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Gordo

What is the ideal IGF-1 level for longevity?

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As I wrote in another thread, My IGF-1 turned to be pretty low, 90 ng/ml at age 60. My protein intake is pretty significant, often RDA+30% and higher, with dairy proteins rich in methionine.

So it is the reverse of what it should be according to theory. 

My total testosterone instead turned out to be pretty high, almost at the upper bound of the interval for my age.

Edited by mccoy

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3 hours ago, mccoy said:

So it is the reverse of what it should be according to theory. 

Well,  a lot of factors determine IGF-1 levels apart from protein intake.   Besides, there's still the issue of IGF-1/IGFBP-3 ratio  / IGF-1 bioactivity.  Re-reading this thread I find there are a lot of open questions-- hard to make sense of it all.

Edited by Sibiriak

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Sorry Sibiriak, McCoy --  I read some of my old posts and found that across the board most of the historical posts were at a minimum amateur, poorly cited, and low in quality, or else worse incomplete, inaccurate, or outdated.  I was concerned that maintaining it could lead to misappropriation of information and potentially harm.  As my knowledge base has expanded substantially I now hold myself to a new standard.... I felt it better for the board to repopulate with more newer, more timely, and accurate information than to maintain information that potentially may lead others astray.  Information can change, but qualifications, citations, etc. can at least be supported and appropriately qualified, as I now feel is an appropriate standard for a semi-permanent medium.  Preferences for discourse can change too - recall Dean used to have an active link to his biomarkers which was subsequently removed.  I respect this personal choice, and can understand.  Ultimately though, given the voluminous nature, it was more realistic to systematically remove than curate individually - this was the only way to ensure it was systematic and provide confidence I would not be negligent in my intention. 

Thank you for understanding - I regard the posts by MR and Dean to be the closest to a gold standard here, with lots of excellent contributions worthy of evergreen status by others throughout the community.  Not all is lost.  I am happy to provide helpful info - please PM me if I can help with anything.

Best,

Mechanism.

Edited by Mechanism

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The following article on the relationship between IGF-1 levels,  glucose metabolism,  fat utilization  etc. during fasting  raises a lot of very interesting issues.  (Forgive me if it's been posted and discussed elsewhere.)    I highlighted some key points  in the discussion,  and I'd like to hear what others think of  their significance.

 

Low Circulating Levels of IGF-1 in Healthy Adults Are Associated With Reduced β-Cell Function, Increased Intramyocellular Lipid, and Enhanced Fat Utilization During Fasting

 
Quote
Context: Low serum IGF-1 levels have been linked to increased risk for development of type 2 diabetes. However, the physiological role of IGF-1 in glucose metabolism is not well characterized.
 
Objective:  Our objective was to explore glucose and lipid metabolism associated with variations in serum IGF-1 levels.
 
Design, Setting and Participants:  IGF-1 levels were measured in healthy, nonobese male volunteers aged 18 to 50 years from a biobank (n = 275) to select 24 subjects (age 34.8 ± 8.9 years), 12 each in the lowest (low-IGF) and highest (high-IGF) quartiles of age-specific IGF-1 SD scores.
 
Evaluations were undertaken after a 24-hour fast and included glucose and glycerol turnover rates using tracers, iv glucose tolerance test to estimate peripheral insulin sensitivity (IS) and acute insulin and C-peptide responses (indices of insulin secretion), magnetic resonance spectroscopy to measure intramyocellular lipids (IMCLs), calorimetry, and gene expression studies in a muscle biopsy.
 
Main Outcome Measures:  Acute insulin and C-peptide responses, IS, and glucose and glycerol rate of appearance (Ra) were evaluated.
 
Results:  Fasting insulin and C-peptide levels and glucose Ra were reduced (all P < .05) in low-IGF compared with high-IGF subjects, indicating increased hepatic IS. Acute insulin and C-peptide responses were lower (both P < .05), but similar peripheral IS resulted in reduced insulin secretion adjusted for IS in low-IGF subjects (P = 0.044).
 
Low-IGF subjects had higher overnight levels of free fatty acids (P = .028) and β-hydroxybutyrate (P = .014), increased accumulation of IMCLs in tibialis anterior muscle (P = .008), and a tendency for elevated fat oxidation rates (P = .058); however, glycerol Ra values were similar. Gene expression of the fatty acid metabolism pathway (P = .0014) was upregulated, whereas the GLUT1 gene was downregulated (P = .005) in the skeletal muscle in low-IGF subjects.
 
Conclusions:  These data suggest that serum IGF-1 levels could be an important marker of β-cell function and glucose as well as lipid metabolic responses during fasting.

 

Quote

Discussion

The main findings of the study are the reduced insulin secretion and increased hepatic IS in healthy adult males with serum IGF-1 levels in the lowest quartile compared with those in the highest quartile. Enhanced lipid metabolism, increased accumulation of IMCLs, and upregulation of genes for fat oxidation pathways in skeletal muscle were also observed in low-IGF subjects.

Both genetic factors and environmental influences such as diet are associated with variations in IGF-1 levels in adults (19, 20). However, nutrition is unlikely to be a confounding factor in this study because the body composition was similar in the groups. Adults born small for gestational age (SGA) also have low IGF-1 levels (21), suggesting a role for developmental programming in modulating the GH/IGF-1 axis.

Our observations of reduced insulin secretion in low-IGF compared with high-IGF subjects support similar associations between IGF-1 levels and the insulin secretion derived from oral glucose tolerance tests reported in children and adults (6, 22). Higher HOMA-IS and lower endogenous glucose production suggest increased hepatic IS in low-IGF subjects. Greater suppression of triglyceride levels after the insulin bolus during the IVGTT in low-IGF compared with high-IGF subjects despite similar reductions in FFA levels may also reflect enhanced IS for inhibiting hepatic triglyceride synthesis (23).

Yet, the whole-body IS assessed during the IVGTT and the peripheral IS measured using tracer techniques were similar. Prolongation of fasting from 12 to 24 hours decreases the whole-body IS by 50% (12) and could have reduced the power of the study in detecting changes in peripheral IS. Nevertheless, reduced expression of the GLUT1 gene, which mediates basal glucose transport into skeletal muscle and is upregulated by IGF-1 (24, 25), may explain the trend for higher glucose levels during the IVGTT in low-IGF subjects and supports an effect of IGF-1 on peripheral glucose disposal.

Population studies have reported a conflicting relationship between circulating IGF-1 levels and IS ranging from none (26) to U-shaped (4) and positive associations (5, 27). The inconsistent associations in heterogeneous populations could be due to the strong inverse relationship between adiposity and IGF-1 levels (27). However, in selected populations such as lean SGA children, lower IGF-1 levels are associated with increased HOMA-IS (11, 28). Higher IGFBP-1 levels presumably related to lower insulin levels (29) in low-IGF subjects may result in even further reductions in free IGF-1 levels and bioactivity.

Our findings suggest that in contrast to the pharmacological effects of rhIGF-1, the relationship between circulating IGF-1 levels and hepatic IS in healthy adults is not direct but possibly dependent on the overall effect of the GH/IGF-1 axis.

We speculate that the increased hepatic IS in low-IGF subjects is a compensatory mechanism for the reduced insulin secretion. Increased insulin receptor numbers in liver as reported in lean growth-restricted or GH receptor KO mouse models (30, 31), which have enhanced IS but reduced insulin secretion, may explain the greater IS in low-IGF subjects. However, the levels of adiponectin, a mediator of increased IS associated with GH receptor mutations (31), were similar in the study groups.

Elevated FFA and β-hydroxybutyrate levels and trends for increased fat oxidation suggest enhanced mobilization and utilization of lipids in low-IGF compared with high-IGF subjects and is supported by the upregulation of relevant genes and metabolic pathways in skeletal muscle. Genes for the key regulators of β-oxidation were either significantly upregulated (malonyl coenzyme A decarboxylase [MYLCD] and carnitine palmitoyltransferase 1A [CPT1A]) or showed directional changes (hydroxyacyl-coenzyme A dehydrogenase [HADH], acyl coenzyme A synthetase 1 [ACSL1], and aldehyde dehydrogenase 1 [ALDH1]) (32, 33). A pronounced increase in β-hydroxybutyrate levels suggests upregulation of hepatic ketogenic pathways in low-IGF subjects. Although upregulation of the genes could reflect greater substrate availability (34), hormonal regulation of transcription and posttranscriptional modifications may also be important. Despite these differences between study groups, the absence of changes in glycerol Ra could be related to the inability of the technique to detect changes in splanchnic lipolysis (35).

IMCLs constitute a highly active storage pool and the main source of lipids for oxidation in skeletal muscle (36). Higher IMCLs in low-IGF subjects may reflect increased FFA levels (36, 37). Increased IMCLs in obesity and T2D is associated with reduced IS and is proposed to result from defective fat utilization related to impaired mitochondrial function (36).

However, the trends for higher fat oxidation and upregulation of the related mitochondrial genes but no reductions in vivo mitochondrial function or peripheral IS suggest that increased IMCLs in low-IGF compared with high-IGF subjects signify enhanced lipid utilization in skeletal muscle during fasting.

Although GH is the key hormone driving metabolic responses to fasting (9, 38), significant differences in secretion were not observed. Although our study was underpowered to detect differences in pulsatile GH secretion, alterations in GH sensitivity could also be important in determining the metabolic responses. Whereas exogenous GH administration is associated with enhanced fat utilization, but reduced hepatic IS (38), the low-IGF subjects who showed increased fat metabolism had higher hepatic IS. We did not evaluate catecholamines, cortisol, or glucagon, which may also augment lipid metabolism during fasting. However, these hormones are less likely to be related to the metabolic changes we observed in low-IGF subjects because they reduce IS (38).

We speculate that lower insulin levels resulting from reduced insulin secretion mediate an enhanced fasting response in low-IGF subjects.

The differences in substrate metabolism (12, 38) suggest a more efficient switching from glucose to fat metabolism in low-IGF compared with high-IGF subjects. 

These changes are consistent with physiological responses during fasting and may improve the tolerance of fasting (9).

Furthermore, increased IMCL deposition provides an immediate energy source for skeletal muscles and is a potentially important adaptive mechanism during fasting (37).

Yet, the reduced β-cell function could predispose the low-IGF subjects for early metabolic decompensation when exposed to nutrient overload and may underlie the associations between low IGF-1 levels and increased risk for T2D (6, 7).

Alterations in the GH/IGF-1 system have been proposed as a mechanism for the developmental programming which underlie the reduced statural growth and increased metabolic risks in low-birth-weight individuals (39). Changes similar to low-IGF subjects such as reduced insulin secretion but increased IS are reported in young growth-restricted animals, whereas worsening of glucose tolerance occurs later with increasing adiposity (30). SGA compared with normal-birth-weight children and neonates also have lower IGF-1 levels; higher FFA, β-hydroxybutyrate, and IGFBP-1 levels; and increased IS (40). Our findings that metabolic responses to fasting are linked to IGF-1 levels support the hypothesis that the GH/IGF-1 axis may be a mediator of adaptive programming during early life.

Whereas we have argued that low a IGF-1 level is a marker of reduced insulin secretion based on the observational data, the converse may be true (8). Further intervention studies using rhIGF-1 or a low GH dose may help to address the questions of reverse causality. Follow-up studies including assessment of insulin secretion and IS after an overnight fast would also be useful to characterize the subjects further because these parameters decrease with a prolonged fast (41).The main advantages of the study are selection of healthy subjects in the extremes of serum IGF-1 concentrations from a bioresource and blinded evaluation. However, our findings would need to be replicated in other studies, which should include females.

Conclusion

The associations of low IGF-1 levels with reduced insulin secretion but increased hepatic IS and enhanced fat metabolism during a fast suggest that IGF-1 levels could be an important marker of β-cell function and glucose as well as lipid metabolic responses during fasting.

The potentially adaptive metabolic changes associated with low IGF-1 levels may result in increased risk for abnormal glucose metabolism when exposed to an excessive nutrient load and may reflect a thrifty phenotype

 

 

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Thanks, Sibiriak. Interesting. But I am still as confused as ever about IGF-1 and have stopped worrying about it for now. For what its worth, my IGF-1 has dropped from 185 last year to 161 this year, while my testosterone has dropped to the mid-600.  But these fluctuate, and a month earlier my T was in the 900s, so I am not sure what to make of it.

What makes some sense to me is that IGF-1 is tightly connected to glucose handling and that maybe insulin sensitivity is a better marker, as seen in the study posted earlier in this thread:
 

 

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I just got my IGF-1 and IGBP-3 results, I kept forgetting to do them both.

IGF-1 is 0.171mg/L (171ng/mL) and IGFBP-3 is 4.8mg/L, for a ratio of 0.0356.

What's the prevailing opinion here about such a ratio?  It seems that there are other factors that affect bioavailability too, so I am not really sure what to make of it.

My protein intake over the last three months is at 118% of RDA according to Cronometer, all plant-based (top four sources are almonds, non-fortified nutritional yeast, tomatoes (?!!), and natto).

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Can someone look at my calculation and tell me if I screwed up?

I am thinking that my IGF-1/IGFBP-3 ratio seems too low at 0.0356. 

 

572758789_ScreenShot2021-02-11at17_36_48.png.e4815458c0d935aa50fcc3aada976057.png

 

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3 hours ago, Ron Put said:

Can someone look at my calculation and tell me if I screwed up?

I am thinking that my IGF-1/IGFBP-3 ratio seems too low at 0.0356. 

Might try converting each to mmol/L and then take the ratio.

Edited by Todd Allen

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MMmmmmm...., if I'm not wrong, 4.8 mg/L = 4.8 micrograms /mL 

4.8 ug/ml  = 4800 ng/ml, the same unit as IGF-1

171/4800 = about 0.035625, so Ron's calcs appear to be right, unless the lab has mixed the units up...

I don't know if that value is just low or impossible.

Edited by mccoy

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3 hours ago, mccoy said:

I don't know if that value is just low or impossible. It would mean that about 3.5% of the total IGF-1 is unbound

Yep, that's why I was doubting my calculations....

I am still confused about IGF, but while my IGF-1 is on the higher end for my age (171 at 58), it appears that the freely circulating IGF-1 is about one-third of what is considered "low range" for the IGF-1/IGFBP-3 ratio. Am I wrong?

I realize that I am a few years late to this discussion, but what is the ratio for the CR population here?

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3 hours ago, mccoy said:

171/4800 = about 0.035625, so Ron's calcs appear to be right, unless the lab has mixed the units up...

I think the problem is the concept.  The ratio of how many molecules is of more interest than the ratio of masses of the two substances.  IGF-1 is small, the binding protein much larger.

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6 minutes ago, Todd Allen said:

I think the problem is the concept.  The ratio of how many molecules is of more interest than the ratio of masses of the two substances.  IGF-1 is small, the binding protein much larger.

Thanks, Todd. Now I am even more confused.  Do you mind elaborating or pointing me to something that explains this?

BTW, I tried converting to mmol/L, but from the calculator I found errored and said it's an incompatible measurement with ng/mL.

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1 minute ago, Ron Put said:

Thanks, Todd. Now I am even more confused.  Do you mind elaborating or pointing me to something that explains this?

IGF-1 is a peptide hormone of about 70 amino acids.  The binding proteins are much bigger roughly 200 to 300 amino acids.  Thus the ratio of molecules might be nearly 4 times higher than your ratio of masses.  Thus I guesstimate your free IGF-1 to be roughly 12%.

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Just went and looked up the real numbers:

IGF-1 7,649 daltons
IGFBP-3 28,806 daltons 

So multiply your result by 3.766 to correct for mass and we get 13.416% free IGF-1

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1 hour ago, Todd Allen said:

IGF-1 is a peptide hormone of about 70 amino acids.  The binding proteins are much bigger roughly 200 to 300 amino acids.  Thus the ratio of molecules might be nearly 4 times higher than your ratio of masses.  Thus I guesstimate your free IGF-1 to be roughly 12%.

Todd, you are right on the money, 12.86%!

Thanks for the explanation, my chemistry classes are a distant memory for me :D

I found the formula here:

Nutritional Predictors of Insulin-like Growth Factor I and Their Relationships to Cancer in Men

"We calculated the IGF-I:IGFBP-3 ratio as an indicator of bioactive IGF-I using the following equivalents for conversion: 1 ng/ml IGF-I = 0.130 nm IGF-I, and 1 ng/ml IGFBP-3 = 0.036 nm IGFBP-3."

Based on that:

IGF-1: 
171 ng/mL x 0.130 nm = 22.23 nm

IGFBP-3:
4800 ng/mL x 0.036 = 172.8 nm

IGF-1/IGFBP-3 Ratio = 22.23/172.8 = 0.1286

This is close to 12.9%, although in reality probably a bit lower, as IGF-1 binds to other stuff too, if I remember right.

I am not quite sure if this is good or bad in general, but at least I know my ratio.

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1 hour ago, Ron Put said:

This is close to 12.9%, although in reality probably a bit lower, as IGF-1 binds to other stuff too, if I remember right.

Yes, I misspoke earlier this ratio does not directly give free %, indicator of bioactive percent is the appropriate phrasing.  There are 6 IGF binding proteins although they also bind IGF-2 and I think a little insulin but IGFBP-3 is the primary binding protein in circulation much more than all of the others combined.

Edited by Todd Allen

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Posted earlier in this thread:

Michael Rae:

https://www.crsociety.org/topic/11708-blood-testing-lef-super-sale-—-ends-june-13th/?tab=comments#comment-19478

Posted November 9, 2016

-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[...]   the whole point of getting both [ IGF-1 and IGFBP-3 tests] is to assess the biological activity of your IGF-1: a higher level of IGFBP-3 at a given IGF-1 level (hence, a lower IGF-1:IGFBP-3) means less free IGF-1 and lower biological activity. (Note that this is not the case for IGFBP-1, which has a more complex role in the pathway).

IAC, there is an additional and important underlying question, which is the way these tests are reported in American labs. The sensible way to report both IGF-1 and IGFBP3 is in (nano)moles per unit volume, which then tells you about biological relationships between the functions of the proteins.This is why every country in the world except the United States uses molar units. Unfortunately, the US reports them as mass per unit volume, which skews everything because of the different molar masses of the different analates.

You can convert your reported values to molar values and ratio as follows:

IGF-1 (molar concentration) = [iGF-1 [ng/mL] x 0.130

IGFBP-3 (molar concentration) = IGFBP-3 [ng/mL] x 0.036

IGF-1:IGFBP-3 = [iGF-1 [ng/mL] x 0.130]/[iGFBP-3 [ng/mL] x 0.036].

(Incidentally: altho' IGFBP-3 isn't on it, the AMA has a good calculator to convert American lab test units to SI units).

Importantly, the key Aging Cell paper (1) on protein intake and IGF-1 in human CR practitioners, which is probably our best guide on CR-specific reference ranges, uses molar units:

 

nihms95561f2.jpg

 

The "low protein" group in these graphs is a vegan group not intentionally CRed; the "low Calorie" group is the original data from the full CR cohort, including the majority who were getting protein intakes were well in excess of the RDA. We presumably want an IGF-1 level in line with the CR group after reducing their protein intake to RDAish levels (0.95 mg/kg), which was 152 ± 41 ng/mL; or possibly low-normal IGF-1 either for a young person or for our age group.

 

Whatever range of IGF-1 one targets. we presumably want an IGF-1:IGFBP-3 in line with the "low protein" group above.

 

Reference

1: Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008 Oct;7(5):681-7. PubMed PMID: 18843793; PubMed Central PMCID: PMC2673798.

Edited April 17, 2019 by Sibiriak

 

See also Fontana's   Effects of 2‐year calorie restriction on circulating levels of IGF‐1, IGF‐binding proteins and cortisol in nonobese men and women: a randomized clinical trial (2016)

Edited by Sibiriak

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17 hours ago, Todd Allen said:

I think the problem is the concept.  The ratio of how many molecules is of more interest than the ratio of masses of the two substances.  IGF-1 is small, the binding protein much larger.

You' right and my mistake occurred to me a little while after my post, which I edited. And of course, even if calculating a ratio on concentration units is correct, for comparison reasons it is probably conceptually more sensible to express the ratio in molar units, so we have directly a proxy of the % of free IGF-1.

The units adopted in the US ( ng/ml ) appear to be adopted by some countries outside the US as well, like here in Europe.

 

 

Edited by mccoy

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13 hours ago, Sibiriak said:

Importantly, the key Aging Cell paper (1) on protein intake and IGF-1 in human CR practitioners, which is probably our best guide on CR-specific reference ranges, uses molar units:

Actually, looking at the paper, IGF1 is measured in ng/ml, not uU/ml.  So unfortunately it is unclear whether the IGF1/IGFBP3 ratio is comparing ng/ml or uU/ml of these two measurements.  At least one of the reported measurements on in the article is in uU/ml -- namely insulin. Reading the paper as written, it appears that all reported measurements, except insulin, are in mg/ml -- and therefore probably also the IGF1:IGFBP3 ratio.  But unfortunately, this is unclear.

I might email Michael.  (or Luigi).

  --  Saul

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My guess:  Both IGF1 and IGFBP3 are measured in ng/ml.  The article indicates clearly that IGF1 is measured in ng/ml; so one would presume that the same is true for the numerator and denominator of the ratio.

Michael Rae's statement about the paper seems to be false.

??

  --  Saul

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Assuming Michael Rae is correct, my most recently measured ratio (using micromoles/nl instead of micrograms/nl) is about .1.  Using the micrograms per nl, about .03.  I was in the CR group tested by Luigi in that study.  I seem to be lower than average in that ratio in the CR group.

  --  Saul

 

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On 2/12/2021 at 10:05 PM, Sibiriak said:

Posted earlier in this thread

Hah, thanks. I guess I could have saved myself some time....  But it gave me the chance to read a bunch of IGF-related papers.

 

21 hours ago, Saul said:

Actually, looking at the paper, IGF1 is measured in ng/ml, not uU/ml.  So unfortunately it is unclear whether the IGF1/IGFBP3 ratio is comparing ng/ml or uU/ml of these two measurements.

Good point, Saul.  I can't figure out how they came up with the IGF-1:IGFBP-3 ratio of 0.1 based on the provided IFG-1 and IGFBP-3 values, even if both in ng/ml, unless there is some serious rounding going on, or the ratio is the averages of the individual ratios, or something. I'd be curious to know the answer.

Edited by Ron Put

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