40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain

in Journal of Molecular Endocrinology

The insulin-like growth factor 1 (IGF1) signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF1, its role in the aging brain remains complex and controversial. While IGF1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer’s disease, reducing IGF1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF1 in that context. Appreciating the dual, at times opposing ‘Dr Jekyll’ and ‘Mr Hyde’ characteristics of IGF1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF1-related interventions.

Abstract

The insulin-like growth factor 1 (IGF1) signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF1, its role in the aging brain remains complex and controversial. While IGF1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer’s disease, reducing IGF1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF1 in that context. Appreciating the dual, at times opposing ‘Dr Jekyll’ and ‘Mr Hyde’ characteristics of IGF1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF1-related interventions.

Introduction

The growth hormone/insulin-like growth factor 1 (GH/IGF1) signaling pathway, also referred to as the somatotropic axis, has been extensively implicated in the aging process (Bartke et al. 2003, Kenyon 2010, Barzilai et al. 2012, Brown-Borg & Bartke 2012). Attenuation of this conserved signaling pathway has been demonstrated to reduce the incidence of age-related diseases and extend survival in numerous rodent models (Brown-Borg et al. 1996, Kinney et al. 2001a,b, Ikeno et al. 2003). Remarkably, this pathway also appears to be relevant to human aging, as functional mutations in the IGF1R resulting in attenuated IGF1 signaling are enriched in centenarians (Suh et al. 2008, Tazearslan et al. 2011), while stratifying nonagenarian females by IGF1 levels revealed a survival advantage in those with low IGF1 (Milman et al. 2014). Likewise, lower serum IGF1 levels were associated with protection from cognitive impairment late into the tenth decade among women (Perice et al. 2016). The role of IGF1 in the central nervous system (CNS) has been a particularly intriguing, albeit controversial area of investigation, with evidence linking IGF1 to favorable, detrimental and indifferent effects on CNS function and disease risk. In this review, we will delve into the current state of the evidence examining the role of IGF1 in the aging brain, with a particular focus on the consistencies and controversies that have emerged from preclinical and clinical studies.

IGF1 and the brain

Endocrine vs autocrine IGF1

Similar to many other tissues, the brain is exposed to two sources of IGF1, endocrine and autocrine. The regulation of endocrine production of IGF1, which is primarily under the control of GH pulses secreted from the pituitary in response to GH-releasing hormone (GHRH) and ghrelin, consists of a classic negative feedback loop and has been extensively described elsewhere (Berelowitz et al. 1981). In brief, GH binds to the GH receptor to stimulate IGF1 production mainly in the liver and the rise in circulating IGF1 levels results in enhanced binding to IGF1 receptors (IGF1R) in the pituitary and the hypothalamus to inhibit GH and GHRH secretion, respectively. Hepatic-derived IGF1 comprises ~70% of total circulating IGF1 (Ohlsson et al. 2009) levels and can provide input to the CNS by crossing the blood–brain barrier (BBB) at the choroid plexus into the cerebrospinal fluid (CSF) via the IGF1R and low-density lipoprotein receptor-related protein 2 transport protein (also known as megalin) (Carro et al. 2005). During early life, IGF1 is abundantly expressed throughout the CNS and is essential for normal brain development. The critical role of autocrine IGF1 for neuronal development is evidenced by findings that mutations resulting in global IGF1 loss or insensitivity manifest as microcephaly and cognitive deficiencies in children (Woods et al. 1996, Abuzzahab et al. 2003, Netchine et al. 2011). In contrast, mutations that result in GH deficiency or resistance frequently present with normal cognitive ability (Kranzler et al. 1998) suggesting that autocrine brain IGF1 production may be preserved in these individuals (Joseph D’Ercole & Ye 2008). In the circulation, most IGF1 is bound to IGF-binding proteins (IGFBP), with IGFBP-3 being most abundant, and therefore, is inactive (Rajaram et al. 1997, Baxter 2000, Holly & Perks 2012). IGF1 exerts its action in tissues by binding to the high-affinity IGF1R on the cell surface (Holly & Perks 2012); notably, IGF1 also binds to the insulin receptor, but with much lower affinity (Novosyadlyy & Leroith 2012). IGF1 binding to the IGF1R initiates a complex intracellular signaling cascade that includes phosphorylation of the insulin receptor substrate (IRS) molecules and subsequent activation of phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) and the the mitogen-activated protein kinase (MAPK) pathways that regulate, among several downstream effectors, mechanistic target of rapamycin (mTOR) activity and Forkhead box O translocation (FOXO) (Taniguchi et al. 2006). Signaling through these pathways influences autophagy, growth, stress resistance, oxidative stress and lifespan (Barzilai et al. 2012).

IGF1 and the aging brain

In the brain, autocrine IGF1 production is thought to peak during development (Joseph D’Ercole & Ye 2008). Meanwhile, endocrine production of IGF1, and presumably IGF1 input into the CNS, remains high during the early years, peaking during puberty, a period that coincides with rapid cell proliferation and linear growth (Yamamoto et al. 1991). By the third decade, IGF1 production abruptly drops off and then continues steadily declining with aging, raising questions regarding the potential role of reduced IGF1 levels in the manifestations of brain aging (Yamamoto et al. 1991). The endocrine decline in IGF1 has been attributed to diminished GH pulse amplitude and frequency that is observed in aging, at least in part due to decreased ghrelin binding to the GH secretagogue receptor (GHSR) (Sun et al. 2004), thus resulting in steady, but low-level secretion of GH in older individuals (Carlson et al. 1972, Finkelstein et al. 1972). Limited evidence suggests that concomitant with the decline in systemic IGF1 levels, local production, as assessed by CSF and brain tissues levels, also declines with age, in spite of the fact that brain IGF1 production is believed to act independent of GH regulation (Ashpole et al. 2015). In fact, observations from aged rodent models show that IGF1R transcription increases with age in the hippocampal and cortical regions of the brain, possibly in a compensatory attempt to preserve brain IGF1 signaling in the setting of less IGF1 availability; however, this response is inadequate to restore IGF1 back to youthful levels and IGF1 levels in the brain of aged animals remain lower compared to young animals (Ashpole et al. 2015). Beyond the decline in local and systemic IGF1 levels with aging, there is some evidence that the aged brain may be resistant to IGF1 signaling (Muller et al. 2012). Observations of declining autocrine and endocrine IGF1 levels with age, paired with knowledge that aging is associated with increased risk of cognitive decline and diseases affecting the brain, beg the question of whether IGF1 is involved in brain aging.

IGF1 and cognition

Epidemiologic and clinical studies

Age-related cognitive decline, which in its more progressive forms, may be characterized by mild cognitive impairment (MCI) or dementia, secondary to causes such as cerebrovascular ischemia or Alzheimer’s disease (AD), poses a significant burden for an increasingly aging population, raising the urgency to identify underlying contributors to these conditions in order to delay or prevent their onset (Prince et al. 2016, Langa et al. 2017, Wu et al. 2017). Studies in humans and rodents have been conducted into the possible relationship between IGF1 and the cognitive domain, and have uncovered interesting, albeit at times conflicting associations (Frater et al. 2017). A number of cross-sectional studies in middle and older age adults have revealed a positive correlation between IGF1 levels and cognition (Al-Delaimy et al. 2009, Doi et al. 2015, Wennberg et al. 2018). However, this observation was not always consistent between sexes, with significant findings limited only to males or females across different studies (Al-Delaimy et al. 2009, Wennberg et al. 2018). On the other hand, another cross-sectional analysis found an inverse relationship between IGF1 and cognitive processing capacity in men age 60 years and older (Tumati et al. 2016). Likewise, in a cohort of exceptional longevity, females with IGF1 levels in the lowest tertile had a nearly 50% lower prevalence of cognitive impairment compared to females with IGF1 levels in the upper two tertiles (Perice et al. 2016). Similarly, prospective studies have done little to settle this controversy. One study demonstrated a positive association between baseline serum IGF1 levels and future cognitive performance among older women (Okereke et al. 2007), whereas another found no association in men (Green et al. 2014). Yet, a different prospective analysis found lower cognitive scores among men with highest baseline IGF1 levels after 8 years of follow-up (Tumati et al. 2016). Higher serum IGF1 levels were also correlated with greater total brain volume on MRI in older and middle-aged adults without dementia, but no relationship with hippocampal volume was noted (Westwood et al. 2014). Clinical trials have further fueled the uncertainty regarding the role of IGF1 on cognition. A 20-week intervention study showed beneficial effects of GHRH administration on cognitive function in older adults who were healthy or had MCI (Baker et al. 2012). However, a year-long experimental replacement of peripheral IGF1 in older females failed to achieve discernible benefits in cognitive outcomes (Friedlander et al. 2001). Although the results from human studies do not offer a conclusive resolution about the role of IGF1 on cognitive function in aging, they should be interpreted in the context of substantial heterogeneity between cohorts, cognitive assessment tools and definitions of cognitive function. Extended longitudinal follow-up paired with more precise characterization may help clarify this uncertainly in the future.

Molecular and animal studies

In rodents, few studies have been conducted that address cognition in the context of aging. However, one study exploring the potential therapeutic benefit of administering IGF1 by intracerebroventricular (ICV) infusion to old male Fisher-Brown Norway (FBN) rats over a 1 month period demonstrated improved cognitive function, in terms of spatial reference memory and working memory (Markowska et al. 1998, Pardo et al. 2018). It has also been shown that old male FBN rats have a decreased number of newly generated cells in the hippocampus, a brain region important for memory domain acquisition, as well as a significant reduction of newborn cells differentiating into neurons (Lichtenwalner et al. 2001). However, ICV administration of IGF1 significantly restored hippocampal neurogenesis, without an effect on progenitor differentiation or newborn cell survival, which could be related to the observed improvement in cognitive function noted previously in this strain of rats (Lichtenwalner et al. 2001). Furthermore, old female Sprague–Dawley rats injected ICV with an IGF1-expressing adenovirus resulted in increased IGF1 levels in CSF, and restoration of neurogenesis and spatial memory assessed by the Barnes maze (Pardo et al. 2016, 2018). In this model, transcription of genes related to synaptic function and neurogenesis was upregulated (Pardo et al. 2018). Astrocyte-specific knockout of Igf1r gene at 3–4 months of age resulted in impairments in working memory in mice; however, it is not known what effect this intervention may have at an older age (Logan et al. 2018). Interestingly, both male and female long-lived Ames dwarf mice, which are characterized by circulating GH and IGF1 deficiency, have normal cognitive function that is better maintained with age, based on performance in memory tests, when compared to age-matched controls (Kinney et al. 2001b). Although there is some evidence that local IGF1 production in these animals is enhanced (Sun et al. 2005), suggesting that autocrine IGF1 production may be an important contributor to cognitive health, subsequent studies did not confirm these results, finding lower IGF1 levels in the cortex and hippocampus of these mice compared to wild-type controls (Puig et al. 2016). On the contrary, liver-specific IGF1-deficient mice, which have an approximately 70% reduction in systemic IGF1 levels, manifest early hippocampal-dependent cognitive deficits (Trejo et al. 2007), including a reduction in spatial learning and memory (assessed by Water Maze) (Svensson et al. 2006, Trejo et al. 2007) despite maintained autocrine IGF1 production. However, these mice also present with markedly elevated GH levels, due to lack of feedback inhibition by IGF1, resulting in insulin resistance (Haluzik et al. 2003), and these perturbations in GH and insulin may also directly contribute to the neuronal and vascular dysfunction observed in this model (Bailey-Downs et al. 2012, Talbot et al. 2012).

IGF1 and AD

Epidemiologic and clinical studies

AD, characterized by a progressive decline in memory and loss of independent functioning, has become a major burden for older adults, their families and the health care system (Callahan 2017). Although IGF1 has been extensively investigated in AD patients, most of the studies have been observational and substantial controversy continues to surround this topic in epidemiologic literature. A meta-analysis of nine case–control studies did not find an association between IGF1 levels and AD, with individual studies showing higher, similar and lower serum IGF1 levels in AD patients compared to controls (Ostrowski et al. 2016). On the other hand, a prospective study demonstrated an inverse association between baseline serum IGF1 levels and AD risk (Westwood et al. 2014), while an analysis of AD patients reported that lower baseline serum IGF1 was associated with faster progression in cognitive decline over 2 years (Vidal et al. 2016). Additionally, a clinical trial that evaluated the effect of a GH secretagogue on progression of AD revealed a lack of efficacy, despite achieving higher IGF1 levels (Sevigny et al. 2008). Interestingly, higher measured stimulating activity of the IGF1R using a specialized assay was related to greater prevalence and incidence of dementia (de Bruijn et al. 2014). Acknowledging that IGF1 bioavailability is tightly regulated by IGFBPs and that genetic or acquired conditions may predispose to IGF1 resistance (Suh et al. 2008, Tazearslan et al. 2011), this latter study raises the important consideration that IGF1 levels may not always be indicative of action, especially in aging and diseased brains, where IGF1 resistance has been reported to occur (Muller et al. 2012, Talbot et al. 2012).

Molecular and animal studies

Molecular and animal studies attempting to shed light on the role of somatotropic signaling in AD have also not been free of controversy. A number of rodent studies have suggested that relative IGF1 deficiency and/or reduced IGF1 signaling confers protection against progression of AD pathology. For instance, Ames Dwarf mice expressing human mutant amyloid precursor protein (APP) and presenillin-1 (PS1) demonstrated lower brain IGF1 levels and reduced amyloid plaque deposition than controls (Puig et al. 2016). Likewise, heterozygous deletion of the Igf1r in a similar AD model protected from AD-like symptoms, neuroinflammation, neuronal loss and delayed proteotoxicity in 12-to 13-month-old mice compared to age-matched controls (Cohen et al. 2009). Deletion of neuronal Igf1r or Irs2, which signals downstream of IGF1R, demonstrated reduced amyloid plaque accumulation, reduced neuroinflammation, improved spatial memory and delayed death in APP and APP/PS1 models (Freude et al. 2009, Gontier et al. 2015). However, there was no benefit to reducing IGF1 signaling in an advanced model of AD (George et al. 2017), suggesting that there may be a limited window for intervention. Adult-onset deletion of IGF1R specifically in neurons also reduced neuronal size through changes to the soma and dendrites (Gontier et al. 2015, George et al. 2017), suggesting that larger volume does not necessarily equate with better function (Westwood et al. 2014). Of note, subjecting 3×Tg-AD mice to protein restriction cycles, which reduces circulating IGF1 levels by 30–70% (Parrella et al. 2013), alleviated symptoms of working memory and short-term spatial memory deficits, as well as reduced hippocampal Tau phosphorylation (Parrella et al. 2013) that is associated with cognitive deficits in humans with AD (de Leon et al. 2006). In contrast to evidence implicating IGF1 as a detrimental player in AD pathology, age-related decline in IGF1 has been linked with brain metabolic deficiencies in AD mouse models (Carro et al. 2002, Trueba-Saiz et al. 2013) and treatment with IGF1 has been shown to confer protection in hippocampal neurons from the toxic effects of amyloid peptides (Dore et al. 1997). However, results that showed that peripheral administration of IGF1 promoted clearance of Aβ amyloid in aged rats and mutant mice (Carro et al. 2002, 2006) have not been replicated in later studies (Lanz et al. 2008).

Interestingly, a study in human AD brains documented insulin and IGF1 resistance via decreased activation of downstream signaling of IRS-1 and IGF1R/IRS-2, respectively (Talbot et al. 2012). Similar findings have been observed in rodent models (Muller et al. 2012, Trueba-Saiz et al. 2013). Whether brain resistance to IGF1 is a pathologic feature or a protective adaption remains uncertain. However, a recent genome-wide microarray analysis that compared neurons in early-stage AD with IGF1R-knockout neurons demonstrated very similar transcriptomic signatures, suggesting that IGF1 resistance in AD neurons may be an adaptive response intended to protect neurons from further damage (George et al. 2017). In contrast, several investigators have proposed that reduced CNS input of a related hormone, insulin, may underlie cognitive impairment, and data have demonstrated that intranasal delivery of insulin improves cognition in individuals with MCI or early-stage AD (Claxton et al. 2015). While this latter observation seems somewhat contradictory to those results obtained from AD models, it is important to note that data from the intervention trial were obtained from individuals with MCI or early-stage disease. Therefore, the relationship of insulin and IGF1 signaling to cognition could vary based upon disease susceptibility and severity, a possibility that will require further study to confirm.

Mechanistically, many potential pathways and processes are impacted by IGF1, which could have both beneficial and detrimental effects on the CNS to influence brain aging, cognitive decline and AD. Certainly, IGF1 has been linked to neurogenesis, axonal and dendrite growth, synaptogenesis, myelination and neuronal cell survival (Liang et al. 2007, Nieto-Estevez et al. 2016). On the other hand, increased IGF1 signaling could impair macroautophagy in neurons, which is a cellular process shown to confer protection from AD. Macroautophagy is the process that eliminates cellular components through sequestration in autophagosomes followed by degradation upon fusion with lysosomes and plays an important role in eliminating misfolded or aggregated proteins that can be damaging to cells. This process has been shown to be dysfunctional not only in aging, but also in age-related neurodegenerative diseases that include Parkinson’s disease (PD), as well as sporadic and familial AD (Martinez-Vicente & Cuervo 2007, Lee et al. 2010). Indeed, reduced somatotropic signaling has been implicated in increased macroautophagy. In nematodes, loss of IGF1 signaling was associated with improved autophagy, a pathway required for lifespan extension observed in this model (Melendez et al. 2003). Knockout of IGF1R in neurons resulted in better autophagy and clearance of Aβ plaques (Gontier et al. 2015), whereas prolonged exposure to IGF1 resulted in decreased autophagy in human fibroblasts (Bitto et al. 2010). Autophagy was also induced by inhibition of mTOR or AMPK, molecules that signal downstream of IGF1R (Samari & Seglen 1998, Schmelzle & Hall 2000). In summary, most of the experimental evidence suggests that IGF1 acts as ‘Mr. Hyde’ in the progression of AD. However, what character IGF1 signaling plays preceding disease onset remains to be definitively determined.

IGF1 and PD

Epidemiologic and clinical studies

PD is a progressive neurodegenerative disorder distinctively characterized clinically by rest tremor, rigidity and bradykinesia, and pathologically by the destruction of dopaminergic (DA) neurons in the substantia nigra (SN) (Forno 1996) in the basal ganglia. However, PD is often accompanied by several other cognitive and neuropsychiatric dysfunctions, as well as accumulation of Lewy bodies throughout the brain, that include alpha-synuclein among other proteins, suggesting that the neurodegenerative process also targets other brain areas (Mu et al. 2017, Schapira et al. 2017). Circulating IGF1 has been proposed as a potential biomarker for PD. Significantly sustained elevations of IGF1 levels, without concomitant elevations in GH levels, were noted among patients with drug-treated, stable PD compared to healthy controls (Godau et al. 2010). Similarly, a small group of drug-naïve patients demonstrated elevations in serum IGF1 levels compared to controls (Godau et al. 2011). Higher IGF1 levels were also found among individuals with shorter duration of PD, with levels falling with longer disease duration (Numao et al. 2014), sometimes even reaching near-control levels (Godau et al. 2010). This was confirmed by other studies that noted that elevations in IGF1, GH and IGFBP-3 were less pronounced among patients with longer disease duration and more advanced PD (Tuncel et al. 2009). Interestingly, even individuals who did not meet criteria for PD diagnosis, but with some movement impairment and SN abnormalities on transcranial ultrasound, had higher IGF1 levels compared to controls without any abnormalities (Godau et al. 2011), suggesting that elevated IGF1 may be a potential risk factor for progression to PD. Indeed, a prospective study that followed early-stage PD patients for up to 2 years found that individuals with baseline IGF1 levels in the top quartile demonstrated worse motor impairment and Parkinsonian symptoms throughout the duration of the study, compared to those with baseline IGF1 in the lower quartiles (Picillo et al. 2013), with a caveat that the symptoms had not significantly progressed in either group due to effective medical treatment. It was also noted that patients with PD did not only manifest elevations in serum IGF1 and IGFBP levels compared to controls, but also had elevated levels of these proteins in the CSF (Mashayekhi et al. 2010), suggesting that circulating IGF1 crosses the BBB in PD. However, it still remains unresolved whether PD is associated with elevations of systemic or autocrine IGF1 levels, or both.

Serum IGF1 levels have also been studied in association with other symptoms of PD. Patients with PD have an approximate 6-fold increased risk for developing dementia, compared to the general population (Aarsland et al. 2001). In contrast to those reports described earlier, PD patients with higher baseline IGF1 levels demonstrated better attention and executive functions after 2 years of follow-up (Pellecchia et al. 2014). In addition, a recent study of a large cohort of early, drug-naïve PD patients found worse executive function, attention and verbal memory among individuals with IGF1 levels in the lowest quartile (Picillo et al. 2017). These observations may indicate that higher IGF1 levels are in fact protective against PD-associated cognitive decline, although reverse causality cannot be ruled out, such that patients with lower IGF1 may actually have more advanced and sustained PD that is associated with more severe cognitive impairments, as suggested by studies above.

Molecular and animal studies

Some of the earlier evidence suggesting the relevance of IGF1 to DA neurons and PD was derived from autoradiographic studies demonstrating the presence of IGF1R in moderate densities in the SN of middle and older age adults (De Keyser et al. 1994). Experiments involving human and animal cell cultures have demonstrated neuroprotective actions of IGF1 on DA neurons (Zawada et al. 1996, Offen et al. 2001, Sun et al. 2010). Treatment of cell cultures obtained from E15 rat ventral mesencephalon with IGF1 resulted in a two-fold increased preservation the number of DA neurons. Follow-up studies further demonstrated that administration of IGF1 to rat cerebellar granular neurons increased protein expression of B-cell lymphoma-2 (Bcl-2), placing this potent cell survival factor downstream of IGF1 signaling to provide protection against DA apoptosis (Offen et al. 2001).

The role of IGF1 signaling has also been investigated in several models of PD. One such model uses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a prodrug to the neurotoxin 1-methyl-4-phenyl pyridinium, to induce DA cell injury that is characteristic of PD. MPTP intoxication resulted in upregulated IGF1R levels that was not accompanied by changes in Akt phosphorylation levels (D’Astous et al. 2006). Using the same PD model, a different study found that intraperitoneal injection of MPTP resulted in more severe lesions in Igf1r haploinsufficient mice, as compared to controls (Nadjar et al. 2009), and further suggested that IGF1 signaling may oppose the anti-inflammatory and pro-oxidative effects provoked by this insult (Nadjar et al. 2009). Another PD model utilizing 6-hydroxydopamine induced unilateral nigrostriatal lesions in rats and also showed reduced neuronal loss and sustained motor function with peripherally or centrally administered IGF1 (Quesada & Micevych 2004). Interestingly, in this study, peripherally administered estrogen was also protective, but an IGF1R antagonist blocked the neuroprotective effects of both estrogen and IGF1, suggesting that the neuroprotective effect of estrogen may be mediated via IGF1 signaling.

In summary, both central and peripheral administrations of IGF1 have resulted in neuroprotection in animal PD models. However, it is important to note that the above referenced studies used PD models that introduced SN lesions using acute injury strategies, which is distinct from the etiology of the human disease that is characterized by slow, progressive neurodegenerative changes accompanied by abnormal deposition of proteins, such as alpha-synuclein. For instance, in Drosophila and Caenorhabditis elegans, reduced IGF1/insulin-like signaling (IIS) resulted in reduced neurotoxicity and alpha-synuclein misfolding, a feature of PD (Knight et al. 2014). Additionally, impaired autophagic function, a process that is inhibited by IGF1, has been implicated in PD pathogenesis (Menzies et al. 2017). Thus, the role of IGF1 needs to be further investigated in PD models that better represent the human disease.

IGF1 and cerebrovascular disease

Epidemiologic and clinical studies

Whether circulating levels of IGF1 are associated with the risk of cerebrovascular events remains somewhat equivocal. A recent prospective study of older adults from the Framingham cohort demonstrated a 2.3-fold increase in incident stroke among individuals with baseline IGF1 in the lowest quintile (Saber et al. 2017). Free IGF1 was also inversely related to carotid artery intima-media thickness (Schwab et al. 1997, Van den Beld et al. 2003); however, no association was identified between IGF1, IGFBP-3 and IGF1:IGFBP-3 molar ratios and the risk of stroke among older participants in the Cardiovascular Health Study (Kaplan et al. 2007). On the other hand, a nested case–control analysis found an increase in stroke risk among individuals in the bottom quartile IGFBP-3, but the association between IGF1 and stroke was non-significant after adjustment for IGFBP-3 levels (Johnsen et al. 2005).

A number of studies have investigated IGF1 levels in patients who sustained strokes and its prognostic role in neurologic outcomes. One of the earlier studies found that levels of IGF1 and IGFBP-3 were lower in patients within 24 h of an acute ischemic stroke, as compared to age-matched subjects with non-ischemic neurological illness, and this difference persisted for at least 10 days after the event (Schwab et al. 1997). Several other studies similarly found reduced serum IGF1 and IGFBP-3 levels in patients with acute ischemic (Denti et al. 2004) and hemorrhagic strokes ( Iso et al. 2012), while post-stroke serum IGF1 and IGFBP-3 levels were also inversely associated with infarct volume (Schwab et al. 1997, Tang et al. 2014). However, not all results have been consistent. One study described higher IGF1 levels within the first 10 days of ischemic stroke that remained elevated 3 months out from the event (Åberg et al. 2011). Another study did not find an association between IGF1 levels obtained within 6 h of stroke onset and stroke severity (De Smedt et al. 2011). However, in the same study, higher IGF1 levels during the acute stroke period and during the rehabilitation period were associated with better cognitive and functional recovery after the stroke. Åberg et al. showed that higher IGF1 levels acutely and at 3 months post stroke positively correlated with better functional recovery between 3 and 24 months (Åberg et al. 2011). Higher serum IGF1 levels among individuals during their rehabilitation after stroke were associated with better cognitive and functional recovery (Bondanelli et al. 2006). On the other hand, lower serum IGF1 levels on admission have been associated with unfavorable functional outcomes following acute ischemic stroke (Klionsky et al. 2016). Similarly, serum samples obtained from individuals with persistent chronic hemiparesis of ≥6 months duration showed lower IGF1 and IGFBP-3 serum levels (Silva-Couto et al. 2014).

In addition to functional outcomes, IGF1 levels have been investigated in relationship to survival and hospital discharge after a cerebrovascular event. Lower IGF1 serum levels have been associated with death at 90 days following ischemic stroke (Tang et al. 2014). IGF1 level of less than 60 ng/mL measured 24 h after an ischemic stroke was associated with higher 6-month mortality, but not with the severity of neurologic impairment (Denti et al. 2004); yet, the studied cohort was substantially older, therefore, the low IGF1, as well as the high mortality may have been attributable to older age. In contrast, another report found reduced serum IGF1 levels and IGF1/IGFBP ratios measured within 72 h and at 1 week following a stroke to be associated with a shorter hospital length of stay. However, patients with higher serum IGF1 had larger infarcts, and the higher levels may have been reflective of a more robust compensatory protective response (Mattlage et al. 2016).

Molecular and animal studies

In the setting of ischemic neural injury, IGF1 has been demonstrated to have neurotropic and neuroprotective activities (Knusel et al. 1990, Gluckman et al. 1992, Chung et al. 2007, Hu et al. 2009). Circulating IGF1 that can cross the BBB (De Geyter et al. 2016) and local IGF1 that is produced by proliferating microglia have been implicated in promoting neurological recovery after a stroke (Ploughman et al. 2005, Lalancette-Hébert et al. 2007, Thored et al. 2009). Following a middle cerebral artery occlusion (MCAO) in rats, IGF1 expression was found to be upregulated in the astrocytes surrounding the ischemic penumbra and neuronal progenitors (Yan et al. 2006), whereas the administration of an IGF1-neutralizing antibody significantly reduced progenitor proliferation, suggesting that IGF1 may be an important growth factor for neuronal recovery after a stroke. Evidence also indicates that neurological and functional recovery in the context of physical therapy is associated with marked activation of IGF1 and downstream Akt signaling in the peri-infarct region (Zheng et al. 2014). On the other hand, higher serum IGF1 levels prior to MCAO procedure in mice correlated with a larger infarct size (Endres et al. 2007).

Impaired cerebrovascular function has also been demonstrated in several GH and/or IGF1 deficient models. One such model is the Lewis dwarf rat, which has a genetic GH deficiency that, among other outcomes, results in an increased incidence of late-life stroke (Sonntag et al. 2005). Similarly, studies in a mouse model of post-developmental liver knockdown of Igf1 show that IGF1 deficiency has a negative effect on cerebrovascular adaptation to hypertension, and this dysfunction is most likely associated with BBB disruption, as well as neuroinflammation, mimicking the aging phenotype (Toth et al. 2014). Moreover, neurovascular coupling, which is a process that adjusts local cerebral blood flow to the energy requirements of activated neurons, is known to decrease with age (Toth et al. 2015). Using the same IGF1-deficient mouse model, Toth et al. showed that circulating IGF1 deficiency led to neurovascular dysregulation and a concomitant decline in cognitive function, akin to what is seen with aging (Toth et al. 2015). Therefore, these studies support the contention that circulating IGF1 has supportive and protective effects on cerebromicrovascular function.

Several therapeutic interventions involving GH/IGF1 have been investigated in ischemic stroke models. In hippocampal cell cultures deprived of oxygen and nutrients, IGF1 and IGFBP-ligand inhibitor prevented cell death (Mackay et al. 2003). Likewise, ICV administration of IGF1 resulted in reduced neuronal loss and improved neurological outcomes in several rodent models of hypoxic ischemic brain injury induced by arterial ligation (Guan et al. 1993, 2001, Schäbitz et al. 2001, Mackay et al. 2003) and IGF1 was more effective than insulin in protecting from neuronal loss (Guan et al. 1993). Similar results were reported in fetal sheep subjected to cerebral ischemia (Johnston et al. 1996). GH treatment via ICV administration improved motor function in endothelin-induced stroke in rats (Pathipati et al. 2009). Additional routes of IGF1 administration post neural ischemic injury, including intranasal (Liu et al. 2001, Fletcher et al. 2009, Lin et al. 2009), subcutaneous (Schäbitz et al. 2001), intramuscular (Chang et al. 2010) and intravenous (Rizk et al. 2007), have also been shown to be effective. Interestingly, administration of human marrow stromal cells improved functional recovery in rats with MCAO-induced ischemic infarcts and was associated with an increase in IGF1 mRNA expression and IGF1R immunoreactivity in cells at the ischemic boundary and subventricular zones (Zhang et al. 2004). Administration of IGF1 also ameliorated the negative effect of estrogen on ischemic stroke in middle-aged rats (Selvamani & Sohrabji 2010). ICV injection of adeno-associated viral vectors containing human IGF1 has been shown to promote prolonged functional recovery and enhanced neurogenesis after ischemic injury in mice (Zhu et al. 2008, Liu et al. 2017). In another study, antagonists targeted at IGF1 signaling-related miRNAs promoted neuroprotection (Selvamani et al. 2012). Although the evidence examining the links between IGF1 and cerebrovascular disease has been somewhat ambiguous in humans, when paired together with molecular and animal studies, the results indicate that IGF1 is likely a beneficial factor for cerebral vasculature and aids in neuronal recovery after an ischemic injury.

The ‘strange case’ of IGF1 in the aging brain: Dr Jekyll or Mr Hyde?

When taking into account the full breadth and depth of the evidence examining the role of IGF1 on brain aging and its related diseases, as summarized in Fig. 1, substantial uncertainty continues to surround many aspects related to this pleiotropic hormone in the CNS. While it is not yet entirely clear how to reconcile many of these conflicting findings reported across animal and human studies, a closer look at the subtle, but important, nuances and inconsistencies could begin to shed some light on the subject.

Figure 1
Figure 1

IGF1 playing the roles of Dr Jekyll and Mr Hyde in the brain. IGF1 exerts its beneficial effects on the brain by stimulating neurogenesis, synaptogenesis, neurite growth, myelination and promoting cell survival. These processes are important during early life for proper brain development and growth, whereas during aging, they contribute to repair of injured neural tissue, as may result from a stroke. On the other hand, the adverse effects of IGF1 on the brain include generation of reactive oxygen species and inhibition of both autophagy and stress responses. Inhibition of these functions results in diminished cell resilience and accumulation of cellular debris, which are characteristic of age-related neurodegenerative conditions such as AD and PD. AD, Alzheimer’s disease; IGF1, insulin-like growth factor-1; PD, Parkinson’s disease.

Citation: Journal of Molecular Endocrinology 61, 1; 10.1530/JME-18-0093

The effect of aging on the brain

Whereas it has been well-established that IGF1 is required for normal brain development (Woods et al. 1996, Kranzler et al. 1998, Abuzzahab et al. 2003, Netchine et al. 2011), its role in the aging brain has been less clear. Although most evidence from rodent models suggests that interventions that raise IGF1 level in the brain are beneficial to an otherwise healthy aging brain, studies in humans or disease models have not been consistently confirmatory. After early life development, the CNS shifts priorities from growth and expansion to preservation. Thus, maintaining the same robustness of IGF1 signaling throughout the lifespan, as during development, may actually be counterproductive or even harmful, as IGF1 signaling is known to attenuate pathways that promote cell preservation through stress resistance, reduction of oxidative stress and proteostasis (Barzilai et al. 2012). Since aging is the greatest risk factor for neurodegenerative disorders that are accompanied by abnormal protein deposition, such as AD and PD (Martinez-Vicente & Cuervo 2007, Kaushik & Cuervo 2015), the physiologic decline in IGF1 that accompanies aging may serve a protective role against these disorders by promoting an environment favoring clearance of dysfunctional proteins and cell maintenance. On the other hand, older adults may benefit from temporary elevations of IGF1 in settings of acute neuronal injury, such as a stroke or traumatic brain injury (Bianchi et al. 2017), where neuroregeneration regains priority over maintenance. This hypothesis is supported by findings that most models of AD benefit from reduced IGF1 signaling. On the contrary, in models of acute ischemic injury, higher IGF1 improves recovery (Bondanelli et al. 2006, Åberg et al. 2011). However, PD models need to be interpreted with caution. While IGF1 appears to be protective against DA neuron loss in models that induce SN injury, this approach is more reminiscent of acute neuronal injury that occurs with sudden ischemic or traumatic injury rather than the progressive, neuronal degeneration that is characteristic of PD in humans. Interestingly, decreased signaling via the IIS in invertebrates conferred protection from abnormal alpha-synuclein accumulation (Knight et al. 2014). Thus, the role of IGF1 in PD should be further investigated in more representative models of the disease.

Limitations of human observational studies

Endocrine pathways, including the somatotropic axis, are dynamic, adaptive and complex. Therefore, hormone secretion and bioavailability may vary widely in response to physiologic stressors in an effort to maintain desired homeostasis. This was highlighted by a study in which trajectories of IGF1 levels predicted mortality better than absolute levels (Sanders et al. 2017). Stress and illness can attenuate somatotropic signaling via changes in GH pulsatility and GH resistance (Van den Berghe 2001). Alternatively, a low IGF1 level may be a consequence of AD or PD and serve as a marker of more severe disease, as there is evidence that amyloid plaques and neurofibrillary tangles accumulate in the hypothalamus in patients with neurodegenerative diseases and disrupt endocrine function (Ishii & Iadecola 2015). Yet another theory, for which there is some supportive evidence, is that the reduction in IGF1 may be a compensatory mechanism employed by the body to shift resources away from proliferation and toward cell maintenance, in an effort to preserve neuronal function (George et al. 2017), and thereby limit the accumulation of cellular debris and damage during the aging process. On the other hand, a low IGF1 level may reflect lifelong low IGF1 due to presence of genetic variants. Similarly, an elevated IGF1 level may be inherited (Suh et al. 2008). Furthermore, peripheral levels may have no association with CNS signaling due to adaptive responses induced to protect vulnerable cells in the brain (Talbot et al. 2012, George et al. 2017). In contrast, IGF1 levels may rise in response to neuronal injury in an effort to repair damaged neural tissue. These biological scenarios demonstrate that the same measured IGF1 level may reflect different physiologic processes that may be distinguished only through long-term longitudinal follow-up and genetic studies.

IGF1 levels versus function

Most clinical observational studies focus on a single molecular phenotype, such as level of IGF1, as a surrogate of the somatotropic axis signaling (Al-Delaimy et al. 2009, Westwood et al. 2014, Doi et al. 2015, Ostrowski et al. 2016, Tumati et al. 2016). However, given the complexity of the pathway and its many interacting components, it is apparent that the function of the pathway cannot be reliably interpreted by merely measuring IGF1 levels. For example, such an approach could be misleading in individuals harboring functional IGF1R mutations that result in elevated IGF1 levels due to IGF1R resistance, thereby misclassifying them as having enhanced IGF1 signaling rather than reduced (Suh et al. 2008, Tazearslan et al. 2011). Similarly, IGF1 resistance at the level of the IGF1R and IRS-2 in the brain that accompanies certain disease states could potentially explain the compensatory elevations observed in serum IGF1(Talbot et al. 2012, Trueba-Saiz et al. 2013). More accurate characterization of IGF1 signaling in human studies can be achieved by accounting for the functional genetic variants in the genes that code for key intermediates of the somatotropic pathway and through functional studies.

Conclusion

Undeniably, genetic disruptions of endocrine GH/IGF1 signaling in experimental models have extended health span and lifespan. Although the models of brain aging are more complex, substantial advancements have been made in understanding the role of IGF1 in the aging brain. What ultimately determines the effect of IGF1 on the aging brain is the process that occurs in every dynamic biologic system: It is the ability of cells to modulate IGF1 signaling in an adaptation to the changing physiologic environment. Thus, the function of IGF1 in the CNS likely differs across the lifespan and different pathologic conditions. The results summarized above suggest that long-term maintenance of aging neurons, which are prone to the accumulation of cellular debris and damage that result in age-related neurodegenerative disorders such as AD and PD, benefits from reduced IGF1 signaling. On the other hand, recovery from an acute neuronal insult, such as a stroke, is augmented in the setting of higher IGF1. This evidence points to the fact that IGF1 indeed plays a double role in the aging brain, sometimes that of a good actor and at other times that of a bad actor, depending on the circumstance. Embracing this complexity may ultimately lead to better-targeted therapies for conditions that could benefit the aging brain.

However, before such strategies could be considered there still remain a number of important questions that need answers. These include (1) What is the relative contribution of autocrine vs endocrine-derived IGF1 in the aged CNS? (2) What is the effect of IGF1 on neurons vs on other cells found in the CNS, such as microglia, smooth muscle cells, endothelial cells and astrocytes? (3) What are the effects of acute vs chronic elevations of IGF1 in the aging brain? (4) Is low IGF1 a sign of accelerated aging or a genetically encoded protective mechanism in aging? (5) Is there an interaction between sex and IGF1 in the aging brain, as some studies suggest? (6) Are current experimental models of AD and PD good representations of human pathophysiology? (7) What is the effect of IGF1 signaling through the insulin receptor? (8) Are current genetic models of life-long disruptions of GH/IGF1 signaling representative of age-related IGF1 decline? (9) What are the differential effects of GH and IGF1? (10) Is low or high IGF1 a cause for, an adaptation to, or a consequence of disease? Some of these questions can be investigated in humans using longitudinal follow-up studies that thoroughly characterize participants phenotypically and genetically. However, many other questions will need to rely for answers on animal models. Therefore, the attempt to understand the relationship of IGF1 to brain aging and CNS diseases presents important challenges and opportunities to gain greater insight into how to invoke Dr Jekyll, rather than Mr Hyde qualities of IGF1 in the aging brain.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by the National Institutes of Health (grant numbers P30AG038072, P30DK250541, P01AG021654, R37AG18381, R01AG044829, R01AG046949, R01AG057909, R00AG037574, K23AG051148); the Paul Glenn Foundation for Medical Research and the American Federation for Aging Research.

References

  • AarslandDAndersenKLarsenJLolkANielsenHKragh–SørensenP 2001 Risk of dementia in Parkinson’s disease a community-based, prospective study. Neurology 56 730–736. (https://doi.org/10.1212/WNL.56.6.730)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ÅbergDJoodKBlomstrandCJernCNilssonMIsgaardJÅbergND 2011 Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke. Journal of Clinical Endocrinology and Metabolism 96 E1055–E1064. (https://doi.org/10.1210/jc.2010-2802)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AbuzzahabMJSchneiderAGoddardAGrigorescuFLautierCKellerEKiessWKlammtJKratzschJOsgoodD, et al. 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. New England Journal of Medicine 349 2211–2222. (https://doi.org/10.1056/NEJMoa010107)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Al-DelaimyWKvon MuhlenDBarrett-ConnorE 2009 Insulinlike growth factor-1, insulinlike growth factor binding protein-1, and cognitive function in older men and women. Journal of the American Geriatrics Society 57 1441–1446. (https://doi.org/10.1111/j.1532-5415.2009.02343.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AshpoleNMSandersJEHodgesELYanHSonntagWE 2015 Growth hormone, insulin-like growth factor-1 and the aging brain. Experimental Gerontology 68 76–81. (https://doi.org/10.1016/j.exger.2014.10.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bailey-DownsLCMitschelenMSosnowskaDTothPPintoJTBallabhPValcarcel-AresMNFarleyJKollerAHenthornJC, et al. 2012 Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 67 313–329. (https://doi.org/10.1093/gerona/glr164)

    • Search Google Scholar
    • Export Citation
  • BakerLDBarsnessSMBorsonSMerriamGRFriedmanSDCraftSVitielloMV 2012 Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Archives of Neurology 69 1420–1429. (https://doi.org/10.1001/archneurol.2012.1970)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BartkeAChandrashekarVDominiciFTurynDKinneyBStegerRKopchickJJ 2003 Insulin-like growth factor 1 (IGF-1) and aging: controversies and new insights. Biogerontology 4 1–8. (https://doi.org/10.1023/A:1022448532248)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • BarzilaiNHuffmanDMMuzumdarRHBartkeA 2012 The critical role of metabolic pathways in aging. Diabetes 61 1315–1322. (https://doi.org/10.2337/db11-1300)

  • BaxterRC 2000 Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. American Journal of Physiology: Endocrinology and Metabolism 278 E967–E976. (https://doi.org/10.1152/ajpendo.2000.278.6.E967)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • BerelowitzMSzaboMFrohmanLAFirestoneSChuLHintzRL 1981 Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 212 1279–1281. (https://doi.org/10.1126/science.6262917)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BianchiVELocatelliVRizziL 2017 Neurotrophic and neuroregenerative effects of GH/IGF1. International Journal of Molecular Sciences 18 E2441. (https://doi.org/10.3390/ijms18112441).

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BittoALernerCTorresCRoellMMalagutiMPerezVLorenziniAHreliaSIkenoYMatzkoME, et al. 2010 Long-term IGF-I exposure decreases autophagy and cell viability. PLoS ONE 5 e12592. (https://doi.org/10.1371/journal.pone.0012592)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BondanelliMAmbrosioMROnofriABergonzoniALavezziSZatelliMCValleDBasagliaNdegli UbertiEC 2006 Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome. Journal of Clinical Endocrinology and Metabolism 91 3928–3934. (https://doi.org/10.1210/jc.2006-1040)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Brown-BorgHMBartkeA 2012 GH and IGF1: roles in energy metabolism of long-living GH mutant mice. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 67 652–660. (https://doi.org/10.1093/gerona/gls086)

    • Search Google Scholar
    • Export Citation
  • Brown-BorgHMBorgKEMeliskaCJBartkeA 1996 Dwarf mice and the ageing process. Nature 384 33. (https://doi.org/10.1038/384033a0)

  • CallahanCM 2017 Alzheimer’s disease: individuals, dyads, communities, and costs. Journal of the American Geriatrics Society 65 892–895. (https://doi.org/10.1111/jgs.14808)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CarlsonHEGillinJCGordenPSnyderF 1972 Abscence of sleep-related growth hormone peaks in aged normal subjects and in acromegaly. Journal of Clinical Endocrinology and Metabolism 34 1102–1105. (https://doi.org/10.1210/jcem-34-6-1102)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • CarroETrejoJLGomez-IslaTLeRoithDTorres-AlemanI 2002 Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nature Medicine 8 1390–1397. (https://doi.org/10.1038/nm1202-793)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CarroESpuchCTrejoJLAntequeraDTorres-AlemanI 2005 Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. Journal of Neuroscience 25 10884–10893. (https://doi.org/10.1523/JNEUROSCI.2909-05.2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • CarroETrejoJLGerberALoetscherHTorradoJMetzgerFTorres-AlemanI 2006 Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiology of Aging 27 1250–1257. (https://doi.org/10.1016/j.neurobiolaging.2005.06.015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ChangH-CYangY-RWangPSKuoC-HWangR-Y 2010 Effects of insulinlike growth factor 1 on muscle atrophy and motor function in rats with brain ischemia. Chinese Journal of Physiology 53 337–348. (https://doi.org/10.4077/CJP.2010.AMK080)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ChungHSeoSMoonMParkS 2007 IGF-I inhibition of apoptosis is associated with decreased expression of prostate apoptosis response-4. Journal of Endocrinology 194 77–85. (https://doi.org/10.1677/JOE-07-0073)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ClaxtonABakerLDHansonATrittschuhEHCholertonBMorganACallaghanMArbuckleMBehlCCraftS 2015 Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. Journal of Alzheimer’s Disease 44 897–906. (https://doi.org/10.3233/JAD-141791)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • CohenEPaulssonJFBlinderPBurstyn-CohenTDuDEstepaGAdameAPhamHMHolzenbergerMKellyJW, et al. 2009 Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139 1157–1169. (https://doi.org/10.1016/j.cell.2009.11.014)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • D’AstousMMendezPMorissetteMGarcia-SeguraLMDi PaoloT 2006 Implication of the phosphatidylinositol-3 kinase/protein kinase B signaling pathway in the neuroprotective effect of estradiol in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice. Molecular Pharmacology 69 1492–1498. (https://doi.org/10.1124/mol.105.018671)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • de BruijnRFJanssenJABrugtsMPvan DuijnCMHofmanAKoudstaalPJIkramMA 2014 Insulin-like growth factor-I receptor stimulating activity is associated with dementia. Journal of Alzheimer’s Disease 42 137–142. (https://doi.org/10.3233/JAD-140186)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • De GeyterDDe SmedtAStoopWDe KeyserJKooijmanR 2016 Central IGF-I receptors in the brain are instrumental to neuroprotection by systemically injected IGF-I in a rat model for ischemic stroke. CNS Neuroscience and Therapeutics 22 611–616.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • De KeyserJWilczakNDe BackerJPHerroelenLVauquelinG 1994 Insulin-like growth factor-I receptors in human brain and pituitary gland: an autoradiographic study. Synapse 17 196–202. (https://doi.org/10.1002/syn.890170309)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • de LeonMJDeSantiSZinkowskiRMehtaPDPraticoDSegalSRusinekHLiJTsuiWSaint LouisLA, et al. 2006 Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiology of Aging 27 394–401. (https://doi.org/10.1016/j.neurobiolaging.2005.07.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • De SmedtABrounsRUyttenboogaartMDe RaedtSMoensMWilczakNLuijckxG-JDe KeyserJ 2011 Insulin-like growth factor I serum levels influence ischemic stroke outcome. Stroke 42 2180–2185. (https://doi.org/10.1161/STROKEAHA.110.600783)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • DentiLAnnoniVCattadoriESalvagniniMAVisioliSMerliMFCorradiFCeresiniGValentiGHoffmanAR 2004 Insulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly. American Journal of Medicine 117 312–317. (https://doi.org/10.1016/j.amjmed.2004.02.049)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • DoiTShimadaHMakizakoHTsutsumimotoKHottaRNakakuboSSuzukiT 2015 Association of insulin-like growth factor-1 with mild cognitive impairment and slow gait speed. Neurobiology of Aging 36 942–947. (https://doi.org/10.1016/j.neurobiolaging.2014.10.035)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • DoreSKarSQuirionR 1997 Insulin-like growth factor I protects and rescues hippocampal neurons against beta-amyloid- and human amylin-induced toxicity. PNAS 94 4772–4777. (https://doi.org/10.1073/pnas.94.9.4772)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • EndresMPirizJGertzKHarmsCMeiselAKronenbergGTorres-AlemanI 2007 Serum insulin-like growth factor I and ischemic brain injury. Brain Research 1185 328–335. (https://doi.org/10.1016/j.brainres.2007.09.053)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FinkelsteinJWRoffwargHPBoyarRMKreamJHellmanL 1972 Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. Journal of Clinical Endocrinology and Metabolism 35 665–670. (https://doi.org/10.1210/jcem-35-5-665)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • FletcherLKohliSSpragueSMScrantonRALiptonSAParraAJimenezDFDigicayliogluM 2009 Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Journal of Neurosurgery 111 164–170. (https://doi.org/10.3171/2009.2.JNS081199)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FornoLS 1996 Neuropathology of Parkinson’s disease. Journal of Neuropathology and Experimental Neurology 55 259–272. (https://doi.org/10.1097/00005072-199603000-00001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FraterJLieDBartlettPMcGrathJJ 2017 Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: a review. Ageing Research Reviews 42 14–27. (https://doi.org/10.1016/j.arr.2017.12.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • FreudeSHettichMMSchumannCStohrOKochLKohlerCUdelhovenMLeeserUMullerMKubotaN, et al. 2009 Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer’s disease. FASEB Journal 23 3315–3324. (https://doi.org/10.1096/fj.09-132043)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • FriedlanderALButterfieldGEMoynihanSGrilloJPollackMHollowayLFriedmanLYesavageJMatthiasDLeeS, et al. 2001 One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 86 1496–1503. (https://doi.org/10.1210/jcem.86.4.7377)

    • Search Google Scholar
    • Export Citation
  • GeorgeCGontierGLacubePFrancoisJCHolzenbergerMAidS 2017 The Alzheimer’s disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons. Brain 140 2012–2027. (https://doi.org/10.1093/brain/awx132)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GluckmanPKlemptNGuanJMallardCSirimanneEDragunowMKlemptMSinghKWilliamsCNikolicsK 1992 A role for IGF-1 in the rescue of CNS neurons following hypoxic-ischemic injury. Biochemical and Biophysical Research Communications 182 593–599. (https://doi.org/10.1016/0006-291X(92)91774-K)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GodauJHerfurthMKattnerBGasserTBergD 2010 Increased serum insulin-like growth factor 1 in early idiopathic Parkinson’s disease. Journal of Neurology, Neurosurgery and Psychiatry 81 536–538. (https://doi.org/10.1136/jnnp.2009.175752)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GodauJKnauelKWeberKBrockmannKMaetzlerWBinderGBergD 2011 Serum insulin like growth factor 1 as possible marker for risk and early diagnosis of Parkinson disease. Archives of Neurology 68 925–931. (https://doi.org/10.1001/archneurol.2011.129)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GontierGGeorgeCChakerZHolzenbergerMAidS 2015 Blocking IGF signaling in adult neurons alleviates Alzheimer’s disease pathology through amyloid-beta clearance. Journal of Neuroscience 35 11500–11513. (https://doi.org/10.1523/JNEUROSCI.0343-15.2015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GreenCJHollyJMBayerAFishMEbrahimSGallacherJBen-ShlomoY 2014 The role of IGF-I, IGF-II, and IGFBP-3 in male cognitive aging and dementia risk: the Caerphilly Prospective Study. Journal of Alzheimer’s Disease 41 867–875. (https://doi.org/10.3233/JAD-132183)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GuanJWilliamsCGunningMMallardCGluckmanP 1993 The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats. Journal of Cerebral Blood Flow and Metabolism 13 609–616. (https;//doi.org/10.1038/jcbfm.1993.79)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GuanJMillerOWaughKMcCarthyDGluckmanP 2001 Insulin-like growth factor-1 improves somatosensory function and reduces the extent of cortical infarction and ongoing neuronal loss after hypoxia–ischemia in rats. Neuroscience 105 299–306. (https://doi.org/10.1016/S0306-4522(01)00145-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HaluzikMYakarSGavrilovaOSetserJBoisclairYLeRoithD 2003 Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes 52 2483–2489. (https://doi.org/10.2337/diabetes.52.10.2483)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HollyJMPerksCM 2012 Insulin-like growth factor physiology: what we have learned from human studies. Endocrinology and Metabolism Clinics of North America 41 249–263. (https://doi.org/10.1016/j.ecl.2012.04.009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HuMZhangXLiuWCuiHDiN 2009 Longitudinal changes of defensive and offensive factors in focal cerebral ischemia-reperfusion in rats. Brain Research Bulletin 79 371–375. (https://doi.org/10.1016/j.brainresbull.2009.05.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • IkenoYBronsonRTHubbardGBLeeSBartkeA 2003 Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 58 291–296. (https://doi.org/10.1093/gerona/58.4.B291)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • IshiiMIadecolaC 2015 Metabolic and non-cognitive manifestations of Alzheimer’s disease: the hypothalamus as both culprit and target of pathology. Cell Metabolism 22 761–776. (https://doi.org/10.1016/j.cmet.2015.08.016)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • IsoHMaruyamaKIkeharaSYamagishiKTamakoshiA 2012 Cellular growth factors in relation to mortality from cardiovascular disease in middle-aged Japanese: the JACC study. Atherosclerosis 224 154–160. (https://doi.org/10.1016/j.atherosclerosis.2012.05.026)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • JohnsenSPHundborgHHSørensenHTØrskovHTjønnelandAOvervadKJørgensenJOL 2005 Insulin-like growth factor (IGF) I,-II, and IGF binding protein-3 and risk of ischemic stroke. Journal of Clinical Endocrinology and Metabolism 90 5937–5941. (https://doi.org/10.1210/jc.2004-2088)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • JohnstonBMMallardECWilliamsCEGluckmanPD 1996 Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs. Journal of Clinical Investigation 97 300–308. (https://doi.org/10.1172/JCI118416)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • JosephD’ErcoleAYeP 2008 Expanding the mind: insulin-like growth factor I and brain development. Endocrinology 149 5958–5962. (https://doi.org/10.1210/en.2008-0920)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KaplanRCMcGinnAPPollakMNKullerLHStricklerHDRohanTECappolaARXueXPsatyBM 2007 Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. Journal of Clinical Endocrinology and Metabolism 92 1319–1325. (https://doi.org/10.1210/jc.2006-1631)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KaushikSCuervoAM 2015 Proteostasis and aging. Nature Medicine 21 1406–1415. (https://doi.org/10.1038/nm.4001)

  • KenyonCJ 2010 The genetics of ageing. Nature 464 504–512. (https://doi.org/10.1038/nature08980)

  • KinneyBACoschiganoKTKopchickJJStegerRWBartkeA 2001a Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiology and Behavior 72 653–660. (https://doi.org/10.1016/S0031-9384(01)00423-1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KinneyBAMeliskaCJStegerRWBartkeA 2001b Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Hormones and Behavior 39 277–284. (https://doi.org/10.1006/hbeh.2001.1654)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KlionskyDJAbdelmohsenKAbeAAbedinMJAbeliovichHAcevedo ArozenaAAdachiHAdamsCMAdamsPDAdeliK, et al. 2016 Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12 1–222. (https://doi.org/10.1080/15548627.2015.1100356)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KnightALYanXHamamichiSAjjuriRRMazzulliJRZhangMWDaigleJGZhangSBoromARRobertsLR 2014 The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson’s models. Cell Metabolism 20 145–157. (https://doi.org/10.1016/j.cmet.2014.04.017)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KnuselBMichelPSchwaberJHeftiF 1990 Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. Journal of Neuroscience 10 558–570. (https://doi.org/10.1523/JNEUROSCI.10-02-00558.1990)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KranzlerJHRosenbloomALMartinezVGuevara-AguirreJ 1998 Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: a controlled study in a genetically homogeneous population. Journal of Clinical Endocrinology and Metabolism 83 1953–1958. (https://doi.org/10.1210/jcem.83.6.4863)

    • Search Google Scholar
    • Export Citation
  • Lalancette-HébertMGowingGSimardAWengYCKrizJ 2007 Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. Journal of Neuroscience 27 2596–2605. (https://doi.org/10.1523/JNEUROSCI.5360-06.2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • LangaKMLarsonEBCrimminsEMFaulJDLevineDAKabetoMUWeirDR 2017 A comparison of the prevalence of dementia in the United States in 2000 and 2012. JAMA Internal Medicine 177 51–58. (https://doi.org/10.1001/jamainternmed.2016.6807)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LanzTASalattoCTSemproniARMarconiMBrownTMRichterKESchmidtKNelsonFRSchachterJB 2008 Peripheral elevation of IGF-1 fails to alter Abeta clearance in multiple in vivo models. Biochemical Pharmacology 75 1093–1103. (https://doi.org/10.1016/j.bcp.2007.11.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LeeJHYuWHKumarALeeSMohanPSPeterhoffCMWolfeDMMartinez-VicenteMMasseyACSovakG, et al. 2010 Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141 1146–1158. (https://doi.org/10.1016/j.cell.2010.05.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiangGClineGWMacicaCM 2007 IGF-1 stimulates de novo fatty acid biosynthesis by Schwann cells during myelination. Glia 55 632–641. (https://doi.org/10.1002/glia.20496)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LichtenwalnerRJForbesMEBennettSALynchCDSonntagWERiddleDR 2001 Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107 603–613. (https://doi.org/10.1016/S0306-4522(01)00378-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LinSFanL-WRhodesPGCaiZ 2009 Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Experimental Neurology 217 361–370. (https://doi.org/10.1016/j.expneurol.2009.03.021)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiuX-FFawcettJRThorneRGDeForTAFreyWH 2001 Intranasal administration of insulin-like growth factor-I bypasses the blood–brain barrier and protects against focal cerebral ischemic damage. Journal of the Neurological Sciences 187 91–97. (https://doi.org/10.1016/S0022-510X(01)00532-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiuYWangXLiWZhangQLiYZhangZZhuJChenBWilliamsPRZhangY 2017 A sensitized IGF1 treatment restores corticospinal axon-dependent functions. Neuron 95 817.e814–833.e814. (https://doi.org/10.1016/j.neuron.2017.07.037)

    • Search Google Scholar
    • Export Citation
  • LoganSPharaohGAMarlinMCMasserDRMatsuzakiSWronowskiBYeganehAParksEEPremkumarPFarleyJA, et al. 2018 Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-beta uptake in astrocytes. Molecular Metabolism 9 141–155. (https://doi.org/10.1016/j.molmet.2018.01.013)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MackayKBLoddickSANaeveGSVanaAMVergeGMFosterAC 2003 Neuroprotective effects of insulin-like growth factor-binding protein ligand inhibitors in vitro and in vivo. Journal of Cerebral Blood Flow and Metabolism 23 1160–1167. (https://doi.org/10.1097/01.WCB.0000087091.01171.AE)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • MarkowskaALMooneyMSonntagWE 1998 Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience 87 559–569. (https://doi.org/10.1016/S0306-4522(98)00143-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Martinez-VicenteMCuervoAM 2007 Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurology 6 352–361. (https://doi.org/10.1016/S1474-4422(07)70076-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • MashayekhiFMirzajaniENajiMAzariM 2010 Expression of insulin-like growth factor-1 and insulin-like growth factor binding proteins in the serum and cerebrospinal fluid of patients with Parkinson’s disease. Journal of Clinical Neuroscience 17 623–627. (https://doi.org/10.1016/j.jocn.2009.08.013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • MattlageAERippeeMASandtJBillingerSA 2016 Decrease in insulin-like growth factor-1 and insulin-like growth factor-1 ratio in the first week of stroke is related to positive outcomes. Journal of Stroke and Cerebrovascular Diseases 25 1800–1806. (https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.054)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • MelendezATalloczyZSeamanMEskelinenELHallDHLevineB 2003 Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301 1387–1391. (https://doi.org/10.1126/science.1087782)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • MenziesFMFlemingACaricasoleABentoCFAndrewsSPAshkenaziAFullgrabeJJacksonAJimenez SanchezMKarabiyikC, et al. 2017 Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93 1015–1034. (https://doi.org/10.1016/j.neuron.2017.01.022)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MilmanSAtzmonGHuffmanDMWanJCrandallJPCohenPBarzilaiN 2014 Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 13 769–771. (https://doi.org/10.1111/acel.12213)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MuJChaudhuriKRBielzaCde Pedro-CuestaJLarranagaPMartinez-MartinP 2017 Parkinson’s disease subtypes identified from cluster analysis of motor and non-motor symptoms. Frontiers in Aging Neuroscience 9 301. (https://doi.org/10.3389/fnagi.2017.00301)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MullerAPFernandezAMHaasCZimmerEPortelaLVTorres-AlemanI 2012 Reduced brain insulin-like growth factor I function during aging. Molecular and Cellular Neuroscience 49 9–12. (https://doi.org/10.1016/j.mcn.2011.07.008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • NadjarABertonOGuoSLeneuvePDoveroSDiguetETisonFZhaoBHolzenbergerMBezardE 2009 IGF-1 signaling reduces neuro-inflammatory response and sensitivity of neurons to MPTP. Neurobiology of Aging 30 2021–2030. (https://doi.org/10.1016/j.neurobiolaging.2008.02.009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • NetchineIAzziSLe BoucYSavageMO 2011 IGF1 molecular anomalies demonstrate its critical role in fetal, postnatal growth and brain development. Best Practice and Research: Clinical Endocrinology and Metabolism 25 181–190. (https://doi.org/10.1016/j.beem.2010.08.005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nieto-EstevezVDefteraliCVicario-AbejonC 2016 IGF-I: a key growth factor that regulates neurogenesis and synaptogenesis from embryonic to adult stages of the brain. Frontiers in Neuroscience 10 52. (https://doi.org/10.3389/fnins.2016.00052)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • NovosyadlyyRLeroithD 2012 Insulin-like growth factors and insulin: at the crossroad between tumor development and longevity. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 67 640–651. (https://doi.org/10.1093/gerona/gls065)

    • Search Google Scholar
    • Export Citation
  • NumaoASuzukiKMiyamotoMMiyamotoTHirataK 2014 Clinical correlates of serum insulin-like growth factor-1 in patients with Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy. Parkinsonism and Related Disorders 20 212–216. (https://doi.org/10.1016/j.parkreldis.2013.11.005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • OffenDShtaifBHadadDWeizmanAMelamedEGil-AdI 2001 Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: possible implications for Parkinson’s disease. Neuroscience Letters 316 129–132. (https://doi.org/10.1016/S0304-3940(01)02344-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • OhlssonCMohanSSjogrenKTivestenAIsgaardJIsakssonOJanssonJOSvenssonJ 2009 The role of liver-derived insulin-like growth factor-I. Endocrine Reviews 30 494–535. (https://doi.org/10.1210/er.2009-0010)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • OkerekeOKangJHMaJHankinsonSEPollakMNGrodsteinF 2007 Plasma IGF-I levels and cognitive performance in older women. Neurobiology of Aging 28 135–142. (https://doi.org/10.1016/j.neurobiolaging.2005.10.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • OstrowskiPPBarszczykAForstenpointnerJZhengWFengZP 2016 Meta-analysis of serum insulin-like growth factor 1 in Alzheimer’s disease. PLoS ONE 11 e0155733. (https://doi.org/10.1371/journal.pone.0155733)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PardoJUriarteMConsoleGMReggianiPCOuteiroTFMorelGRGoyaRG 2016 Insulin-like growth factor-I gene therapy increases hippocampal neurogenesis, astrocyte branching and improves spatial memory in female aging rats. European Journal of Neuroscience 44 2120–2128. (https://doi.org/10.1111/ejn.13278)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • PardoJAbbaMCLacunzaEOgundeleOMPaivaIMorelGROuteiroTFGoyaRG 2018 IGF-I gene therapy in aging rats modulates hippocampal genes relevant to memory function. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 73 459–467. (https://doi.org/10.1093/gerona/glx125)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ParrellaEMaximTMaialettiFZhangLWanJWeiMCohenPFontanaLLongoVD 2013 Protein restriction cycles reduce IGF-1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer’s disease mouse model. Aging Cell 12 257–268. (https://doi.org/10.1111/acel.12049)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • PathipatiPSurusAWilliamsCEScheepensA 2009 Delayed and chronic treatment with growth hormone after endothelin-induced stroke in the adult rat. Behavioural Brain Research 204 93–101. (https://doi.org/10.1016/j.bbr.2009.05.023)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PellecchiaMSantangeloGPicilloMPivonelloRLongoKPivonelloCVitaleCAmboniMRosaAMocciaM 2014 Insulin-like growth factor-1 predicts cognitive functions at 2-year follow-up in early, drug-naïve Parkinson’s disease. European Journal of Neurology 21 802–807. (https://doi.org/10.1111/ene.12137)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PericeLBarzilaiNVergheseJWeissEFHoltzerRCohenPMilmanS 2016 Lower circulating insulin-like growth factor-I is associated with better cognition in females with exceptional longevity without compromise to muscle mass and function. Aging 8 2414–2424. (https://doi.org/10.18632/aging.101063)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PicilloMErroRSantangeloGPivonelloRLongoKPivonelloCVitaleCAmboniMMocciaMColaoA 2013 Insulin-like growth factor-1 and progression of motor symptoms in early, drug-naïve Parkinson’s disease. Journal of Neurology 260 1724–1730. (https://doi.org/10.1007/s00415-013-6851-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PicilloMPivonelloRSantangeloGPivonelloCSavastanoRAuriemmaRAmboniMScannapiecoSPierroAColaoA 2017 Serum IGF-1 is associated with cognitive functions in early, drug-naïve Parkinson’s disease. PLoS ONE 12 e0186508. (https://doi.org/10.1371/journal.pone.0186508)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PloughmanMGranter-ButtonSChernenkoGTuckerBMearowKCorbettD 2005 Endurance exercise regimens induce differential effects on brain-derived neurotrophic factor, synapsin-I and insulin-like growth factor I after focal ischemia. Neuroscience 136 991–1001. (https://doi.org/10.1016/j.neuroscience.2005.08.037)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PrinceMAliG-CGuerchetMPrinaAMAlbaneseEWuY-T 2016 Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimer’s Research and Therapy 8 23. (https://doi.or/10.1186/s13195-016-0188-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • PuigKLKulasJAFranklinWRakoczySGTaglialatelaGBrown-BorgHMCombsCK 2016 The Ames dwarf mutation attenuates Alzheimer’s disease phenotype of APP/PS1 mice. Neurobiology of Aging 40 22–40. (https://doi.org/10.1016/j.neurobiolaging.2015.12.021)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • QuesadaAMicevychPE 2004 Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxdopamine lesions. Journal of Neuroscience Research 75 107–116. (https://doi.org/10.1002/jnr.10833)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RajaramSBaylinkDJMohanS 1997 Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocrine Reviews 18 801–831. (https://doi.org/10.1210/edrv.18.6.0321)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • RizkNNMyatt-JonesJRafolsJDunbarJC 2007 Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine 31 66–71. (https://doi.org/10.1007/s12020-007-0012-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SaberHHimaliJJBeiserASShoamaneshAPikulaARoubenoffRRomeroJRKaseCSVasanRSSeshadriS 2017 Serum insulin-like growth factor 1 and the risk of ischemic stroke: the Framingham Study. Stroke 48 1760–1765. (https://doi.org/10.1161/STROKEAHA.116.016563)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SamariHRSeglenPO 1998 Inhibition of hepatocytic autophagy by adenosine, aminoimidazole-4-carboxamide riboside, and N6-mercaptopurine riboside. Evidence for involvement of amp-activated protein kinase. Journal of Biological Chemistry 273 23758–23763. (https://doi.org/10.1074/jbc.273.37.23758)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SandersJLGuoWO’MearaESKaplanRCPollakMNBartzTMNewmanABFriedLPCappolaAR 2017 Trajectories of IGF-I predict mortality in older adults: the Cardiovascular Health Study. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences Epub. (https://doi.org/10.1093/gerona/glx143)

    • Search Google Scholar
    • Export Citation
  • SchäbitzW-RHoffmannTTHeilandSKollmarRBardutzkyJSommerCSchwabS 2001 Delayed neuroprotective effect of insulin-like growth factor-I after experimental transient focal cerebral ischemia monitored with MRI. Stroke 32 1226–1233. (https://doi.org/10.1161/01.STR.32.5.1226)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SchapiraAHVChaudhuriKRJennerP 2017 Non-motor features of Parkinson disease. Nature Reviews Neuroscience 18 435–450. (https://doi.org/10.1038/nrn.2017.62)

  • SchmelzleTHallMN 2000 TOR, a central controller of cell growth. Cell 103 253–262. (https://doi.org/10.1016/S0092-8674(00)00117-3)

  • SchwabSSprangerMKrempienSHackeWBettendorfM 1997 Plasma insulin-like growth factor I and IGF binding protein 3 levels in patients with acute cerebral ischemic injury. Stroke 28 1744–1748. (https://doi.org/10.1161/01.STR.28.9.1744)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SelvamaniASohrabjiF 2010 The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1. Journal of Neuroscience 30 6852–6861. (https://doi.org/10.1523/JNEUROSCI.0761-10.2010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SelvamaniASathyanPMirandaRCSohrabjiF 2012 An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model. PLoS ONE 7 e32662. (https://doi.org/10.1371/journal.pone.0032662)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SevignyJJRyanJMvan DyckCHPengYLinesCRNesslyML & Group MKPS 2008 Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology 71 1702–1708. (https://doi.org/10.1212/01.wnl.0000335163.88054.e7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Silva-CoutoMdAPrado-MedeirosCLOliveiraABAlcântaraCCGuimaraesATSalviniTdFMattioliRRussoTLd 2014 Muscle atrophy, voluntary activation disturbances, and low serum concentrations of IGF-1 and IGFBP-3 are associated with weakness in people with chronic stroke. Physical Therapy 94 957–967. (https://doi.org/10.2522/ptj.20130322)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SonntagWECarterCSIkenoYEkenstedtKCarlsonCSLoeserRFChakrabartySLeeSBennettCIngramR, et al. 2005 Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 146 2920–2932. (https://doi.org/10.1210/en.2005-0058)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SuhYAtzmonGChoMOHwangDLiuBLeahyDJBarzilaiNCohenP 2008 Functionally significant insulin-like growth factor I receptor mutations in centenarians. PNAS 105 3438–3442. (https://doi.org/10.1073/pnas.0705467105)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SunYWangPZhengHSmithRG 2004 Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. PNAS 101 4679–4684. (https://doi.org/10.1073/pnas.0305930101)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SunLYAl-RegaieyKMasternakMMWangJBartkeA 2005 Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiology of Aging 26 929–937. (https://doi.org/10.1016/j.neurobiolaging.2004.07.010)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SunXHuangLZhangMSunSWuY 2010 Insulin like growth factor-1 prevents 1-mentyl-4-phenylphyridinium-induced apoptosis in PC12 cells through activation of glycogen synthase kinase-3beta. Toxicology 271 5–12. (https://doi.org/10.1016/j.tox.2010.01.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SvenssonJDiezMEngelJWassCTivestenAJanssonJOIsakssonOArcherTHokfeltTOhlssonC 2006 Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice. Journal of Endocrinology 189 617–627. (https://doi.org/10.1677/joe.1.06631)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • TalbotKWangHYKaziHHanLYBakshiKPStuckyAFuinoRLKawaguchiKRSamoyednyAJWilsonRS, et al. 2012 Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. Journal of Clinical Investigation 122 1316–1338. (https://doi.org/10.1172/JCI59903)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • TangJ-HMaL-LYuT-XZhengJZhangH-JLiangHShaoP 2014 Insulin-like growth factor-1 as a prognostic marker in patients with acute ischemic stroke. PLoS ONE 9 e99186. (https://doi.org/10.1371/journal.pone.0099186)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TaniguchiCMEmanuelliBKahnCR 2006 Critical nodes in signalling pathways: insights into insulin action. Nature Reviews Molecular Cell Biology 7 85–96. (https://doi.org/10.1038/nrm1837)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TazearslanCHuangJBarzilaiNSuhY 2011 Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. Aging Cell 10 551–554. (https://doi.org/10.1111/j.1474-9726.2011.00697.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ThoredPHeldmannUGomes-LealWGislerRDarsaliaVTaneeraJNygrenJMJacobsenSEWEkdahlCTKokaiaZ 2009 Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia 57 835–849. (https://doi.org/10.1002/glia.20810)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TothPTucsekZTarantiniSSosnowskaDGautamTMitschelenMKollerASonntagWECsiszarAUngvariZ 2014 IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. Journal of Cerebral Blood Flow and Metabolism 34 1887–1897. (https://doi.org/10.1038/jcbfm.2014.156)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • TothPTarantiniSAshpoleNMTucsekZMilneGLValcarcel-AresNMMenyhartAFarkasESonntagWECsiszarA, et al. 2015 IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14 1034–1044. (https://doi.org/10.1111/acel.12372)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TrejoJLPirizJLlorens-MartinMVFernandezAMBolosMLeRoithDNunezATorres-AlemanI 2007 Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects. Molecular Psychiatry 12 1118–1128. (https://doi.org/10.1038/sj.mp.4002076)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Trueba-SaizACavadaCFernandezAMLeonTGonzalezDAFortea OrmaecheaJLleoADel SerTNunezATorres-AlemanI 2013 Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice. Translational Psychiatry 3 e330. (https://doi.org/10.1038/tp.2013.102)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TumatiSBurgerHMartensSvan der SchouwYTAlemanA 2016 Association between cognition and serum insulin-like growth factor-1 in middle-aged & older men: an 8 year follow-up study. PLoS ONE 11 e0154450. (https://doi.org/10.1371/journal.pone.0154450)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TuncelDInanc TolunFToruI 2009 Serum insulin-like growth factor-1 and nitric oxide levels in Parkinson’s disease. Mediators of Inflammation 2009. (https://doi.org/10.1155/2009/132464)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Van den BeldABotsMJanssenJPolsHLambertsSGrobbeeD 2003 Endogenous hormones and carotid atherosclerosis in elderly men. American Journal of Epidemiology 157 25–31. (https://doi.org/10.1093/aje/kwf160)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Van den BergheG 2001 The neuroendocrine response to stress is a dynamic process. Best Practice and Research: Clinical Endocrinology and Metabolism 15 405–419. (https://doi.org/10.1053/beem.2001.0160)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • VidalJSHanonOFunalotBBrunelNViolletCRigaudASSeuxMLle-BoucYEpelbaumJDuronE 2016 Low serum insulin-like growth factor-I predicts cognitive decline in Alzheimer’s disease. Journal of Alzheimer’s Disease 52 641–649. (https://doi.org/10.3233/JAD-151162)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • WennbergAMVHagenCEMachuldaMMHollmanJHRobertsROKnopmanDSPetersenRCMielkeMM 2018 The association between peripheral total IGF-1, IGFBP-3, and IGF-1/IGFBP-3 and functional and cognitive outcomes in the Mayo Clinic Study of Aging. Neurobiology of Aging 66 68–74. (https://doi.org/10.1016/j.neurobiolaging.2017.11.017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • WestwoodAJBeiserADecarliCHarrisTBChenTCHeXMRoubenoffRPikulaAAuRBravermanLE, et al. 2014 Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy. Neurology 82 1613–1619. (https://doi.org/10.1212/WNL.0000000000000382)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • WoodsKACamacho-HubnerCSavageMOClarkAJ 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. New England Journal of Medicine 335 1363–1367. (https://doi.org/10.1056/NEJM199610313351805)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • WuY-TBeiserASBretelerMMFratiglioniLHelmerCHendrieHCHondaHIkramMALangaKMLoboA 2017 The changing prevalence and incidence of dementia over time—current evidence. Nature Reviews Neurology 13 327. (https://doi.org/10.1038/nrneurol.2017.63)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • YamamotoHSohmiyaMOkaNKatoY 1991 Effects of aging and sex on plasma insulin-like growth factor I (IGF-I) levels in normal adults. Acta Endocrinologica 124 497–500. (https://doi.org/10.1530/acta.0.1240497)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • YanYPSailorKAVemugantiRDempseyRJ 2006 Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. European Journal of Neuroscience 24 45–54. (https://doi.org/10.1111/j.1460-9568.2006.04872.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ZawadaWMKirschmanDLCohenJJHeidenreichKAFreedCR 1996 Growth factors rescue embryonic dopamine neurons from programmed cell death. Experimental Neurology 140 60–67. (https://doi.org/10.1006/exnr.1996.0115)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhangJLiYChenJYangMKatakowskiMLuMChoppM 2004 Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Research 1030 19–27. (https://doi.org/10.1016/j.brainres.2004.09.061)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhengH-QZhangL-YLuoJLiL-LLiMZhangQHuX-Q 2014 Physical exercise promotes recovery of neurological function after ischemic stroke in rats. International Journal of Molecular Sciences 15 10974–10988. (https://doi.org/10.3390/ijms150610974)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhuWFanYFrenzelTGasmiMBartusRTYoungWLYangG-YChenY 2008 Insulin growth factor-1 gene transfer enhances neurovascular remodeling and improves long-term stroke outcome in mice. Stroke 39 1254–1261. (https://doi.org/10.1161/STROKEAHA.107.500801)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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    IGF1 playing the roles of Dr Jekyll and Mr Hyde in the brain. IGF1 exerts its beneficial effects on the brain by stimulating neurogenesis, synaptogenesis, neurite growth, myelination and promoting cell survival. These processes are important during early life for proper brain development and growth, whereas during aging, they contribute to repair of injured neural tissue, as may result from a stroke. On the other hand, the adverse effects of IGF1 on the brain include generation of reactive oxygen species and inhibition of both autophagy and stress responses. Inhibition of these functions results in diminished cell resilience and accumulation of cellular debris, which are characteristic of age-related neurodegenerative conditions such as AD and PD. AD, Alzheimer’s disease; IGF1, insulin-like growth factor-1; PD, Parkinson’s disease.

  • AarslandDAndersenKLarsenJLolkANielsenHKragh–SørensenP 2001 Risk of dementia in Parkinson’s disease a community-based, prospective study. Neurology 56 730–736. (https://doi.org/10.1212/WNL.56.6.730)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ÅbergDJoodKBlomstrandCJernCNilssonMIsgaardJÅbergND 2011 Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke. Journal of Clinical Endocrinology and Metabolism 96 E1055–E1064. (https://doi.org/10.1210/jc.2010-2802)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AbuzzahabMJSchneiderAGoddardAGrigorescuFLautierCKellerEKiessWKlammtJKratzschJOsgoodD, et al. 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. New England Journal of Medicine 349 2211–2222. (https://doi.org/10.1056/NEJMoa010107)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Al-DelaimyWKvon MuhlenDBarrett-ConnorE 2009 Insulinlike growth factor-1, insulinlike growth factor binding protein-1, and cognitive function in older men and women. Journal of the American Geriatrics Society 57 1441–1446. (https://doi.org/10.1111/j.1532-5415.2009.02343.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AshpoleNMSandersJEHodgesELYanHSonntagWE 2015 Growth hormone, insulin-like growth factor-1 and the aging brain. Experimental Gerontology 68 76–81. (https://doi.org/10.1016/j.exger.2014.10.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bailey-DownsLCMitschelenMSosnowskaDTothPPintoJTBallabhPValcarcel-AresMNFarleyJKollerAHenthornJC, et al. 2012 Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 67 313–329. (https://doi.org/10.1093/gerona/glr164)

    • Search Google Scholar
    • Export Citation
  • BakerLDBarsnessSMBorsonSMerriamGRFriedmanSDCraftSVitielloMV 2012 Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Archives of Neurology 69 1420–1429. (https://doi.org/10.1001/archneurol.2012.1970)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BartkeAChandrashekarVDominiciFTurynDKinneyBStegerRKopchickJJ 2003 Insulin-like growth factor 1 (IGF-1) and aging: controversies and new insights. Biogerontology 4 1–8. (https://doi.org/10.1023/A:1022448532248)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • BarzilaiNHuffmanDMMuzumdarRHBartkeA 2012 The critical role of metabolic pathways in aging. Diabetes 61 1315–1322. (https://doi.org/10.2337/db11-1300)

  • BaxterRC 2000 Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. American Journal of Physiology: Endocrinology and Metabolism 278 E967–E976. (https://doi.org/10.1152/ajpendo.2000.278.6.E967)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • BerelowitzMSzaboMFrohmanLAFirestoneSChuLHintzRL 1981 Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 212 1279–1281. (https://doi.org/10.1126/science.6262917)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BianchiVELocatelliVRizziL 2017 Neurotrophic and neuroregenerative effects of GH/IGF1. International Journal of Molecular Sciences 18 E2441. (https://doi.org/10.3390/ijms18112441).

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BittoALernerCTorresCRoellMMalagutiMPerezVLorenziniAHreliaSIkenoYMatzkoME, et al. 2010 Long-term IGF-I exposure decreases autophagy and cell viability. PLoS ONE 5 e12592. (https://doi.org/10.1371/journal.pone.0012592)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BondanelliMAmbrosioMROnofriABergonzoniALavezziSZatelliMCValleDBasagliaNdegli UbertiEC 2006 Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome. Journal of Clinical Endocrinology and Metabolism 91 3928–3934. (https://doi.org/10.1210/jc.2006-1040)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Brown-BorgHMBartkeA 2012 GH and IGF1: roles in energy metabolism of long-living GH mutant mice. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 67 652–660. (https://doi.org/10.1093/gerona/gls086)

    • Search Google Scholar
    • Export Citation
  • Brown-BorgHMBorgKEMeliskaCJBartkeA 1996 Dwarf mice and the ageing process. Nature 384 33. (https://doi.org/10.1038/384033a0)

  • CallahanCM 2017 Alzheimer’s disease: individuals, dyads, communities, and costs. Journal of the American Geriatrics Society 65 892–895. (https://doi.org/10.1111/jgs.14808)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CarlsonHEGillinJCGordenPSnyderF 1972 Abscence of sleep-related growth hormone peaks in aged normal subjects and in acromegaly. Journal of Clinical Endocrinology and Metabolism 34 1102–1105. (https://doi.org/10.1210/jcem-34-6-1102)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • CarroETrejoJLGomez-IslaTLeRoithDTorres-AlemanI 2002 Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nature Medicine 8 1390–1397. (https://doi.org/10.1038/nm1202-793)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CarroESpuchCTrejoJLAntequeraDTorres-AlemanI 2005 Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. Journal of Neuroscience 25 10884–10893. (https://doi.org/10.1523/JNEUROSCI.2909-05.2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • CarroETrejoJLGerberALoetscherHTorradoJMetzgerFTorres-AlemanI 2006 Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiology of Aging 27 1250–1257. (https://doi.org/10.1016/j.neurobiolaging.2005.06.015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ChangH-CYangY-RWangPSKuoC-HWangR-Y 2010 Effects of insulinlike growth factor 1 on muscle atrophy and motor function in rats with brain ischemia. Chinese Journal of Physiology 53 337–348. (https://doi.org/10.4077/CJP.2010.AMK080)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ChungHSeoSMoonMParkS 2007 IGF-I inhibition of apoptosis is associated with decreased expression of prostate apoptosis response-4. Journal of Endocrinology 194 77–85. (https://doi.org/10.1677/JOE-07-0073)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ClaxtonABakerLDHansonATrittschuhEHCholertonBMorganACallaghanMArbuckleMBehlCCraftS 2015 Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. Journal of Alzheimer’s Disease 44 897–906. (https://doi.org/10.3233/JAD-141791)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • CohenEPaulssonJFBlinderPBurstyn-CohenTDuDEstepaGAdameAPhamHMHolzenbergerMKellyJW, et al. 2009 Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139 1157–1169. (https://doi.org/10.1016/j.cell.2009.11.014)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • D’AstousMMendezPMorissetteMGarcia-SeguraLMDi PaoloT 2006 Implication of the phosphatidylinositol-3 kinase/protein kinase B signaling pathway in the neuroprotective effect of estradiol in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice. Molecular Pharmacology 69 1492–1498. (https://doi.org/10.1124/mol.105.018671)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • de BruijnRFJanssenJABrugtsMPvan DuijnCMHofmanAKoudstaalPJIkramMA 2014 Insulin-like growth factor-I receptor stimulating activity is associated with dementia. Journal of Alzheimer’s Disease 42 137–142. (https://doi.org/10.3233/JAD-140186)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • De GeyterDDe SmedtAStoopWDe KeyserJKooijmanR 2016 Central IGF-I receptors in the brain are instrumental to neuroprotection by systemically injected IGF-I in a rat model for ischemic stroke. CNS Neuroscience and Therapeutics 22 611–616.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • De KeyserJWilczakNDe BackerJPHerroelenLVauquelinG 1994 Insulin-like growth factor-I receptors in human brain and pituitary gland: an autoradiographic study. Synapse 17 196–202. (https://doi.org/10.1002/syn.890170309)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • de LeonMJDeSantiSZinkowskiRMehtaPDPraticoDSegalSRusinekHLiJTsuiWSaint LouisLA, et al. 2006 Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiology of Aging 27 394–401. (https://doi.org/10.1016/j.neurobiolaging.2005.07.003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • De SmedtABrounsRUyttenboogaartMDe RaedtSMoensMWilczakNLuijckxG-JDe KeyserJ 2011 Insulin-like growth factor I serum levels influence ischemic stroke outcome. Stroke 42 2180–2185. (https://doi.org/10.1161/STROKEAHA.110.600783)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • DentiLAnnoniVCattadoriESalvagniniMAVisioliSMerliMFCorradiFCeresiniGValentiGHoffmanAR 2004 Insulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly. American Journal of Medicine 117 312–317. (https://doi.org/10.1016/j.amjmed.2004.02.049)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • DoiTShimadaHMakizakoHTsutsumimotoKHottaRNakakuboSSuzukiT 2015 Association of insulin-like growth factor-1 with mild cognitive impairment and slow gait speed. Neurobiology of Aging 36 942–947. (https://doi.org/10.1016/j.neurobiolaging.2014.10.035)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • DoreSKarSQuirionR 1997 Insulin-like growth factor I protects and rescues hippocampal neurons against beta-amyloid- and human amylin-induced toxicity. PNAS 94 4772–4777. (https://doi.org/10.1073/pnas.94.9.4772)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • EndresMPirizJGertzKHarmsCMeiselAKronenbergGTorres-AlemanI 2007 Serum insulin-like growth factor I and ischemic brain injury. Brain Research 1185 328–335. (https://doi.org/10.1016/j.brainres.2007.09.053)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FinkelsteinJWRoffwargHPBoyarRMKreamJHellmanL 1972 Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. Journal of Clinical Endocrinology and Metabolism 35 665–670. (https://doi.org/10.1210/jcem-35-5-665)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • FletcherLKohliSSpragueSMScrantonRALiptonSAParraAJimenezDFDigicayliogluM 2009 Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Journal of Neurosurgery 111 164–170. (https://doi.org/10.3171/2009.2.JNS081199)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FornoLS 1996 Neuropathology of Parkinson’s disease. Journal of Neuropathology and Experimental Neurology 55 259–272. (https://doi.org/10.1097/00005072-199603000-00001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FraterJLieDBartlettPMcGrathJJ 2017 Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: a review. Ageing Research Reviews 42 14–27. (https://doi.org/10.1016/j.arr.2017.12.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • FreudeSHettichMMSchumannCStohrOKochLKohlerCUdelhovenMLeeserUMullerMKubotaN, et al. 2009 Neuronal IGF-1 resistance reduces Abeta accumulation and protects against premature death in a model of Alzheimer’s disease. FASEB Journal 23 3315–3324. (https://doi.org/10.1096/fj.09-132043)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • FriedlanderALButterfieldGEMoynihanSGrilloJPollackMHollowayLFriedmanLYesavageJMatthiasDLeeS, et al. 2001 One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 86 1496–1503. (https://doi.org/10.1210/jcem.86.4.7377)

    • Search Google Scholar
    • Export Citation
  • GeorgeCGontierGLacubePFrancoisJCHolzenbergerMAidS 2017 The Alzheimer’s disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons. Brain 140 2012–2027. (https://doi.org/10.1093/brain/awx132)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GluckmanPKlemptNGuanJMallardCSirimanneEDragunowMKlemptMSinghKWilliamsCNikolicsK 1992 A role for IGF-1 in the rescue of CNS neurons following hypoxic-ischemic injury. Biochemical and Biophysical Research Communications 182 593–599. (https://doi.org/10.1016/0006-291X(92)91774-K)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GodauJHerfurthMKattnerBGasserTBergD 2010 Increased serum insulin-like growth factor 1 in early idiopathic Parkinson’s disease. Journal of Neurology, Neurosurgery and Psychiatry 81 536–538. (https://doi.org/10.1136/jnnp.2009.175752)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GodauJKnauelKWeberKBrockmannKMaetzlerWBinderGBergD 2011 Serum insulin like growth factor 1 as possible marker for risk and early diagnosis of Parkinson disease. Archives of Neurology 68 925–931. (https://doi.org/10.1001/archneurol.2011.129)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GontierGGeorgeCChakerZHolzenbergerMAidS 2015 Blocking IGF signaling in adult neurons alleviates Alzheimer’s disease pathology through amyloid-beta clearance. Journal of Neuroscience 35 11500–11513. (https://doi.org/10.1523/JNEUROSCI.0343-15.2015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GreenCJHollyJMBayerAFishMEbrahimSGallacherJBen-ShlomoY 2014 The role of IGF-I, IGF-II, and IGFBP-3 in male cognitive aging and dementia risk: the Caerphilly Prospective Study. Journal of Alzheimer’s Disease 41 867–875. (https://doi.org/10.3233/JAD-132183)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GuanJWilliamsCGunningMMallardCGluckmanP 1993 The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats. Journal of Cerebral Blood Flow and Metabolism 13 609–616. (https;//doi.org/10.1038/jcbfm.1993.79)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • GuanJMillerOWaughKMcCarthyDGluckmanP 2001 Insulin-like growth factor-1 improves somatosensory function and reduces the extent of cortical infarction and ongoing neuronal loss after hypoxia–ischemia in rats. Neuroscience 105 299–306. (https://doi.org/10.1016/S0306-4522(01)00145-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HaluzikMYakarSGavrilovaOSetserJBoisclairYLeRoithD 2003 Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes 52 2483–2489. (https://doi.org/10.2337/diabetes.52.10.2483)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HollyJMPerksCM 2012 Insulin-like growth factor physiology: what we have learned from human studies. Endocrinology and Metabolism Clinics of North America 41 249–263. (https://doi.org/10.1016/j.ecl.2012.04.009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HuMZhangXLiuWCuiHDiN 2009 Longitudinal changes of defensive and offensive factors in focal cerebral ischemia-reperfusion in rats. Brain Research Bulletin 79 371–375. (https://doi.org/10.1016/j.brainresbull.2009.05.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • IkenoYBronsonRTHubbardGBLeeSBartkeA 2003 Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 58 291–296. (https://doi.org/10.1093/gerona/58.4.B291)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • IshiiMIadecolaC 2015 Metabolic and non-cognitive manifestations of Alzheimer’s disease: the hypothalamus as both culprit and target of pathology. Cell Metabolism 22 761–776. (https://doi.org/10.1016/j.cmet.2015.08.016)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • IsoHMaruyamaKIkeharaSYamagishiKTamakoshiA 2012 Cellular growth factors in relation to mortality from cardiovascular disease in middle-aged Japanese: the JACC study. Atherosclerosis 224 154–160. (https://doi.org/10.1016/j.atherosclerosis.2012.05.026)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • JohnsenSPHundborgHHSørensenHTØrskovHTjønnelandAOvervadKJørgensenJOL 2005 Insulin-like growth factor (IGF) I,-II, and IGF binding protein-3 and risk of ischemic stroke. Journal of Clinical Endocrinology and Metabolism 90 5937–5941. (https://doi.org/10.1210/jc.2004-2088)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • JohnstonBMMallardECWilliamsCEGluckmanPD 1996 Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs. Journal of Clinical Investigation 97 300–308. (https://doi.org/10.1172/JCI118416)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • JosephD’ErcoleAYeP 2008 Expanding the mind: insulin-like growth factor I and brain development. Endocrinology 149 5958–5962. (https://doi.org/10.1210/en.2008-0920)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KaplanRCMcGinnAPPollakMNKullerLHStricklerHDRohanTECappolaARXueXPsatyBM 2007 Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. Journal of Clinical Endocrinology and Metabolism 92 1319–1325. (https://doi.org/10.1210/jc.2006-1631)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KaushikSCuervoAM 2015 Proteostasis and aging. Nature Medicine 21 1406–1415. (https://doi.org/10.1038/nm.4001)

  • KenyonCJ 2010 The genetics of ageing. Nature 464 504–512. (https://doi.org/10.1038/nature08980)

  • KinneyBACoschiganoKTKopchickJJStegerRWBartkeA 2001a Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiology and Behavior 72 653–660. (https://doi.org/10.1016/S0031-9384(01)00423-1)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KinneyBAMeliskaCJStegerRWBartkeA 2001b Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Hormones and Behavior 39 277–284. (https://doi.org/10.1006/hbeh.2001.1654)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KlionskyDJAbdelmohsenKAbeAAbedinMJAbeliovichHAcevedo ArozenaAAdachiHAdamsCMAdamsPDAdeliK, et al. 2016 Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12 1–222. (https://doi.org/10.1080/15548627.2015.1100356)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KnightALYanXHamamichiSAjjuriRRMazzulliJRZhangMWDaigleJGZhangSBoromARRobertsLR 2014 The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson’s models. Cell Metabolism 20 145–157. (https://doi.org/10.1016/j.cmet.2014.04.017)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KnuselBMichelPSchwaberJHeftiF 1990 Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. Journal of Neuroscience 10 558–570. (https://doi.org/10.1523/JNEUROSCI.10-02-00558.1990)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KranzlerJHRosenbloomALMartinezVGuevara-AguirreJ 1998 Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: a controlled study in a genetically homogeneous population. Journal of Clinical Endocrinology and Metabolism 83 1953–1958. (https://doi.org/10.1210/jcem.83.6.4863)

    • Search Google Scholar
    • Export Citation
  • Lalancette-HébertMGowingGSimardAWengYCKrizJ 2007 Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. Journal of Neuroscience 27 2596–2605. (https://doi.org/10.1523/JNEUROSCI.5360-06.2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • LangaKMLarsonEBCrimminsEMFaulJDLevineDAKabetoMUWeirDR 2017 A comparison of the prevalence of dementia in the United States in 2000 and 2012. JAMA Internal Medicine 177 51–58. (https://doi.org/10.1001/jamainternmed.2016.6807)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LanzTASalattoCTSemproniARMarconiMBrownTMRichterKESchmidtKNelsonFRSchachterJB 2008 Peripheral elevation of IGF-1 fails to alter Abeta clearance in multiple in vivo models. Biochemical Pharmacology 75 1093–1103. (https://doi.org/10.1016/j.bcp.2007.11.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LeeJHYuWHKumarALeeSMohanPSPeterhoffCMWolfeDMMartinez-VicenteMMasseyACSovakG, et al. 2010 Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141 1146–1158. (https://doi.org/10.1016/j.cell.2010.05.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiangGClineGWMacicaCM 2007 IGF-1 stimulates de novo fatty acid biosynthesis by Schwann cells during myelination. Glia 55 632–641. (https://doi.org/10.1002/glia.20496)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LichtenwalnerRJForbesMEBennettSALynchCDSonntagWERiddleDR 2001 Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 107 603–613. (https://doi.org/10.1016/S0306-4522(01)00378-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LinSFanL-WRhodesPGCaiZ 2009 Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Experimental Neurology 217 361–370. (https://doi.org/10.1016/j.expneurol.2009.03.021)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiuX-FFawcettJRThorneRGDeForTAFreyWH 2001 Intranasal administration of insulin-like growth factor-I bypasses the blood–brain barrier and protects against focal cerebral ischemic damage. Journal of the Neurological Sciences 187 91–97. (https://doi.org/10.1016/S0022-510X(01)00532-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiuYWangXLiWZhangQLiYZhangZZhuJChenBWilliamsPRZhangY 2017 A sensitized IGF1 treatment restores corticospinal axon-dependent functions. Neuron 95 817.e814–833.e814. (https://doi.org/10.1016/j.neuron.2017.07.037)

    • Search Google Scholar
    • Export Citation
  • LoganSPharaohGAMarlinMCMasserDRMatsuzakiSWronowskiBYeganehAParksEEPremkumarPFarleyJA, et al. 2018 Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-beta uptake in astrocytes. Molecular Metabolism 9 141–155. (https://doi.org/10.1016/j.molmet.2018.01.013)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MackayKBLoddickSANaeveGSVanaAMVergeGMFosterAC 2003 Neuroprotective effects of insulin-like growth factor-binding protein ligand inhibitors in vitro and in vivo. Journal of Cerebral Blood Flow and Metabolism 23 1160–1167. (https://doi.org/10.1097/01.WCB.0000087091.01171.AE)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • MarkowskaALMooneyMSonntagWE 1998 Insulin-like growth factor-1 ameliorates age-related behavioral deficits. Neuroscience 87 559–569. (https://doi.org/10.1016/S0306-4522(98)00143-2)

    • Crossref
    • PubMed