Selenium and Selenoproteins: Protecting Cells from Age‑Related Damage

Selenium is a trace element that has captured the attention of researchers and health‑conscious individuals alike because of its unique ability to be incorporated directly into proteins as the amino acid selenocysteine. This “21st amino acid” endows selenoproteins with chemical properties that are difficult to achieve with the more common sulfur‑containing cysteine, allowing them to perform highly specialized biochemical tasks. As we age, the cumulative burden of oxidative stress, DNA lesions, protein misfolding, and dysregulated signaling pathways contributes to cellular decline. While many of these processes intersect with antioxidant defenses, the protective repertoire of selenoproteins extends far beyond simple radical scavenging, influencing hormone activation, redox signaling, protein quality control, and immune competence. Understanding how selenium and its protein partners operate at the cellular level provides a foundation for leveraging this mineral to support healthy aging.

Selenium Metabolism and Cellular Incorporation

The journey of dietary selenium to functional selenoproteins is a multi‑step process that begins in the gut and ends in the ribosome. Selenium is ingested primarily as selenomethionine (SeMet) from plant sources (e.g., Brazil nuts, whole grains) and as selenocysteine (Sec) or selenite from animal products and supplements. Once absorbed, SeMet can be nonspecifically incorporated into general body proteins in place of methionine, creating a storage pool that can be mobilized during periods of low intake. In contrast, selenite is reduced to selenide (HSe⁻) and then used for the de novo synthesis of Sec.

The synthesis of Sec is a unique translational event. A specialized tRNA^[Sec] is first charged with serine, which is subsequently phosphorylated and converted to Sec by selenophosphate synthetase 2 (SEPHS2) using selenide as the selenium donor. The Sec‑tRNA^[Sec] recognizes the UGA codon—normally a stop signal—only when a downstream selenocysteine insertion sequence (SECIS) element in the 3′‑untranslated region of the mRNA recruits the SECIS‑binding protein 2 (SBP2) and the elongation factor eEFSec. This elaborate machinery ensures that Sec is inserted precisely where needed, allowing the cell to produce a defined set of selenoproteins despite the limited number of UGA codons in the genome.

The Diverse Family of Selenoproteins and Their Functions

To date, more than 25 human selenoproteins have been identified, each belonging to distinct functional families:

While the glutathione peroxidases and thioredoxin reductases are often highlighted for their antioxidant capacity, many selenoproteins exert influence through more nuanced mechanisms such as hormone modulation, calcium handling, and protein quality control—processes that become increasingly dysregulated with age.

Selenoproteins in DNA Maintenance and Repair

Genomic integrity is a cornerstone of cellular longevity. Several selenoproteins intersect with DNA repair pathways:

• TXNRD1 and TXNRD2 maintain the reduced state of ribonucleotide reductase, the enzyme that supplies deoxyribonucleotides for DNA synthesis and repair. By ensuring a steady pool of dNTPs, thioredoxin reductases indirectly support base excision repair (BER) and homologous recombination.
• MSRB1 reverses oxidation of methionine residues in DNA‑binding proteins, including transcription factors that regulate the expression of repair genes. This repair of methionine sulfoxide helps preserve the fidelity of DNA‑damage response signaling.
• SELENOP delivers selenium to tissues with high proliferative demand (e.g., bone marrow, intestinal epithelium). Adequate selenium supply enables the synthesis of the full complement of selenoproteins required for DNA repair during rapid cell turnover.

Animal studies have demonstrated that selenium deficiency impairs the expression of key repair enzymes such as OGG1 (8‑oxoguanine DNA glycosylase) and reduces the efficiency of double‑strand break repair, leading to an accumulation of mutagenic lesions that accelerate cellular senescence.

Modulation of Cellular Signaling Pathways by Selenoproteins

Redox‑sensitive signaling cascades—such as those mediated by NF‑κB, MAPKs, and the PI3K/Akt pathway—govern inflammation, apoptosis, and metabolic adaptation. Selenoproteins fine‑tune these pathways through reversible oxidation of cysteine residues on signaling proteins:

• TXNRD1 reduces oxidized cysteines on transcription factors, thereby modulating their DNA‑binding activity. For instance, the reduced form of NF‑κB p50 subunit is more transcriptionally active, influencing the expression of anti‑apoptotic genes.
• SELENOK interacts with the palmitoyl‑transferase DHHC6, facilitating the palmitoylation of proteins involved in calcium signaling and immune cell activation. This post‑translational modification is essential for the proper trafficking of receptors that trigger downstream signaling.
• DIO2 converts the pro‑hormone thyroxine (T4) to the active triiodothyronine (T3) within cells, thereby influencing metabolic rate, mitochondrial biogenesis, and the expression of genes involved in oxidative phosphorylation.

Through these mechanisms, selenium status can shape the cellular decision matrix that determines whether a cell repairs damage, enters a quiescent state, or undergoes programmed death—choices that are pivotal in the context of aging tissues.

Selenoproteins and Mitochondrial Quality Control

Mitochondria are both sources and targets of reactive species. While the classic antioxidant role of GPXs is well recognized, selenoproteins also contribute to mitochondrial dynamics and mitophagy:

• TXNRD2 resides in the mitochondrial matrix, where it sustains the reduced state of peroxiredoxin 3 (PRDX3). This partnership limits mitochondrial hydrogen peroxide accumulation, preserving the integrity of mitochondrial DNA (mtDNA) and respiratory chain proteins.
• SELENON (also known as SEPN1) is localized to the sarcoplasmic reticulum and interacts with calcium‑handling proteins that influence mitochondrial calcium uptake. Proper calcium flux prevents mitochondrial permeability transition pore (mPTP) opening, a key event in apoptosis.
• SELENOS participates in the removal of misfolded proteins from the inner mitochondrial membrane via the ER‑mitochondria contact sites, thereby reducing proteotoxic stress that can trigger mitochondrial fragmentation.

Collectively, these actions help maintain a healthy mitochondrial network, which is essential for sustaining cellular energy production and preventing the age‑related decline in oxidative phosphorylation efficiency.

Immune Cell Function and Inflammaging

The aging immune system exhibits a paradoxical state: reduced capacity to combat infections alongside chronic low‑grade inflammation, termed “inflammaging.” Selenoproteins are integral to both arms of this phenomenon:

• SELENOK is required for the proper assembly of the immunological synapse in cytotoxic T lymphocytes and natural killer (NK) cells. Deficiency impairs granule exocytosis, diminishing the ability to clear virally infected or transformed cells.
• GPX4, a phospholipid hydroperoxide peroxidase, prevents ferroptosis—a form of iron‑dependent cell death—in macrophages. By safeguarding macrophage viability, GPX4 supports the resolution phase of inflammation.
• SELENOP modulates the production of pro‑inflammatory cytokines (e.g., IL‑6, TNF‑α) by acting as a selenium reservoir that can be mobilized during acute immune challenges, thereby limiting excessive oxidative bursts.

Clinical observations link low plasma selenium levels with heightened inflammatory markers and poorer vaccine responses in older adults, underscoring the relevance of adequate selenium for immune resilience.

Age‑Related Changes in Selenium Status and Selenoprotein Expression

Multiple epidemiological studies have reported a gradual decline in serum selenium concentrations after the fifth decade of life, even in populations with historically sufficient dietary intake. This decline is multifactorial:

1. Reduced gastrointestinal absorption due to age‑related changes in mucosal surface area and transporter expression.
2. Altered hepatic synthesis of SELENOP, limiting systemic selenium distribution.
3. Epigenetic silencing of selenoprotein genes, particularly those with lower hierarchy (e.g., GPX1) in response to chronic oxidative stress.

The concept of a “selenoprotein hierarchy” describes how, under conditions of limited selenium, the body preferentially synthesizes essential selenoproteins (e.g., DIO1, TXNRD1) at the expense of others. With advancing age, this hierarchy can shift, leading to suboptimal levels of proteins that are critical for maintaining proteostasis and immune function.

Optimizing Selenium Intake for Longevity

Given the nuanced role of selenium in cellular health, a balanced approach to intake is essential. The following practical guidelines can help individuals achieve an optimal status:

It is crucial to respect the narrow therapeutic window of selenium. Chronic intake above 400 µg/day increases the risk of selenosis, characterized by hair loss, nail brittleness, and, in severe cases, neurological disturbances.

Potential Risks and Interactions

• Interaction with Heavy Metals – Selenium can form inert complexes with mercury and arsenic, reducing their toxicity. However, excessive selenium may also interfere with the detoxification pathways of these metals, necessitating careful monitoring in exposed populations.
• Thyroid Hormone Modulation – Because DIO enzymes regulate thyroid hormone activation, high selenium intake can amplify the effects of thyroid medications, potentially leading to hyperthyroid symptoms.
• Cancer Risk – While adequate selenium appears protective against certain cancers, supraphysiologic doses have been linked to increased risk of type 2 diabetes and possibly prostate cancer in specific genetic backgrounds (e.g., rs7579 polymorphism in the SELENOP gene).

Personalized assessment—considering genetic variants, existing medical conditions, and concurrent supplement use—is advisable before initiating high‑dose selenium regimens.

Future Directions in Selenium Research for Aging

The field is moving beyond static measurements of selenium status toward dynamic, systems‑level investigations:

• Omics Approaches – Transcriptomic and proteomic profiling of selenoprotein networks in centenarians reveal up‑regulation of SELENOK and TXNRD2, suggesting a signature of successful aging.
• Selenoprotein Mimetics – Small‑molecule compounds that replicate the catalytic activity of GPX4 or TXNRD are being explored to bypass the limited capacity of the Sec insertion machinery in aged cells.
• Gene‑Editing Strategies – CRISPR‑mediated up‑regulation of high‑hierarchy selenoproteins in animal models has shown promise in extending healthspan by improving mitochondrial function and reducing inflammatory cytokine production.
• Microbiome Interplay – Gut microbes capable of converting inorganic selenium to organic forms may influence host selenium bioavailability, opening avenues for probiotic‑based interventions.

These emerging lines of inquiry aim to translate the molecular insights of selenium biology into actionable strategies that support cellular resilience throughout the lifespan.

In summary, selenium’s contribution to cellular health is multifaceted. By serving as the cornerstone of a diverse family of selenoproteins, it influences hormone activation, redox‑sensitive signaling, DNA repair, mitochondrial quality control, and immune competence—all processes that become increasingly vulnerable with age. Maintaining an adequate, but not excessive, selenium status through diet and, when necessary, targeted supplementation can help preserve the functional integrity of these pathways, offering a practical tool for those seeking to age with vitality and reduced cellular damage.