Growth Hormone Conference: Forestalling The Inexorable Changes Associated with Aging

This key conference on growth hormone therapy, drawing some of the most distinguished names in the field, laid out the significant linkages between the frailties of aging and the decline in GH.

How far along are we in harnessing the power of growth hormone and related natural substances to combat the consequences of aging? Some 100 of the world's leading growth hormone scientists convened at a site near the National Institutes of Health in Bethesda, Md., April 14-15, to explore a key piece of this puzzle, at a conference titled "Assessment of the Growth Hormone/IGF-1 Axis in Aging."

Recent studies have confirmed that aging is associated with a continuous decline in growth hormone (GH) production and secretion. The insulin-like growth factor (IGF) system is a key player in this equation.

Sponsored by the National Institute on Aging with corporate assistance, the meeting enabled researchers to pool their knowledge about how these substances affect the aging process, and to postulate as to how they might be harnessed to slow the detrimental effects that accompany aging.

The Somatopause: A Fact of Later Life?

Significantly, the tone of the conference was one of caution. Conference speaker Andrew R. Hoffman, M.D., reflected the majority view in noting that numerous beneficial effects on body composition, strength and quality of life have been reported in some studies, but that "other studies have reported only marginal functional improvements."

Moreover, he warned, it is clear that both growth hormone and its partner, insulin-like growth hormone factor-1 (IGF-1), can cause significant morbidity, meaning that complications and even illness can result from GH therapy in certain instances.

Dr. Hoffman is with Stanford University and the VA Palo Alto Health Care System, and is one of nine National Institute on Aging grantees directing long-term studies of the effects and safety of growth hormone and related substances. He noted that "the decline of the function of the GHRH/GH/IGF-1 axis has been termed the somatopause."

Much of the bodily breakdown have been attributed to the decrease in circulating GH and IGF-1. In order to pursue the possibility of hormone replacement therapy for the somatopause, researchers have given elderly subjects GH, IGF-1, or both hormones together.

Clues to Therapeutic Intervention

Clifford J. Rosen, M.D., was conference chair. Chief of medicine at St. Joseph Hospital and research professor of nutrition at the University of Maine, Bangor, Rosen said that the advent of recombinant technology -- that is, for example, GH, IGF-1, IGF-1 coupled to IGFBP-3 (IGFBP being insulin-like growth factor binding protein), and the synthesis of innovative GH secretagogues -- has led to a vast array of potential anabolic agents.

Secretagogues are agents that stimulate secretion, in this case the natural secretion of growth hormone.

"These compounds may provide an unprecedented opportunity for investigators to attempt to forestall some of the inexorable changes associated with frailty in the elderly," said Rosen.

Anabolic treatment for elders with recombinant human growth hormone (rhGH) or insulin-like growth factor-1 (rhIGF-1) is a tantalizing possibility that still remains both experimental and controversial.

Following the opening remarks, J.D. Veldhuis, M.D., of the University of Virginia Health Sciences Center in Charlottesville, gave an intriguing talk on "Elements in the Pathophysiology of Diminished Growth Hormone Secretion in Aging Humans: Altered GH/IGF-1 Network Control." He fingered obesity, especially visceral fat, and lack of exercise as two major players in the pathophysiology of diminished GH secretion in aging people.

Noting a "very strong interaction between the aging process and body composition," he reported that obesity very strongly suppresses GH secretion. Intra-abdominal fat is one of the chief negatives linked to lowered GH levels.

Age And Gender Impacts GH Release

In addition, whereas GH release is characterized by a rhythmical pulsation, studies indicate that age markedly disrupts and gender modulates the orderliness of the 24-hour GH release process. Forms of growth hormone-releasing protein (GH-RP) partially restore GH secretion and increase plasma IGF-1 concentrations in older men and women.

Concluded Dr. Veldhuis, "The pathophysiology of diminished GH secretion in aging humans is confounded by important secondary variables such as body composition, gender, sex-steroid hormone concentrations, aerobic capacity, etc., and likely reflects the combined impact of deficient GH-RH stimulation and excessive somatostatin inhibition of somatotrophs. Greater disorderliness of GH release patterns in aging further suggest disruption of network coordination with the GH-RH/somatostatin/GH/IGF-1 axis."

GH Secretagogues as Therapeutic Agents in Aging

Considerable interest is being evoked by the actions of GH secretagogues, which stimulate the body's own GH secretion. Researcher George R. Merriam, M.D., of the University of Washington school of medicine, noted that "the aging pituitary remains responsive to these compounds." As a result, they are being studied both as potential probes for assessing the GH axis and as "potential therapeutic agents for enhancing endogenous GH as an alternative to GH administration."

Merriam cited several advantages that secretagogues appear to offer, including:

- Preserving feedback modulation of patient growth hormone responses;

- Generating a pulsating pattern of growth hormone-releasing; and

- Offering the ability to be given orally.

Two general classes of growth hormone secretagogues are attracting the most attention among scientists: growth hormone-releasing hormone, and the peptide and non-peptidyl ligands for the growth hormone-release protein receptor.

Dr. Merriam termed the oral activity of the growth hormone-releasing proteins "a clear practical advantage." While GH response to secretagogues may be blunted by obesity and increased somatostatin tone, various enhancing agents -- for example, beta-adrenergic antagonists, arginine, and the combination of GH-RH and GH-RPs -- can boost this response.

The jury is still out concerning the benefit/risk results of GH secretagogue treatment, and awaits further results.

Thomas R. Ziegler, M.D., of Atlanta's Emory University Medical School and Hospital, reported on the importance of complex interactions between nutrition and human growth hormones. He noted that growth factors, general nutritional status, and specific nutrients are interactive in protein and tissue anabolism...the process by which the body converts substances into other components of its chemical architecture.

He noted that both general nutritional status and administration of specific nutrients help regulate internal production of nutrients, as well as plasma concentrations of IGF-1 and certain IGFBPs.

Stressing the importance of good, and informed, nutrition, Ziegler told his audience that deficiencies of zinc, magnesium, potassium and/or thiamine can damage the circulating IGF system.

Zinc depletion is common in hospitalized patients, as well as in those suffering catabolism, a destructive process by which the body converts substances into excreted compounds. Ziegler said zinc depletion is associated with poor wound healing, reduced protein synthesis, immunosuppression, diarrhea, dermatitis and reduced gonadal steroid concentrations. Zinc levels have been shown to markedly influence the GH/IGF-1 axis.

Monitoring Micronutrients in the Elderly

"Many elderly people have full-body potassium and magnesium depletion," he noted. In addition, many are zinc-deficient. He recommended that physicians monitor the levels of these micronutrients in their patients, especially in elderly patients who are on a continuous treatment of diuretics, and also those who have chronic disability, look malnourished, have been experiencing weight loss, and/or exhibit elements of wasting. If deficiencies are found in any of the above minerals, supplementation should be started, as medically indicated.

Several lines of evidence support the concept that nutrient metabolism and IGF system physiology are interactive. He added that the energy source seems to play a role in growth hormone activity. "A high carbohydrate diet," he said, "is superior to a lipid diet." Ziegler concluded that adequate intake of certain nutrients appears to be critical to ensure optimal anabolic responses mediated by the GH/IGF-1 action pathway.

On the Horizon: GF/IGFBP-3 Potential Therapeutic Utility

Zeroing in enthusiastically on this topic was Steve Adams, Ph.D., from Celtrix Pharmaceuticals. Adams told of Celtrix research on a novel IGFBP-3 complex that the company has named SomatoKine, which has been found to have "exciting anabolic effects" in animal models. Studies are under way to refine the specific dosage needed for optimum results with a minimum risk of side effects such as headache and nausea. The most promising dosages, currently under investigation, are 0.5 and 1.0 milligram per kilogram of body weight per day, which appears to be "very well-tolerated."

Celtrix scientists have successful completed three phase-one human clinical studies of SomatoKine, demonstrating, according to Celtrix, not only safety at high doses but also biological activity in the elderly. Phase-two clinical feasibility studies are currently in progress for recovery from hip fracture surgery. Additional treatment targets include severe burns, osteoporosis and wasting diseases associated with cancer, AIDS and other life-threatening conditions.

Adams warned that IGF-1 administration can cause hypoglycemia.

Preceding Dr. Adams' presentation was a talk by endocrinologist Marie C. Gelato, M.D., of State University of New York, Stony Brook. She noted that IGFBP-3 is the major binding protein (BP) in serum and circulates as a large molecular weight (150kDa) ternary complex. This BP complex may be a major reservoir of IGFs in circulation available for use by the organism during stress, she said.

A round table followed on "The Use of Serum IGFBPs to Assess Disease Status in the Elderly." During the lively question-and-answer period, Gelato noted that in the elderly, insulin affects BP production and synthesis because of mild insulin resistance. IGFBP-3 problems, she said, are changes that occur late in the disease state, as the individual has become more compromised.

"Once you lose that functional pool, you're on the way down" unless there is effective intervention, she said.

During the ensuing break for lunch, Life Extension magazine spoke with Claes Ohlsson, M.D., Ph.D. Asked about the troubling side-effect of carpal tunnel syndrome in some GH therapy investigations, he said this was probably caused by the GH-increased bone density and edema, and added that the level of supplementation needs to be adjusted. "This [carpal tunnel syndrome] problem with GH administration," he said, "is not seen in GH-deficient patients, as opposed to `normal' elderly."

Ohlsson has been on loan to the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) for the past year and will be returning to his native Scandinavia this summer.

Chronic Inflammation

During a later Q&A session, Tamara M.S. Harris, M.D., of the National Institute on Aging, spoke about the effects of chronic inflammation on the GH system, which, thus impacted, could then retard recovery. Gelato added that BP1 "goes up quickly in ill people and stays up."

Derek LeRoith, M.D., Ph.D., chief of the diabetes branch of the NIDDK, presented findings of his research on the effects of IGF-1 in inhibiting apoptosis (programmed cell death), with the implication that IGF-1 may promote cell survival and be therapeutically relevant to neurodegenerative disorders.

NIDDK and studies elsewhere "confirm the importance of IGFs and the IGF-1R in nervous tissue function and particularly in neuronal survival," noted LeRoith. Furthermore, he said, these results suggest "a possible therapeutic role for the IGFs in nervous tissue disorders such as degenerative diseases and ischemia (deficiency of blood supply) with secondary apoptosis, both prevalent in aging."

Youngman Oh, Ph.D., of the Oregon Health Sciences University in Portland, reported that the IGF system plays an important role in the neoplastic process.

"Aberrant expression of IGFs and type 1 IGF receptor is involved in deregulation of cell growth and, to some extent, transformation and tumorigenesis (the production of tumors)," he said. Many tumors and neoplastic cells also produce IGFBPs, which can regulate the biological activity of the IGFs in those cells. Breast cancer cells also secrete various types of IGFBPs.

The Mayo Clinic's Cheryl Conover, Ph.D., said that the IGFs are "potent anabolic agents, structurally related to insulin, that bind to specific membrane receptors and influence a variety of normal growth processes."

The IGFs have an established role in many of the organ-specific areas where age-related changes are prominent, she said, including bone, muscle and skin. Unlike insulin, these peptides associate with special binding proteins (IGFBPs) that can modulate IGF action in diverse and distinctive ways that we are only beginning to appreciate.

Conover predicted that, with increasing availability of recombinant proteins, antibodies, and other genetic tools related to various components of the IGF system, "this information may have important therapeutic value in geriatric medicine."

P53, IGFBP-3, and Cellular Senescence

Nikolai Kley, Ph.D., of Boston's Genome Therapeutics Corp., offered a sobering discussion of the interaction of p53, IGFBP-3 and cell aging. IGF-1, which has so many other good properties, is unfortunately an ally of the production of tumors. The very property that makes IGF-1 so attractive as a possible therapy -- enhancing cell growth and lifespan -- is the one that portends dangers by enabling tumorigenesis.

Ordinarily, cancerous cells are attacked and, when we are lucky, killed by the body's defenses; when additional IGF-1 is introduced into the equation, however, those defenses are weakened and the diseased cells get a new lease on life.

An abstract of Kley's prepared remarks noted that the "loss or functional inactivation of tumor suppressor genes seems to be one of the most fundamental genetic mechanisms of tumorigenesis."

Kley noted that "Elucidation of novel pathways downstream of the p53 tumor suppressor protein has led to the identification of new targets whose inhibition appears to be associated with the reversal of the malignant phenotype, such as inhibition of the IGF-1 receptor that is linked to the p53 via trans activation of IGFBP-3."

GH, the IGF System, and Osteoporosis

Robert Marcus, M.D., of Stanford University, stated, "The possibility that GH might be anabolic to bone is attractive because the hormone directly stimulates osteoblastic functions." Deficits in bone mineral density (BMD) observed in GH-deficient adults are particularly striking when GH deficiency emerged during childhood. Uncertainty persists over the BMD response to GH replacement by adults with acquired GH-deficiency.

Some, but not all, recent studies indicate eventual increases in bone mineral density with growth hormone replacement, sometimes to a substantial and clinically meaningful degree, Marcus said. Using recombinant GH, his research group reported that findings from seven days of GH administration to healthy older people suggested that bone remodeling had been activated.

One six-month trial in elderly men found that growth hormone increased spine bone mineral density by 1.6 percent. However, other studies have failed to replicate this result.

Subburaman Mohan, Ph.D., and colleagues at the V.A. Medical Center in Loma Linda, Calif., are studying the role of the IGF system in age-related impairment of bone formation. They propose a model in which, 1) underproduction of the stimulatory components and overproduction of an inhibitory component of the IGF system occur as a consequence of aging; and 2) these changes lead to an age-related decrease in the local (autocrine/paracrine) as well as hormonal (endocrine) actions of the IGFs, which in aggregate could contribute to the decrease in osteoblast cell proliferation and deficiency in bone formation.

K. Sreekumaran Nair, M.D., Ph.D., of the Mayo Clinic, said that sarcopenia of aging, characterized by a decline in muscle mass and strength and increased fatigue, is related to a decline in growth hormone, IGF-1, and DHEA levels in both men and women and free testosterone levels in men. Insulin resistance also plays a role.

Sarcopenia of Aging

Seeking to determine the mechanism of sarcopenia, he and his colleagues measured synthesis rates of specific muscle proteins in young, middle-aged, and old subjects. These studies found an age-related decline in mitochondrial protein synthesis, which occurs by middle age.

"It is likely," he said, "that the ability to produce ATP by mitochondria is the cause of the decline in endurance capacity." Decline in muscle mass and strength in aging could be explained on the basis of declining muscle protein synthesis.

Stephen E. Borst, Ph.D., of the V.A. Medical Center and the University of Florida, Gainesville, prophesied that a useful strategy will be found for restoring muscle mass and strength to the frail elderly. He noted that after the initial findings of Dr. Daniel Rudman of the Medical College of Wisconsin and his associates, there was optimism for the use of growth hormone in reversing the losses in strength and functional independence that often accompany aging. Borst warned, however, about findings that question whether the GH/IGF pathway can be stimulated safely, given the number of unexplained adverse effects.

Exploring Ways to Lessen the Side Effects of GH

The potential of growth hormone therapy acknowledged by presenters at the "Assessment of Growth Hormone" conference in Bethesda was tempered by caution.

While Mark Stene, Ph.D., with Endocrine Sciences in Calabasas Hills, Calif., foresees an oral growth hormone preparation on the near horizon, perhaps in a few years, scientists continue to pursue a conservative approach to what they consider indiscriminate growth hormone supplementation, especially when not supervised by a physician.

Possible dangers include cancer, blood pressure reduced to dangerous and perhaps life-threatening levels, congestive heart disease, uncontrolled bleeding, carpal tunnel syndrome, reduced insulin sensitivity, hypoglycemia, severe gastrointestinal problems, gynecomastia (excessive growth of the male mammary glands) and edema.

It is only with time and continued study, many researchers said, that we can hope to isolate those possible dangers from the potential good effects of growth hormone therapy.

Clifford J. Rosen, M.D., conference chairman, noted that some of the noted side effects could possibly be avoided by administering oral growth hormone secretagogues or systemic IGF-1 bound to IGFBP-3

However, Rosen cautioned that the long-term consequences of GH or IGF-1 therapy in older individuals still are not known. There is considerable concern that chronically high ("young normal") levels of IGF-1 could increase the risk of cancer. Hence, the potential to counter frailty and improve quality of life for elders by giving them growth hormone or growth hormone secretagogues "requires far more investigation," especially with respect to safety.

Marc Blackman, M.D., of Johns Hopkins University Medical Center in Baltimore, Md., said that, since even "so-called low-dose growth hormone supplementation has a high side-effect profile, the way to go, if we're going to give back repletion of the GH/IGF-1 axis, is not growth hormone, but rather secretagogues of some form." He noted that secretagogues are more likely to lead to positive physiological effects, and also are less apt to be associated with adverse side effects.

Stephen E. Borst of the V.A. Medical Center and the University of Florida, warned that "the drawbacks of GH therapy have now become clear. GH causes side effects, even at doses which do not excessively elevate IGF-I." Even though GH increases lean mass, it does not increase muscle mass or strength in the healthy elderly. To date, he said, GH administration has not proven effective in stimulating the GH-IGF pathway to increase strength in the elderly. Possible strategies for doing this include IGF-1, as well as IGF-1 in combination with either GH or IGFBPs. GH and IGF-1 have greater anabolic actions in combination than does either agent alone. Combination therapy would allow for lower doses and fewer side effects.

Life Extension Foundation.

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By Doris Margolis

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