CLINICAL STUDIES  - ADDITIONAL INFORMATION      

 

 

Part One:

Summary

 

One of the frontiers of current medical science is the challenge of slowing down the process of aging in an effort to prolong life and combat the debilitation caused by aging-related disorders. In this arena, human growth hormone (GH) therapy has gained both prominence and notoriety. The natural decline of growth hormone levels with age has provided a rationale for anti-aging therapies that are based on regenerating growth hormone levels in the body.

 

However, treatment using recombinant growth hormone has been criticized for its enhanced cancer risk, primarily through its potential to increase concentrations of its hepatic metabolite, IGF-1 (insulin-like growth factor 1) to physiologically harmful levels. IGF-1 is an antiapoptotic promoter of cellular proliferation, and is present in high concentrations during the initial stages of cancer. A clear need, therefore, exists for GH-based therapies that address this important safety concern, accompanied with detailed clinical validation.

 

Renouva* is a transdermally administered analog of growth hormone releasing hormone (GHRH). GHRH is manufactured in the hypothalamus, and is the natural stimulant that promotes human growth hormone release from the pituitary. Through its mimicry of GHRH, Renouva indirectly boosts endogenous growth hormone production, vastly improving on the efficacy and safety when compared to recombinant growth hormone therapy. In an effort to quantify the remarkable properties of Renouva in humans, a series of clinical trials have been conducted as follows:

•A pilot study on 30 patients that studies several subjective parameters;

•A small clinical study on 53 patients that evaluates the efficacy of GH release and suppression of IGF-1 production;

•An 8-week long exhaustive, multi-centered, double blind, placebo-controlled clinical study on 117 patients that measures GH release, IGF-1 suppression and several other biochemical/hematological parameters.

These clinical studies have shed light on the ability of Renouva to maintain sustained growth hormone release at optimum physiological concentrations, while simultaneously suppressing the levels of IGF-1. This has broken through the commonly held paradigm that high serum GH leads to increased levels of IGF-1. It should be noted that the high GH and low IGF-1 levels prevalent in youth, naturally and inversely change to low GH and high IGF-1 levels with the progress of age.

 

Renouva seeks to reverse that trend, and brings us one step closer to the proverbial “fountain of youth”.

 

 

Part Two:

Introduction

 

One of the ultimate frontiers of medical science is the victory over the process of aging. The ability to reduce physiological age vis-`-vis chronological age would enable people to not only prolong, but also improve the quality of their lives. A youthful physiology is characterized by an abundance of human growth hormone (GH), a marker that is shown to steadily decline with increasing age. Growth hormone therapy has consequently gained prominence as a therapeutic measure to control the aging process. However, GH is known to undergo hepatic conversion into the mitogen, type 1 insulin-like growth factor (IGF-1) (see Figure 1). Mounting evidence, indicates that in the early stages of cancer, higher levels of circulating serum IGF-1 are present, either through its enhanced production or via the downregulation of the IGF-1 receptor. This implies that artificially raising GH levels in the body should be viewed with caution.

 

How can growth hormone therapy be safely applied to anti-aging strategies? The answer to this question lies in properly understanding the mechanism that controls the growth hormone concentrations in the serum: the hypothalamic-pituitary axis (HPA) (Figure 1). The hypothalamus produces two key substances, somatostatin and growth hormone releasing hormone (GHRH). Acting on the pituitary, somatostatin inhibits and GHRH stimulates the release of endogenous growth hormone. With that knowledge, it is logically possible to control growth hormone levels in the body by either (a) exogenous administration of artificially prepared growth hormone, or (b) tweaking the inhibitory or stimulatory effector system of the HPA.

 

One of the challenges faced by exogenous GH therapy is the natural body regulatory mechanism that counteracts increasing GH levels through an inhibitory feedback loop. The balance shifts from stimulation with GHRH to inhibition by somatostatin, thereby creating a potentially chronic inhibitory state over time, dangerously depleting natural GH reserves in the pituitary.

 

It is conceivable that stimulation of the HPA towards maximizing its production of endogenous GH may be a much better and safer alternative than exogenous administration. This strategy would be expected to have the following advantages over conventional GH therapy:

•Optimization of the endogenous GH levels within the physiological limits of the system;

•Improvement of GH stores in the pituitary for continued release;

•Minimization of the negative feedback loop by providing a source of pituitary stimulation;

•No undesired stimulation of potentially harmful levels of IGF-1, as has been reported for recombinant GH therapy.

 

 

 

 

 

 

Figure 1. The Hypothalamic-Pituitary Axis: The regulation of endo-genous growth hormone

 

In practice, this form of GH therapy is achieved through the administration of GHRH analogs. Currently, only two clinically validated GHRH analogs are commercially available. The first one is Geref, a 22 amino acid analog of GHRH, produced by Serono Labs in Nowell, MA.

 

The second GHRH analog is Renouva. Renouva is a polypeptide combinant, consisting of four different naturally conjugated amino acid sequences that are not recombinant in nature. Unlike Geref which is administered via subcutaneous injection, Renouva has the distinct advantage of being administered non-invasively through transdermal delivery.

 

Clinical trials described here have shed light on the remarkable properties of Renouva. In a nutshell, Renouva treatment clearly exceeds the expectations of the idealized GH therapy by increasing endogenous GH levels without stimulating the inhibitory feedback loop, and by actually suppressing the production of IGF-1.

 

Part Three:

What about IGF-1?

 

IGF-1 (Type 1 Insulin-like growth factor) is a product of the biotransformation of growth hormone that takes place in the liver. According to a commonly held belief, growth hormone activity manifests itself through the action of IGF-1 to the extent that IGF-1 levels are quite commonly used to monitor the progress of GH treatment. There is a growing consensus that this relationship is false, since low levels of IGF-1 are not correlated with growth hormone deficiency and IGF-1 levels have been shown to be modulated by factors completely independent of GH levels. In the clinical studies profiled here, endogenous GH levels have been measured independent of IGF-1 levels using a radioimmunoassay method.

 

On the other end of the consensus, increasing pathophysiological correlation has been discovered between high IGF-1 levels and the development of cancer. Interestingly, these findings also argue against a correlation between IGF-1 and GH levels, since the peak period of endogenous GH levels, i.e. adolescence, would then also coincide with a peak in cancer cases. The reality is that cancer afflicts a much larger percentage of the older population where GH activity has naturally declined, but not necessarily IGF-1 levels.

 

While the amino acid sequences of IGF-1 and insulin are extremely similar, it is also remarkable that, even though they are flexible polypeptides, they show strong similarities in their crystallographic secondary structure (see figure on left). In addition to that, their receptor sites are also interchangeably identical. This suggests a close functional relationship between the two sequences.

 

Similarity in secondary X-ray structures of IGF-1 (left) and insulin (right) (PDB codes: 1IMX, 1ZNI)

 

This relationship can be best understood by examining the role of physical activity in promoting longevity. The physiological impact of exercise includes the increase of levels of hormones in general (including GH), increase in lean body mass, a decrease in insulin levels, and an increase in insulin sensitivity. Higher insulin sensitivity implies that it takes less insulin to transport the same amount of glucose into cells. The higher metabolic rates of an exercising individual result in more efficient use of glucose, leading to lower levels of circulating glucose. All these factors combine to increase the longevity in an individual committed to regular physical activity, thus producing an anti-aging effect. In contrast, a sedentary person shows lowered insulin sensitivity, i.e. he/she requires higher insulin levels for the same level of processing, and thereby larger reserves of circulating glucose. These factors obviously do not promote longevity, making a sedentary lifestyle prone to the rapid advance of physiological age. The similar patterns observed for IGF-1 and insulin are illustrated in the study below3:

 

In a small clinical outcome based study, 38 patients yet unexposed to hormonal therapy were evaluated for their IGF-1 levels. The first set comprised of 21 sedentary male and female patients with no history of prior exercise with a mean age of 55.3 years, an age range between 30 and 84 years, and a median age of 57 years. The second set comprised 17 athletic male and female patients who were defined to have had regular activity including aerobic and resistance exercise every 48 hours for at least 2 years. The mean age of this group was 34.1 years, with an age range of 25 to 42 years, and a median age of 33.5 years.

 

A comparison of IGF-1 levels showed that the sedentary group had mean and median IGF-1 levels of 153 ng/ml and 182.5 ng/ml, respectively, while the same values for the athletic group were 149.4 ng/ml and 142.0 ng/ml, respectively. More revealing was a comparison of the range of IGF-1 values which varied from 61 – 304 ng/ml in the sedentary group, compared to a tighter range of 88 – 196 ng/ml in the athletic group.

 

In conclusion, higher levels of IGF-1 correlate well with advancing physiological age, but are controlled by several factors other than simply the serum levels of growth hormone. Any anti-aging strategy would clearly benefit from maintaining lowered levels of IGF-1 and insulin, a factor that becomes particularly important as we evaluate growth hormone based therapies. As demonstrated below, one of the strengths of Renouva therapy lies in its ability to reduce IGF-1 levels while increasing endogenous GH levels.

 

 

CLINICAL STUDIES - ADDITIONAL INFORMATION

RENOUVA CLINICAL STUDIES
(formally VitaLife)

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