While insulin-like growth factor-1 (IGF-1) is a well-established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF-1 levels and clinical disease. We examined prospective associations of serum IGF-1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns: First, IGF-1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF-1 are protected from disease, while older individuals with high IGF-1 are at increased risk for incident disease or death. Second, the association between IGF-1 and risk is generally U-shaped, indicating that both high and low levels of IGF-1 may be detrimental. With the exception of a more uniformly positive relationship between IGF-1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age-associated diseases. These data suggest that IGF-1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.
The company Loyal for Dogs is coming out with a new IGF-1 inhibition drug to extend life in dogs (and eventually humans). But there is already an IGF-1 inhibition drug approved for people.
I came across this paper:
see this section:
Inhibitors of the GH/IGF-1 axis
Although the lack of global IGF-1 signaling is lethal, data from studies conducted in animal models have shown that a reduction in IGF-1 levels or IGF-1 action can extend lifespan. Additionally, human IGF-1 receptor gene polymorphisms are associated with exceptional longevity (Suh et al., 2008), and recently, Barzilai and colleagues have shown that low plasma IGF-1 concentrations predict survival in long-lived people (Milman et al., 2014), specifically in women with a history of cancer. In animals, dwarf, long-lived mice lacking the growth hormone receptor (GHR-/-) have reduced levels of IGF-1, are insulin sensitive despite obesity, and have decreased risk for cancer and diabetes (Zhou et al., 1997; Shevah & Laron, 2007; Ikeno et al., 2009). Importantly, similar results have been reported in growth hormone receptor-deficient Laron syndrome (LS) patients. In this regard, no formal aging studies have been performed on patients with LS; however, they are protected from diabetes and fatal neoplasms. (Guevara-Aguirre et al., 2011; Steuerman et al., 2011). Thus, pharmaceutical interventions that directly lower IGF-1 levels in adults could improve health and prolong lifespan.
Pharmacological targets for lowering IGF-1 action include those that act directly or indirectly on cells/tissues that produce or respond to GH and/or IGF-1. In this regard, human or humanized monoclonal antibodies and drugs directed against the IGF-1R have been used in clinical trials to treat several types of cancer (Warshamana-Greene et al., 2005; Carboni et al., 2009); however, none have been approved for clinical use. We are unaware of the development of any antibody against GH or IGF-1, but several classes of compounds that inhibit the GH/IGF-1 axis have been approved for use in patients with acromegaly. Recently, a consensus document has been developed for the use of this therapeutics (Giustina et al., 2014). One of these drug classes, somatostatin analogues, lower serum GH levels by suppressing GH secretion by pituitary somatotrophs, thereby ultimately decreasing serum IGF-1 levels. Unfortunately, these compounds also suppress secretion of other endocrine hormones, including insulin. Furthermore, only 20-50% of patients with acromegaly respond to these drugs, and significant adverse events have been documented including gallstones, diarrhea, and anorexia. Thus, the use of somatostatin analogues to increase longevity or healthspan appears to be unwarranted at this time.
The second approved drug for treating acromegaly is the GH receptor antagonist pegvisomant (Trainer et al., 2000; van der Lely et al., 2001; Kopchick et al., 2002; van der Lely & Kopchick, 2006). Pegvisomant is unique in that it does not inhibit GH secretion, but rather inhibits GH action by binding to and blocking the GHR (Kopchick et al., 2002). Notably, a dose-dependent decrease of IGF-1 levels is seen in up to 90% of pegvisomant-treated patients (Trainer et al., 2000; van der Lely et al., 2001; Kopchick et al., 2002; van der Lely & Kopchick, 2006). Additionally, pegvisomant is an insulin sensitizer that blocks the diabetogenic action of GH and thus produces beneficial effects on glucose metabolism. Pegvisomant, therefore, could have positive effects on both longevity and healthy aging by lowering serum IGF-1 and increasing insulin sensitivity. Regarding adverse effects, van der Lely et al. (2012)reported that Long-term data on the efficacy and safety profile of pegvisomant are reassuring and few long-term serious adverse events have been reported but ongoing vigilance is required to monitor liver function and tumor size. Thus, pegvisomant is an approved drug that should be tested for its effects on longevity and healthy aging. Future therapeutics targeted at inhibiting the GH/IGF-1 axis could include small inhibitory RNAs directed against the GHR or IGF-1 receptor mRNAs, monoclonal antibodies directed against GH or IGF-1, or novel GHR or IGF-1R tyrosine kinase inhibitors.
Another way to reduce global IGF-1 action may be to inhibit IGF-1 availability. For example, loss of PAPP-A, a protease that cleaves and inactivates the IGF-1 sequestering protein IGFBP-4, reduces IGF-1-induced signaling without affecting overall serum IGF-1 levels and not only extends mouse lifespan, but has many other beneficial effects on healthspan and age-related diseases (Conover, 2012).
In summary, reducing the activity of the GH/IGF-I somatotrophic axis is perhaps the most validated and consistent genetic intervention to extend mouse lifespan and healthspan. In addition GHR/IGF-I deficiency is also among the few phenotypes that is well characterized in humans (patients with Laron syndrome) with very few side effects in adults, even considering the extreme level of GH receptor deficiency and the resulting >80% reduction in circulating IGF-I. Notably, a pharmaceutical intervention targeting this pathway may or may not be designed to achieve such a low level of hepatic IGF-I secretion
and this paper:
its extremely likely that this drug called somavert extends lifespan in mammalsâŚ
âPegvisomant is unique in that it does not inhibit GH secretion, but rather inhibits GH action by binding to and blocking the GHR. pegvisomant is an insulin sensitizer that blocks the diabetogenic action of GH and thus produces beneficial effects on glucose metabolism. Pegvisomant, therefore, could have positive effects on both longevity and healthy aging by lowering serum IGF-1 and increasing insulin sensitivityâ
âReducing protein intake from an average of 1.67 g kgâ1 of body weight per day to 0.95 g kgâ1 of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mLâ1 to 152 ng mLâ1âŚIn addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.â
These seem to be very important and under-appreciated data, hypotheses and conclusions?
Does anyone have experience of testing IGF-1 levels? What provider/type of test do you prefer, any things one should take into account before starting a testing program for it? How infra day (or hour) variable is it?
It seems the data is pretty messy⌠but a target range on the lower end of this range seems reasonable: âthe lowâ to midârange levels of IGFâ1 (120â160 ng/ml) are reflective of the âhealthiestâ status.â (but Laron Syndrome people have almost zero IGF-1 and have many health benefits).
Association between IGFâ1 levels ranges and allâcause mortality: A metaâanalysis
A series of studies have shown that high levels of IGFâ1 are associated with an increased risk of tumors including prostate, preâ and postmenopausal breast, lung, thyroid, and colorectal cancers (Ma et al., 1999; Renehan et al., 2004; Shi et al., 2001). An increase in serum IGFâ1 level of 100 ng/ml was shown to correspond to a 69% increase in colorectal cancer risk (Ma et al., 1999). High levels of IGFâ1 were also shown to be associated with a 49% increase in prostate cancer, 65% increase in breast cancer (Renehan et al., 2004), and a 106% increase in lung cancer risk (Yu et al., 1999). Furthermore, in worms, flies, and mice insulin/IGFâ1 signaling reduces lifespan and healthspan (Bartke et al., 2013; Fontana et al., 2010; Kenyon, 2010; Podshivalova et al., 2017).
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In mice, very low levels of IGFâ1 are associated with reduction in a range of diseases and conditions including cancer, diabetes, and cognitive decline and with record longevity (Bartke et al., 2013). In fact, mice with severe IGFâ1 deficiency, achieved by either growth hormone receptor (GHRD) or GH deficiency, display a 40% extended longevity (Bartke et al., 2013). Also, GHRD mice are protected from ageârelated decline in memory and perform similarly to young normal mice. Additionally, insulin/IGFâsignaling (IIS) pathway accelerates aging in Caenorhabditis elegans and the fly D. melanogaster (Bartke et al., 2013).
In humans, studies on patients with Laron syndrome (LS), whose IGFâ1 levels are extremely low, have reported a reduction in proâaging signaling, cancer, diabetes, and cognitive decline (GuevaraâAguirre et al. 2011; Nashiro et al. 2017). Steuerman et al. (2011) also surveyed 230 individuals with LS and found no cases of cancer.
On the contrary, other studies reported an association between low levels of IGFâ1 and conditions like CVD, diabetes mellitus, osteoporosis, and sarcopenia although a causal relationship has not been established (Brioche et al., 2014; Katsanos et al., 2001; Lenk et al., 2010; Saki et al., 2017).
In summary, because extensive data in both mice and humans consistently show that even extremely low levels of IGFâ1 are associated with increased lifespan or healthspan and in agreement with the metaâanalysis presented here, we propose that lowâ to midârange levels of IGFâ1 (120â160 ng/ml) are reflective of the âhealthiestâ status.
Methionine restriction (MR) dramatically extends the healthspan of several organisms. Methionine-restricted rodents have less age-related pathology and increased longevity as compared with controls, and recent studies suggest that humans might benefit similarly. Mechanistically, it is likely that the decreased IGF-1 signaling that results from MR underlies the benefits of this regimen. Thus, we hypothesized that interventions that decrease IGF-1 signaling would also produce MR-like healthspan benefits. Selenium supplementation inhibits IGF-1 signaling in rats and has been studied for its putative healthspan benefits. Indeed, we show that feeding mice a diet supplemented with sodium selenite results in an MR-like phenotype, marked by protection against diet-induced obesity, as well as altered plasma levels of IGF-1, FGF-21, adiponectin, and leptin. Selenomethionine supplementation results in a similar, albeit less robust response, and also extends budding yeast lifespan. Our results indicate that selenium supplementation is sufficient to produce MR-like healthspan benefits for yeast and mammals.
This really fits with things Iâm trying to find and create strategies for - cancer and neurodegen as 2 of the bid 4 seems so much less under our control than cardiovascular and metabolic diseaseâŚ
âIGF-1 appears constant over a 24-hour period, making it useful as a bio-marker to help assess blood levels of GH.â
And
âFasting is not required for this test. Take all medications as prescribed.â
And from Marek it seems like it one the tests that (at least with some assays) can get wacko results if done while having somewhat recent vitamin B7 supplementation:
âNote: This test may exhibit interference when sample is collected from a person who is consuming a supplement with a high dose of biotin. Cease biotin supplementation at least 72 hours prior to blood draw.â
Here are my test results. Seems that as long as I keep working on muscle and resistance training as a foundation against osteoporosis and sarcopenia and Iâm not worried about those then lower might be even better?
After taking rapamycin for a couple of years, I am on a 2 month break that probably ends in March. Before I restart, Iâll report on my IGF-1 as a baseline and get it remeasured three months after that. Any problems with allowing 3 months to establish a possible change in results?
My test results, after a 2 month layoff of rapamycin, followed by 4mg rapamycin with 10oz grapefruit on a Friday, then the IGF-1 test on Monday: 74ng/mL (reference: 68-247). Iâm in the 25th percentile as a 60yo male, which sounds good to me for longevity purposes. Iâll test again after a couple of months of intermittent rapamycin.
New Open Access Paper Reduced insulin/IGF-1 signalling upregulates two anti-viral immune pathways, decreases viral load and increases survival under viral infection in C. elegans by Elizabeth M. L. Duxbury & AlexeiMaklakov et al.