Growth Hormone (GH/IGF−1) Replacement

by Ben Best

Growth Hormone (GH) levels in the blood decline about 14% per decade after age 25 due to decreased GH releasing hormone. Additionally, much as insulin resistance increases with age, GH receptors become less responsive to GH with aging ("GH resistance"). GH decline is blamed for much age-related adiposity as well as loss of muscle mass & bone mineral.

Attempts have been made to use GH injections to restore youthful bone & muscle in a manner analogous to anabolic steroids, but without the negative side effects. In the initial trials increased muscle mass & bone strength was acheived, but was associated with edema and pain in joints & muscles. The doses had been calculated by extrapolation by weight from doses used on children lacking GH, but when dosage levels were reduced, the side effects mostly disappeared.

Many of the effects of GH are due to IGF−1 (Insulin-like Growth Factor−1), which is produced in the liver as a result of GH stimulation and is also produced in exercised skeletal muscle to increase growth of the muscle. But although exercise can increase GH and IGF−1 concentrations in healthy young subjects, no such effect is seen for older subjects (who benefit, nonetheless, from increased aerobic capacity, muscle strength and fat-free mass) [JOURNALS OF GERONTOLOGY; Vitiello,M; 52A(3):M149-M154 (1997)].

Men and women taking GH replacement therapy showed lower serum LDL cholesterol and lower LDL/HDL ratios, reduced body fat and increased lean mass [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Hoffman,AR; 89(5):2048-2056 (2004)]. IGF−1 improvement in vascular density can reduce age-associated ischemia in the heart & brain [JOURNAL OF ANTI-AGING MEDICINE; Sonntag, WE; 4(4):311-329 (2001)]. GH replacement significantly reduced plasma inflammatory cytokines (IL-6 & TNF-alpha) [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Serri,O ; 84(1):58-63 (1999)].

GH/IGF−1 has a positive effect on immune system function. IGF−1 appears to stimulate the activity of Natural Killer (NK) cells [ENDOCRINOLOGY; Auernhammer,CJ; 137(12):5332-5336 (1996)]. IGF−1 decline may cause much of the decline in T-lymphocyte activity with aging [CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY 88(3):264-270 (1998)]. In fact, GH/IGF−1 replacement can reverse the age-related involution of the thymus gland [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Khorram,O; 82(11):3590-3596 (1997)].

In one study, centenarians showed a higher than expected incidence of loss-of-function mutations in IGF−1 receptor genes [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Suh,Y; 105(9):3438-3442 (2008)]. Nonetheless, centenarians with lower IGF−1 plasma levels show greater degrees of cognitive impairment than those with higher IGF−1 [JOURNALS OF GERONOTOLOGY; Arai,Y; 56A(2):M79-M82 (2001)]. IGF−1 replacement in senescent rats restores neurogenesis in the hippocampus [NEUROSCIENCE; Lichtenwalner,RJ; 107(4):603-613 (2001)] and increases brain glucose utilization [ENDOCRINOLOGY; Lynch,CD; 142(1):506-509 (2001)]. IGF−1 counteracts declining neurogenesis in the hippocampus with age and has been shown to improve performance by older men in cognitive tests [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Aleman,A; 84(2):471-475 (1999)], which is puzzling in light of the studies demonstrating improved cognitive parameters in GH-depleted mice [HORMONES AND BEHAVIOR; Kinney,BA; 72(5):653-660 (2001)]. IGF−1 is very prominent in brain development.

GH reduces insulin sensitivity [THE JOURNAL OF CLINICAL INVESTIGATION; Clemmons,DR; 113(1):25-27 (2004)], which raises concerns about the potential for adult-onset diabetes with GH replacement. IGF−1 improves insulin sensitivity so much that it has been used in diabetes therapy [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Crowne,EC; 86(6):3686-3691 (2001)].

Despite concerns about possible GH promotion of cancer, in 1997 the FDA approved adult GH replacement therapy for Genentech. IGF−1 is a mitogenic, antiapoptotic growth factor that has been shown to be a risk factor for prostate cancer [SCIENCE; Chan,JM; 279:563-566 (1998)] as well as for cancer of the breast, lung and gastrointestinal tract [ENDOCRINE REVIEWS; Khanduala,HM; 21(3):215-244 (2000)]. CRAN (Caloric Restriction with Adequate Nutrition) animals (which have reduced IGF−1 blood levels and increased longevity) show a 6-fold increase in cancer cell proliferation when IGF−1 serum levels are artificially restored to "normal" [CANCER RESEARCH; Dunn,SE; 57(21):4667-4672 (1997)]. (Fasting reduces both IGF−1 & GH in rats, but does not reduce GH in humans [AMERICIAN JOURNAL OF PHYSIOLOGY; Frystyk,J; 277(2 Pt 1):E245-E252 (1999)].

GH replacement therapy for aging adults probably is an exchange of short-term benefits for long-term harms. Short-term improved bone and muscle condition (and other such benefits) must be weighed against increased insulin resistance and risk of cancer. Acromegaly patients (who have abnormally high GH) have low life expectancy due to a high incidence of diabetes, cardiovascular disease and (by some accounts) cancer. Transgenic mice with low growth hormone — or reduced growth hormone sensitivity — show increased longevity and reduced cancer incidence (see LONGEVITY GENES).

A convincing case has been made that CRAN operates by evolutionarily-conserved mechanisms of nutrient-sensing molecular pathways (insulin/IGF-1) in yeast, worms, flies, and mammals [SCIENCE; Fontana,L; 328:321-326 (2010)]. CRAN does not increase insulin sensitivity or extend the lifespan of Growth-Hormone Receptor Knock-out mice, suggesting that insulin sensitivity plays a key role in life extension by CRAN [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Bonkowski,MS; 103(20):7901-7905 (2006)]. Exercise, however, increases insulin sensitivity without increasing maximum lifespan [AGE; Fontana,L; 32(1):97-108 (2010)]. Reduced body size within a species often correlates with longer lifespan and reduced plasma IGF−1. Great Danes (400 ng/mL plasma IGF−1) live about 7 years, whereas Chihuahuas (40 ng/mL plasma IGF−1) can live over 15 years. Insulin increases IGF-1 activity by lowering serum IGF-binding protein [JOURNAL OF BIOLOGICAL CHEMISTRY; Powell,DR; 266(28):18868-18876 (1991)].

Longevity in humans is correlated with a genetic predisposition to low plasma IGF-1 [JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Bonafe,M; 88(7):3299-3304 (2003)]. Rodents consistantly show reduced plasma IGF-1 on CRAN, but for humans plasma IGF-1 is reduced by protein restriction, not calorie restriction [AGING CELL; Fontana,L; 7(5):681-687 (2008)]. Rhesus monkey studies suggest that the lifespan increase seen with CRAN in other species applies to primates, but the rhesus monkey studies are still in progress [SCIENCE; Roth,GS; 297:811 (2002)].

Humans who have practiced CRAN for about six years show considerable reduction in risk factors for atherosclerosis, including reduced LDL-cholesterol, increased HDL-cholesterol, reduced serum triglycerides, and reduces systolic and diastolic blood pressure [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Fontana,L; 101(17):6659-6663 (2004)]. It is also to be expected that CRAN reductions of inflammatory cytokines and growth factors would result in reduced cancer in humans, as has been seen in rodents and monkeys [TRENDS IN PHARMACOLOGICAL SCIENCES; Longo,VD; 31(2):89-98 (2010)].

DHEA may be a safer means of raising serum IGF−1 than growth hormone replacement.