Targeting Sirt1, AMPK, Nrf2, CK2, and Soluble Guanylate Cyclase with Nutraceuticals: A Practical Strategy for Preserving Bone Mass

Abstract

There is a vast pre-clinical literature suggesting that certain nutraceuticals have the potential to aid the preservation of bone mass in the context of estrogen withdrawal, glucocorticoid treatment, chronic inflammation, or aging. In an effort to bring some logical clarity to these findings, the signaling pathways regulating osteoblast, osteocyte, and osteoclast induction, activity, and survival are briefly reviewed in the present study. The focus is placed on the following factors: the mechanisms that induce and activate the RUNX2 transcription factor, a key driver of osteoblast differentiation and function; the promotion of autophagy and prevention of apoptosis in osteoblasts/osteoclasts; and the induction and activation of NFATc1, which promotes the expression of many proteins required for osteoclast-mediated osteolysis. This analysis suggests that the activation of sirtuin 1 (Sirt1), AMP-activated protein kinase (AMPK), the Nrf2 transcription factor, and soluble guanylate cyclase (sGC) can be expected to aid the maintenance of bone mass, whereas the inhibition of the serine kinase CK2 should also be protective in this regard. Fortuitously, nutraceuticals are available to address each of these targets. Sirt1 activation can be promoted with ferulic acid, N1-methylnicotinamide, melatonin, nicotinamide riboside, glucosamine, and thymoquinone. Berberine, such as the drug metformin, is a clinically useful activator of AMPK. Many agents, including lipoic acid, melatonin, thymoquinone, astaxanthin, and crucifera-derived sulforaphane, can promote Nrf2 activity. Pharmacological doses of biotin can directly stimulate sGC. Additionally, certain flavonols, notably quercetin, can inhibit CK2 in high nanomolar concentrations that may be clinically relevant. Many, though not all, of these agents have shown favorable effects on bone density and structure in rodent models of bone loss. Complex nutraceutical regimens providing a selection of these nutraceuticals in clinically meaningful doses may have an important potential for preserving bone health. Concurrent supplementation with taurine, N-acetylcysteine, vitamins D and K2, and minerals, including magnesium, zinc, and manganese, plus a diet naturally high in potassium, may also be helpful in this regard.

Oxidative stress, inflammation, dysfunctional redox homeostasis and autophagy cause age-associated diseases

“…Co-activation of AMPK and Sestrins could prevent metabolic diseases, including obesity, NAFLD, and diabetes [149]. Activation of AMPK, SIRT1, and Nrf2 can help preserve bone mass and prevent osteoporosis [171]. Activation of Sestrins and AMPK together with inhibition of mTOR1 can prevent metabolic disorders, neurodegenerative diseases, CVD, cancer, as well as musculoskeletal diseases [172].…”

“…The other approach that can alleviate and prevent AADs is the intake of natural products as nutraceuticals, notably, polyphenols [e.g., berberine, quercetin, myricetin, caffeic acid (CA), and CA ethanolamide (CAEA), CA phenyl ester (CAPE), epigallocatechin-3-gallate (EGCG), gallic acid (GA), curcumin], flavonoids (e.g., resveratol), terpenoids (e.g., ginsenoside and triterpene glycosides), carotenoids, xanthophyll (e.g., astaxanthin), spermidine, and sulforaphane, all of which could act as CR mimetics. Most of these natural compounds have high antioxidation properties, and they can also directly stimulate AMPK (e.g., curcumin, EGCG, spermidine, GA, and CAPE) or SIRT1 (e.g., berberine, EGCG, quercetin, and myricertin) or both (e.g., resveratol, CA, and CAEA), and consequently causing the upregulations of Nrf2 and AP (also see Figure 1) [29,32,171,172,[192][193][194][195]. Some natural compounds can also suppress inflammation (e.g., curcumin, EGCG, and spermidine) [192].…”

Role of Diet in Stem and Cancer Stem Cells

“…Some phytochemicals stimulate autophagy, through SIRT1, AMPK or mTOR pathways in both normal and CSCs [ 7 , 61 , 97 ]. The activation of SIRT1 by thymoquinone, ferulic acid and melatonin has been demonstrated to act on MSCs and preserve bone mass [ 98 ]. Spermidine, a polyamine abundant in the Mediterranean diet and found in whole grains, corn, mushrooms, legumes, soy products, and aged cheese, is able to activate autophagy by acting on the same pathways [ 99 ].…”

Effects of Metformin Delivery via Biomaterials on Bone and Dental Tissue Engineering

“…The anti-inflammatory effects of metformin were achieved not only by altering body metabolic parameters, such as hyperglycemia and insulin resistance, but also by activating anti-inflammatory pathways or the immune system. Metformin was reported to have a direct anti-inflammatory action by inhibition of nuclear factor κB via adenosine monophosphate activated protein kinase (AMPK) dependent and independent pathways [ 21 , 22 ]. AMPK is involved in various upstream and downstream pathways such as the AMPK/mechanistic target of rapamycin kinase (mTOR) pathway in mammals, extracellular regulated kinase (ERK)/AMPK with carbon dots, and the liver kinase B1 (LKB1)/AMPK pathway [ 23 ].…”