Phosphatidylserine protects neurons

Phosphatidylserine (PS), a phospholipid component of cell membranes, is being intensively studied from new perspectives—including cell structure maintenance, signal transduction regulation, and oxidative stress resistance—for its neuroprotective effects and anti-aging value. The following analysis explores its molecular mechanisms and anti-aging correlations:

I. The "Dynamic Guardian" of Neuronal Cell Membranes

Maintaining Membrane Structural Integrity and Fluidity

In the phospholipid bilayer of neuronal cell membranes, phosphatidylserine primarily localizes to the inner membrane. Its unique negatively charged polar head and fatty acid chain structure interacts with membrane proteins (e.g., receptors, ion channels) to maintain microdomain structures (e.g., lipid rafts). With aging, neuronal membrane phospholipids are lost due to oxidative damage or metabolic imbalance, leading to reduced membrane fluidity and abnormal ion channel function. Phosphatidylserine repairs damaged membrane structures by replenishing membrane phospholipid pools:

In aging model mice, PS supplementation increases the cholesterol-phospholipid ratio in synaptic vesicle membranes, delaying age-related membrane hardening and improving neurotransmitter release efficiency.

In vitro experiments show PS promotes correct localization of voltage-gated sodium channel Nav1.2 on neuronal axonal membranes, maintaining action potential conduction stability and alleviating age-related decline in nerve conduction velocity.

The "Molecular Switch" Regulating Membrane-Related Signaling Pathways

Phosphatidylserine participates in the initiation of multiple cellular signal transduction processes:

Apoptosis Signal Regulation: When cells are damaged by oxidative stress, PS flips from the inner to outer membrane, serving as a signal recognized by macrophages. Exogenous PS supplementation competitively inhibits this flipping, reducing neuronal apoptosis. In Alzheimer's disease (AD) models, PS decreases β-amyloid (Aβ)-induced neuronal PS externalization rate and reduces cell apoptosis by >40%.

Neurotrophic Factor Signal Enhancement: PS binds to Trk receptors (e.g., TrkA, TrkB), promoting signal transduction of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), thereby activating the PI3K-AKT pathway to enhance neuronal viability. In aging mice, PS supplementation increases BDNF expression in the hippocampus by 25%–30%.

II. "Dual Defense" Against Oxidative Stress and Mitochondrial Aging

Free Radical Scavenging and Lipid Peroxidation Inhibition

During aging, declining mitochondrial function in neurons generates abundant reactive oxygen species (ROS), causing phospholipid peroxidation damage. While PS's fatty acid chains (mostly polyunsaturated fatty acids like arachidonic acid or DHA) are susceptible to oxidation, their oxidation products act as signaling molecules to activate antioxidant enzymes (e.g., superoxide dismutase SOD). More importantly, PS blocks oxidative cascades by:

Acting as a free radical "decoy": PS's unsaturated fatty acid chains preferentially react with ROS, reducing oxidative damage to other membrane components (e.g., cholesterol, proteins). PS pretreatment reduces hydrogen peroxide-induced neuronal lipid peroxidation products (e.g., malondialdehyde MDA) by 50% in vitro.

Regulating antioxidant enzyme localization: PS promotes anchoring of Mn-SOD on mitochondrial membranes, enhancing ROS scavenging in the mitochondrial matrix—critical for improving age-related mitochondrial dysfunction.

Mitochondrial Function Protection and Energy Metabolism Optimization

Neurons have high energy demands, and mitochondrial aging directly leads to neurodegeneration. PS protects mitochondria by:

Maintaining mitochondrial membrane potential: PS inserts into mitochondrial membranes to regulate potential stability, reducing cytochrome C release and inhibiting apoptosis pathway activation. In aging fruit fly models, PS supplementation delays mitochondrial membrane potential decline by 30% and extends lifespan by 15%.

Promoting mitochondrial biogenesis: By activating the PPARγ-CoR1α pathway, PS upregulates mitochondrial transcription factor TFAM expression, promoting mitochondrial DNA replication and new mitochondrial generation to alleviate age-related mitochondrial loss.

III. The "Repair Agent" for Synaptic Plasticity and Cognitive Aging

Synaptic Structure Maintenance and Regeneration

Aging is associated with reduced synaptic density and function. Phosphatidylserine improves synaptic plasticity via:

Promoting synaptic vesicle recycling: PS participates in the endocytosis-exocytosis cycle of presynaptic membrane vesicles, increasing neurotransmitter (e.g., glutamate, acetylcholine) release efficiency. In aging rat models, PS supplementation increases the number of synaptic vesicles in the hippocampal CA1 region by 20% and restores postsynaptic density (PSD) thickness to youthful levels.

Supporting dendritic spine development: PS acts as an activator of Rho family GTPases (e.g., Cdc42), regulating actin cytoskeleton reorganization to promote dendritic spine formation and stability. In vitro-cultured neurons, PS treatment increases dendritic spine density by 35%.

Clinical Evidence of Cognitive Function Improvement

Multiple clinical trials confirm PS's intervention effects on aging-related cognitive decline:

A study in 50–70-year-olds with cognitive impairment showed that 300 mg daily PS supplementation for 12 weeks improved Mini-Mental State Examination (MMSE) scores by 1.5 points and visual-spatial memory test performance by 22%.

In early AD patients, PS combined with DHA supplementation delays the decline of cerebrospinal fluid Aβ42 and reduces hippocampal volume atrophy by 18% compared to the placebo group, indicating its role in delaying neurodegeneration.

IV. New Anti-Aging Perspectives: From Cellular Protection to Systemic Regulation

Regulation of the Blood-Brain Barrier and Neurovascular Coupling

Aging increases blood-brain barrier (BBB) permeability, triggering brain inflammation. Phosphatidylserine improves the brain microenvironment by:

Promoting tight junction protein (e.g., ZO-1, claudin-5) expression in BBB endothelial cells to reduce permeability. In animal experiments, PS reduces lipopolysaccharide-induced BBB leakage by 40%.

Enhancing neurovascular coupling (NVC) responses, i.e., the matching of neuronal activity and cerebral blood flow. PS improves cerebral blood perfusion by regulating endothelial nitric oxide synthase (eNOS) activity to promote NO release, significantly reducing the risk of cerebral ischemia in aging.

Potential Regulation of the Gut-Brain Axis

Recent studies reveal PS may indirectly regulate brain aging by influencing gut microbiota:

Oral PS is metabolized by gut microbiota into short-chain fatty acids (e.g., butyric acid), which enter the brain via the bloodstream to activate an anti-inflammatory phenotype (M2 type) in microglia, reducing pro-inflammatory factor (e.g., TNF-α) release.

PS selectively promotes the proliferation of beneficial bacteria like Akkermansia in the gut, improves intestinal barrier function, reduces aging-related "leaky gut"-induced systemic inflammation, and thereby lowers the risk of brain neuroinflammation.

Phosphatidylserine's neuroprotective effects exceed the traditional understanding of "membrane component supplementation," forming a three-dimensional anti-aging defense network through multi-target mechanisms (membrane structure repair, oxidative stress resistance, mitochondrial function optimization, synaptic plasticity maintenance). From molecular mechanisms to clinical evidence, PS demonstrates potential to delay neural aging and improve cognitive function.