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 anti-aging 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 multi-million 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 exist 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 anti-aging 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 clearer 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

1. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE. Effects of human growth hormone in men over 60 years old. N Engl J Med. 1990 Jul 5;323(1):1-6.
2. 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.
3. 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
4. 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.
5. 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.
6. https://thinksteroids.com/articles/most-effective-growth-hormone-protocol-for-hypertrophy/
7. Vance ML. Growth hormone for the elderly? N Engl J Med. 1990 Jul 5;323(1):52-4.
8. Liu H, Bravata DM, Olkin I, Nayak S, Roberts B, Garber AM, Hoffman AR. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med. 2007 Jan 16;146(2):104-15. Review.
9. https://www.worldhealth.net/news/analysis_of_faulty_data_yields_inaccurat/
10. Ahmad AM, Hopkins MT, Thomas J, Ibrahim H, Fraser WD, Vora JP. Body composition and quality of life in adults with growth hormone deficiency; effects of low-dose growth hormone replacement. Clin Endocrinol (Oxf). 2001 Jun;54(6):709-17.
11. Gillberg P, Bramnert M, Thorén M, Werner S, Johannsson G. Commencing growth lipoproteins, glucose metabolism, body composition, and cardiovascular function. Growth Horm IGF Res. 2001 Oct;11(5):273-81.
12. Götherström G, Svensson J, Koranyi J, Alpsten M, Bosaeus I, Bengtsson B, Johannsson G. A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices. J Clin Endocrinol Metab. 2001 Oct;86 10):4657-65.
13. Hernberg-Ståhl E, Luger A, Abs R, Bengtsson BA, Feldt-Rasmussen U, Wilton P, Westberg B, Monson JP; KIMS International Board; KIMS Study Group. Pharmacia International Metabolic Database. Healthcare consumption decreases in parallel with improvements in quality of life during GH replacement in hypopituitary adults with GH deficiency. J Clin Endocrinol Metab. 2001 Nov;86(11):5277-81.
14. Murray RD, Wieringa GE, Lissett CA, Darzy KH, Smethurst LE, Shalet SM. Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome. Clin Endocrinol (Oxf). 2002 Apr;56(4):525-32.
15. Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Shalet SM, Vance ML; Endocrine Society’s Clinical Guidelines Subcommittee, Stephens PA. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2006 May;91(5):1621-34.
16. Sonntag WE, Csiszar A, deCabo R, Ferrucci L, Ungvari Z. Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci. 2012 Jun;67(6):587-98.
17. Roehr B. The many faces of human growth hormone. BETA. 2003 Winter;15(4):12-6.
18. Gharib H, Cook DM, Saenger PH, Bengtsson BA, Feld S, Nippoldt TB, Rodbard HW, Seibel JA, Vance ML, Zimmerman D; American Association of Clinical Endocrinologists Growth Hormone Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in adults and children–2003 update. Endocr Pract. 2003 Jan-Feb;9(1):64-76.
19. Bartke A. Growth hormone and aging: a challenging controversy. Clin Interv Aging. 2008;3(4):659-65. Review.
20. Mehlman MJ, Binstock RH, Juengst ET, Ponsaran RS, Whitehouse PJ. Anti-aging medicine: can consumers be better protected? Gerontologist. 2004 Jun;44(3):304-10. Review.
21. Perls TT. Anti-aging quackery: human growth hormone and tricks of the trade–more dangerous than ever. J Gerontol A Biol Sci Med Sci. 2004 Jul;59(7):682-91.
22. The New Anti-Aging Revolution: Stopping the Clock for a Younger, Sexier, Happier You – Dr. Ronald Klatz
23. Staying Young: Growth Hormone and Other Natural Strategies to Reverse the Aging Process – Gilbert Elian, MD
24. HGH (Human Growth Hormone): Age-Reversing Miracle – Rita Elkins, M.H.
25. Grow Young with HGH: The Amazing Medically Proven Plan to Reverse Aging – Dr. Ronald Klatz
26. Perls TT, Reisman NR, Olshansky SJ. Provision or distribution of growth hormone for “antiaging”: clinical and legal issues. JAMA. 2005 Oct 26;294(16):2086-90.
27. Vance ML. Can growth hormone prevent aging? N Engl J Med. 2003 Feb 27;348(9):779-80.
28. Cohn L, Feller AG, Draper MW, Rudman IW, Rudman D. Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations. Clin Endocrinol (Oxf). 1993 Oct;39(4):417-25.
29. Harman SM, Blackman MR. Use of growth hormone for prevention or treatment of effects of aging. J Gerontol A Biol Sci Med Sci. 2004 Jul;59(7):652-8. Review.
30. Wüster C, Melchinger U, Eversmann T, Hensen J, Kann P, von zur Mühlen A, Ranke MB, Schmeil H, Steinkamp H, Tuschy U. [Reduced incidence of side-effects of growth hormone substitution in 404 patients with hypophyseal insufficiency. Results of a multicenter indications study]. Med Klin (Munich). 1998 Oct 15;93(10):585-91.
31. Ghigo E, Arvat E, Gianotti L, Ramunni J, DiVito L, Maccagno B, Grottoli S, Camanni F. Human aging and the GH-IGF-I axis. J Pediatr Endocrinol Metab. 1996 Jun;9 Suppl 3:271-8. Review.
32. Marcus R, Butterfield G, Holloway L, Gilliland L, Baylink DJ, Hintz RL, Sherman BM. Effects of short term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab. 1990 Feb;70(2):519-27.
33. Rudman D, Feller AG, Cohn L, Shetty KR, Rudman IW, Draper MW. Effects of human growth hormone on body composition in elderly men. Horm Res. 1991;36 Suppl 1:73-81. Review.
34. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 1993 Feb;14(1):20-39. Review.
35. Taaffe DR, Pruitt L, Reim J, Hintz RL, Butterfield G, Hoffman AR, Marcus R. Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J Clin Endocrinol Metab. 1994 Nov;79(5):1361-6.
36. Taaffe DR, Jin IH, Vu TH, Hoffman AR, Marcus R. Lack of effect of recombinant human growth hormone (GH) on muscle morphology and GH-insulin-like growth factor expression in resistance-trained elderly men. J Clin Endocrinol Metab. 1996 Jan;81(1):421-5.
37. Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schambelan M, Grunfeld C. Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med. 1996 Apr 15;124(8):708-16.
38. Lange KH, Isaksson F, Rasmussen MH, Juul A, Bülow J, Kjaer M. GH administration and discontinuation in healthy elderly men: effects on body composition, GH-related serum markers, resting heart rate and resting oxygen uptake. Clin Endocrinol (Oxf). 2001 Jul;55(1):77-86
39. Blackman MR, Sorkin JD, Münzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O’Connor KG, Christmas C, Tobin JD, Stewart KJ, Cottrell E, St Clair C, Pabst KM, Harman SM. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA. 2002 Nov 13;288(18):2282-92.
40. Feldt-Rasmussen U, Wilton P, Jonsson P; KIMS Study Group; KIMS International Board. Aspects of growth hormone deficiency and replacement in elderly hypopituitary adults. Growth Horm IGF Res. 2004 Jun;14 Suppl A:S51-8.
41. Jørgensen JO, Pedersen SA, Thuesen L, Jørgensen J, Ingemann-Hansen T, Skakkebaek NE, Christiansen JS. Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet. 1989 Jun 3;1(8649):1221-5.
42. Salomon F, Cuneo RC, Hesp R, Sönksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 1989 Dec 28;321(26):1797-803.
43. Salomon F, Cuneo RC, Hesp R,Jørgensen JO, Thuesen L, Müller J, Ovesen P, Skakkebaek NE, Christiansen JS. Three years of growth hormone treatment in growth hormone-deficient adults: near normalization of body composition and physical performance. Eur J Endocrinol. 1994 Mar;130(3):224-8.Sönksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 1989 Dec 28;321(26):1797-803.
44. Holmes SJ, Shalet SM. Which adults develop side-effects of growth hormone replacement? Clin Endocrinol (Oxf). 1995 Aug;43(2):143-9.
45. Baum HB, Biller BM, Finkelstein JS, Cannistraro KB, Oppenhein DS, Schoenfeld DA, Michel TH, Wittink H, Klibanski A. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial. Ann Intern Med. 1996 Dec 1;125(11):883-90.
46. Verhelst J, Abs R, Vandeweghe M, Mockel J, Legros JJ, Copinschi G, Mahler C, Velkeniers B, Vanhaelst L, Van Aelst A, De Rijdt D, Stevenaert A, Beckers A. Two years of replacement therapy in adults with growth hormone deficiency. Clin Endocrinol (Oxf). 1997 Oct;47(4):485-94.
47. Baum HB, Katznelson L, Sherman JC, Biller BM, Hayden DL, Schoenfeld DA, Cannistraro KE, Klibanski A. Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency. J Clin Endocrinol Metab. 1998 Sep;83(9):3184-9.
48. Abs R, Bengtsson BA, Hernberg-Stâhl E, Monson JP, Tauber JP, Wilton P, Wüster C. GH replacement in 1034 growth hormone deficient hypopituitary adults: demographic and clinical characteristics, dosing and safety. Clin Endocrinol (Oxf). 1999 Jun;50(6):703-13.
49. Biller BM, Sesmilo G, Baum HB, Hayden D, Schoenfeld D, Klibanski A. Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency. J Clin Endocrinol Metab. 2000 Mar;85(3):970-6.
50. Ezzat S, Fear S, Gaillard RC, Gayle C, Landy H, Marcovitz S, Mattioni T, Nussey S, Rees A, Svanberg E. Gender-specific responses of lean body composition and non-gender-specific cardiac function improvement after GH replacement in GH-deficient adults. J Clin Endocrinol Metab. 2002 Jun;87(6):2725-33.
51. Kehely A, Bates PC, Frewer P, Birkett M, Blum WF, Mamessier P, Ezzat S, Ho KK, Lombardi G, Luger A, Marek J, Russell-Jones D, Sönksen P, Attanasio AF. Short-term safety and efficacy of human GH replacement therapy in 595 adults with GH deficiency: a comparison of two dosage algorithms. J Clin Endocrinol Metab. 2002 May;87(5):1974-9.
52. Monson JP. Long-term experience with GH replacement therapy: efficacy and safety. Eur J Endocrinol. 2003 Apr;148 Suppl 2:S9-14. Review.
53. Arwert LI, Veltman DJ, Deijen JB, van Dam PS, Drent ML. Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional MRI study. Neuroendocrinology. 2006;83(1):12-9.
54. Reed ML, Merriam GR, Kargi AY. Adult growth hormone deficiency – benefits, side effects, and risks of growth hormone replacement. Front Endocrinol (Lausanne). 2013 Jun 4;4:64.
55. Kargi AY, Merriam GR. Diagnosis and treatment of growth hormone deficiency in adults. Nat Rev Endocrinol. 2013 Jun;9(6):335-45.
56. Elbornsson M, Götherström G, Bosæus I, Bengtsson BÅ, Johannsson G, Svensson J. Fifteen years of GH replacement improves body composition and cardiovascular risk factors. Eur J Endocrinol. 2013 Apr 15;168(5):745-53.
57. Savine R, Sönksen PH. Is the somatopause an indication for growth hormone replacement? J Endocrinol Invest. 1999;22(5 Suppl):142-9. Review.
58. Hoffman AR, Ceda GP. Should we treat the somatopause? J Endocrinol Invest. 1999;22(10 Suppl):4-6. Review.
59. Jørgensen JO. Two hot topics in the field of GH therapy: quality of life in hypopituitary adults, and clinical implications of the somatopause. Report from an interactive discussion. J Endocrinol Invest. 1999;22(5 Suppl):150-6. Review.
60. Savine R, Sönksen P. Growth hormone – hormone replacement for the somatopause? Horm Res. 2000;53 Suppl 3:37-41. Review.
61. Lamberts SW. The somatopause: to treat or not to treat? Horm Res. 2000;53 Suppl 3:42-3. Review.
62. Drake WM, Coyte D, Camacho-Hübner C, Jivanji NM, Kaltsas G, Wood DF, Trainer PJ, Grossman AB, Besser GM, Monson JP. Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults. J Clin Endocrinol Metab. 1998 Nov;83(11):3913-9.
63. Ashpole NM, Logan S, Yabluchanskiy A, Mitschelen MC, Yan H, Farley JA, Hodges EL, Ungvari Z, Csiszar A, Chen S, Georgescu C, Hubbard GB, Ikeno Y, Sonntag WE. IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. Geroscience. 2017 Apr;39(2):129-145.
64. Bartke A. Minireview: role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology. 2005 Sep;146(9):3718-23.
65. Fontana L, Partridge L, Longo VD. Extending healthy life span–from yeast to humans. Science. 2010 Apr 16;328(5976):321-6.
66. Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell. 2005 Feb 25;120(4):449-60. Review.
67. Bansal A, Zhu LJ, Yen K, Tissenbaum HA. Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):E277-86.
68. Patronek GJ, Waters DJ, Glickman LT. Comparative longevity of pet dogs and humans: implications for gerontology research. J Gerontol A Biol Sci Med Sci. 1997 May;52(3):B171-8.
69. Greer KA, Canterberry SC, Murphy KE. Statistical analysis regarding the effects of height and weight on life span of the domestic dog. Res Vet Sci. 2007 Apr;82(2):208-14.
70. Silberberg R. Articular aging and osteoarthrosis in dwarf mice. Pathol Microbiol (Basel). 1972;38(6):417-30.
71. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature. 1996 Nov 7;384(6604):33.
72. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6736-41.
73. Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS. Extending the lifespan of long-lived mice. Nature. 2001 Nov 22;414(6862):412.
74. Carter CS, Ramsey MM, Sonntag WE. A critical analysis of the role of growth hormone and IGF-1 in aging and lifespan. Trends Genet. 2002 Jun;18(6):295-301. Review.
75. Rollo CD. Growth negatively impacts the life span of mammals. Evol Dev. 2002 Jan-Feb;4(1):55-61.
76. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology. 2003 Sep;144(9):3799-810.
77. Holzenberger M, Dupont J, Ducos B, Leneuve P, Géloën A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003 Jan 9;421(6919):182-7.
78. Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A. Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci. 2003 Apr;58(4):291-6.
79. Bartke A, Brown-Borg H. Life extension in the dwarf mouse. Curr Top Dev Biol. 2004;63:189-225. Review.
80. Sonntag WE, Carter CS, Ikeno Y, Ekenstedt K, Carlson CS, Loeser RF, Chakrabarty S, Lee S, Bennett C, Ingram R, Moore T, Ramsey M. Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology. 2005 Jul;146(7):2920-32.
81. Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7901-5.
82. Conover CA, Bale LK. Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell. 2007 Oct;6(5):727-9.
83. Ikeno Y, Hubbard GB, Lee S, Cortez LA, Lew CM, Webb CR, Berryman DE, List EO, Kopchick JJ, Bartke A. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci. 2009 May;64(5):522-9
84. Svensson J, Sjögren K, Fäldt J, Andersson N, Isaksson O, Jansson JO, Ohlsson C. Liver-derived IGF-I regulates mean life span in mice. PLoS One. 2011;6(7):e22640.
85. Kinney BA, Coschigano KT, Kopchick JJ, Steger RW, Bartke A. Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav. 2001 Apr;72(5):653-60.
86. Koopman JJ, van Heemst D, van Bodegom D, Bonkowski MS, Sun LY, Bartke A. Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling. Aging (Albany NY). 2016 Mar;8(3):539-46.
87. Bartke A, Chandrashekar V, Bailey B, Zaczek D, Turyn D. Consequences of growth hormone (GH) overexpression and GH resistance. Neuropeptides. 2002 Apr-Jun;36(2-3):201-8. Review.
88. Bartke A. Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology. 2003 Oct;78(4):210-6.
89. Berryman DE, List EO, Coschigano KT, Behar K, Kim JK, Kopchick JJ. Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res. 2004 Aug;14(4):309-18
90. Sattler FR. Growth hormone in the aging male. Best Pract Res Clin Endocrinol Metab. 2013 Aug;27(4):541-55.
91. Bartke A, Sun LY, Longo V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev. 2013 Apr;93(2):571-98.
92. Bartke A. Somatic growth, aging, and longevity. NPJ Aging Mech Dis. 2017 Sep 29;3:14.
93. Samaras TT, Storms LH. Impact of height and weight on life span. Bull World Health Organ. 1992;70(2):259-67.
94. Samaras TT, Storms LH. Secular growth and its harmful ramifications. Med Hypotheses. 2002 Feb;58(2):93-112.
95. Tretli S. Height and weight in relation to breast cancer morbidity and mortality. A prospective study of 570,000 women in Norway. Int J Cancer. 1989 Jul 15;44(1):23-30.
96. Gunnell D, Okasha M, Smith GD, Oliver SE, Sandhu J, Holly JM. Height, leg length, and cancer risk: a systematic review. Epidemiol Rev. 2001;23(2):313-42. Review.
97. Batty GD, Barzi F, Woodward M, Jamrozik K, Woo J, Kim HC, Ueshima H, Huxley RR; Asia Pacific Cohort Studies Collaboration. Adult height and cancer mortality in Asia: the Asia Pacific Cohort Studies Collaboration. Ann Oncol. 2010 Mar;21(3):646-54.
98. Green J, Cairns BJ, Casabonne D, Wright FL, Reeves G, Beral V; Million Women Study collaborators. Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. Lancet Oncol. 2011 Aug;12(8):785-94.
99. Emerging Risk Factors Collaboration. Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. Int J Epidemiol. 2012 Oct;41(5):1419-33.
100. Burgers AM, Biermasz NR, Schoones JW, Pereira AM, Renehan AG, Zwahlen M, Egger M, Dekkers OM. Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality. J Clin Endocrinol Metab. 2011 Sep;96(9):2912-20.
101. Lamberts SW, van den Beld AW, van der Lely AJ. The endocrinology of aging. Science. 1997 Oct 17;278(5337):419-24. Review.
102. Yang J, Anzo M, Cohen P. Control of aging and longevity by IGF-I signaling. Exp Gerontol. 2005 Nov;40(11):867-72. Epub 2005 Sep 8. Review.
103. van Heemst D, Beekman M, Mooijaart SP, Heijmans BT, Brandt BW, Zwaan BJ, Slagboom PE, Westendorp RG. Reduced insulin/IGF-1 signalling and human longevity. Aging Cell. 2005 Apr;4(2):79-85.
104. Krzisnik C, Grgurić S, Cvijović K, Laron Z. Longevity of the hypopituitary patients from the island Krk: a follow-up study. Pediatr Endocrinol Rev. 2010 Jun;7(4):357-62.
105. Barbieri M, Rizzo MR, Papa M, Boccardi V, Esposito A, White MF, Paolisso G. The IRS2 Gly1057Asp variant is associated with human longevity. J Gerontol A Biol Sci Med Sci. 2010 Mar;65(3):282-6.
106. Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP, Cohen P, Barzilai N. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell. 2014 Aug;13(4):769-71.
107. Teumer A, et al CHARGE Longevity Working Group. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. Aging Cell. 2016 Oct;15(5):811-24.
108. van der Spoel E, Jansen SW, Akintola AA, Ballieux BE, Cobbaert CM, Slagboom PE, Blauw GJ, Westendorp RG, Pijl H, Roelfsema F, van Heemst D. Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity. Aging Cell. 2016 Sep 7.
109. Bonafè M, Barbieri M, Marchegiani F, Olivieri F, Ragno E, Giampieri C, Mugianesi E, Centurelli M, Franceschi C, Paolisso G. Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. J Clin
110. Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3438-42.Endocrinol Metab. 2003 Jul;88(7):3299-304.
111. Tazearslan C, Huang J, Barzilai N, Suh Y. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. Aging Cell. 2011 Jun;10(3):551-4.
112. Laron Z. Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity? Mech Ageing Dev. 2005 Feb;126(2):305-7. Review.
113. Menezes Oliveira JL, Marques-Santos C, Barreto-Filho JA, Ximenes Filho R, de Oliveira Britto AV, Oliveira Souza AH, Prado CM, Pereira Oliveira CR, Pereira RM, Ribeiro Vicente Tde A, Farias CT, Aguiar-Oliveira MH, Salvatori R. Lack of evidence of premature atherosclerosis in untreated severe isolated growth hormone (GH) deficiency due to a GH-releasing hormone receptor mutation. J Clin Endocrinol Metab. 2006 Jun;91(6):2093-9.
114. Shevah O, Laron Z. Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Horm IGF Res. 2007 Feb;17(1):54-7.
115. Shevah O, Kornreich L, Galatzer A, Laron Z. The intellectual capacity of patients with Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene. Correlation with CNS abnormalities. Horm Metab Res. 2005 Dec;37(12):757-60.
116. Besson A, Salemi S, Gallati S, Jenal A, Horn R, Mullis PS, Mullis PE. Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab. 2003 Aug;88(8):3664-7.
117. Aguiar-Oliveira MH, Oliveira FT, Pereira RM, Oliveira CR, Blackford A, Valenca EH, Santos EG, Gois-Junior MB, Meneguz-Moreno RA, Araujo VP, Oliveira-Neto LA, Almeida RP, Santos MA, Farias NT, Silveira DC, Cabral GW, Calazans FR, Seabra JD, Lopes TF, Rodrigues EO, Porto LA, Oliveira IP, Melo EV, Martari M, Salvatori R. Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. J Clin Endocrinol Metab. 2010 Feb;95(2):714-21.
118. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011 Feb 16;3(70):70ra13.
119. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, Ravussin E; Pennington CALERIE Team. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006 Apr 5;295(13):1539-48.
120. Holloszy JO, Fontana L. Caloric restriction in humans. Exp Gerontol. 2007 Aug;42(8):709-12. Epub 2007 Mar 31. Review.
121. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009 Jul 10;325(5937):201-4.
122. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012 Sep 13;489(7415):318-21.
123. Jadresic A, Banks LM, Child DF, Diamant L, Doyle FH, Fraser TR, Joplin GF. The acromegaly syndrome. Relation between clinical features, growth hormone values and radiological characteristics of the pituitary tumours. Q J Med. 1982 Spring;51(202):189-204.
124. Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998 Aug;83(8):2730-4.
125. Chanson P, Salenave S. Acromegaly. Orphanet J Rare Dis. 2008 Jun 25;3:17.
126. Ayuk J, Sheppard MC. Does acromegaly enhance mortality? Rev Endocr Metab Disord. 2008 Mar;9(1):33-9. Review.
127. Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009 Nov;119(11):3189-202.
128. Holdaway IM, Bolland MJ, Gamble GD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol. 2008 Aug;159(2):89-95.
129. Saccà L, Cittadini A, Fazio S. Growth hormone and the heart. Endocr Rev. 1994 Oct;15(5):555-73. Review.
130. Saccà L, Napoli R, Cittadini A. Growth hormone, acromegaly, and heart failure: an intricate triangulation. Clin Endocrinol (Oxf). 2003 Dec;59(6):660-71. Review.
131. Trainer PJ. ACROSTUDY: the first 5 years. Eur J Endocrinol. 2009 Nov;161 Suppl 1:S19-24.
132. van der Lely AJ, Biller BM, Brue T, Buchfelder M, Ghigo E, Gomez R, Hey-Hadavi J, Lundgren F, Rajicic N, Strasburger CJ, Webb SM, Koltowska-Häggström M. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J Clin Endocrinol Metab. 2012 May;97(5):1589-97.
133. Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol. 2013 Jun;9(6):366-376.
134. Brugts MP, van den Beld AW, Hofland LJ, van der Wansem K, van Koetsveld PM, Frystyk J, Lamberts SW, Janssen JA. Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality. J Clin Endocrinol Metab. 2008 Jul;93(7):2515-22.
135. van Bunderen CC, van Nieuwpoort IC, Arwert LI, Heymans MW, Franken AA, Koppeschaar HP, van der Lely AJ, Drent ML. Does growth hormone replacement therapy reduce mortality in adults with growth hormone deficiency? Data from the Dutch National Registry of Growth Hormone Treatment in adults. J Clin Endocrinol Metab. 2011 Oct;96(10):3151-9.
136. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993 Dec 2;366(6454):461-4.
137. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 1997 Oct 30;389(6654):994-9.
138. Lin K, Dorman JB, Rodan A, Kenyon C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science. 1997 Nov 14;278(5341):1319-22.
139. Dillin A, Crawford DK, Kenyon C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science. 2002 Oct 25;298(5594):830-4.
140. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92.
141. Anselmi CV, Malovini A, Roncarati R, Novelli V, Villa F, Condorelli G, Bellazzi R, Puca AA. Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res. 2009 Apr;12(2):95-104.
142. Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv E; Study of Osteoporotic Fractures. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell. 2009 Aug;8(4):460-72.
143. Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2700-5.
144. Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, Li W, Zheng GY, Cui H, Chen X, Zhu Z, He H, Dong B, Mo X, Zeng Y, Tian XL. Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations.Hum Mol Genet. 2009 Dec 15;18(24):4897-904.
145. Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, Bohr VA, Christiansen L. Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell. 2010 Dec;9(6):1010-7.
146. Kleindorp R, Flachsbart F, Puca AA, Malovini A, Schreiber S, Nebel A.
Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human
longevity in Germans. Aging Cell. 2011 Aug;10(4):622-8.
147. McCormick MA, Tsai SY, Kennedy BK. TOR and ageing: a complex pathway for a complex process. Philos Trans R Soc Lond B Biol Sci. 2011 Jan 12;366(1561):17-27.
148. Blagosklonny MV. Aging is not programmed: genetic pseudo-program is a shadow of developmental growth. Cell Cycle. 2013 Dec 15;12(24):3736-42.
149. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006 Feb 10;124(3):471-84. Review.
150. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5.
151. Wang M, Miller RA. Augmented autophagy pathways and MTOR modulation in fibroblasts from long-lived mutant mice. Autophagy. 2012 Aug;8(8):1273-4.
152. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013 Jan 17;493(7432):338-45
153. Stout MB, Tchkonia T, Pirtskhalava T, Palmer AK, List EO, Berryman DE, Lubbers ER, Escande C, Spong A, Masternak MM, Oberg AL, LeBrasseur NK, Miller RA, Kopchick JJ, Bartke A, Kirkland JL. Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY). 2014 Jul;6(7):575-86.
154. Sadagurski M, Landeryou T, Cady G, Kopchick JJ, List EO, Berryman DE, Bartke A, Miller RA. Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice. Aging Cell. 2015 Dec;14(6):1045-54.
155. Bartke A. Healthspan and longevity can be extended by suppression of growth hormone signaling. Mamm Genome. 2016 Aug;27(7-8):289-99.
156. Murakami S. Stress resistance in long-lived mouse models. Exp Gerontol. 2006 Oct;41(10):1014-9.
157. Fulda S, Gorman AM, Hori O, Samali A. Cellular stress responses: cell survival and cell death. Int J Cell Biol. 2010;2010:214074.
158. Masternak MM, Panici JA, Bonkowski MS, Hughes LF, Bartke A. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J Gerontol A Biol Sci Med Sci. 2009 May;64(5):516-21.
159. Sonntag WE, Lynch CD, Cefalu WT, Ingram RL, Bennett SA, Thornton PL, Khan AS. Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals. J Gerontol A Biol Sci Med Sci. 1999 Dec;54(12):B521-38. Review.
160. Bartke A, Brown-Borg H, Kinney B, Mattison J, Wright C, Hauck S, Coschigano K, Kopchick J. Growth hormone and aging. J Am Aging Assoc. 2000 Oct;23(4):219-25.
161. Richardson A, Liu F, Adamo ML, Van Remmen H, Nelson JF. The role of insulin and insulin-like growth factor-I in mammalian ageing. Best Pract Res Clin Endocrinol Metab. 2004 Sep;18(3):393-406. Review.
162. Rincon M, Rudin E, Barzilai N. The insulin/IGF-1 signaling in mammals and its relevance to human longevity. Exp Gerontol. 2005 Nov;40(11):873-7.
163. Markowska AL, Mooney M, Sonntag WE. Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience. 1998 Dec;87(3):559-69.
164. Sonntag WE, Lynch C, Thornton P, Khan A, Bennett S, Ingram R. The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing. J Anat. 2000 Nov;197 Pt 4:575-85. Review.
165. Ramsey MM, Weiner JL, Moore TP, Carter CS, Sonntag WE. Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning. Neuroscience. 2004;129(1):119-27.
166. Panici JA, Harper JM, Miller RA, Bartke A, Spong A, Masternak MM. Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. FASEB J. 2010 Dec;24(12):5073-9.
167. Yuan R, Tsaih SW, Petkova SB, Marin de Evsikova C, Xing S, Marion MA, Bogue MA, Mills KD, Peters LL, Bult CJ, Rosen CJ, Sundberg JP, Harrison DE, Churchill GA, Paigen B. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell. 2009 Jun;8(3):277-87.
168. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998 Jan 23;279(5350):563-6.
169. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000 Sep 20;92(18):1472-89. Review.
170. Swerdlow AJ, Higgins CD, Adlard P, Preece MA. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet. 2002 Jul 27;360(9329):273-7.
171. Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004 Apr 24;363(9418):1346-53. Review.
172. Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007 Feb;28(1):20-47.
173. Chhabra Y, Waters MJ, Brooks AJ Role of the growth hormone-IGF-1 axis in cancer. Expert Rev. Endocrinol. Metab. 2011;6:71–84.
174. Mukhina S, Mertani HC, Guo K, Lee KO, Gluckman PD, Lobie PE. Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15166-71.
175. Steuerman R, Shevah O, Laron Z. Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol. 2011 Apr;164(4):485-9.
176. Dalle C, Claude V. Growth hormone for “antiaging”. JAMA. 2006 Feb 22;295(8):889; author reply 889-90.
177. Banerjee I, Clayton PE. Growth hormone treatment and cancer risk. Endocrinol Metab Clin North Am. 2007 Mar;36(1):247-63. Review.
178. Swerdlow AJ, Reddingius RE, Higgins CD, Spoudeas HA, Phipps K, Qiao Z, Ryder WD, Brada M, Hayward RD, Brook CG, Hindmarsh PC, Shalet SM. Growth hormone treatment of children with brain tumors and risk of tumor recurrence. J Clin Endocrinol Metab. 2000 Dec;85(12):4444-9.
179. Tacke J, Bolder U, Herrmann A, Berger G, Jauch KW. Long-term risk of gastrointestinal tumor recurrence after postoperative treatment with recombinant human growth hormone. JPEN J Parenter Enteral Nutr. 2000 May-Jun;24(3):140-4.
180. Svensson J, Bengtsson BA, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004 Jul;89(7):3306-12.
181. Pollak M, Blouin MJ, Zhang JC, Kopchick JJ. Reduced mammary gland carcinogenesis in transgenic mice expressing a growth hormone antagonist. Br J Cancer. 2001 Aug 3;85(3):428-30.
182. Ramsey MM, Ingram RL, Cashion AB, Ng AH, Cline JM, Parlow AF, Sonntag WE. Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. Endocrinology. 2002 Oct;143(10):4139-42.
183. Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA. Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci. 2004 Dec;59(12):1244-50.
184. Majeed N, Blouin MJ, Kaplan-Lefko PJ, Barry-Shaw J, Greenberg NM, Gaudreau P, Bismar TA, Pollak M. A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. Oncogene. 2005 Jul 7;24(29):4736-40.
185. Giordano R, Bonelli L, Marinazzo E, Ghigo E, Arvat E. Growth hormone treatment in human ageing: benefits and risks. Hormones (Athens). 2008 Apr-Jun;7(2):133-9.