Interestingness: 2
Paper by JD Veldhuis in the Journal of Anti-Aging Medicine, Volume 1, Issue 3, Fall 1998.
(((This issue seems to consist mostly of the papers from the conference on endocrine and molecular interventions in aging reported on in the previous issue. Could get heavy)))
(((First repeat subject: growth hormone. Not one I find particularly interesting)))
Giving growth hormone (GH) to people with GH deficiency helps with many of their problematic psychological symptoms (reduced energy and sense of well-being, social isolation, depressed mood and increased anxiety) and physical symptoms (reduction in lean body mass, bone mineral density, basal metabolic rate, strength, glomerular filtration rate (((kidneys))), increase in body fat and cholesterol). Old people share many of the same problems. Maybe GH would be good for them too. (((The underlying drive in the paper is that increasing growth hormone would be a good thing. Considering the correlation between GH and IGF-1, and it and shortened lifespan, I think the assumption nowadays would be the opposite))). There are some side effects with GH supplementation (fluid retention, myalgia (((muscle pain))), arthralgia (((joint pain))), carpal tunnel syndrome, gynecomastia (((man-boobs))), glucose intolerance) but maybe by triggering it with growth hormone releasing hormone (GHRH) or growth hormone releasing peptides (GHRP) to secrete in its usual pulse-like manner the side-effects can be reduced or eliminated (((as in the previous GH post)))
GH secretion goes down by 50% every seven years in healthy men after hitting 20 years of age (((That's quite a different number from the 14% every decade cited in the previous paper. The graph shown purportedly showing that decline has 21 data points, a line of best fit that looks like it's not going down by half every 7 years after age 35. It also looks like if you were to take the 6 data points of men under 30 out, you'd be left with a horizontal line of best fit))). In pre-menopausal women, the rate of decline is half as fast but it becomes the same as men's after menopause. It is also lower to begin with (((The graph showing young male and female declines of total GH concentration (it integrates concentration over 24 hours) also seems remarkably dodgy for women. Taking out one outlier out of the 32 data points would seem to make it almost flat. Also, these declines are modeled as linear, which doesn't merge with the exponential declines in secretion. I think I'm missing something in the difference between secretion amounts and total concentrations))). The reason for the difference between the sexes is unknown but probably related to estradiol stimulating GH production.
There's also an exponentially declining link between BMI and GH, with a 1.5 kg/m^2 increase leading to a halving of secretion. (((Accompanying dodgy graph, but this one seems reasonable, except for what seems to me to be too little data to be doing exponential regression))) (((Personal hypohypothesis aside: could this be related to why higher BMI doesn't lead to higher mortality even in the presence of the high heart disease risk?))). This interacts with the age link since there's an increase in BMI with age as well. Abdominal fat also dampens the normally strong link between testosterone serum levels and GH secretion, although this dampening isn't as strong in women. The action of testosterone also seems to be by conversion to estradiol.
There are other covariates with age that might influence GH secretion such as fitness, disturbed sleep, different diet, medication, and illness. Little is known about these to be able to differentiate among causes of decline.
I'll skip for a bit to the model of influences presented later since it helps. The model suggested involves a lot of negative feedback loops to stop GH and IGF-1 from being too high. So GH induces IGF-1 which switches GH off. GHRH induces GH secretion, so both GH and IGF-1 turn GHRH off. Somatostatin turns off GH and GHRH secretion so GHRH, GH and IGF-1 all raise somatostatin secretion. Then there are substances that act on GHRH and somatostatin separately. GHRH is raised by GABA-B, galanin, alpha2-adrenergic and the suggested GHRP. Somatostatin is raised by B-2 adrenergic, but lowered by dopamine, serotonin (1-D), L-arginine, muscarinic cholinergic neurotransmission, and the imagined GHRP.
(((The backing of the above confuses me a bit, and is really not very useful, but here it goes))) Pyridostigmine, a cholinergic agonist, given over two days doubles the daily GH secretions by increasing the amount secreted in the pulse, not by increasing rate of pulsing. This link is attenuated with increased body fat. The equivalent of pyridostigmine in sheep stimulates GHRH and triggers a large GH secretions. The paper then suggests that pyridostigmine limits somatostatin, and that this suggests that the reduction in GH with age is due to both an increase in somatostatin and a lack of GHRH.
Alpha-2 adrenergic agonists increase GH in lots of mammals, including the human, partly by increasing GHRH secretion, and possibly by reducing somatostatin. Clonidine, an alpha-2 adrenergic agonist, is a weak GH inducer in humans though. Beta-2 adrenergic agonists lower GH production, and that's believed to be through somatostatin because they lower GH even in the presence of GHRH.
Dopamine is also a GH secretion inducer, but not much is known about how it changes with aging or across sexes. Also, serotoninergic (5-HT) stimulate GH by reducing somatostatin. Galanin also, being more effective in women than in men and the effect decreasing with age. Same with GABA-B, which works better in older women than in men. Corticotropin releasing hormone, leptin and neuropeptide Y are also mentioned as requiring more study (((but I assume they are also inducers of GH secretion)))
(((Back to the main thread))) Most external drivers of higher GH secretion are dampened with age, including GHRH, GHRP, opiates, GABA agonists, fasting, galanin, sleep, exercise,pyridostigmine, L-arginine, clonidine and L-dopa, but some are not, eg insulin-induced hypoglycemia, and combining L-arginine and GHRH or GHRP. This is consistent with somatostatin excess being one of the main culprits in the decline of GH with age since L-arginine hammers somatostatin. But since L-arginine alone doesn't restore the levels of GH fully, too much somatostatin is probably not the only cause, and there is likely a shortfall in GHRH and/or GHRP as well. Combinations of GHRH, synthetic ligands for the GHRP receptor and L-arginine are very effective at raising GH and IGF-1 secretion.
Finally, the level of randomness in the network of hormones around GH increases with age. This is common in many other hormonal networks, and is also triggered by fasting in the GH network by lowering IGF-1. This also needs more study.
(((That was a painful paper. I know too little about the subject. The graphs didn't inspire much confidence. Growth hormone isn't that interesting to me. Too many details that I'll forget by next week.)))
Abstract follows:
A central enigma in neuroendocrine pathophysiology is the virtually uniform, but mechanistically incompletely explicable, attenuation of secretory and trophic activity of the growth hormone (GH)—insulin-like growth factor type I (IGF-I) axis in healthy aging in mammalian species, including the primate and human. Indeed, in humans, the calculated daily GH secretion rate falls approximately 50% every 7 years beginning at age 18 to 21, but this diminution in GH secretion is approximately twofold less rapid in premenopausal women. In contrast, the magnitude of relative GH deficiency appears to be similar in individuals of older (e.g., postmenopausal) age of either gender. Interpreting the mechanisms that underlie such marked attenuation of secretory activity of the GH-IGF-I axis is confounded by endocrinemetabolic covariates that accompany healthy aging, such as an accumulation of (visceral) adiposity, a decline in physical fitness, a reduction in sex steroids, disruption of slow-wave sleep, and concurrent illness and medications. Available clinical investigations point to a partial endogenous GHRH deficiency state, in this so-called somatopause. An important additional age-related fall in brain cholinergic activity (which regulates somatostatin secretion) is likely, thus arguing for combined hypothalamic somatostatin excess and GHRH, GHRP, or both deficiency. This article also evaluates the novel hypothesis that the GH impoverishment of aging is marked by disrupted network function of the GH-IGF-I feedback axis. Given this background, available and new technologies applied in patient-oriented investigations will likely unravel further the presumptively multiple mechanisms that subserve the hyposomatotropism of healthy aging, and begin to address the relative risks and benefits of restoring secretory activity of the aging GH-IGF-I axis.
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