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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historical posts were at a minimum amateur, poorly cited, and low in quality, or else worse incomplete, inaccurate, or outdated.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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