Abstract
Aging is associated with a decline in hormones and an associated decline in GABAergic function and calcium and ion current dysregulation. Neurosteroid hormones act as direct calcium channel blockers, or they can act indirectly on calcium channels through their interaction with GABA receptors. The calcium channel dysfunction associated with hormone loss further leads to an excitatory cell state, which can ultimately lead to cell death. The calcium theory of aging posits that cellular mechanisms, which maintain the homeostasis of cytosol Ca2+ concentration, play a key role in brain aging and that sustained changes in Ca2+ homeostasis provide the final common pathway for age-associated brain changes. There is a link between hormone loss and calcium dysregulation. Loss of calcium regulation associated with aging can lead to an excitatory cell state, primarily in the mitochondria and nerve cells, which can ultimately lead to cell death if not kept in check. A decline in GABAergic function can also be specifically tied to declines in progesterone, allopregnanolone, and DHEA levels associated with aging. This decline in GABAergic function associated with hormone loss ultimately affects GABAergic inhibition or excitement and calcium regulation throughout the body. In addition, declines in GABAergic function can also be tied to vitamin status and to toxic chemicals in the food supply. The decline in GABAergic function associated with aging has an effect on just about every body organ system. Nutritional support of the GABAergic system with supportive foods, vitamins, and GABA or similar GABA receptor ligands may address some of the GABAergic dysfunction associated with aging.
Highlights
3α-reduced metabolites of progesterone and deoxycorticosterone, allopregnanolone, 3α, 5α-THDOC, or androstenediol) are positive allosteric modulators of gamma-aminobutyric acid (GABA) AR, enhancing GABA-evoked chloride current
The administration of Monosodium Glutamate (MSG) causes an increase in fasting blood glucose levels and type 2 diabetes mellitus (T2DM). e higher doses of parenteral MSG (4 mg/g body weight) cause insulin resistance (IR) in mice evidenced by the significant increase in plasma glucose in oral glucose tolerance test and severe visceral fat accumulation
Neurosteroid hormones act as direct calcium channel blockers, or they act indirectly on calcium channels through their action on GABA receptors
Summary
3α-reduced metabolites of progesterone and deoxycorticosterone, allopregnanolone, 3α, 5α-THDOC, or androstenediol) are positive allosteric modulators of GABA AR, enhancing GABA-evoked chloride current. Hormones, binding to GABA B receptors, may function as calcium channel blockers through a cascade involving G protein couples. Positive GABA A receptor modulators, including neurosteroids, can inhibit L-type voltage-gated calcium channels (L-VGCCs), which contributes to reduced neuronal excitability [4]. E loss of hormones with aging, through their decline in function as GABA receptor agonists, leads to dysregulation of calcium channels and can lead to cell excitotoxicity and cell death. E failure of the inhibitory function of GABA B receptors in response to neurosteroid hormones or GABA amino acid in particular, to keep calcium channels/calcium regulatory systems in check, further exacerbates the cell excitotoxicity, cell dysfunction, and cell death associated with aging. Reviewed are the many body systems which may be affected by changes to the GABAergic system in aging and nutritional support for the aging GABAergic system
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