We examined the effects of treatment with GHRH on cognition and serum IGF-1 level in healthy older adults and adults with amnestic MCI in light of our previous findings showing treatment benefits for those with lower baseline MMSE scores and reports by others linking lower IGF-1 levels with poorer cognitive performance.11,13,32–34
Five months of daily subcutaneous injections of GHRH increased circulating IGF-1 to young adult normal levels and had a favorable effect on executive function in adults with MCI and healthy older adults. A trend indicated a positive GHRH effect on verbal memory. Although treatment with GHRH reduced body fat and increased lean muscle mass, these effects did not modulate cognitive response.
To our knowledge, there are only 2 other randomized controlled studies examining the cognitive effects of an intervention that promotes natural stimulation of GH secretion in older adults: our first 5-month trial of GHRH administration in cognitively normal adults31
and a large, multisite 12-month trial of a ghrelin mimetic in patients with mild to moderate AD.59
In the present study, we used a different GHRH analog than that administered in our previous trial31
in light of its preferred safety profile and robust IGF-1–elevating effect, we refined the cognitive battery to better assess executive function and episodic memory, and we expanded the sample to include older adults with MCI. Although we cannot make head-to-head comparisons of GHRH effects on specific cognitive tests across our 2 trials, the therapeutic promise of GHRH is strengthened by the consistency of overall findings.
In the AD trial,59
the hormone administered was an orally active GH secretagogue (MK-677) and biologically similar to ghrelin, which is produced by the stomach. MK-677 increased serum IGF-1 concentrations by 73% at 12 months, but the results of the primary analyses indicated no treatment effects on disease progression as measured by standard outcomes in AD clinical trials. The results of the clinician-based assessment at 12 months, however, indicated a trend for improvement (P
= .06) in the MK-677 group, particularly for noncarriers of the apolipoprotein E (APOE) ε4 allele (ie, ε4-negative adults). Although APOE genotyping was not performed in our study, it is possible that a high proportion of our participants were noncarriers of the ε4 allele, given the inclusion of a sizeable group of well-characterized cognitively normal participants who are less likely to be ε4 carriers.60
Other differences between our study and the MK-677 study relate to the specific hormone administered (GHRH vs ghrelin mimetic), with different physiological effects (MK-677 increased blood glucose levels and hemoglobin A1c
levels, and GHRH did not), treatment efficacy on serum IGF-1 level (117% with GHRH vs 73% with MK-677), and sensitivity of cognitive outcomes to treatment effects on executive function and episodic memory. Despite methodological dissimilarities in the 2 trials, it may be that the key difference is the timing of the intervention relative to stage of disease, such that stimulation and restoration of GH and IGF-1 activities result in beneficial effects but only when pathologic processes that cause decline in cognitive function can still be prevented, delayed, or reversed.
In our study, treatment with GHRH increased fasting plasma insulin levels in adults with MCI but not in normal controls. Insulinlike growth factor 1 and insulin have similar metabolic effects,61
and IGF-1 is a potent insulin sensitizer.62
Early AD pathology is linked to subclinical changes in insulin activity in the periphery and in the central nervous system63,64
such that adults with amnestic MCI may be particularly sensitive to metabolic changes affecting insulin availability.28,65
Our data suggest that IGF-1 plays a role in treatment response on executive function, whereas, for verbal memory, both IGF-1 and insulin are likely to contribute. Although speculative, GHRH-stimulated increases in circulating insulin may help to override the early negative effects of AD pathology to boost performance on abilities (such as declarative memory) that are particularly sensitive to insulin-related dysfunction.47
Although somatotrophic hormone levels decrease with advancing age,5,6
with a potential adverse effect on cognition,5,6,11–13
lower GH and IGF-1 levels are not always associated with negative consequences. In animal models of GH and IGF-1 deficiency and in studies of caloric restriction, reduced GH and IGF-1 levels and activity are associated with a longer life span.66,67
Moreover, transgenic mice that produce abnormally high levels of GH and IGF-1 have a shorter life span and early age-related cognitive changes.68
The relationship between lower levels of IGF-1 and “delayed aging,” attributed to improved insulin signaling and glucose metabolism,66
contrasts with reports in human studies indicating no effect of caloric restriction on GH and IGF-169
and no effect of reduced GH and IGF-1 levels on life span in GH-deficient adults70
who paradoxically present with glucose intolerance and insulin resistance.71
In addition, increasing GH and IGF-1 levels in GH-deficient adults does not affect glucose and insulin response to a glucose challenge.72
Nonetheless, the favorable effects of increased GH and IGF-1 levels on cardiovascular health,73
adiposity, lean muscle mass, and potentially cognition may tip the scales in favor of restoration of somatotrophic hormone activity in older adults, particularly in those at increased risk of decline in cognitive function.
The generalizability of our findings is limited by the small sample size, particularly for subgroup analyses by diagnosis, and by sample demographics, including educational level (mean level, 16.4 years) and minority representation (90% of participants were white), that do not accurately represent the larger US population. The MCI group was older than the normal control group; however, age was included as a covariate in all analyses, and significant differences were observed between treatment groups that were comparable with regard to age. Although more women than men reported adverse events (eTable) with potential effects on unblinding and treatment efficacy (adverse event–related dose adjustments were made for 11 women and 2 men), the achieved serum IGF-1 concentration and cognitive response to GHRH administration did not differ by sex. Growth hormone–releasing hormone was administered for only 5 months, which limits our ability to assess longer-term cognitive efficacy and safety of the hormone for older adults, particularly in the absence of important mechanistic studies to account for cognition-enhancing effects of GHRH analogs in the brain. Although we achieved statistical significance in our omnibus completer analysis showing medium to large effect sizes for executive function and verbal memory, improvement on the individual tests was small (~0.25 SDs), and without information about functional status (data not collected), the clinical significance of our findings remains unclear. Finally, our findings describe GHRH effects for a group of older adults that includes those with and without MCI. It can be argued that the inclusion of healthy adults in our study weakens the therapeutic relevance of GHRH for cognitively impaired populations. However, we observed comparable benefits of GHRH on cognition in adults with MCI and in normal controls. Alternatively, the added value of including healthy adults may relate to notable GHRH-related improvements in cognitive abilities characteristically compromised with advancing age that can precede or mask early neurodegenerative disease, a finding with potential implications for the role of GHRH in secondary and primary prevention.
The potential to preserve, or even enhance, cognitive function in normal aging and in populations where cognitive functions are failing rapidly owing to neurodegenerative disease clearly has important implications not only for the affected individual but also for the support system that bears the social and financial burdens of long-term caregiving. Studies attempting to prevent or arrest cognitive decline in MCI using a variety of different approaches such as cholinesterase inhibitors, vitamins B and E, anti-inflammatories, antihypertensives, and statins have been largely negative.74–78
In normal aging, similar drug intervention trials have also been unsuccessful. The common goal of promising nonpharmacological approaches, such as those that target diet or exercise,79,80
is to augment or restore health to optimum levels. Restoration of age-related changes in somatotrophic axis activity, with consequences for GH and IGF-1 availability, may represent an analogous strategy that optimizes the health of the neuroendocrine environment with multiple protective and restorative effects on brain function, including cognition. Our results replicate and expand our earlier positive findings,31
demonstrating that GHRH administration has favorable effects on cognitive function not only in healthy older adults but also in adults at increased risk of cognitive decline and dementia. Larger and longer-duration treatment trials are needed to firmly establish the therapeutic potential of GHRH administration to promote brain health in normal aging and “pathological aging.”