IGF-1 inhibitors and lifespan extension?

[Joseph_Lavelle]

I hope you will look into it with your usual thoroughness. My understanding is GH is important for body repair, and is produced mostly during deep sleep. IGF-1 is longer lasting and is a signal of the amount of GH produced. That sounds overly simplistic to me.

[Neo]

@LukeMV

wouldnt be comfortable with this at all. If it were me, I would take 1-2iu of HGH per day

At what point would that kick in do you think? Would you say the same to me, here is my data:

IGF-1 inhibitors and lifespan extension?

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 I’m not worried about those then lower might be even better? [IMG_6403]

[Neo]

And would you consider sharing your T and free T levels?

[adssx]

@Neo

@adssx may I ask what your exercise routine is like? How much resistance training do you do? And what is your body composition/muscle mass like? (+the HIIT also)

Not enough exercise To simplify, weekly:

• 5x30–45 min zone 2 cycling (daily on weekdays)
• 1h dynamic yoga
• 1h taichi
• 30 min resistance training
• 30 min HIIT (4x4 skipping rope)

Body composition from my March 2024 DEXA scan:

• Total Body % Fat: 14.9
• Est. VAT Mass (g): 297
• Est. VAT Volume (cm3): 321
• Est. VAT Area (cm2): 61.7

@Neo

And would you consider sharing your T and free T levels?

• Testosterone: 27.4 nmol/L
• Free Testosterone: 0.437 nmol/L

@约瑟夫_拉维尔, thanks. So far I’ve found a lot of interesting things:

• Revisiting the Relationship Between Blood Pressure and Insulin-Like Growth Factor-1 2014: potential U-shape of IGF-1 with hypertension with also the development of IGF-1 resistance which might explain some weird findings and “could mask the vasoprotective functions of IGF-1”
• Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype 2017: the title says it all
• Causal relationship between circulating insulin-like growth factor-1 and Parkinson’s disease: a two-sample Mendelian randomization study 2024: “This study unearthed evidence indicating that heightened IGF-1 levels might be causally correlated with an increased risk of PD.”
• Circulating insulin-like growth factor-1 and brain health: Evidence from 369,711 participants in the UK Biobank 2023: “Apart from the diverse associations with neuroimaging features, both low and high IGF-1 concentrations are associated with increased risks of dementia and stroke and higher IGF-1 concentrations are linked to a higher risk of PD, highlighting the potential of IGF-1 as a biomarker for risk stratification of brain health.”
• Machine learning analysis of the UK Biobank reveals IGF-1 and inflammatory biomarkers predict Parkinson’s disease risk 2023: “In vivo studies have demonstrated IGF-1 deficiency results in increased oxidative stress, inflammation, neuronal cell death and cognitive deficits that can be improved by exogenous IGF-1 [19, 20]. It is well documented that IGF-1 is elevated in serum at diagnosis in PD patients, and levels at this time correlate with disease severity [5, 7]. To account for the discrepancy in the beneficial effects of IGF-1 and the fact it is increased in PD, it has been hypothesised that IGF-1 signalling is defective in PD, resulting in a decrease in the neuroprotective effects and reduction in the brains ability to buffer oxidative damage.”
• Protective role of IGF-1 and GLP-1 signaling activation in neurological dysfunctions 2022: “There is substantial evidence that IGF-1 and GLP-1 analogues penetrate the blood-brain barrier (BBB) and exhibit neuroprotective functions, including synaptic formation, neuronal plasticity, protein synthesis, and autophagy.”
• Cardioprotective Mechanisms of Exenatide in Isoprenaline-induced Myocardial Infarction: Novel Effects on Myocardial α-Estrogen Receptor Expression and IGF-1/IGF-2 System 2018: “Treatment with exenatide and/or 17β-estradiol, commenced 8 weeks before ISO insult, ameliorated these anomalies with maximum cardioprotection achieved with combined treatment. This was associated with upregulation of both ERα and IGF-1R, and downregulation of IGF-2R in left ventricles.”
• Serum IGF-1 is associated with cognitive functions in early, drug-naïve Parkinson’s disease 2017: “lowest quartile ≤ 97.9 ng/ml; second quartile = 97.9001–124 ng/ml; third quartile = 124.0001–162.200 ng/ml; highest quartile ≥ 162.2001 ng/ml.” (=> looks aligned with @LukeMV’ suggestion that 120–170 ng/mL is the optimal: Cardiovascular Health - #488 by LVareilles ).
• Unexpected role for IGF-1 in starvation: Maintenance of blood glucose: hypoglycemia reversed by IGF-1

So based on all the above (and my elevated BP + regular hypoglycemic episodes), I’m now convinced that my IGF-1 is too low and should be > 100 ng/mL at least. I’m not sure what the best way to do this given potential signaling issues + resistance risk.

[LukeMV]

Going on TRT can raise IGF1. If only suggest it if testosterone is low though, of course.

With an IGF1 of 100, I think you would benefit from GH therapy for sure.

“Both high and low levels of IGF‐1 increase mortality risk, with a specific 120–160 ng/ml range being associated with the lowest mortality.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844108/#:~:text=Both%20high%20and%20low%20levels,associated%20with%20the%20lowest%20mortality.

@adssx

[Neo]

@LukeMV

only suggest it if testosterone is low though, of course.

Testosterone is 738 (Reference Range: 250-1100 ng/dL)
Free T is 65.8 (Reference Range: 35.0-155.0 pg/mL)

I had been holding above as good and perhaps the total T being too high from an optimal longevity goal (vs short term health/feeling good goal).

[adssx]

Thanks. I don’t know enough about GH to take it for now. Instead I looked at the effect of other “longevity” drugs on IGF-1:

• “Both Simvastatin and Ezetimibe could protect against AD-induced dementia, evidenced by reducing amyloid and tau proteins through up regulation of IGF-1 receptors in the hippocampus and cerebral cortex.” (Neuroprotective Effects of Ezetimibe versus Simvastatin in Alzheimer’s Induced Dementia: Perspectives from Female Rats. (P5.205) 2016)
• “When comparing Metformin+SGLT2i group to Metformin group, SGLT2i significantly improved HOMA-IR [P = 0.04], and elevated IGF1/IGFBP3 ratio [P = 0.04], SGLT2i showed a tendency of increasing IGF1 (P = 0.10), but this was not statistically meaningful.” (The effect of SGLT2i on the GH/IGF1 axis in newly diagnosed male T2D patients – a prospective, randomized case–control study 2024)
• “In this study, although higher IGF-1 levels were associated with renal outcomes, canagliflozin failed to lower IGF-1 levels and beneficial effects of canagliflozin in lowering adverse outcomes were observed across IGF-1 and IGFBP-3 levels.” (Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial 2023)
• Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics 2022
• For ARBs, I found contradictory results (decrease, increase, or neutral)
• GLP-1RAs might be interesting as well: Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis 2022
  
  

I already take most of the above though

[Neo]

Will see if I can engage this a bit deeper later. For now, one question is what would happen if you shifted (or added) some more of your exercise towards resistance straining.

[Neo]

@LukeMV

GH therapy for sure

@约瑟夫_拉维尔 are you on this or TRT?

[adssx]

I agree. Exercise is the safest and most effective way to increase IGF-1 I found so far. (again, I don’t know much about HGH).

@LukeMV

I would take 1-2iu of HGH per day.

Where do you get that btw?

[Joseph_Lavelle]

@Neo No. I do not take either or any pharma that would boost T. My total and free T are on the low end but I don’t have obvious symptoms of T being TOO low so I am working on improving T via lifestyle. Sleep, mostly. I already lift pretty hard and have significant muscle mass.

[Neo]

@LukeMV

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844108/#:~:text=Both%20high%20and%20low%20levels,associated%20with%20the%20lowest%20mortality

@adssx while these are only association type of studies, might be interested to look at this section the table if contains and compare against your diet and nutrient status

For instance your low B vitamins discussed elsewhere could be related to your low IGF-1

Note also that from these food associations you can also again see the potential trade off between (current) health optimization vs longevity optimization as more protein, more carbs, more dairy, more growth might be good for health near term but not perhaps for longevity. (My guess is that you might see similar patterns from going from CR to non CR).

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).

[Neo]

@LukeMV

With an IGF1 of 100, I think you would benefit from GH therapy for sure.

I’ll keep looking into this more as I was quite happy with my level before given my decision longevity vs near term health state/growth mode.

One small data point for people and @adssx here is what Blueprint / BJ said they thought was optimal mid last year (last time in found mention of it):

Potentially long term ideal range for people age 45+ is 75-150 ng/mL based on clinical outcome epidemiological studies

[Neo]

@adssx

through up regulation of IGF-1 receptors

Do you know how we should think about this in relation to blood levels of IGF-1?

I.e. for insulin we’d think low fasting insulin is generally better, but we’d want the receptors to be very sensitive and “up regulated”?

Is that how we should think about IGF-1 receptors or were you suggested it would be the opposite in this case?

[DrFraser]

So through Access Labs (through Labcorp) IGF-1 is $20, but needs a doctor’s order. I however learned about a new test IGF-BP-3 which is $29 through them … and here is some information on it.
https://endocrinology.testcatalog.org/show/IGFB3

I guess I usually use IGF-1 as a measure of how much ongoing growth vs. not is going on and I like to see people around the average for their age. This particularly comes up when I have patients wanting to push their GH/Testosterone etc. With some trepidation, if the IGF-1 isn’t getting stimulated, it’s possibly okay - but at the point this is going off, I warn them they are expediting death.

On the other side of things, an IGF inhibitor might make you live longer, but possibly in a fashion in which you’d not enjoy living?

Anyway, this test IGF-BP3 is an interesting addition, no sure how/when to use it yet. Any experience or thoughts on this?

[adssx]

Thanks. These are good questions to which I don’t have an answer but my guess is that signaling (number of receptors and their sensitivity) might be more important than the quantity of IGF-1 itself.

What about rapamycin? It lowers IGF-1 levels but does it impact the signaling as well?

[adssx]

@Neo

Potentially long term ideal range for people age 45+ is 75-150 ng/mL based on clinical outcome epidemiological studies

If the optimal range for longevity is based on your current age, this makes things even harder…

[RapAdmin]

A GH/ IGF-1 lowering drug has gone generic so should be available soon from Indian suppliers… (should you want to lower your GH/IGF-1 for longevity purposes).

Cipla receives final approval for the generic version of Somatuline® Depot (Lanreotide) Injection

MUMBAI, India and WARREN, N.J., May 22, 2024 /PRNewswire/ – Cipla Limited (BSE: 500087; NSE: CIPLA EQ; and hereafter referred to as “Cipla”) and its wholly owned subsidiary Cipla USA Inc., (hereafter referred to as “Cipla”), today announced that it has received the final approval for its Abbreviated New Drug Application (ANDA) for Lanreotide Injection 120 mg/0.5 mL, 90 mg/0.3 mL, 60 mg/0.2 mL from the United States Food and Drug Administration (USFDA).

Cipla’s Lanreotide Injection is AP-rated therapeutic equivalent generic version of Somatuline® Depot (Lanreotide) Injection. Lanreotide Injection is supplied as 120 mg/0.5 mL, 90 mg/0.3 mL, 60 mg/0.2 mL single-dose, pre-filled, ready-to-inject syringe. Cipla’s Lanreotide injection is indicated for the treatment of patients with Acromegaly and Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs).

According to IQVIA (IMS Health), Somatuline® Depot (Lanreotide) had US sales of approximately $898M for the 12-month period ending March 2024.

Lanreotide

Lanreotide: Uses, Dosage, Side Effects, Warnings - Drugs.com

[RapAdmin]

Here is an interesting question… I wonder if targeted delivery of IGF-1 (into skin via mesotherapy, etc.) or muscle (IM injection), etc. might be beneficial when done on a pulsed dosing schedule. This would avoid the systemic issues of IGF-1 delivery, while maintaining some of the benefits of IGF-1?

A new review paper that got me thinking about this:

Study Uncovers Trove of Hormones That Could Freeze Time on Aging Skin

Endocrine Controls of Skin Aging

Skin is the largest organ of the human body and undergoes both intrinsic (chronological) and extrinsic aging. While intrinsic skin aging is driven by genetic and epigenetic factors, extrinsic aging is mediated by external threats such as UV irradiation or fine particular matters, the sum of which is referred to as exposome. The clinical manifestations and biochemical changes are different between intrinsic and extrinsic skin aging, albeit overlapping features exist, eg, increased generation of reactive oxygen species, extracellular matrix degradation, telomere shortening, increased lipid peroxidation, or DNA damage. As skin is a prominent target for many hormones, the molecular and biochemical processes underlying intrinsic and extrinsic skin aging are under tight control of classical neuroendocrine axes. However, skin is also an endocrine organ itself, including the hair follicle, a fully functional neuroendocrine “miniorgan.” Here we review pivotal hormones controlling human skin aging focusing on IGF-1, a key fibroblast-derived orchestrator of skin aging, of GH, estrogens, retinoids, and melatonin. The emerging roles of additional endocrine players, ie, α-melanocyte-stimulating hormone, a central player of the hypothalamic-pituitary-adrenal axis; members of the hypothalamic-pituitary-thyroid axis; oxytocin, endocannabinoids, and peroxisome proliferator-activated receptor modulators, are also reviewed. Until now, only a limited number of these hormones, mainly topical retinoids and estrogens, have found their way into clinical practice as anti-skin aging compounds. Further research into the biological properties of endocrine players or its derivatives may offer the development of novel senotherapeutics for the treatment and prevention of skin aging.

Paywalled article:

https://academic.oup.com/edrv/advance-article-abstract/doi/10.1210/endrev/bnae034/8029650#google_vignette

[DeStrider]

I think that’s a plausible solution.