What is the ideal IGF-1 level for longevity?

[mccoy]

Just to make things even more confused (although Valter Longo seems to make it simple). I'll have to read the article at least a dozen more times, but it seems to make the point that the ideal IGF-1 range for longevity is 120-160 ug/ml.

The data are inhomogeneous and very variable, the method is everything but clear, either the authors are statistical geniuses or they stretched the data pretty far. Maybe I just need to read and re-read it until it makes some sense.

Association between IGF‐1 levels ranges and all‐cause mortality: A meta‐analysis

[mccoy]

OK, I'm going to make a stab at it. The following figure seems to show that there is no difference in HR among the highest ad the lowest amounts of circulating IGF-1. HRs are in a log scale.

 

[mccoy]

This other figure is would seem not very useful since it has such wide uncertainty bands (95% confidence) but it would suggest a U curve in all-cause mortality HR versus IGF-1 concentrations in blood. The optimum would lie into the 140 +- 20 ng/ml (120-160 interval). In this interval, the uncertain bands are also more narrow.

[IgorF]

This https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349399/

study was included in a dedicated book on IGF https://www.mdpi.com/journal/cells/special_issues/Insulin_Like

Authors there describe their motivation like:

 

Quote

First, the activity of the GH/IGF-1 axis and levels of circulating IGF-1 are affected by acute [31] and chronic illness [32]; this introduces the possibility of “reverse causation” in some studies conducted in high-risk populations [25]. Second, numerous epidemiologic studies investigated associations between IGF-1 and morbidity and mortality in cohorts with wide age-ranges under the assumption that the effect of IGF-1 would be similar in younger and older adults [33,34]. Furthermore, total IGF-1 does not represent bioavailable IGF-1 [21]: Almost all circulating IGF-1 is bound to six IGF-binding proteins (IGFBP-1-6), leaving <1% of IGF-1 in a free form, bioavailable to bind to its receptors [35]. In addition to providing a long-lasting pool of circulating IGF-1, IGFBPs closely regulate biological functions of IGF-1 through controlled inhibition and promotion of IGF-1 interactions with its receptor [36]. Since measuring free IGF-1 remains challenging [37], the molar ratio of total IGF-1 to IGFBP-3, the most abundant IGFBP in circulation, is commonly used as a proxy for bioavailable IGF-1 [21]. Finally, other elements of the GH/IGF-1 system, including IGFBP-3 and IGFBP-1, have been implicated in human disease and survival, independent of IGF-1 [38,39]. Therefore, our aim was to prospectively investigate the associations between several components of the GH/IGF-1 pathway, including total IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1, with mortality and incidence of major age-associated diseases in a cohort of independently-living older adults with majority in general good health at enrollment.

As for me it looks like "too many moving parts" to derive any conclusion about optimality levels, the context in its strongest part is like - some people with exceptional longevity have naturally low activity of gh/igf axis but it seems very unlikely that our current understanding and tooling could anyhow mimic this thing. Simple decrease with low protein diet perhaps will make it low and maybe even not only igf1 in the tests but all these more complex ratios but will it make any difference on the functional side?

 

EDITED TO ADD:

"moving parts" in the aging mitochondria topic, the same book

https://www.mdpi.com/2073-4409/9/6/1384

Quote

Finally, it is widely accepted that GH/IGF-1 are involved in cell senescence and apoptosis.
The molecular mechanisms involved in GH/IGF-1-mediated cellular senescence are still poorly
understood. Both hormones exert a dual function and promote, on one hand, cell proliferation and,
on the other hand, cellular senescence. Therefore, it is conceivable that the dose and duration of
GH/IGF-1 exposure might regulate senescence, and that the effects of GH/IGF-1 on senescence are tissue-
and cell type-specific.

AFAIR it was mentioned in many places about "locality" of IGF in people demonstrated exceptional longevity - it seems worked "just enough time to do the main job and no longer" or something like that, don't remember the exact formula.

Edited August 10, 2023 by IgorF

[mccoy]

1 hour ago, IgorF said:

As for me it looks like "too many moving parts" to derive any conclusion about optimality levels,

I agree, on top of free IGF-1 and IGFBPs there is also the IGF1R (receptors) issue, that is a lack of receptors may decrease the signal of high IGF-1 and vice versa.

It remains a fact that most longevity experts seem to agree that IGF-1 is the single most powerful parameter which governs longevity (cited by Valter Longo, I must find the article on that poll). So, the topic apparently deserves a high degree of attention.

The possibility to develop viable IGF-1 antagonists which bind to the IGF-1 receptors is definitely a very interesting hypothesis  which has been hinted at in the article you posted:

Quote

In conclusion, our findings indicate that higher IGF-1 levels and/or bioavailability are predictive of mortality and morbidity risk. These results support the hypothesis that diminished signaling via GH/IGF-1 pathway may contribute to longevity and health-span in humans. If the detrimental effects of high IGF-1 signaling in older adults are confirmed by larger studies with longer follow-up time, then the GH/IGF-1 pathway may represent a promising target for therapies that delay aging. A monoclonal antibody that targets IGF-1 receptor (IGF-1R) and decreases IGF-1 signaling has already been shown to increase health-span and lifespan in middle-age female mice [96]. In fact, several FDA approved drugs that inhibit GH/IGF-1 signaling are currently in clinical use for other indications. For example, pegvisomant, a growth hormone receptor antagonist, is used for normalizing IGF-1 levels in acromegaly [97] and teprotumumab, which antagonizes IGF-1R, is used to treat thyroid eye disease [98]. These drugs could be readily repurposed for slowing aging in clinical trials. 

 

[mccoy]

By the way, simon hill in his podcast made two recent (2022) interviews with Valter Longo, in great part dedicated to IGF1. Valter tends to simplify the issue, concentrating on total IGF1 and, in the Q&A episode, suggesting that values over 180, definitely over 200 ng/ml may be too high and result in some countermeasures. The cutoff for a full-fledged disorder (acromegaly) is in the region of 300-350 ng/ml. Perhaps Valter stresses too much the protein/EAAs factor. In presence of optimal values of IGF1, who minds about the amoutn of protein ingested? In teh AMA episode he seems set aback by the fact that Simon Hill has a IGF1 around 150 ng/ml and eating significant protein. He concludes that EAAS actually govern IGF-1 concentration and that probably the vegan diet of Simon hill is not too detrimental in this respect. personally, I had a very low (91 ng/ml) total IGF-1 when practicing a diet rich in dairy products, so there is not an absolute truth in the protein aspect. There may have been other confounding factors, my priority now is to have another measurement of total IGF1, maybe pairing a IGFBP measurement with it, while continuing to practice a diet rich in healthy dairy products.

 

 

[mccoy]

From the previously linked Rahmani et al. article, the relationship between food and IGF-1. Please note that IGF-1 is sensitive not only to protein but also to carbs concentration in the blood. The table 2 published is not too clear, are those average concentrations of IGF1 in the respective quintiles, why are they so high and why do they differ so little from the 1st and 5th quintiles? I don't know you guys, but I would guess from the table that all the nutrients listed elevate IGF1, no matter what, with little difference among the averages. Maybe the results should be exhibited in a different way.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844108/

 

2.6. Epidemiological diet study

Because nutrition is perhaps the most relevant modulator of IGF‐1 levels (Key, 2011; Levine et al., 2014; Watling et al., 2021), third national health and nutrition examination survey (NHANES III, 1988–1994) data were used to investigate the relationship between IGF‐1 and the daily intake of specific nutrients. The study population included 1152 men and 1453 women. Mean age of participants was 45.11 ± 17.97 years.

Mean serum IGF‐1 concentrations increased in subjects reporting a higher protein or carbohydrate intake (p‐value = 0.007). The intake of vitamins and minerals was also associated with higher IGF‐1 levels (Table 2A,B). We next determined the type of food whose consumption was correlated to circulating serum IGF‐1. High consumption of dairy products including milk, cheese and yogurt, and margarines was associated with increased IGF‐1 levels in agreement with previous studies, while high consumption of butter, eggs, and egg products was associated with decreased levels of IGF‐1 (Giovannucci et al., 2003) (Table (Table2C2C).

 

Edited August 16, 2023 by mccoy

[mccoy]

Table 2 in rahmani et al. article. OK, maybe I figured out the meaning. They are reporting the differences in IGF1 with 1st and 5th quintiles of specific nutrients. But it remains a little unclear, how did they separate the subgroups, maybe 'plant proteins' refers to vegans only? My first conclusion is that averages are really not that much different, always too high according to Longo, what do you guys think about it. Here I'm pasting only one part of the table

[IgorF]

Hm,

two small studies amongst others similar shows a small but significant correlation between egf1 and glucose tolerance

https://link.springer.com/content/pdf/10.1007/s13258-021-01209-6.pdf?pdf=button sticky

https://journals.viamedica.pl/clinical_diabetology/article/download/DK.a2022.0002/65532

The first one is interesting because it has several blood markers together which allows to guess more on people involved in the study. The second one is curious because it shows correllation with vitD (but for vitD ancestry is a huge factor, maybe other ancestries will not show such).

While sizes are small and for such a crossroad thing like igf1 there is probably impossible to design a good study with control for everything that matters, my guess is that a correlation of igf1 and glucose metabolism impairments are something that mangles the data in a large scope all cause mortality data grinding. In other words - for people without known to be bad glucose issues it could be the case that lower igf1 could be beneficial and some rationale regarding this exists (e.g. - we do not want it to be available active everywhere all the time which will happen implicitely due to higher levels).

But the ground of such topics is probably not possible to be generalized - crossroads things are known to be dependent on the flux intensity in many cases due to more complicated math describing their operations (closer to saturation they are more prone to create problems but there is no way we can calculate individual saturation levels for such a complex system as metabolism of a dedicated person).

Br,

Igor

 

[IgorF]

Some interesting remarks on igf topic and possibilities to extrapolate observations (and hypotheses on mechanisms) from more simple organisms on human cases

https://books.google.com/books?id=nVh7DwAAQBAJ&pg=PA650&lpg=PA650&dq=As+aconsequence,+in+humans,+caloric+restriction+may+have+become+disassociated+from+factors+controlling+longevity,+with+factors+linkedto+human+longevity+no+longer+simply+associated+with+caloric+restriction.&source=bl&ots=QFoQZI5AMF&sig=ACfU3U17-ZWa58CjMVWNOtyleMVa3zbhpw&hl=en&sa=X&ved=2ahUKEwjLm9Xv39yAAxW9FRAIHRocDxwQ6AF6BAgHEAM#v=onepage&q=As aconsequence%2C in humans%2C caloric restriction may have become disassociated from factors controlling longevity%2C with factors linkedto human longevity no longer simply associated with caloric restriction.&f=false