Is Growth Hormone Truly a Fountain of Youth?

[01dragonslayer]

Is Growth Hormone Truly a Fountain of Youth?

Ever since the landmark 1990 trial performed by Rudman et al [1] claimed that GH reversed decades of age-related changes in otherwise healthy elderly males, this single-chain polypeptide has gained a lot of buzz in anti-aging circles as a panacea of sorts. Despite its popularity, the question still remains – is there legitimacy behind this buzz, or is it all just a marketing tool for anti-aging proponents helping them make money by promising a fountain of youth in a vial?

It is well-established that, as we age, GH and IGF levels decline exponentially [2-3]. This can occur at a very substantial rate with some measures showing the decline occurring at 14% per decade after puberty [4]. To put this into perspective, elderly males may produce as little as 50 mcgs/day of GH as compared to teenage boys who can produce as much as 1.0-1.5 mg/day [5]. The scientific community has coined the term somatopause to describe this phenomenon that leaves nearly 40% of elderly males clinically GH deficient [1]. I’ve written about this topic in some depth previously, so I won’t be doing another deep-dive here, but I would urge you all to review [6] before moving on.

When looking to answer this broad question, I think we must attempt to break this out into two smaller and more distinct elements – longevity and healthspan. In other words, how does GH administration impact our overall lifespan and how does it impact the quality of those years? Fortunately for us, there is an absolute treasure trove of literature that exists which can assist us in trying to make sense of this complicated topic.

Anti-Aging Controversy
As previously mentioned, the landmark trial by Rudman et al [1] back in 1990 created a lot of excitement when it demonstrated significant improvements in body composition, skin thickness, and bone density in a small group of otherwise healthy elderly males after six months of GH therapy. Due to the excitement generated by those results, many subsequent trials have taken place, since that time, in an attempt to help answer many of the questions that were originally unanswered by the research team. Some of the more pressing questions include those on long-term safety and effective dosing strategies. For example, the Rudman trial used three doses of rHGH per week, which does not even come close to mimicking endogenous secretory patterns. At the time, and also a concern today, was the financial implications associated with GH therapy for the elderly, as costs for a HRT protocol ultimately being in the tens of thousands per year [7].

To cut right to the chase, the vast majority of research scientists who study the clinical actions of GH and IGF-1 do not advocate its long-term use in humans. One of the more famously opposed reviews [8] summarized the scientific community’s stance as follows – “Use of GH as an antiaging therapy is widespread and has been advocated in the lay press and in scientific literature. Our analysis shows that this practice is not supported by a robust evidence base, offers little clinical benefit to the healthy elderly, and is associated with high rates of adverse events.”

When the A4M (American Academy of Anti-Aging Medicine) heard about this non-flattering review, they offered their own rebuttal [9]. The basis of their dispute resides in the fact that Liu et al neglected to include numerous trials in their analysis which actually painted a positive picture of GH therapy [10-15]. And herein lies the crux of the debate, GH replacement has the potential for both positive and negative pathological effects as it relates to aging, and age-related disease prevention. In essence, there are going to be “tradeoffs” between somatic growth, quality of life, reproductive potential, and longevity [16]. The individual is really going to need to be properly educated on all of these aspects before deciding if GH therapy is worth considering.

Legalities
Before we get too far ahead of ourselves, I would be remiss if I did not include a brief passage on the legalities of using GH therapy for anti-aging purposes. Please note that this will be FDA (USA) specific, so folks outside of US jurisdictions should take it upon themselves to review the legalities in their home country.

The clinical use of GH in geriatric anti-aging medicine is considered off-label usage and therefore technically illegal in the US. GH therapy is currently approved only for the treatment of GHD (growth hormone deficiency), ISS (idiopathic short stature), and HIV/AIDS [17-19]. Furthermore, unlike most FDA-approved medications, GH can only be distributed for indications specifically authorized by the Secretary of Health and Human Services —aging and its related disorders are not among such indications.

Despite this disclaimer, the distribution of GH via websites and anti-aging clinics has grown into a multimillion dollar industry [20-21], and numerous best selling books have been published on the topic over the years [22-25]. Although measurements are not going to be precise, it has been estimated that between 20,000-30,000 individuals used GH in the US in 2004 for anti-aging purposes [26]. This is a significant increase from the 1990s, and it would not be unreasonable to assume that this number has grown even higher with it being over ten years old now. The amount spent on GH worldwide totals in the billions, with nearly a half of that amount estimated to be for off-label usage [27].

In the past, some folks have tried to skirt around this legal requirements by claiming GH is a dietary supplement, however this will also not work. GH was approved as a drug by the FDA way back in 1940, prior to enactment of the 1994 Dietary Supplements Health and Education Act. By definition, dietary supplements must be intended for ingestion. GH is bioavailable only in its injectable form, and therefore it cannot be classified as a dietary supplement [26].

Healthspan – Quality of Life
The administration of GH to healthy elderly adults has generally been associated with predictably positive, yet modest, effects on body composition, skin elasticity, and bone mass while also inducing side-effects including joint pain, soft tissue edema, CTS, gynecomastia, and insulin resistance [28-29]. It must be noted that dosing protocols vary a lot between individual trials and so these listed adverse events may simply be a result of overdosing. If that is the case, many of the side effects may likely be avoided by dose reductions and proper monitoring [30].

The literature is going to be split into two distinct categories of trials – those that provide GH therapy to otherwise healthy elderly subjects as well as those who suffer from AGHD (Adult-Onset Growth Hormone Deficiency). Although healthy adults are likely the most applicable to the topic of anti-aging, both categories can help us glean useful information as the symptoms from each group are really quite similar to one another [31]. Again, the effects of GH treatment are very predictable so I will stop short from doing a review on each trial individually. However, for those that like to explore the literature themselves, I will reference many of the individual trials and reviews done on both the healthy elderly [1,28,32-40] as well as AGHD subjects [41-56] for your convenience. And, for those wanting an even deeper-dive on the topic, here are some additional reviews specifically discussing the use of GH therapy to treat somatopause [57-61].

One additional point worth mentioning is that AGHD subjects have been shown to demonstrate the same modest improvements to body composition as the elderly, yet they tend to taper off after 18-24 months of treatment [46]. This very well could be the point at which the previously hormonal-deficient body achieves a form of GH homeostasis, although this is entirely speculative. It is also reasonable to speculate that the lifestyle changes subjects are urged to improve upon, as part of treatment, may also contribute positively to these observed body composition improvements [26].

Once again, I’m very sorry ladies. As I’ve talked about previously, GH therapy is sexually dimorphic in nature and women respond quite different to therapy than men. For instance, significantly higher GH doses administered to women resulted in no increased lean body mass and significantly less body fat reduction than in men. Therefore, women may require higher doses of GH for longer periods of time than men to achieve physiological replacement levels [50-51,62]. Women also tend to have higher rates of side effects, particularly soft tissue edema. Of course, this could be confounded by the fact they are using these higher doses than their male subject counterparts.

Longevity – Animal Models
I speculate, based upon private discussions with folks in addition to what I read, that the majority of individuals equate GH and anti-aging with improved health and quality of life (healthspan) as opposed to a literal increase in lifespan. However, there are certainly still some folks that do believe that aging is caused by age-related suppression of GH levels, and therefore GH supplementation can stop or literally reverse aging. For this reason, I feel it is important to look at the evidence to see if this belief is in any way supported in the literature.

One of the central dogmas that exists within the field of aging is that the loss of growth factor signaling, including IGF-1, equates to beneficial effects on longevity. To this end, decreased GH and IGF-1 levels throughout life have been shown to increase lifespans in various model systems. However, please understand that this is still quite controversial as numerous models have also shown no effect, or even negative effects, of decreased IGF-1 signaling on overall lifespan. And furthermore, IGF-1 is required for normal tissue development and maintenance of these tissues throughout life [63]. Because of this, there is often a correlation seen between increased lifespan and decreased healthspan. This further suggests that measured IGF-1 levels are going to be highly pleiotropic, and suppression does not necessarily support health in advanced age. In other words, IGF-1 deficiency may suppress some age-related pathways but accelerate others.

Generally speaking, diminished GH/IGF axis signaling has been associated with increased longevity across many species [64-65]. Some of the more popular species tested include invertebrates [66-67], canines [68-69], and rodents [70-84]. The increased longevity seen in these rodent studies can often be striking, ranging from 25% to over 60%! These effects are readily reproducible, present in both genders, and not limited to a particular inbred or heterogeneous genetic background or diet formulation. In addition, these long-lived mutant mice exhibit numerous characteristics of delayed aging and maintain youthful appearance, energy levels, and cognitive abilities at ages where control animals exhibit significant physical and functional decline. The rate of aging seems to typically shift later in life, with initially slower signs of aging than in control animals. Aging accelerates only later in their life, after most of the control animals have already died [85-86]. Conversely, transgenic lines that overexpress GH result in shortened lifespans [19,87-89].

Longevity – Human Models
Unfortunately, the evidence in humans is not quite as clear as these animal models, with the available data indicating that genetic disruptions of GH/IGF-1 signaling does not result in increased life span and may actually result in shorter-lived individuals [16,90]. The answer to the longevity question in humans may therefore be located somewhere in the middle, as the amount of GH normally secreted by the pituitary is critically needed for growth, maturation, and enhanced reproductive potential. However, it may also limit life expectancy as there are intrinsic growth related “costs” to aging/longevity. In other words, growth and greater body size, tends to predispose us to earlier and/or faster aging and overall shorter lifespans [91-92]. This is a bit of a controversial topic in humans though because deciphering relationships between growth and longevity in human populations is difficult. Both can be powerfully influenced by either environmental or lifestyle factors. With that said, there are still strong correlations available between height and decreased lifespan potential [93-94]. There is also strong evidence indicating a relationship between height and increased cancer risk [95-99]. I’ll specifically discuss the topic of cancer in more depth, shortly.

A thorough analysis of over 12 studies, with nearly 15,000 total subjects, clearly demonstrated a U-shaped association between circulating IGF-1 levels and all-cause mortality. An important item to reemphasize here is that low levels of IGF-1 translated into a significantly increased mortality risk in the general population. This was predominantly due to an increased incidence of cardiovascular diseases. Conversely, higher IGF-1 levels are associated with an increased rate of cancer mortality [100]. In further support of this, various genetic studies have also indicated that reduced IGF-1 levels protect from some age-related diseases such as cancer but increase the risk of others such as cardiovascular disease [101-102]. Unlike in animals, a simple reduction in IGF signaling in humans does not necessarily appear to result in longer lifespans.

To put it more succinctly, it has been observed that diminished GH/IGF signaling has the ability to either increase longevity or shorten it in humans. Again, with IGF having such pleiotropic characteristics, it can become very difficult to provide singular answers. When casting the net widely, it can be common to observe a relationship between diminished somatotropic signaling and increased longevity [103-108]. Of course, correlation doesn’t equal causation but it does give us a starting point for further analysis.

Natural mutations within the IGF-1 receptor, producing cellular resistance to IGF-1, have been identified and these result in both a shorter stature and extended longevity. These very same mutations have also been observed to be over-represented in human centenarians [109-111]. Even though they have been seen frequently in the long-lived, it is still not entirely understood how these receptor mutations relate to increased longevity. It may be possible they are both directly responsible as well as secondarily responsible, by way of decreasing the risk of age-related diseases [16].

Along these lines, there have been populations of GHD subjects observed which do have a reduced risk of overall mortality, atherosclerosis, diabetes, cancer, as well as increased life-spans [16,112-114]. One such population of Laron Syndrome dwarfs in Brazil actually had zero reported malignancies as compared to the 9–24% rate by which family members developed cancer [115]. To continue with our theme of why can’t this stuff be straight-forward, there are also numerous population studies showing that diminished GH/IGF signaling is actually detrimental to longevity [116-117]. Interestingly, some populations even had an almost zero occurrence rate of cancer but still had comparable, if not shorter, lifespans [118].

One of the stronger hypotheses floating around scientific circles would be that subtle, long-term, reductions in GH release and/or activity may have the potential to slow aging, protect from age-related disease, and increase lifespan [19,159]. One such method of doing this is via calorie restriction, and there are clear beneficial effects of calorie restriction, which have been observed in many species. In addition, important predictors of life expectancy in humans can be elicited, and somatotropic signaling can be suppressed, by modest calorie restriction [65,119-120]. Although done on rhesus monkeys, it is important to note that both genetics and dietary composition, and not merely calorie restriction, may also play important roles in this increased longevity [121-122].

We can also use GH axis disorders in an attempt to further extrapolate the effects of GH overexpression on longevity in humans. In acromegaly, the hypersecretion of GH reduces life expectancy due to increased incidence of cardiovascular disease, diabetes, and cancer [123-127]. The overall mortality rate is higher in untreated patients with acromegaly than it is in the normal population. Yet treatment that successfully normalizes IGF-1 levels (such as surgery, radiotherapy or pharmacological treatment with somatostatin analogues or the GH antagonist pegvisomant) reduces the mortality rate back to that which is comparable to the general population [128]. Both GHD and GH excess are detrimental for cardiac function in the human with GH-deficient patients benefiting from GH therapy and acromegalics benefiting from suppression of GH levels [129-130].

Speaking of which, there are actually some who have thrown out the option of using GH antagonists such as pegvisomant to slow the aging process [131-132] in otherwise healthy individuals. Given the current price of somatostatin analogues and pegvisomant, these agents are probably not cost-effective for treating ‘healthy’ individuals over extended periods of time. More importantly, the long-term consequences of agents that lower GH action need to be carefully studied before their use is indicated in an antiageing scenario. Thus, the future will have to dictate whether either of these treatment modalities will be useful to combat aging [133]. With that said, the symptoms associated with congenital or acquired GHD clearly indicate that severe or complete suppression of GH actions cannot be recommended or even seriously considered for the enhancement of human longevity [134-135].

Longevity Pathways
Fortunately for us, there has been some really exciting research recently that has gone a long way towards isolating the specific signaling pathways and genes associated with aging. One of the earliest, and groundbreaking, discoveries was uncovered when Kenyon et al observed that suppressing DAF-2 signaling doubled lifespans [136]. The insulin/IGF-1 pathway in mammals shares a common signaling pathway with invertebrates, and the discovery that DAF-2 signaling influences life span in this species is an important landmark in the biology of aging. The DAF-2 receptor is a homolog of the human insulin/IGF receptor and both DAF-2 and DAF-16 are members of the FOXO family of transcription factors [137-138]. It was later found that this same lifespan-enhancing effect can be induced during development as well as in adulthood [139].

The FOXO pathway is downstream of insulin and IGF-1, and a specific variant known as FOXO3a has been identified as a very important gene as it relates to human longevity. This relationship has been independently confirmed in numerous human populations [140-145]. A recent study on Germans helped further clarify that FOXO1, FOXO4, or FOXO6 were not associated with longevity, suggesting that increased lifespan is associated exclusively with FOXO3a [146]. This really does bring up a lot of possibilities and it will be intriguing to see where the research takes us in the coming years as we learn more about manipulating FOXO3a.

There are also some other key mechanisms of action that GH/IGF have which are likely involved in the aging process and worth mentioning. The ability of GH to directly or indirectly activate the mTOR signaling pathway provides one of the most likely explanations of how this hormone can exert positive effects on somatic growth while simultaneously having negative effects on overall lifespan. While activation of mTOR signaling prevents cell death, promotes protein synthesis, growth, and cell divisions, it apparently can also accelerate aging [147-148]. Evidence of this can be observed when suppression of mTOR signaling pathways directly results in increased longevity within various organisms [149-152].

GH activity was found to be positively associated with senescent cell accumulation in adipose tissues. Results of these trials demonstrate an association between GH activity, age-related WAT dysfunction, and WAT senescent cell accumulation in mice. Cellular senescence has been shown to be a cause of many age-related phenotypes [133,153]. GH has also been shown to promote low-grade inflammation and cellular stress. The promotion of this low-grade inflammation by GH may negatively contribute to longevity [154-155]. Conversely, increased stress resistance has been observed in several species with increased longevity [156-157].

Lastly, although far from conclusive, insulin resistance has been long suspected of having negative impacts on the aging process and GH’s ability to promote resistance could have an indirect effect on longevity [158]

Age of Onset – GH/IGF Deficiency
One other recent discovery that I feel must be discussed has to do with how organisms age as compared to when hormonal deficiency occurs. For awhile now it was known that a common variable among all the mutant and transgenic animals that demonstrate increased lifespans is that the reduction in circulating GH and/or IGF-1 levels occurs early during the lifespan [67,71,159-162]. It was therefore hypothesized that the disparate effects observed with IGF-1 on healthspan and lifespan are possibly related to the specific period of life in which IGF-1 is suppressed. In contrast, treatment with GH or IGF later in life tends to reverse transgenic models with lengthened life-spans, and is detrimental to the overall aging process [163-166].

A very thorough comparison of over 30 mice strains provided supporting evidence of this hypothesis, as an inverse correlation with IGF-1 levels at 6 months of age and overall lifespans was observed [167]. Circulating IGF-1 levels rise immediately prior to puberty in both rodents and humans (beginning around day 30 in rodent models). Therefore the levels seen at 6 months of age likely reflect earlier time points identified in those prior studies. One of the potential takeaway points from these studies is that the stage of life when GH and IGF-1 levels are deficient is probably the most important variable in whether or not they impact lifespan [16]. Taking this a step further, one might speculate that low levels of GH/IGF-1 exposure during a short peripubertal period may result in permanent epigenetic modifications within the genome that ultimately affects both healthspan and lifespan.

Recently, a very elegant study was conducted that hoped to provide further evidence in support of this hypothesis [63]. It went on to demonstrate that IGF-1 deficiency induced early in life increased lifespans in female mice with no substantial improvement in the healthspans of these mice. Increased lifespans were only apparent when deficiency started early in life, indicating that decreasing IGF-1 levels in late adulthood is not a viable option for increasing lifespan. The data from this study also suggested that the normal age-related reduction in circulating IGF-1 levels is not a robust contributor to enhanced longevity. The effects of IGF-1 deficiency are both dependent on the sex of the animal as well as being tissue-dependent, which could really help explain discrepancies seen in some of the past rodent trials.

Cancer
Before wrapping this up, I wanted to devote a specific section of the article to cancer risks, because this tends to be one of the more asked about items when it comes to GH therapy. The potential association between GH therapy and increased cancer risk is not entirely without merit, as chronically elevated IGF-1 levels have been associated with the development of several types of cancers, such as breast and colon, in mammals [168-173]. And humans with chronically elevated IGF-1 are at increased risk for abnormal growths, whether they are benign or malignant. In fact, many tumors express a high density of IGF-1 receptors and become almost their own IGF-1 ecosystem, producing their own autocrine IGF-1 that directly facilitates cellular proliferation. Autocrine GH has also been identified as being a contributing factor to tumor growth and, because of this, has the potential to become a therapeutic target [174].

For these reasons, there are valid concerns that chronically elevated GH and IGF-1 levels may increase cancer risks. Although there are studies in humans that support such a relationship [118,175], an actual causative link has not yet been clearly established. In addition, questions related to the specific levels of hormones required and the duration of treatment necessary to increase cancer risk remain unanswered [16]. Part of this lack of clarity has to do with the fact that some data is contradictory to the hypothesis. For example, results from various cohort studies do not demonstrate that GH therapy results in increased cancer risk [176-177]. These cover a wide variety of subject-types, however one of the common themes tends to be that subjects were deficient in GH and restoring their levels to therapeutic levels [178-180].

Rodent models do paint a more clear picture on the relationship between GH/IGF and cancer risk. As we briefly touched on above, transgenic rodent models that result in deficient levels of GH/IGF lead to longer lifespans. A likely contributor to these longer lifespans could be the significantly decreased tumor rates in these lines of rodents, which is normally a leading cause of death in control animals [78,80,83,181-184]. There is also a sexual dimorphic pattern to this relationship that will need to be explored further, as recent studies do suggest the developmental time window in which IGF-1 deficiency occurs has a significant impact on long-term cancer risk [63].

Summary / Wrap-Up
So what can we take away from all this? I think there is ultimately going to be a give and take here, in the sense that an individual must factor in the well-known deleterious symptoms that occur with aging and compare them against the risks associated with chronically elevated hormone levels to find their happy medium. As has been discussed earlier, data suggests that those at high risk are going to be individuals with either elevated or suppressed hormone levels [185]. It would stand to reason then that someone interested in GH therapy would want to ensure their dosing protocol leaves them with hormone levels within those ranges associated with lower risk of all cause mortality. Working with a highly-qualified, cooperative endocrinologist can help dial-in these numbers. Again, due to legalities in many jurisdictions around the world, this is not always an option.

Another question which should be asked, can simple lifestyle adjustments provide similar benefits to GH therapy without the assumed risks? Dialing in your diet, ensuring proper sleep patterns, and regular exercise have been shown to be comparably beneficial, and significantly less costly, than all-out hormone replacement therapy [27]. Although GH therapy has certainly shown some beneficial effects in many trials on the elderly, it should be noted that improvements to other outcomes such as strength, glucose metabolism, and functional capacity are far from conclusive. A phrase that comes to mind is don’t run before you learn to walk properly. If one does not have their foundational lifestyle elements in place, I would advise them to not use hormone replacement therapy as a crutch.

If you do decide to utilize GH as part of an HRT protocol, don’t expect miracles. When you read the websites of anti-aging practitioners, they promise an awful lot. The truth is that subtle improvements may be seen with regard to body composition, cognition, and overall quality of life. These effects can become more pronounced for those that have naturally lower hormone levels. However, for the vast majority of otherwise healthy individuals, improvements are going to be very subtle. Set yourself up with proper expectations to prevent a potential letdown. And as I’ve previously mentioned [6], please stick to FDA approved brands of rHGH. This becomes even more critical if one is using GH long-term, for quality of life benefits.

Finally, anyone looking into GH therapy for lifespan extension is likely barking up the wrong tree, unless one actually suffers from clinical GHD. However, on the flip side of the coin, it is a very unattractive idea for most of us to become one of those, all too commonly seen, individuals that possess a body which degrades slowly over time. Again, the use of GH can help maintain a youthful look and appearance, as well as stave off many of other the symptoms that come with age-related somatopause, but at what cost? At present, no definitive answers can be provided with regard to the safety of long-term hormone replacement therapy in otherwise healthy individuals.



References
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Rudman D, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest. 1981 May;67(5):1361-9.

Zadik Z, Chalew SA, McCarter RJ Jr, Meistas M, Kowarski AA. The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J Clin Endocrinol Metab. 1985 Mar;60(3):513-6

Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab. 1991 Nov;73(5):1081-8.

Veldhuis JD, Liem AY, South S, Weltman A, Weltman J, Clemmons DA, Abbott R, Mulligan T, Johnson ML, Pincus S, et al. Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab. 1995 Nov;80(11):3209-22.