Aging and Immune Receptor Signaling: Molecular Mechanism Investigation to Pharmacological Intervention

INTRODUCTION

Cell signalling cascades produce immunological responses (Yousefpour et al., 2023 and Lukácsi et al., 2020). Immunity-boosting synthetics in immunocompromised or elderly patients, several synthetic medications and pharmacological substances have been tested for immunity-boosting properties.

Multiple infections share proteins produced and receptors on innate immune system cells (Cerny and Striz et al., 2019). After identification, these receptors activate signaling pathways by transcribed inflammation-related genes and antimicrobial defenses (Figure 1).

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RECEPTOR ENGAGEMENT

Antigens or Pathogen-Associated Molecular Patterns (PAMPs) are recognized and bound by immune receptors. T cells have TCRs, B cells have BCRs, and innate immune cells, including macrophages and dendritic cells have PRRs. (Zhang et al., 2022) By beginning a cascade of intracellular signaling events, these receptors help the immune system recognize and respond to infections (Stogerer and Stager et al., 2020; Dominguez et al., 2023).

Initiation of Signalling Cascade

Immune receptors cluster or dimerize, conform, and attract kinases and adaptor proteins when they engage with their ligands, such as antigens or pathogen targets (Li and Wu et al., 2021).

Activation of Intracellular Signalling Pathways

Immune receptor activation activates kinases like ZAP-70 and SYK and phosphatases. Diacylglycerol (DAG), Inositol Trisphosphate (IP3), and Calcium Ions (Ca²^⁺) are released throughout this signaling cascade as second messengers. These chemical intermediates boost signaling, activating immune cells (Sim et al., 2020).

Many biological activities depend on key signaling routes, which are limitless:

NF-κB pathway: Involved in inflammation and immune response gene transcription (Asl et al., 2021).

MAPK pathway: Controls cell proliferation, differentiation, and survival (Zhang et al., 2021).

PI3K-Akt pathway: Important for cell growth, survival, and metabolism (Liu et al., 2020).

JAK-STAT pathway: Common in cytokine signaling, controlling gene expression (Philips et al., 2022) (Figure 2).

Transcriptional Activation

Intracellular signaling pathways promote immune response gene transcription by translocating transcription factors like NF-κB, NFAT, and AP-1 into the nucleus (Figure 3). Genes encode Cytokines (IL-2, TNF-α), Chemokines (CXCL8), surface proteins (CD40L on T cells), and antibodies (B cells) (Zhang et al., 2020; Gulow et al., 2024).

Effector Functions

Signaling proliferates and differentiates regulatory, cytotoxic, and helper T cells. Encourages B cells to mature into antibody-secreting plasma cells. Pathogen-infected or cancerous cells are targeted by NK cells (Tang et al., 2021 and Goodier et al., 2020).

Signal Termination and Regulation

Phosphate recruitment (SHP-1/2) dephosphorylates key signaling molecules via detrimental feedback mechanisms that strictly control immune receptor signalling (Laletin et al., 2023). To prevent excessive immune activation and autoimmunity, checkpoint molecules like PD-1 and CTLA-4 limit ubiquitin-mediated signaling component degradation (Hu et al., 2021).

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AGING AND IMMUNE RECEPTOR SIGNALLING (IMMUNOSENESCENCE)

Immunosenescence-a reduction in innate and adaptive immunity-occurs as people age. It modulates immune receptor signaling as follows:

T-Cell Receptor (TCR) Signalling

Age-related T-Cell Receptor (TCR) signaling changes reduce T cell antigen sensitivity (Zhang et al., 2021). Lck and ZAP-70, which initiate TCR signaling, can be affected. Aged T cells have decreased calcium signaling, NF-κB, and NFAT transcription factor translocation, affecting their fundamental function (Ono et al., 2020).

B-Cell Receptor (BCR) Signalling

Seniors' B cells produce fewer high-affinity antibodies (de Mol et al., 2021) Impaired B Cell Receptor (BCR) signaling decreases downstream pathway activity, such as the PI3K and MAPK pathways, and alters critical signaling molecule expression, including SYK (Liu et al., 2020).

Innate Immune Receptor Signalling

Pattern Recognition Receptors (PRRs), like Toll-Like Receptors (TLRs), lose signaling capacity with age (Connors et al., 2022). Reduced pathogen detection and pro-inflammatory cytokine production. During aging, low-level inflammation called "inflammaging" fuels age-related diseases (Yue et al., 2021).

Protein constancy and proteostatistic mechanisms throughout aging are discussed (Figure 4). Abnormal protein ROS buildup, ubiquitin-proteasome pathway failure, chaperone overload, and autophagy degeneration all contribute to protein homeostasis and functional decrease in senior age. Recent research highlights the importance of BAG 3 sesquestosome and HDAC6 in aggresome formation, modulating HDAC 6, histone deacetylase 6 (Gray and Gibbs et al., 2022).

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PHARMACOLOGICAL INTERVENTIONS TARGETING IMMUNE RECEPTOR SIGNALLING IN AGING

Multiple pharmaceutical approaches are being investigated to reverse aging-related immune receptor signaling decrease. These include:

Immune Modulators: PD-1 inhibitor nivolumab activates T-cells in elderly adults. Antibiotic and cancer inhibitors may strengthen older people's immune systems (Federico et al., 2020).

mTOR Inhibitors

Cell growth and immune responses are mediated by mTOR. Rapamycin (Figure 5) boosts vaccination responses, age-related inflammation, and T-cell function. It may restore youthful immunology by balancing immune receptor signalling (Bjedov and Rallis et al., 2020).

Palmitoyl-cysteine

Palmitoyl-cysteine (Figure 5) thioester attaches a 16-carbon fatty acid, palmitate, to a protein's cysteine residue, "anchoring" it to a cell membrane by making it more hydrophobic. Palmitoyl Acyltransferases (PATs) "ping-pong" the palmitate group from palmitoyl-CoA to the target protein's cysteine residue to influence protein localization and function in the cell (Federico et al., 2020).

Senolytics

These compounds selectively release inflammatory molecules and kill non-proliferating senescent cells. Dasatinib and quercetin (Figure 5) can reduce chronic inflammation and improve immunological function in older persons by suppressing senescent cell pro-inflammatory signals (Zhang et al., 2022).

Cytokine Therapies

Increase immunity, cytokine treatments are being explored because aging damages immune receptor signaling pathways. IL-7 may increase older people's T-cell responses by maintaining homeostasis (Pereira et al., 2020).

Antioxidants and Anti-inflammatory Drugs

NSAIDs and TNF-α inhibitors can reduce chronic inflammation caused by immune receptor modifications. Despite reducing inflammation, their extensive immune modulation effects require caution (Stromsnes et al., 2021).

Anti-PD-1 Checkpoint Inhibitors

Anti-PD-1 checkpoint medicines or other immunotherapies that block the PD1/PDL1 immune checkpoint proteins can destroy cancer cells. Many PD1 and PDL1 checkpoint inhibitors have been launched recently. Table 1 lists class essential medications. Programmed Death-1 (PD-1) on T-cells controls immune tolerance and prevents autoimmunity. Malignant cells avoid immune recognition by overexpressing PD-L1, which causes T-cell fatigue and immunological suppression. The immune system's ability to fight cancer is boosted by anti-PD-1 checkpoint inhibitors, which block PD-1. T cells can destroy tumor cells when PD-1 attaches to PD-L1, a protein in some normal or cancerous cells. This protein tells the T cell to leave the other cell alone by preventing PD-L1 from connecting to PD-1 (Figure 6).

Immunity booster: Immunostimulants, which can be chemically or naturally created, boost biological defences. Some immunostimulants are:

Acute lung infections and COPD may be treated with immunostimulants. Ex vivo immune cell modification for in vivo use and protein design for logical immune system modification have been studied extensively. Table 2 lists some synthetic immunostimulants and their mechanisms and uses.

Synthetic drugs used as an immunity booster

Pharmacological and synthetic drugs have been researched for immune enhancement, especially in elderly or immunocompromised patients. These drugs reduce chronic inflammation, boost innate and adaptive immune responses, or modify immune receptor signaling. Table 3 covers many crucial synthetic immunity-boosting drugs.

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AGING-RELATED CHANGES IN DRUG METABOLISM AND PHARMACODYNAMICS

In older adults, immune receptor signaling drugs must be processed differently due to aging.

Altered Pharmacokinetics: Aging-related liver and renal function changes can affect drug metabolism and clearance, requiring dose adjustments. Methotrexate, an immunologic receptor, regulates immune responses in autoimmune diseases. A cell membrane usually contains this receptor (Sameer and Nissar et al., 2021).

Types of receptors

The main immune system receptors are PRRs, TLRs, Killer-Activated and Killer Inhibitor Receptors (KARs and KIRs), complement receptors, Fc receptors, B cell receptors, and T cell receptors. The receptor targets and their functions are listed in Table 4 (Weinan et al., 2021 and Alexander et al., 2021).

Natural immunomodulator and immunostimulator

Chemical drugs have negative effects, thus natural immunomodulators may substitute them (Table 4) (Shariatinia et al., 2019). Most R&D efforts focus on biochemicals, biologics, or single molecules that target disease targets. It's difficult to create single-molecule medicines with low toxicity, high selectivity, and efficacy for molecular/cellular targets and diseases.

Natural Immunomodulators and Immunostimulators

Naturomodulators and immunostimulators from fungus, plants, and other sources control and stimulate immune responses. They boost or suppress immunity depending on biological needs. Table 5 lists its key categories and instances.

Signaling Through Immune System Receptors

Cells can interact with their surroundings via cell-surface receptors that bind extracellular chemicals (Ruckert and Romagnani et al., 2024). Since T and B lymphocytes respond to antigens, their antigen receptors are the most important and well-studied. The present work will focus on intracellular signals from antigens binding to these receptors that change cell behaviour (Muntjewerff et al., 2020).

CONCLUSION

Immune receptor signaling, aging, and pharmacology ends with immunology, aging biology, and drug development. Desenescence affects innate and adaptive immunity. Age reduces the efficiency or dysregulation of immunological receptor signaling, such as TCRs, PPRs, and cytokine receptors. Immune system changes weaken it, making it more prone to infections, cancer, and inflammatory disease, and poor vaccination response. Age-related alterations may be reversed by immune receptor signaling medications. They boost immune surveillance, resolve chronic inflammation, and restore immunological function. Older individuals' immune systems are being examined with immune checkpoint inhibitors, cytokine modulators, senolytics, and mTOR inhibitors. This review includes immune receptor signaling, aging, and immunological senescence pharmacological treatments, but the subject is evolving. Researchers are discovering the complex link between immune receptor networks and age-related immunological decline. Investigating innovative routes and medicinal methods to understand immune-senescence and its regulation.

Acknowledgement

The authors acknowledge Assam down town University, DmbH Institute of Medical Science, and NEF College of Pharmaceutical Education and Research for providing the library facility for the manuscript's preparation and Dr. Faruk Alam for contributions with discussion and language revisions. In Addition NEF College of Pharmaceutical Education & Research, Royal School of Pharmacy, the Assam Royal Global University, Betkuchi, Guwahati, Assam, India.

Conflict of Interest

The authors declare that there is no conflict of interest.