Emerging Vistas for the Nutraceutical Withania somnifera in Inflammaging

Abstract

Inflammaging, a coexistence of inflammation and aging, is a persistent, systemic, low-grade inflammation seen in the geriatric population. Various natural compounds have been greatly explored for their potential role in preventing and treating inflammaging. Withania somnifera has been used for thousands of years in traditional medicine as a nutraceutical for its numerous health benefits including regenerative and adaptogenic effects. Recent preclinical and clinical studies on the role of Withania somnifera and its active compounds in treating aging, inflammation, and oxidative stress have shown promise for its use in healthy aging. We discuss the chemistry of Withania somnifera, the etiology of inflammaging and the protective role(s) of Withania somnifera in inflammaging in key organ systems including brain, lung, kidney, and liver as well as the mechanistic underpinning of these effects. Furthermore, we elucidate the beneficial effects of Withania somnifera in oxidative stress/DNA damage, immunomodulation, COVID-19, and the microbiome. We also delineate a putative protein-protein interaction network of key biomarkers modulated by Withania somnifera in inflammaging. In addition, we review the safety/potential toxicity of Withania somnifera as well as global clinical trials on Withania somnifera. Taken together, this is a synthetic review on the beneficial effects of Withania somnifera in inflammaging and highlights the potential of Withania somnifera in improving the health-related quality of life (HRQoL) in the aging population worldwide.

Keywords: COVID-19; DNA damage; Withania somnifera; aging; healthy aging; immunomodulation; inflammaging; inflammation; microbiome; oxidative stress.

Figure 1

Active compounds of Withania somnifera (A) Withanolide A; (B) Withaferin; (C) 12-Deoxy-withastramonolide; (D) Withanoside V; (E) Withanone; (F) Withanoside IV; (G) Withanolide B; (H) 27-Hydroxywithanone; (I) Withanoside VI; (J) Physagulin-d. All the chemical structures were drawn using ChemDraw version 20.1.1.125.

Figure 1

Active compounds of Withania somnifera (A) Withanolide A; (B) Withaferin; (C) 12-Deoxy-withastramonolide; (D) Withanoside V; (E) Withanone; (F) Withanoside IV; (G) Withanolide B; (H) 27-Hydroxywithanone; (I) Withanoside VI; (J) Physagulin-d. All the chemical structures were drawn using ChemDraw version 20.1.1.125.

Figure 2

Molecular pathways for Withania somnifera in inflammaging. Withaferin A, an active compound of Withania somnifera, activates NRF2 by dissociating it from Keap1 which translocates to the nucleus and further binds to sMaf leading to transcription of antioxidant HO-1, which reduces oxidative stress. EGF binds to EGFR activating RAS/RAF pathway and phosphorylates ERK /p38/JNK; this further activates NF-κB, which transcribes cytokines that increase inflammation and aging. WAD inhibits p38, JNK, and ERK, while also suppressing ROS. SIRT1 can be activated by Withania somnifera, which inhibits NF-κB. IGF-1 binds to TLR and activates the PI3K/AKT pathway, which activates FOXO and transcribes MnSOD. Ubiquitination that leads to aging can be prevented by Withania somnifera. Also, Withania somnifera increases FOXO activity. Oxidative stress leads to DNA damage and inflammation, which can be reduced by Withania somnifera. Withania somnifera acts on FOXO3A and SIRT3, which helps in increasing cell longevity. Abbreviations: Keap1: Kelch like ECH associated protein 1; NRF2: Nuclear factor erythroid 2-related factor 2; GSK3β: Glycogen synthase kinase 3 beta; HO-1: Heme oxygenase-1; SOD: Superoxide dismutase; sMaf: Small musculoaponeurotic fibrosarcoma; ROS: Reactive oxygen species; ONOO⁻: Peroxynitrite; NO⁻: Nitric oxide; O₂^.−: Superoxide; L-Arg: Arginine; iNOS: Inducible nitric oxide synthase; COX-2: Cyclooxygenase-2; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; WAD: Withagenin A diglucoside; PTK/PTP: Protein tyrosine kinase/Protein tyrosine phosphatase; RAS: Rat sarcoma; RAF: Rapidly accelerated fibrosarcoma; JNK: c-Jun N-terminal kinase; ERK: Extracellular signal-regulated kinase; NF-κB: Nuclear factor-kappa B; IκB: Nuclear factor-kappa-B inhibitor; IGF-1: Insulin-like growth factor 1; TLR: Toll-like receptor; SIRT: Sirtuin; PI3K: Phosphatidylinositol 3-kinase; PIP2: Phosphatidylinositol 4,5-bisphosphate; PIP3: Phosphatidylinositol-3,4,5-trisphosphate; PDK: Pyruvate Dehydrogenase Kinase; AKT: Protein kinase; BSGK1: Serum/glucocorticoid regulated kinase 1; FOXO: Forkhead box O; NAD+: Oxidized nicotinamide adenine dinucleotide; NADH: Reduced nicotinamide adenine dinucleotide; MnSOD2: Manganese superoxide dismutase.

Figure 3

Molecular pathways for Withania somnifera in inflammaging modulated by COVID-19 and the microbiome. Microbiome releases LPS that activate TLR4 that initiates the activation of NF-κB pathway via MyD88 and IKBα. Withania somnifera inhibits TLR4 receptor as well as NF-κB. Angiotensinogen converts Ang I to Ang II, while Ang II activates the AT1R receptor; this also leads to activation of NF-κB via pro-oxidants and NOX2. Ang II activates Ang I–VII via the ACE receptor. S-protein of SARS-CoV-2 binds to ACE2 receptor to enter the cell; Withania somnifera inhibits the ACE2 receptor. TNF-α binds to TNFR receptor and activates the TRADD/TRAF pathway, which upregulates AP1 via p38 and transcribes inflammatory cytokines. IL-6 binds to IL-6R and activates the JAK1/STAT3 pathway, which leads to tissue injury by release of inflammatory cytokines. Withania somnifera inhibits TNF-α and IL-6, which help in the suppression of tissue injury. SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; DAMP: Damage-Associated Molecular Pattern; PAMP: Pathogen-Associated Molecular Pattern; Ang: Angiotensin; LPS: Lipopolysaccharide; S-Protein: Spike Protein; TLR4: Toll-like Receptor 4; Ang I: Angiotensin I; Ang II: Angiotensin II; Ang I-VII: Angiotensin I-VII; AT1R: Angiotensin II Receptor Type 1; ACE2 receptor: Angiotensin-Converting Enzyme 2 Receptor; IL-6: Interleukin-6; TNF-α: Tumor Necrosis Factor Alpha; IL-6R gp130: Interleukin-6 Receptor Glycoprotein 130; TNF/TNFR complex: Tumor Necrosis Factor/Tumor Necrosis Factor Receptor Complex; MyD88: Myeloid Differentiation Primary Response 88; Pro-oxidant: Substances promoting oxidative stress; TRAF2: Tumor Necrosis Factor Receptor Associated Factor 2; TRADD: Tumor Necrosis Factor Receptor Type 1-Associated DEATH Domain Protein; TRAF6: Tumor Necrosis Factor Receptor Associated Factor 6; p38: mitogen-activated protein kinases; NOX2: NADPH Oxidase 2; JAK1: Janus Kinase 1; TAB1: TGF-beta-Activated Kinase 1-Binding Protein 1; TAB2: TGF-beta-Activated Kinase 1-Binding Protein 2; IKBα: Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Alpha; IKBβ: Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Beta; NF-κB: Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells; STAT3: Signal Transducer and Activator of Transcription 3; AP1: Activator Protein 1; ROS: Reactive Oxygen Species; IL-6: Inflammatory cytokine-6; IL-8: Inflammatory cytokine-8; IL-12: Inflammatory cytokine-12.

Figure 4

Withania somnifera-modulated putative protein–protein interaction network in inflammaging. Protein–protein interaction (PPI) network comprising upregulated and downregulated proteins modulated by Withania somnifera in inflammaging. The PPI with 21 nodes and 262 edges was constructed using STRING database [143] and Cytoscape version 3.10.1 [144]. FOXO3: Forkhead box O3; MAPK8: Mitogen-activated protein kinase 8; AKT1: RAC-alpha serine/threonine-protein kinase; PTGS2: Prostaglandin-endoperoxide synthase 2; MMP-1: Matrix metalloproteinase-1; IL-4: Interleukin-4; TNF: Tumor necrosis factor; IL-8: Interleukin-8; JCHAIN: Joining chain of multimeric IgA and IgM; HSPA4: Heat shock 70 kDa protein 4; TGFβ1: Transforming growth factor beta-1; SOD1: Superoxide dismutase; FCGRT: Fc fragment of IgG receptor and transporter; AIF1: Allograft inflammatory factor 1; IL-6: Interleukin-6; IL-10: Interleukin-10; SIRT3: Sirtuin-3; IFN_γ: Interferon-gamma; NOX4: NADPH oxidase 4; IL-12β: Interleukin-12 subunit beta; TLR4: Toll-like receptor 4.