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Early cell membrane models placed most proteins external to lipid bilayers in trimolecular structures or as modular lipoprotein units. These thermodynamically untenable structures did not allow lipid lateral movements independent of membrane proteins. The Fluid–Mosaic Membrane Model accounted for these and other properties, such as membrane asymmetry, variable lateral mobilities of membrane components and their associations with dynamic complexes. Integral membrane proteins can transform into globular structures that are intercalated to various degrees into a heterogeneous lipid bilayer matrix. This simplified version of cell membrane structure was never proposed as the ultimate biomembrane description, but it provided a basic nanometer scale framework for membrane organization. Subsequently, the structures associated with membranes were considered, including peripheral membrane proteins, and cytoskeletal and extracellular matrix components that restricted lateral mobility. In addition, lipid–lipid and lipid–protein membrane domains, essential for cellular signaling, were proposed and eventually discovered. The presence of specialized membrane domains significantly reduced the extent of the fluid lipid matrix, so membranes have become more mosaic with some fluid areas over time. However, the fluid regions of membranes are very important in lipid transport and exchange. Various lipid globules, droplets, vesicles and other membranes can fuse to incorporate new lipids or expel damaged lipids from membranes, or they can be internalized in endosomes that eventually fuse with other internal vesicles and membranes. They can also be externalized in a reverse process and released as extracellular vesicles and exosomes. In this Special Issue, the use of membrane phospholipids to modify cellular membranes in order to modulate clinically relevant host properties is considered.

Most patients with COVID-19 disease caused by the SARS-CoV-2 virus recover from this infection, but a significant fraction progress to a fatal outcome. As with some other RNA viruses, co-infection or activation of latent bacterial infections along with pre-existing health conditions in COVID-19 disease may be important in determining a fatal disease course. Mycoplasma spp. (M. pneumonaie, M. fermentans, etc.) have been routinely found as co-infections in a wide number of clinical conditions, and in some cases this has progressed to a fatal disease. Although preliminary, Mycoplasma pneumoniae has been identified in COVID-19 disease, and the severity of some signs and symptoms in progressive COVID-19 patients could be due, in part, to Mycoplasma or other bacterial infections. Moreover, the presence of pathogenic Mycoplasma species or other pathogenic bacteria in COVID-19 disease may confer a perfect storm of cytokine and hemodynamic dysfunction, autoimmune activation, mitochondrial dysfunction and other complications that together cannot be easily corrected in patients with pre-existing health conditions. The positive responses of only some COVID-19 patients to antibiotic and anti-malaria therapy could have been the result of suppression of Mycoplasma species and other bacterial co-infections in subsets of patients. Thus it may be useful to use molecular tests to determine the presence of pathogenic Mycoplasma species and other pathogenic bacteria that are commonly found in atypical pneumonia in all hospitalized COVID-19 patients, and when positive results are obtained, these patients should treated accordingly in order to improve clinical responses and patient outcomes.

Hydrogen has been shown in several clinical trials to be completely safe without adverse events and there are no warnings in the literature of its toxicity or adverse effects during long-term exposure. Molecular hydrogen has proven useful and convenient as a novel antioxidant and modifier of gene expression in many conditions where oxidative stress and changes in gene expression result in cellular damage. Our intracellular biomarker studies have shown that a hydrogenized water drink formula containing 2.6 ppm dissolved hydrogen was able to penetrate cellular membranes and function as an antioxidant in human liver cells (HePG2) utilizing the Cellular Antioxidant Assay (CAA). This assay uses the protection of a florescent probe as a marker for cellular damage by reactive oxygen species (ROS), such as peroxyl radical, and compares this to the known antioxidant standard, Quercetin. Using this system oxidative damage was reduced in a dose-dependent manner. One ml of hydrogenized water was found to possess antioxidant capacity equivalent to 0.05 µmole of quercetin. When examined in a human colon cell line (Caco-2 cells), hydrogenized water demonstrated a dose- and time-dependent permeability inhibition of an intracellular fluorescent glucose derivative (2-NBDG), indicating decreased glucose uptake. In another study, the impact of hydrogenized water on Akt phosphorylation (Ser473), a biomarker for insulin signaling, was monitored in human skeletal muscle cells. The hydrogenized water treatment markedly elevated the level of phosphorylation of Akt (Ser473) in a dose-dependent manner. The anti-aging effects of hydrogenized water were examined utilizing SIRT1 expression as a biomarker of aging in human umbilical cells (HUVECs). Hydrogenized water increased dose-dependent SIRT1 gene expression. Hydrogenized water also increased telomerase activity (an anti-aging biomarker in HUVEC cells) up to 148% when cells were treated with media containing 25% hydrogenized water formula. Increased telomerase activity caused by hydrogenized water may be able to protect telomeres from degradation, suggesting the possible use of hydrogenized water in therapeutic interventions of age-related diseases. These studies show that commercial hydrogenized water improved the levels or activities of a few intracellular biomarkers specific for antioxidant activity, glucose uptake, insulin signaling and SIRT 1 and telomerase activities. Industrial Relevance: The molecular hydrogen used in this study indicates that certain commercial sources of hydrogenized water can provide similar antioxidant and gene expression modifications seen in other sources of molecular hydrogen. The biomarkers evaluated here lend well to hydrogenized water’s biological activity relating to health conditions and aging.

Membrane Lipid Replacement (MLR) is the use of functional dietary supplements containing cell membrane glycerolphospholipids and antioxidants to safely replace and remove damaged essential membrane phospholipids that accumulate during aging and in various chronic and acute illnesses. Most, if not all, clinical conditions and aging are characterized by cellular membrane phospholipid free radical oxidative damage, resulting in loss of membrane and cellular functions. In particular, loss of mitochondrial function, the key organelle responsible for over 90% of cellular energy production, can result in excess fatigue and other symptoms, and this is a common problem in almost all, if not all, age-related chronic diseases. Clinical trials have shown the benefits of MLR supplements in replenishing damaged membrane phospholipids and restoring mitochondrial function, resulting in reductions in fatigue and other symptoms in aged subjects and patients with a variety of clinical diagnoses. Here we have specifically reviewed the beneficial results of MLR on subjects older than 60 years. MLR provides general membrane and nutritional support during aging and illnesses to improve membrane function and overall health without risk of adverse effects. The case reports here and elsewhere and published clinical trials demonstrate that this is a safe and effective alternative or addition to pharmaceutical approaches for alleviating fatigue, pain, gastrointestinal and other symptoms associated with normal aging and age-related chronic illnesses.Keywords: Aging, Fatigue, Pain, Gastrointestinal symptoms, Phospholipids, Clinical trials, Case reports, Cellular membranes

Here we review the literature on the effects of molecular hydrogen (H2) on normal human subjects and patients with a variety of diagnoses, such as metabolic, rheumatic, cardiovascular and neurodegenerative and other diseases, infections and physical and radiation damage as well as effects on aging and exercise. Although the effects of H2 have been studied in multiple animal models of human disease, such studies will not be reviewed in depth here. H2 can be administered as a gas, in saline implants or infusions, as topical solutions or baths or by drinking H2-enriched water. This latter method is the easiest and least costly method of administration. There are no safety issues with hydrogen; it has been used for years in gas mixtures for deep diving and in numerous clinical trials without adverse events, and there are no warnings in the literature of its toxicity or long-term exposure effects. Molecular hydrogen has proven useful and convenient as a novel antioxidant and modifier of gene expression in many conditions where oxidative stress and changes in gene expression result in cellular damage.

Lead ions (Pb2+) possess characteristics similar to Ca2+. Because of this and its redox capabilities, lead causes different toxic effects. The neurotoxic effects have been well documented; however, the toxic effects on cardiac tissues remain allusive. We utilized isolated guinea pig hearts and measured the effects of Pb2+ on their contractility and excitability. Acute exposure to extracellular Pb2+ had a negative inotropic effect and increased diastolic tension. The speed of contraction and relaxation were affected, though the effects were more dramatic on the speed of contraction. Excitability was also altered. Heart beat frequency increased and later diminished after lead ion exposure. Pro-arrhytmic events, such as early after-depolarization and a reduction of the action potential plateau, were also observed. In isolated cardiomyocytes and tsA 201 cells, extracellular lead blocked currents through Cav1.2 channels, diminished their activation, and enhanced their fast inactivation, negatively affecting their gating currents. Thus, Pb2+ was cardiotoxic and reduced cardiac contractility, making the heart prone to arrhythmias. This was due, in part, to Pb2+ effects on the Cav1.2 channels; however, other channels, transporters or pathways may also be involved. Acute cardiotoxic effects were observed at Pb2+ concentrations achievable during acute lead poisoning. The results suggest how Cav1.2 gating can be affected by divalent cations, such as Pb2, and also suggest a more thorough evaluation of heart function in individuals affected by lead poisoning.

Membrane Lipid Replacement is the use of functional oral supplements containing cell membrane glycerolphospholipids and antioxidants to safely replace damaged membrane lipids that accumulate during aging and in various chronic and acute diseases. Most if not all clinical conditions and aging are characterized by membrane phospholipid oxidative damage, resulting in loss of membrane and cellular function. Clinical trials have shown the benefits of Membrane Lipid Replacement supplements in replenishing damaged membrane lipids and restoring mitochondrial function, resulting in reductions in fatigue in aged subjects and patients with a variety of clinical diagnoses. Recent observations have indicated that Membrane Lipid Replacement can be a useful natural supplement strategy in a variety of conditions: chronic fatigue, such as found in many diseases and disorders; fatiguing illnesses (fibromyalgia and chronic fatigue syndrome); chronic infections (Lyme disease and mycoplasmal infections); cardiovascular diseases; obesity, metabolic syndrome and diabetes; neurodegenerative diseases (Alzheimer's disease); neurobehavioral diseases (autism spectrum disorders); fertility diseases; chemical contamination (Gulf War illnesses); and cancers (breast, colorectal and other cancers). Membrane Lipid Replacement provides general membrane nutritional support during aging and illness to improve membrane function and overall health without risk of adverse effects.