IGF1 Gene Therapy as a Neuroprotective Treatment, Slowing Female Reproductive Aging

Researchers here describe an interesting approach to slowing aspects of neurodegeneration that contribute to, among other things, female reproductive aging. That is the focus of this paper, but numerous other aspects of the aging brain are also involved. IGF1 is well studied in the context of aging, and manipulation of the signaling pathways linking insulin, IGF1, and growth hormone has been shown to extend life span in a number of species. Where we can make direct comparisons between mice and humans, such as between growth hormone receptor knockout mice and humans with Laron syndrome, the effects are nowhere near as large. Suppression of growth hormone signaling can extend life by 70% or so in mice, but Laron syndrome doesn't appear to make humans live meaningfully longer. Many approaches to slowing aging have much larger effects in short-lived mammals than they do in long-lived mammals.

The inflammatory environment characteristic of the aged brain is caused by activation of glial cells, mainly microglia. Several studies report that neuroinflammation leads to reduced gonadotropin-releasing hormone (GnRH) secretion, which is associated with multiple aging-related physiological changes, including bone loss, skin atrophy, muscle weakness, and memory loss. Indeed, GnRH administration amend aging-impaired neurogenesis and decelerates aging in mice. In addition, the same authors also describe that inhibition of NF-κB-directed immunity, specifically in hypothalamic microglia cells, has an anti-aging effect.

GnRH secretion is regulated by hormonal and environmental signals such as kisspeptin. This peptide plays a critical role in controlling the onset of puberty and reproductive function in adulthood. There are two populations of kisspeptin neurons, one in the anteroventral periventricular nucleus (AVPV) and one in the arcuate nucleus (Arc), that are targets of positive and negative feedback regulation of estrogen, respectively. Aging female rats transition from regular to irregular estrus cycles, constant estrus, and finally to an anestrus stage. Changes within the hypothalamic-pituitary-ovarian axis, manifested by altered secretion of neurotransmitters, altered secretion of pituitary hormones and altered follicular development and steroid content, lead to the final cessation of reproductive cycles. These processes that lead to reproductive senescence are associated with an increase in circulating cytokines and proinflammatory markers produced by microglial cells. Indeed, several studies describe that hypothalamic and systemic inflammation affect kisspeptin neurons, which are responsible for regulating GnRH neurons.

IGF1 is a neurotrophic factor with an outstanding neuroprotective action in the central nervous system. Previous studies of our group showed that intraparenchymal hypothalamic IGF1 gene therapy was capable to prolong the operation of reproductive cycles in rats. Indeed, we have demonstrated that intracerebroventricular IGF1 gene therapy restores motor performance and generates cognitive and morphological changes in the dorsal hippocampus in senile rats. In addition, we have reported that IGF1 gene therapy modifies microglia number and phenotype in senile rats and decreases astrocytic inflammatory response in vitro, supporting the extensive idea that IGF1 plays a potent anti-inflammatory effect.

The aim of the present study is to investigate the effect of IGF1 gene therapy on estrous cycle, kisspeptin, and GnRH neurons, and microglial cells in middle-aged female rats. Our data indicate that IGF1 gene therapy prolongs the operation of reproductive cycles in middle-aged rats by modulating kisspeptin/GnRH secretion in the hypothalamus and altering microglial cell number and reactivity. Based on our findings, we propose IGF1 gene therapy to delay reproductive senescence as a potential strategy to optimize lifespan and combat age-related health problems in women.

Link: https://doi.org/10.18632/aging.204360


isn't IGF1 intake highly correlated with cancer in humans?

Posted by: Greg Schulte at November 23rd, 2022 11:55 AM
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