Growth hormone, insulin-like growth factor-1 and the aging brain

Ashpole, Nicole M.; Sanders, J; Hodges, Erik L.; Han, Yan; Sonntag, William E.

doi:10.1016/j.exger.2014.10.002

Cited by 177 publications

(149 citation statements)

References 87 publications

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“…Considering that local IGF-1 production within the bone is important for bone development and mineralization (as reviewed by (52) ), it is possible that the loss of circulating IGF-1 only stunted longitudinal growth while local IGF-1 signaling was maintained or even increased, serving as an anabolic signal even in advanced age. This hypothesis would be supported by previous studies showing that the loss of circulating IGF-1 is associated with an increase in the local production of IGF-1 and the IGF-1 receptor in other cell types (53,54) . Within our study, the loss of circulating IGF-1 in female mice did not result in a significant increase in local production of IGF-1, IGF-2, or the IGF-1 receptor.…”

Section: Discussionsupporting

confidence: 63%

IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms

Ashpole

Herron

Mitschelen

et al. 2015

Journal of Bone and Mineral Research

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Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, while others report that loss of IGF-1 is beneficial as it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igff/f mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan- early in postnatal development (crossing albumin-Cre mice with Igff/f mice), or early adulthood, and late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using microCT and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NFkB-ligand levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2 fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data suggest the age-related loss of vertebral bone density in females can be reduced by modifying circulating IGF-1 levels early in life.

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Section: Discussionsupporting

confidence: 63%

IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms

Ashpole

Herron

Mitschelen

et al. 2015

Journal of Bone and Mineral Research

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“…Indeed, while central insulin was minimally effective at improving whole‐body insulin action in old animals, central IGF‐1 acted via a dual mechanism, involving suppression of HGP and increased glucose disposal, to markedly improve insulin sensitivity. This observation, coupled with the known protective effects of IGF‐1 on disease risk, particularly in the brain (Ashpole et al ., 2014), highlights a larger emerging paradox regarding the relevance of IGF‐1 to aging in humans.…”

Section: Discussionmentioning

confidence: 99%

“…The notion that low IGF‐1 action may be protective from some diseases, such as cancer, but predispose to others, is particularly relevant to older humans, where somatopause leads to age‐related declines in GH/IGF‐1 (Ashpole et al ., 2014). This prompted many investigators to suspect that the decline of this axis may be causal to many aging phenotypes and that replacement could reverse some manifestations of aging (Rudman et al ., 1990).…”

Section: Introductionmentioning

confidence: 99%

Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

et al. 2015

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SummaryLow insulin‐like growth factor‐1 (IGF‐1) signaling is associated with improved longevity, but is paradoxically linked with several age‐related diseases in humans. Insulin‐like growth factor‐1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF‐1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole‐body insulin action in aging. Utilizing hyperinsulinemic‐euglycemic clamps, we show that old insulin‐resistant rats with age‐related declines in IGF‐1 level demonstrate markedly improved whole‐body insulin action, when treated with central IGF‐1, as compared to central vehicle or insulin (P < 0.05). Furthermore, central IGF‐1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P < 0.05). Taken together, IGF‐1 action in the brain and periphery provides a ‘balance’ between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at ‘tipping the balance’ of IGF‐1 action centrally are the optimal approach to achieve healthy aging and longevity in humans.

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“…Studies in rodents focused on the IGF-1 axis have been most well studied, and have revealed that IGF-1 levels in circulation, CSF and brain tissue decline with advancing age in some strains, while expression of the IGF-1R in various regions of the CNS either increases, decreases, or remains unchanged (Ashpole et al, 2015; Huffman et al, 2016). Evidence regarding the role of local GH and IGF-1 in cognition is limited, but expression of GH and IGF-1 in the hippocampus of dwarf mice was found to be paradoxically increased, suggesting that maintenance of adequate IGF-1 levels in the brain may be critical to normal cognitive function in these mice (Sun et al, 2005).…”

Section: Gh/igf-1 Axis and Age-related Diseasesmentioning

confidence: 99%

The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research

2016

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Summary Mutations resulting in reduced signaling of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis are associated with increased life and health-span across model organisms. Similar findings have been noted in human cohorts with functional mutations in the somatotropic axis, suggesting that this pathway may also be relevant to human aging and protection from age-related diseases. While epidemiological data indicates that low circulating IGF-1 level may protect aging populations from cancer, results remain inconclusive regarding most other diseases. We propose that studies in humans and animals need to consider differences in sex, pathway function, organs, and time-specific effects of GH/IGF-1 signaling in order to better define the role of the somatotropic axis in aging. Agents that modulate signaling of the GH/IGF-1 pathway are available for human use, but before they can be implemented in clinical studies that target aging and age-related diseases, researchers need to address the challenges discussed in this review.

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Growth hormone, insulin-like growth factor-1 and the aging brain

Cited by 177 publications

References 87 publications

IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms

IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms

Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research

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