ECM)—is distinct from other tissues due to their structural roles, avascularity (in some cases), and reliance on mechanical stimuli. Below is a detailed breakdown:
1. Circulating (Systemic) IGF-1 in Connective Tissues
Roles & Mechanisms
ECM Maintenance:
Systemic IGF-1 promotes collagen/proteoglycan synthesis by fibroblasts and chondrocytes via PI3K/Akt/mTOR signaling.
Supports baseline ECM turnover and prevents degradation.
Hydrogel-embedded IGF-1 injections for cartilage defects.
MGF gene therapy for rotator cuff tears (promising in animal studies).
Systemic modulation:
Rapamycin caution: While ↑ systemic IGF-1, it blunts local IGF-1 action in tendons → risk of impaired healing.
Key Takeaways
Dominance of Local IGF-1:
Mechanical load/stress responses in connective tissues rely primarily on autocrine/paracrine IGF-1 (especially MGF).
Systemic IGF-1 as a “Primer”:
Supports baseline ECM synthesis but cannot replace local signaling for targeted repair.
Pathology Origins:
Diseases arise from imbalances (e.g., systemic IGF-1 excess in acromegaly vs. local deficiency in aging).
Therapeutic Precision:
Treatments must target tissue-specific IGF-1 dynamics (e.g., MGF for tendons, IGF-1Ea for cartilage).
Final Comment
In connective tissues, local IGF-1 is the master regulator of structural integrity and adaptive repair, while systemic IGF-1 provides generalized metabolic support. This explains why serum IGF-1 levels poorly predict tendon/cartilage health (e.g., athletes may have low systemic IGF-1 but high local MGF). Future anti-aging or injury therapies will need to bypass systemic constraints by directly stimulating tissue-autonomous IGF-1 pathways—especially in avascular environments where circulating factors struggle to penetrate.
Sources:
Tendons: Journal of Orthopaedic Research (2021) on MGF; Nature Reviews Rheumatology (2019).
Cartilage: Osteoarthritis and Cartilage (2020) on IGF-1 resistance; Arthritis & Rheumatology (2018).
General ECM: Matrix Biology (2017) on IGF-1/IGFBPs.
Key Clinical Implications
Tissue Repair vs. Degeneration:
Local IGF-1 (especially MGF) is essential for collagen realignment after tendon injury. Its decline in aging explains poor healing despite normal systemic IGF-1.
Systemic IGF-1 cannot compensate for local deficiency in avascular tissues (e.g., cartilage).
Therapeutic Opportunities:
Local Delivery:
Hydrogel-embedded IGF-1/MGF: Promotes cartilage defect repair (clinical trials for osteoarthritis).
I’ve read a lot on this but haven’t dove deeply into the pathways specifically. When you inhibit mTOR in organisms early in life they are much smaller in size… thus the conclusion that mTOR must cause a reduction in GH / IGF-1 levels… see this paper below:
Development is tightly connected to aging, but whether pharmacologically targeting development can extend life remains unknown. Here, we subjected genetically diverse UMHET3 mice to rapamycin for the first 45 days of life. The mice grew slower and remained smaller than controls for their entire lives.
Analogous to mice, rapamycin exposure during development robustly extended the life span of Daphnia magna and reduced its body size. Overall, the results demonstrate that short-term rapamycin treatment during development is a novel longevity intervention that acts by slowing down development and aging, suggesting that aging may be targeted already early in life.
IGF-1 reduction for longevity is one of the best-researched longevity interventions out there (done over the past 20+ years). Here are some past discussions you may want to read:
I find this surprising… (the above statement). ChatGPT seems to refute some of the Deepseek suggestions… see below:
Here is my first prompt:
how does the use of rapamycin in organisms early in life result in smaller body size in these organisms and mammals? What are the biological pathways that are thought to be involved and causal in this relationship?
ChatGPT response:
My second ChatGPT prompt:
Does rapamycin during early life lower IGF-1 and Growth Hormone levels as part of the process by which is reduces body size of these organisms?
ChatGPT response:
Yes, rapamycin during early life can lead to lower levels of IGF-1 (Insulin-like Growth Factor 1), and potentially affect growth hormone (GH) signaling, although the effect on GH itself is more variable and context-dependent.
Here’s how rapamycin influences IGF-1 and GH, and how this contributes to reduced body size:
In mice there are clear benefits to early life IGF-1 reductions and increased lifespan and healthspan as a result. It’s less clear if the IGF-1 is reduced later in life, in the research.
Moreover, growth hormone helps in may instances… in injury recovery, muscle growth, etc. - and many people have been taking it for many years, swear it makes them feel better, and seems to have had little or no increase in cancer risk that we can detect. So - it seems to make “quality of life” improvements when delivered exogenously to older humans, and the downsides are not at all clear, and its not unreasonable for people to say that given the health benefits they perceive, they are making a rational decision to increase their quality of life in the short term even if there “may” be some relatively minor or undetectable decreases in total lifespan…
After researching this over the years, I can see good arguments on both sides, though ultimately I don’t believe that IGF-1 reduction later in life is going to yield much in the way of lifespan benefits (given the animal research I’ve reviewed).
Yes, I confess I was consciously dismissive of many studies, like some you cited, the Laron dwarfs, and so on. The dwarfs are another example of ‘early in life’ IGF-1, I presume.
But then, we have all the graphs showing an optimum value for mortality, which is not very low, in the region of 120 ng/mL, Longo telling us that 140 ng/mL is the optimum value, the ranges varying with age, the role of IGF binding proteins, the role of local IGF-1 versus systemic IGF-1, so the whole picture to me appears much more complex than simply stating that ’ lower IGf-1 is good for longevity’. so the context maybe is lower, but in relation to some suggested range.
Should I heed the literature, I should target an increase in IGF-1 since I sit below the optimum value.
While it’s true that mTORC1 is a downstream node of the IGF-1R’s canonical PI3K/Akt arm, it’s also true that the liver produces something like 70-80% of circulating IGF-1. If mTORC1 inhibition attenuates hepatic IGF-1 mRNA translation—which is plausible given that mTORC1 promotes cap-dependent translation, the manner in which the vast majority of mammalian mRNAs are translated—then systemic IGF-1 would be considered downstream of hepatic mTOR activity.
Here’s some evidence (in pig neonates) that rapamycin attenuates the feeding-induced stimulation of hepatic protein synthesis:
Although I also found some data in rats that the textbook picture is not appropriate in the liver, as although rapamycin inhibited phosphorylation of both S6 and 4E-BP1, it appeared that cap-dependent translation was insensitive to rapamycin. Instead, rapamycin selectively inhibited translation of rRNAs/ribosome biogenesis, and that this was the process downstream of mTOR governing the liver’s overall capacity for protein accretion.
In mice there are clear benefits to early life IGF-1 reductions and increased lifespan and healthspan as a result. It’s less clear if the IGF-1 is reduced later in life, in the research.
I agree that the consequences of elevated GH and/or IGF-1 in adulthood are an open question. Certainly they possess acute benefits, but perhaps are deleterious when elevated in the long-term. Or are the lifespan increases seen in transgenic GH and IGF-1 mice strictly due to developmental effects? Is this latter statement even meaningful?
For what it’s worth, the GH KO mice generally show even larger lifespan increases. IGF-1 is of course downstream of GH, but the GH receptor’s intracellular cascade has itself been linked to insulin resistance. See, for example, Effects of growth hormone on glucose metabolism and insulin resistance in human. The longest-lived lab mice (1,819 days) was a GHR KO:
That was a lot of reading and I’ll admit I did not read all of it, but a question comes to mind in spite of my ignorance. If Rapamycin causes a rise in IGF-1 by rebound effect or whatever other effect, that is detectable with a blood test for IGF-1, does that increased IGF-1 in the bloodstream have anything to do directly with the actual amount and action of IGF-1 throughout the rest of the body for someone who takes intermittent rapamycin? A medical person would probably say “that’s a dumb question?” But, I’m not a medical person. I’m just curious.
I surely agree, but that’s why I asked Admin why he called IGF-1 downstream when by definition it’s an upstream regulator of mTOR. And the possibility of a downstream effect on IGF-1 synthesis does come to mind when contemplating such a complex networks of signaling that also involves feedback mechanisms.
Also, by definition IGF-1 is an upstream signal in the mTOR mechanism, but this upstream signal may well be affected by other upstream signals, or medical intervantions dimming the activity of mTOR. In the hypothesis you cite, the pharmacological intervention of Rapamycin would attenuate mRNA translation in the hepatic cells responsible for the synthesis of IGF-1 if I understood well.
The same would be true for lifestyle interventions, like CR.
So, just to clarify the picture, let’s hypothesize for the sake of discussion an individual with a plasma with an IGF-1 concentration of 200 ng/mL (in homeostatic conditions).
If we act on the homeostasis by a perturbation factor (which may be Rapa, or CR, or any other intervention), downregulating mTOR, the synthesis of IGF-1 would be downregulated and this would provide a weaker upstream signal to mTOR, until a successive steady state condition or homeostatic level is reached (form example, a concentration of 150 ng/mL).
However, as in one of my previous posts, the literature seems to suggest that different mechanisms trigger a counterintuitive increase in circulating IGF-1. Some of the mechanisms have been illustrated in one of my previous posts. The literature also underlines that Rapa may still cause an mTOR blockade in the presence of higher IGF-1 systemic signaling for different reasons.
The takehome to me is that this is a pretty complex system with multiple interactions and that the overall effect on longevity must be determined by a very articulate conceptual framework, simply saying that lower IGF-1 is advantageous to longevity would seem too simplistic in consideration of the above complexities.
It’s not a dumb question and I myself am in search of plausible clarifications to this complex issue.
Probably, your question should be answered by examining every single tissue or cells.
For example, the muscle tissues are governed by local IGF-1, induced mainly by exercise.
The connective tissue seems to be very little sensitive to circulating IGF-1, whereas the bone tissue seems to be more sensitive than muscles to systemic IGF-1.
Then there are the nervous tissue, the immune system, and so on and so forth. Everyone with its peculiar response to systemic IGF-1.
Circulating IGF-1 still is a main systemic supplier of growth signal, supplying a baseline flow of ‘material’, but the signal is apparently mediated by the foremen, the local IGF-1 amounts present in local tissues and systems, in a more or less strong influence.
On further thought, the answer to your question would be an obvious and simple one.
When The rapamycin-FKBP12 complex docks onto the FRB domain (FKBP12-Rapamycin Binding domain) of mTOR (specifically within mTORC1), downregulating it by allosteric inhibition, that happens downstream from the sites of IGF-1 action (the IGF-1/Insulin receptors).
As a consequence, any increase (or decrease) in circulating IGF-1 would be theoretically irrelevant.
The consequences on local IGF-1 of an intermittent dose plausibly are temporally limited to the peak (greater allosteric inhibition);
when the rapamycin peak in plasma subsides, then the effects of the local isoforms of IGF-1 (and to a more or less extent the effect of the systemic IGF-1) return to a modified steady-state (a homeostatic condition with a rapamycin background), when no perturbations are present.
