Will Low IGF-1 / Growth Hormone Extended Human Lifespan?

[Dean Pomerleau]

All,

 

It's been argued by respected aging researchers like Luigi Fontana that CR is likely to extend human lifespan through its effects on the somatotropic axis [2] - the signalling pathway involving growth hormone, insulin and IGF-1. In fact, Luigi argues that the monkeys in the NIA CR longevity trial may not have benefited because they may not have been restricted enough to show the biomarkers of CR-induced extended longevity, which especially includes low IGF-1, as has been observed in CRed rodents, and like he has observed in long-term human CR practitioners from the CR Society.

 

This new review article [1] begs to differ. It uses two lines of reasoning to argue that modulation of the IGF-1 pathway via CR, genetic manipulation or drugs, won't extend human lifespan. The first argument is an evolutionary one that has been made before (e.g. by Aubrey) - that humans use different strategies unavailable to rodents and other lower organisms for dealing with food shortage - i.e. migration, and so humans wouldn't have had the evolutionary pressure to maintain the genetic machinery to hunker down and boost longevity when faced with famine.

 

The second line of argument looks at data from a variety of non-rodent animal and human studies of the association between the IGF-1 pathway and longevity. He suggests the fact that CR didn't work in the NIA monkeys suggests it won't work in humans, although as mentioned above it's unclear how restricted the NIA CR monkeys were, or whether the CR monkeys' IGF-1 pathway was downregulated (somewhere on these forums Michael points to evidence that it was...).

 

The author also points to data from dwarf humans with congenitally low IGF-1 who he says don't live longer. He looks at studies of gene polymorphisms involving expression of IGF-1 and says people with genetically-low IGF-1 levels don't live longer. He says studies of IGF-1 levels of centenarians and their offspring have been equivocal at best. He criticizes data showing shorter people live longer, and even questions the longevity of traditional Okinawans. He's a real skeptic, concluding:

 

The main conclusion of this article is that modulation of the somatotropic axis does not explain longevity variations of ad libitum-fed animals but is a tool to face food shortage, leading to increased longevity in some species only. One can hope that a better knowledge of this axis could help to fight various pathologies, such as obesity not linked to an excessive food intake. However, one should give up the idea that it could help to modulate the ageing process and increase longevity of people not suffering from metabolic disorders.

 

This post by Brett Black argues that low IGF-1 is likely to be detrimental, while the two that follow it in that thread (by me and Michael), suggest the opposite - that lower IGF-1 is indeed associated with improved longevity in humans, contra what the current paper [1] suggests.

 

It seems hard to say who's right on this, given the evidence available to us about the effect of IGF-1 on human longevity, and (unfortunately) the evidence likely to be available to us during our lifetimes...

 

--Dean

 

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[1] Biogerontology. 2016 Apr;17(2):421-9. doi: 10.1007/s10522-015-9632-6. Epub 2015

Dec 28.

 

The somatotropic axis may not modulate ageing and longevity in humans.

 

Le Bourg É(1).

 

Full text: http://sci-hub.io/10.1007/s10522-015-9632-6

 

Studies in nematodes and mice have shown that the somatotropic axis can modulate 

their longevity and it has been argued that it could also modulate human

longevity. Thus, like nematodes and mice, human beings should live longer when

facing starvation and genetic variation of the somatotropic axis should be linked

to longevity. This article argues that, because the life-history strategies of

humans are very different from those of mice, these hypotheses are not warranted.

 

PMID: 26712318

 

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[2]  Aging (Albany NY). 2013 Jul;5(7):507-14.

 

Will calorie restriction work in humans?

 

Cava E(1), Fontana L.

 

Author information: 

(1)Division of Geriatrics and Nutritional Science and Center for Human Nutrition,

Washington University School of Medicine, St. Louis, MO 63130, USA.

 

Calorie Restriction (CR) without malnutrition slows aging and increases average

and maximal lifespan in simple model organisms and rodents. In rhesus monkeys

long-term CR reduces the incidence of type 2 diabetes, cardiovascular disease and

cancer, and protects against age-associated sarcopenia and neurodegeneration.

However, so far CR significantly increased average lifespan only in the

Wisconsin, but not in the NIA monkey study. Differences in diet composition and

study design between the 2 on-going trials may explain the discrepancies in

survival and disease. Nevertheless, many of the metabolic and hormonal

adaptations that are typical of the long-lived CR rodents did not occur in either

the NIA or WNPRC CR monkeys. Whether or not CR will extend lifespan in humans is 

not yet known, but accumulating data indicate that moderate CR with adequate

nutrition has a powerful protective effect against obesity, type 2 diabetes,

inflammation, hypertension, cardiovascular disease and reduces metabolic risk

factors associated with cancer. Moreover, CR in human beings improves markers of 

cardiovascular aging, and rejuvenates the skeletal muscle transcriptional

profile. More studies are needed to understand the interactions between CR, diet 

composition, exercise, and other environmental and psychological factors on

metabolic and molecular pathways that regulate health and longevity.

 

PMCID: PMC3765579

PMID: 23924667

[AlPater]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940699/table/T1/

 

Table 1

Longevity in growth hormone and IGF-1 deficient animal models.

Animal model Mechanism Outcomes Citations Ames dwarf mice Knockout prophet gene (Prop-1)
GH/GF-1 deficiency ↑ longevity; reduced somatic growth.
↓ adenocarcinoma of lung Ikeno Y, 2003 Snell dwarf mice Knockout of Pit-1
GH deficiency ↑ longevity
↓ body weight Flurkey K, 2001 Little mutation (Ghrhrlit/lit) GHRH-receptor insensitive ↑ longevity marked ↓ in body weight Flurkey K, 2001 Laron dwarf mice Mutation of GH receptor
GH, IGF-1, IGFBP-3 deficiency ↑ longevity
↓ weight, insulin, IGF-1 levels Coschigano K, 2003 GHR-KO mice (“laron” dwarfs) GH receptor knockout, IGF-1 deficiency ↑ longevity; ↓ in neoplasms; ↑ SQa fat, ↑ adiponectin Bonkowski MS, 2006
Berryman DE, 2004 Lewis dwarf rats Mutation causing ↓ GH synthesis, IGF-1 ↓ 50% ↑ longevity; resistance to carcinogen-induced cancer Ramsey MM, 2002

aSubctaneous.

 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940699/table/T2/

 

Table 2

Effects of GH and IGF-1 deficiency and excess on longevity in humans.

Mechanism Clinical outcomes Longevity effects Citations Growth hormone deficiency Ecuadorians – GH receptor mutation ↑ insulin sensitivity, ↓ incidence of diabetes and cancer No ↑ 2/3 die by 65 years-of-age Guevara-Aguirre J, 2011 Laron Syndrome – GH gene deletion Early aging – wrinkled skin, insulin resistance, osteopenia but normal endothelial function May be ↑ to 80–90 years Laron Z, 2004; Schecter M, 2007 Hereditary Dwarfism – 6.7 kb deletion in the GH gene – untreated GHD Small stature and heart problems Shortened versus unaffected sibs Besson A, 2003 Laron Syndrome (n = 222) No malignancies versus 9–24% in family members Expected to be ↑ Shevah O, 2007 Isolated GHRH-receptor mutation; Brazilian dwarfs (untreated) Obesity, ↑ LDL-C; no insulin resistance or premature CVD Not shortened Menezes-Oliveira JL, 2006, IGF-1 deficiency Ashkenazi Jewish centenarians Short stature, over-representation of mutations in the IGF-1 receptor gene (females only) Prolonged Suh Y, 2008 Polymorphic variants of IGF-1 path (IGF-1r, PI3K, IRS-1, FOXO1A) ↓ IGF-1 and variants over-represented in long-lived persons Prolonged Bonafe M, 2003 GH excess or GH treatment Acromegaly ↑ diabetes, CVD, heart failure, colon cancer; tumors have increased IGF-1 receptors Shortened Bartke A, 2008
Sacca L, 2003 Pituitary extract treatment; United Kingdom cohort ↑ incidence of colon cancer and Hodgkin’s disease Shortened Swerdlow AJ, 2002 Pituitary extract treatment; United States cohort ↑ deaths due to hypoglycemia and adrenal insufficiency Death rate ↑ 4-fold Mills JL, 2004 Treatment – children with GHD (n = 6928,17 years later) No ↑ cancer (except bone) but CVD outcomes increased; ↑ risk if dose ≥50 mg/kg/day ↑ mortality Carel J-C, 2012 Treatment – adults with GHD (n = 2694; 13,000 treatment years) Rates of cancer not ↑; mortality ↑ in women (CVD events) Not affected in men Van Bunderen 2011

 

 

[Dean Pomerleau]

Here are the two tables Al tried to post, from [1], suggesting that low GH and/or IGF-1 may increase longevity in rodents and people:

 

 

 

--Dean

 

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[1] Best Pract Res Clin Endocrinol Metab. 2013 Aug;27(4):541-55. doi:

10.1016/j.beem.2013.05.003. Epub 2013 Jun 18.

 

Growth hormone in the aging male.

 

Sattler FR(1).

 

Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940699/

 

Secretion of growth hormone (GH) and IGF-1 levels decline during advancing

years-of-life. These changes (somatopause) are associated with loss of vitality, 

muscle mass, physical function, together with the occurrence of frailty, central 

adiposity, cardiovascular complications, and deterioration of mental function.

For GH treatment to be considered for anti-aging, improved longevity,

organ-specific function, or quality of life should be demonstrable. A limited

number of controlled studies suggest that GH supplementation in older men

increases lean mass by ∼2 kg with similar reductions in fat mass. There is little

evidence that GH treatment improves muscle strength and performance (e.g. walking

speed or ability to climb stairs) or quality of life. The GHRH agonist

(tesamorelin) restores normal GH pulsatility and amplitude, selectively reduces

visceral fat, intima media thickness and triglycerides, and improves cognitive

function in older persons. This report critically reviews the potential for GH

augmentation during aging with emphasis on men since women appear more resistant 

to treatment.

 

Copyright © 2013. Published by Elsevier Ltd.

 

PMCID: PMC3940699

PMID: 24054930

[The Observer]

The answer: Yes to GH, no to IGF-1, perhaps?

 

http://onlinelibrary.wiley.com/doi/10.1111/acel.12519/full

 

Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128–216) mU L−1] compared with controls [238 (193–284) mU L−1]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39–0.53)] compared with controls [0.66 (0.56–0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.

 

So how would one go about lowering GH secretion? Would fasting do the trick or does fasting only lowers IGF-1?

 

[mikeccolella]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199335/

 

This is all about vascular aging and if I understand it I cannot imagine how low IGF -1 would help us?? It seems to be a miracle substance in preventing aging. At least in the sense of moderation in all things or IOWS not too much and not too little. Dean please weigh in on this!

[Dean Pomerleau]

Sorry Mike. I'm pretty much done.

 

--Dean

[mikeccolella]

https://selfhacked.com/2016/03/17/the-truth-about-igf-1-top-10-benefits-and-potential-drawbacks/

 

This site using scientific sources comes to the conclusion that overall igf-1 is more good than bad for humans. of course like everything they emphasize it has downsides and most importantly the old U shaped pattern we are SO SO familiar with! The Greeks had it right of course "moderation".

[Gordo]

Do you remember when HGH was all the rage among life extension gurus? Doctors were prescribing it, celebreties were taking it... Then they found out it accelerated aging and cancer? Seems to me like IGF-1 is similar.

[AlPater]

Yes, guys, it did seem the studies did suggest a nadir in the IGF-1 level occurs.

 

Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality.
Burgers AM, Biermasz NR, Schoones JW, Pereira AM, Renehan AG, Zwahlen M, Egger M, Dekkers OM.
J Clin Endocrinol Metab. 2011 Sep;96(9):2912-20. doi: 10.1210/jc.2011-1377. Epub 2011 Jul 27.
PMID: 21795450
http://press.endocrine.org/doi/10.1210/jc.2011-1377?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&

 

All-cause mortality was increased in subjects with low as well as high IGF-I, with a hazard ratio (HR) of 1.27 (95% CI = 1.08-1.49) and HR of 1.18 (95% CI = 1.04-1.34), respectively. Dose-response metaregression showed a U-shaped relation of IGF-I and all-cause mortality (P = 0.003). The predicted HR for the increase in mortality comparing the 10th IGF-I with the 50th percentile was 1.56 (95% CI = 1.31-1.86); the predicted HR comparing the 90th with the 50th percentile was 1.29 (95% CI = 1.06-1.58). A U-shaped relationship was present for both cancer mortality and cardiovascular mortality.

 

"A random-effects model showed a higher mortality for subjects in the lowest category of IGFBP-3 compared with the middle category with a HR of 1.40 (95% CI = 1.17–1.68). Subjects in the highest category of IGFBP-3 compared with the middle category showed a HR of 0.90 (95% CI = 0.75–1.08)."