IGF1 gene therapy in middle-aged female rats delays reproductive senescence through its effects on hypothalamic GnRH and kisspeptin neurons (original) (raw)
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Experimental Gerontology, 2004
We briefly compare calorie restriction, GHRH-R and Pit-1 mutants with knockout phenotypes of GH receptor, IGF-1 receptor and p66Shc, to make some general conclusions. Growth, fertility and longevity phenotypes may dissociate in some of these mutants, and we try to interpret this. Follows a short discussion on the importance of genetic background for aging studies in mice. We then evoke studies in C. elegans showing that lifespan may be regulated in a non-cell-autonomous fashion, and that the nervous system could play a central role therein. Recent findings on DILP-2 regulation in Drosophila transpose this hypothesis of endocrine lifespan regulation to insects. Work in mice shows that inactivation of the insulin receptor specifically in the adipose tissue is sufficient to increase the mouse lifespan. In summary, exciting findings obtained in very different model organisms are rapidly converging and suggest that animal lifespan may be subject to endocrine regulation. Interestingly, the hypothalamus centralizes many age related hormonal regulations and at the same time participates in the integration of numerous nutritional signals, such that one could ask whether the hypothalamus may be at the crossroads of metabolic and endocrine lifespan regulation. q 2004 Elsevier Inc. All rights reserved.
Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH
Nature, 2013
Aging is a result of gradual and overall functional deteriorations across the body; however, it is unknown if an individual tissue works to primarily mediate aging progress and lifespan control. Here we found that the hypothalamus is important for the development of whole-body aging in mice, and the underlying basis involves hypothalamic immunity mediated by IKKβ/NF-κB and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and lifespan extension are achieved in mice through preventing against aging-related hypothalamic or brain IKKβ/NF-κB activation. Mechanistic studies further revealed that IKKβ/NF-κB inhibits GnRH to mediate aging-related hypothalamic GnRH decline, and GnRH treatment amends aging-impaired neurogenesis and decelerates aging. In conclusion, the hypothalamus has a programmatic role in aging development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating aging-related health problems.
Gene Therapy, 2007
Insulin-like growth factor-I (IGF-I) is emerging as a powerful neuroprotective molecule that is strongly induced in the central nervous system after different insults. We constructed a recombinant adenoviral vector (RAd-IGFI) harboring the gene for rat IGF-I and used it to implement IGF-I gene therapy in the hypothalamus of senile female rats, which display hypothalamic dopaminergic (DA) neurodegeneration and as a consequence, chronic hyperprolactinemia. Restorative IGF-I gene therapy was implemented in young (5 months) and senile (28 months) female rats, which received a single intrahypothalamic injection of 3 Â 10 9 plaque-forming units of RAd-bgal (a control adenoviral vector expressing b-galactosidase) or RAd-IGFI and were killed 17 days post-injection. In the young animals, neither vector modified serum prolactin levels, but in the RAd-IGFI-injected senile rats a nearly full reversion of their hyperprolactinemic status was recorded. Morphometric analysis revealed a significant increase in the total number of tyrosine hydroxylase-positive cells in the hypothalamus of experimental as compared with control senile animals (58747486 and 33907498, respectively). Our results indicate that IGF-I gene therapy in senile female rats is highly effective for restoring their hypothalamic DA dysfunction and thus reversing their chronic hyperprolactinemia.
Neuroendocrinology, 2012
The natural transition to reproductive senescence is an important physiological process that occurs with aging, resulting in menopause in women and diminished or lost fertility in most mammalian species. This review focuses on how rodent models have informed our knowledge of age-related changes in gonadotropin-releasing hormone (GnRH) neurosecretory function and the subsequent loss of reproductive capacity. Studies in rats and
2021
Brain aging is characterized by chronic neuroinflammation caused by activation of glial cells, mainly microglia, leading to alterations in homeostasis of the central nervous system. Microglial cells are constantly surveying their environment to detect and respond to diverse signals. During aging, microglia undergo a process of senescence, characterized by loss of ramifications, spheroid formation, and fragmented processes, among other abnormalities. Therefore, the study of microglia senescence is of great relevance to understand age‐related declines in cognitive and motor function.We have targeted the deleterious effects of aging by implementing gene therapy with IGF-1, employing recombinant adenoviral vectors (RAds) as a delivery system. In this study, we performed intracerebroventricular (ICV) IGF-1 gene therapy on aged female rats and evaluated its effect on Caudate-Putamen unit (CPu) gene expression and inflammatory state. IGF-1 gene therapy modified senescent microglia of the C...
Control of aging and longevity by IGF-I signaling
Experimental Gerontology, 2005
Animal models have established the IGF-I signaling pathway as a key modulator of aging in rodents and invertebrates. Considerable evidence suggests that reduced exposure of tissue to IGF-I is associated with an extended lifespan in these species. In humans, IGF-I is linked to various age-related diseases that are limiting factors for youthful longevity. On one hand, reduced IGF-I activity is associated with significant morbidity in adulthood with an increased risk of developing cardiovascular disease, diabetes, osteoporosis and neurodegenerative diseases. On the other hand, elevated IGF-I levels have been linked to cancer risk given the role of IGF in mediating normal and malignant tissue growth. Thus, IGF is clearly involved in modulating disease of aging; however, the mechanism appears to be complex and interdependent on additional modulating factors. It is attractive to hypothesize that maximal human survival depends on tight regulation of the GH-IGF axis and maintenance of optimal IGF-I action in order to prevent morbidities associated with either deficient or excessive state. Specifically, it is possible that lower levels of IGF-I during early adulthood followed by higher levels of IGF-I later in life may be most beneficial for human longevity by addressing age-specific morbidities. q
IGF-I Gene Therapy in Aging Rats Modulates Hippocampal Genes Relevant to Memory Function
The journals of gerontology. Series A, Biological sciences and medical sciences, 2017
In rats, learning and memory performance decline during normal aging, which makes this rodent species a suitable model to evaluate therapeutic strategies. In aging rats, insulin-like growth factor-I (IGF-I), is known to significantly improve spatial memory accuracy as compared to control counterparts. A constellation of gene expression changes underlie the hippocampal phenotype of aging but no studies on the effects of IGF-I on the hippocampal transcriptome of old rodents have been documented. Here, we assessed the effects of IGF-I gene therapy on spatial memory performance in old female rats and compared them with changes in the hippocampal transcriptome. In the Barnes maze test, experimental rats showed a significantly higher exploratory frequency of the goal hole than controls. Hippocampal RNA-sequencing showed that 219 genes are differentially expressed in 28 months old rats intracerebroventricularly injected with an adenovector expressing rat IGF-I as compared with placebo aden...
Sensitivity to exogenous GH and reversibility of the reduced IGF-I gene expression in aging rats
European Journal of Endocrinology, 2001
BACKGROUND: IGF-I gene expression and IGF-I plasma concentration decline with age. A decreased sensitivity to GH has been suggested to be a contributory mechanism to this, in addition to attenuated GH secretion. OBJECTIVE: This study focuses on the sensitivity to exogenous GH and the reversibility of the reduced IGF-I gene expression in aging male rats. DESIGN: Three groups of male Wistar rats aged 3 months (young adult), 11 months (middle-aged) and 27 months (old), received recombinant human GH (rhGH) (150 microg/12 h s.c.) for seven consecutive days. RESULTS: This rhGH treatment completely reversed plasma immunoreactive IGF-I (IR-IGF-I) and hepatic IGF-I mRNA levels in 11-month-old and 27-month-old animals to the levels of the young group of animals. The sensitivity in the old group (percentage of increment after the same or lower dose of rhGH per body weight) was increased for both parameters; serum IGF-I increment: 15% in 3-month-old, 42.6% in 11-month-old and 119.1% in 27-month...