Growth Hormone, Aging, and Disease

The following post will be fairly speculative, so view it as a researched opinion piece. This post may have its inaccuracies and will evolve as I continue to research this topic. Herein I will be proposing some of my views on growth hormone and its downstream protein IGF-1 with particular respect to its role in aging and longevity.

Growth hormone is, as its name so unambiguously suggests, a hormone of growth. It is produced by the pituitary gland and increases the growth of tissues, including muscle and bone, both directly and by inducing the production of another growth hormone called IGF-1. Due to these effects a lack of or insensitivity to either growth hormone or IGF-1 produces symptoms such as low muscle mass, increased body fat, and, if occurring in childhood, short stature (including dwarfism).

However, despite the obvious downsides to a growth hormone deficiency some have suggested growth hormone is a significant hormonal cause of aging and disease. One of the observations leading to this speculation comes from experiments on rodents where a hypophysectomy (the surgical removal of the pituitary gland) prolongs the animal’s lifespan. However, because the pituitary gland produces numerous hormones (including prolactin, TSH, FSH, LH, ACTH, and more) which themselves induce the production of various other hormones (including estrogen, thyroid hormone, testosterone, and cortisol), it seems incredibly difficult to conclude that decreased growth hormone is responsible for the anti-aging effects of a hypophysectomy.

Additional support for the role of growth hormone as a negative factor in aging, though indirect, comes from observation of animal size. Among animals of the same species there is a tendency for smaller animals to live longer than larger animals. Smaller mice and rats live longer than larger mice and rats, smaller dogs live longer than bigger dogs, and shorter people often live longer than taller people (more on this later). Because growth hormone and IGF-1 have been found to be major factors determining animal size this is consistent with the idea that these growth hormones negatively associate with lifespan. Although one might think the positive correlation between the size of different species of animals and lifespan (e.g. an elephant lives longer than a horse, which lives longer than a cat, which lives longer than a mouse) is inconsistent with the theory of a life shortening effect of growth hormone, this doesn’t seem to be the case. A fair amount of research suggests size differences between species is influenced more strongly by genetic, non-hormonal chemical signaling, rather than the endocrine signaling of growth hormones. In fact, IGF-1 levels seem to somewhat inversely follow lifespan. For example, among humans, elephants, American black bears, golden mantled ground squirrels, and brown rats it is the species with the shorter lifespan, not the largest size, which has higher IGF-1.

Stronger evidence supporting the argument that growth hormone shortens the lifespan comes from observing various genetically manipulated mice. The Ames, Snell, Lit, GHRKO, and IGF1RKO are all breeds of mice which have genetically impaired growth hormone production or downstream signaling and which all tend to live longer than their normal counterparts. However, the Ames and Snell Mice also fail to produce other pituitary hormones such as prolactin and TSH, suggesting other factors could be increasing the longevity of these animals. Additionally, a few experiments have found administering moderate amounts of growth hormone to mice (including the Snell and Balb/c strains) actually increases their lifespan.

Given the conflicting evidence regarding the effects growth hormone on rodents it would seem valuable to look at some of the studies and observations involving growth hormone in human beings, the species I’m assuming most of the readers of this article are. A variety of factors can reduce growth hormone production or signaling. A damaged pituitary (due most commonly to tumors) results in deficient production of growth hormone (as well as other pituitary hormones) and several studies have reported shorter lifespan in people with such conditions. However, these folks usually take a variety of hormones to manage their condition, making extrapolations about their lifespan difficult. Perhaps the better evidence comes from untreated people with mutations of certain growth hormone pathway genes. People with PROP-1 mutations have a low production of most pituitary hormones, including growth hormone, and seem to have a normal, possibly even longer life than unaffected people but yet again the lack of other pituitary hormones make such an observation far less useful.

Three useful populations come from people mutations of their GH-1 gene (which makes growth hormone), GHRH (which signals the pituitary to make growth hormone), and the GHR gene (which produces the receptor for growth hormone). People with a GH-1 mutation have been shown to live shorter lives than their unaffected siblings. People with a GHRH mutation seem to have shorter lifespans, but largely due to a higher mortality rate in childhood and adolescence. Upon surviving to the age of 20 GHRH mutants had lifespans roughly 10 years shorter than their unaffected siblings, a non-statistically significant finding. Finally, people with a GHR mutation, which causes a condition called Laron syndrome, seem to have the same lifespan as the rest of the population.

Although these represent extreme cases, the nonetheless fail to support the alleged negative effects of growth hormone on longevity. So how do we reconcile all the information suggesting growth hormone shortens life? Well, I have a theory. I believe growth hormone has both positive and negative effects on health. These effects are numerous so for simplicity I will be focusing on growth hormone’s effect cardiovascular disease and cancer.

On the one hand, a lack of growth hormone may increase cardiovascular disease risk. Hypopituitary people die more often of strokes and heart attacks and they have higher levels of atherosclerosis, or plaque build up in the arteries characteristic of cardiovascular disease. Some small clinical studies have shown the administration of growth hormone reverses this atherosclerosis, sometimes to normals. Additionally, growth hormone often improves blood lipid levels (particularity raising HDL levels), reduces inflammation (indicated by lowering CRP), and increases thyroid hormone levels, although not always. These characteristics all have a large amount of support for their beneficial role in cardiovascular disease prevention.

Nicotinic acid, a form of vitamin B3 (aka niacin) taken in large quantities for its drug like effects, is an interesting piece of evidence here in my opinion. Nicotinic acid raises growth hormone levels. Interestingly, it also seems to produce many of growth hormone’s effects: it raises HDL, lowers CRP, and can reverse atherosclerosis. Nicotinic also seems to worsen blood sugar control, another feature it shares with growth hormone. Finally, several large, randomized, controlled trials have found nicotinic acid prevents death from cardiovascular disease. Thus, if nicotonic acid not only mimics many of the effects of growth hormone but also increases growth hormone itself the fact that can prevent heart attacks would seem good evidence that growth hormone can as well.

On the other hand, growth hormone seems to be implicated in cancer risk. This may be because growth hormone and IGF-1 encourage growth of cells and tissues, which can be problematic when those cells and tissues are cancerous. A number of growth hormone deficient populations, including people with Laron syndrome, show a resistance to cancer compared to the normal population. Additionally, experiments on mice using the growth hormone and growth hormone pathway blocking drugs JV-1-38, RC-160, and M2-5-156 have reducing cancer risk and progression in a variety of cancer types. A number of phase II trials on humans using the anti-IGF-1 drugs R1507, Gantimab, and IMCA12 have also suggested some benefits to cancer patients, although without a control group it’s very hard to say for sure.

Finally, the last observation supporting these two ideas comes from human height, which again is heavily influenced by growth hormone/IGF-1. A number of studies have shown shorter people (indicating less growth hormone) are more likely to die of a heart attack while taller people (indicating more growth hormone) are more likely to die of cancer.

So, what does all this mean for you? Truthfully, I can’t say. The only take away message I have from this is to view growth hormone as a double edged sword, although the overall effect may not even be so significant as to warrant calling it a sword, perhaps a double edged…fly swatter?

To be continued in part 2…


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