Cognitive decline and impairment, including conditions such as mild cognitive impairment (MCI) and dementia, are prevalent in the aging population. These conditions often progresses to dementia, which can be classified as vascular dementia, Alzheimer’s disease, frontotemporal lobe dementia, and Lewy body dementia (Wilbur, 2023). Without effective treatments, neurodegenerative and cognitive disorders will continue to increase in prevalence, especially among countries like the United States (Alzheimer’s Association, 2019, Murman, 2015). Recently, the Federal Drug Administration approved the first Alzheimer’s disease pathology clearing therapeutic, which demonstrated beneficial effects on cognitive function (Van Dyck et al., 2023). Nonetheless, cognitive impairment and dementia remain an important public health problem and there is an urgent need for additional pharmacological interventions.

In the last sixty years, hormones, specifically, neuroendocrine modulators have become a central focus in the development of novel therapeutics to combat cognitive decline. One of those neuroendocrine modulators is insulin-like growth factor-1 (IGF-1) previously known as Somatomedin-C. IGF-1 is a 70 amino acid polypeptide which has both autocrine and paracrine functions beginning during the embryonic period and continuing throughout the lifespan. Numerous researchers have attempted to delineate the role of IGF-1 throughout the lifespan specifically in concert with disease states like cardiovascular disease and neurodegenerative disease. Overall, the normal ageing process has been associated with both an increased risk for cognitive disease and a significant reduction in the growth hormone (GH)/IGF-1 axis signaling pathway. Thus, clinical studies have attempted to make correlations and associations between reduced IGF-1 levels and cognitive performance while preclinical studies are centered around restoring learning and memory with exogenous IGF-1. In the recent years, scientific and technological advancements have resulted in novel approaches to alter IGF-1 signaling in rodents, to delineate specific processes related to learning and memory in addition to the furtherin our understanding of the cellular and molecular processes that accompany behavioral changes. In this literature review, we provide a summary on the GH/IGF-1 axis, the pulsatile release of IGF-1, and the developmental effects of IGF-1. We further provide evidence of the preclinical and clinical implications of IGF-1 on cognition along with the cellular and molecular processes in which it modulates to influence cognitive performance.

The GH and IGF-1 axis are primarily controlled by the diencephalon brain region, specifically the hypothalamus. The hypothalamus stimulates the release of growth hormone-releasing hormone (GHRH); thereby, stimulating the somatotroph cells of the anterior pituitary gland, which subsequently release GH. GH enters systemic circulation where it targets several tissues, particularly the liver. This will result in GH binding to the GH receptor (GHR) and activating the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways inducing the production and release of IGF-1 into systemic circulation (Al-Samerria and Radovick, 2021, Junnila et al., 2013). Although the majority of IGF-1 is hepatically derived, numerous other cells can produce this neurotrophic growth factor (D’Ercole et al., 1980). The levels of IGF-1 are arguably the lowest during the infantile period; however, there is rapid surge in production during the adolescent pubescent phase of life (Zadik et al., 1985). Yet, following puberty and early adulthood, IGF-1 levels gradually decline throughout lifespan and are almost returned to infantile levels (Juul, 2003). Although this hormesis curve production of IGF-1 can slightly vary across individuals, the pulsatile release of GH and IGF-1 throughout a 24-hour period is extremely stringent and has been characterized extensively (Zadik et al., 1985).

The GH/IGF-1 pulsatile release process from the liver is a complex and finely tuned process that has been extensively researched. Studies have elucidated parts of this process through the administration of a competitive GHRH antagonist, which blocked 75% of GH pulsivity, further highlighting the role of GHRH (Jaffe et al., 1993). Additionally, this release is further regulated by a cyclic rhythm of release and inhibition involving GHRH and somatostatin (SS), an inhibitory peptide hormone (Devesa et al., 1992). While there have been strides in understanding GH and IGF-1 pulsivity, current medical limitations (e.g., inability to directly sample hepatic portal blood) prevent us from gaining a precise understanding of the underlying mechanisms involved in this process.

Despite these challenges, considerable progress has been made in understanding certain dynamic aspects of the GH/IGF-1 release process, such as the duration and amount of GH released during the 24-hour cycle. Several lines of evidence show that in the pre-pubertal years of human life, GH is only secreted at night and further evolves during the adolescent phase of early adulthood, where GH is secreted in large quantities in alignment with sleep cycles, particularly during slow-wave sleep (FINKELSTEIN et al., 1972). Thus, the release of GH is not static but rather, varies significantly across age (Devesa et al., 1992, Jaffe et al., 1993).

Literature has described that the pulsatile production and release of IGF-1 follows a similar trend as that of the previously described GH release process (Hindmarsh et al., 1997, Veldhuis et al., 1995). However, there are certain intricacies reserved to IGF-1, such as the action of IGF-1 as a stimulant to initiate a negative feedback loop reducing the production of GH (Hindmarsh et al., 1997, Veldhuis et al., 1995). For example, the release of GH can be suppressed in goat anterior pituitary cells when they are supplemented with 10 nmol/L of GHRH and 100 ng/ml of IGF-1. Alternatively, those cells cultured in IGF-1 for 48 hours but not induced with IGF-1 saw no suppression of GH from GHRH expression (Katoh et al., 2004). This evidence supports that the pulsatile GH signal is important for the targeted release of IGF-1 from the liver. Further evidence corroborating this relationship has shown that removing liver derived IGF-1 in mice results in IGF-1 serum concentrations decreasing by 75% and GH serum levels increasing (Sjögren et al., 1999). Additionally, two studies have shown that the peak pulsatile release of GH is positively correlated with serum IGF-1 concentrations, furthering our ability to estimate IGF-1 production and release times based on measured GH production (Hindmarsh et al., 1997, Veldhuis et al., 1995). In summary, the estimate for the pulsatile release of GH and IGF-1 is based on the negative feedback mechanism between GH and IGF-1 release.