Multidimensional insights into the repeated electromagnetic field stimulation and biosystems interaction in aging and age-related diseases.

We provide a multidimensional sequence of events that describe the electromagnetic field (EMF) stimulation and biological system interaction. We describe this process from the quantum to the molecular, cellular, and organismal levels. We hypothesized that the sequence of events of these interactions starts with the oscillatory effect of the repeated electromagnetic stimulation (REMFS). These oscillations affect the interfacial water of an RNA causing changes at the quantum and molecular levels that release protons by quantum tunneling. Then protonation of RNA produces conformational changes that allow it to bind and activate Heat Shock Transcription Factor 1 (HSF1). Activated HSF1 binds to the DNA expressing chaperones that help regulate autophagy and degradation of abnormal proteins. This action helps to prevent and treat diseases such as Alzheimer's and Parkinson's disease (PD) by increasing clearance of pathologic proteins. This framework is based on multiple mathematical models, computer simulations, biophysical experiments, and cellular and animal studies. Results of the literature review and our research point towards the capacity of REMFS to manipulate various networks altered in aging (Reale et al. PloS one 9, e104973, 2014), including delay of cellular senescence (Perez et al. 2008, Exp Gerontol 43, 307-316) and reduction in levels of amyloid-ß peptides (Aß) (Perez et al. 2021, Sci Rep 11, 621). Results of these experiments using REMFS at low frequencies can be applied to the treatment of patients with age-related diseases. The use of EMF as a non-invasive therapeutic modality for Alzheimer's disease, specifically, holds promise. It is also necessary to consider the complicated and interconnected genetic and epigenetic effects of the REMFS-biological system's interaction while avoiding any possible adverse effects.

Electromagnetic Field Stimulation Therapy for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative dementia worldwide. AD is a multifactorial disease that causes a progressive decline in memory and function precipitated by toxic beta-amyloid (Aß) proteins, a key player in AD pathology. In 2022, 6.5 million Americans lived with AD, costing the nation $321billion. The standard of care for AD treatment includes acetylcholinesterase inhibitors (AchEIs), NMDA receptor antagonists, and monoclonal antibodies (mAbs). However, these methods are either: 1) ineffective in improving cognition, 2) unable to change disease progression, 3) limited in the number of therapeutic targets, 4) prone to cause severe side effects (brain swelling, microhemorrhages with mAb, and bradycardia and syncope with AchEIs), 5) unable to effectively cross the blood-brain barrier, and 6) lack of understanding of the aging process on the disease. mAbs are available to lower Aß, but the difficulties of reducing the levels of the toxic Aß proteins in the brain without triggering brain swelling or microhemorrhages associated with mAbs make the risk-benefit profile of mAbs unclear. A novel multitarget, effective, and safe non-invasive approach utilizing Repeated Electromagnetic Field Stimulation (REMFS) lowers Aß levels in human neurons and memory areas, prevents neuronal death, stops disease progression, and improves memory without causing brain edema or bleeds in AD mice. This REMFS treatment has not been developed for humans because current EMF devices have poor penetration depth and inhomogeneous E-field distribution in the brain. Here, we discussed the biology of these effects in neurons and the design of optimal devices to treat AD.

Numerical Modeling and Computer Simulation of a Meander Line Antenna for Alzheimer's Disease Treatment, a Feasibility Study.

Alzheimer's disease (AD) is a brain disorder that eventually causes memory loss and the ability to perform simple cognitive functions; research efforts within pharmaceuticals and other medical treatments have minimal impact on the disease. Our preliminary biological studies showed that Repeated Electromagnetic Field Stimulation (REFMS) applying an EM frequency of 64 MHz and a specific absorption rate (SAR) of 0.4 - 0.9 W/kg decrease the level of amyloid-ß peptides (Aß), which is the most likely etiology of AD. This study emphasizes uniform E/H field and SAR distribution with adequate penetration depth penetration through multiple human head layers driven with low input power for safety treatments. In this work, we performed numerical modeling and computer simulations of a portable Meander Line antenna (MLA) to achieve the required EMF parameters to treat AD. The MLA device features a low cost, small size, wide bandwidth, and the ability to integrate into a portable system. This study utilized a High-Frequency Simulation System (HFSS) in the design of the MLA with the desired characteristics suited for AD treatment in humans. The team designed a 24-turn antenna with a 60 cm length and 25 cm width and achieved the required resonant frequency of 64 MHz. Here we used two numerical human head phantoms to test the antenna, the MIDA and spherical head phantom with six and seven tissue layers, respectively. The antenna was fed from a 50-Watt input source to obtain the SAR of 0.6 W/kg requirement in the center of the simulated brain tissue layer. We found that the E/H field and SAR distribution produced was not homogeneous; there were areas of high SAR values close to the antenna transmitter, also areas of low SAR value far away from the antenna. This paper details the antenna parameters, the scattering parameters response, the efficiency response, and the E and H field distribution; we presented the computer simulation results and discussed future work for a practical model.

Insights into the Social Determinants of Health in Older Adults.

In this paper, we review the social determinants of health in older adults and their complex interrelationship with medical diseases. Also, we provide recommendations to address these determinants in the integrated healthcare plan. The social determinants in older adults and its influence in health outcomes have been studied for decades. There is solid evidence for the interrelationship between social factors and the health of individuals and populations; however, these studies are unable to define their complex interrelatedness. Health is quite variable and depends on multiple biological and social factors such as genetics, country of origin, migrant status, etc. On the other hand, health status can affect social factors such as job or education. Addressing social determinants of health in the integrated healthcare plan is important for improving health outcomes and decreasing existing disparities in older adult health. We recommend a person-centered approach in which individualized interventions should be adopted by organizations to improve the health status of older adults at the national and global level. Some of our practical recommendations to better address the social determinants of health in clinical practice are EHR documentation strategies, screening tools, and the development of linkages to the world outside of the clinic and health system, including social services, community activities, collaborative work, and roles for insurance companies.

Numerical Analysis and Design of an EMF Birdcage Wearable Device for the Treatment of Alzheimer's Disease: A Feasibility Study.

In this study, we performed a numerical analysis of a novel EMF Birdcage wearable device for the treatment of Alzheimer's disease (AD). We designed the new device to generate and radiate a frequency of 64 MHz and a specific absorption rate (SAR) of 0.6 W/kg to a simulated human brain tissue. We determined these parameters from our experimental studies on primary human brain cultures at the Indiana University School of Medicine (IUSM). We found that this frequency and SAR decreased the toxic Aß levels in the cell cultures. The frequency of 64 MHZ has good skin depth penetration, which will easily pass through the various head layers, including hair, skin, fat, dura, the cerebrospinal (CSF), and grey matter, and reach deeply into the brain tissues. The SAR of 0.6 W/kg was achieved with lower power input and energy, decreasing the probability of thermal injury. Therefore, these parameters enhance the safety of these potential treatments. This Birdcage device emulates a small-scale MRI machine, producing the same 64 MHz frequency at much lower operating input power. In this work, we utilized a high-frequency simulation system (HFSS/EMPro) software to produce the birdcage structure for the required EMF parameters. The 64 MHz radiating frequency produced the scattering S11 parameter of -15 dbs. We obtained a SAR of 0.6 W/kg when an input power of 100 W was applied. The coil dimensions were found to be near 15 cm in height and 22 cm in diameter, which fits in wearable systems. We found that the distribution of the electric field and SAR radiate homogeneously over the simulated human head with good penetration into the brain, which proves to be an appropriate potential therapeutic strategy for Alzheimer's disease.

EMF Antenna Exposure on a Multilayer Human Head Simulation for Alzheimer Disease Treatments.

In this paper, we follow up with our preliminary biological studies that showed that Repeated electromagnetic field stimulation (REMFS) decreased the toxic amyloid-beta (Aß) levels, which is considered to be the cause of Alzheimer's disease (AD). The REMFS parameters of these exposures were a frequency of 64 MHz and a Specific absorption rate (SAR) of 0.4 to 0.9 W/Kg in primary human neuronal cultures. In this work, an electromagnetic field (EMF) model was simulated using high-frequency simulation system (HFSS/EMPro) software. Our goal was to achieve the EM parameters (EMF Frequency and SAR) required to decrease the toxic Aß levels in our biological studies in a simulated human head. The simulations performed here will potentially lead to the successful development of an exposure system to treat Alzheimer's disease patients. A popular VFH (very high frequency) patch microstrip antenna system was considered in the study. The selection was based on simple and easy construction and appropriateness to the VHF applications. The evaluation of the SAR and temperature distribution on the various head layers, including skin, fat, dura, the cerebrospinal (CSF), and grey matter, brain tissues, were determined for efficacy SAR and safety temperature increase on a simulated human head. Based on a current pulse of 1 A peak current fed to the antenna feeder, a maximum SAR of 0.6 W/Kg was achieved. A range of 0.4 to 0.6 SAR was observed over the various layers of the simulated human head. The initial design of the antenna indicated an antenna size in the order of 1 m in length and width, suggesting a stationary practical model for AD therapy. Future direction is given for wearable antenna and exposure system, featuring high efficiency and patient comfort.

Repeated electromagnetic field stimulation lowers amyloid-ß peptide levels in primary human mixed brain tissue cultures.

Late Onset Alzheimer's Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-ß (Aß) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aß levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aß levels (Aß40 and Aß42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aß40 (p = 001) and Aß42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aß levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aß40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aß precursor protein-α (sAPPα) levels, suggesting the decrease in Aß did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aß deposition.

Electromagnetic field therapy delays cellular senescence and death by enhancement of the heat shock response.

Hormesis may result when mild repetitive stress increases cellular defense against diverse injuries. This process may also extend in vitro cellular proliferative life span as well as delay and reverse some of the age-dependent changes in both replicative and non-replicative cells. This study evaluated the potential hormetic effect of non-thermal repetitive electromagnetic field shock (REMFS) and its impact on cellular aging and mortality in primary human T lymphocytes and fibroblast cell lines. Unlike previous reports employing electromagnetic radiation, this study used a long wave length, low energy, and non-thermal REMFS (50MHz/0.5W) for various therapeutic regimens. The primary outcomes examined were age-dependent morphological changes in cells over time, cellular death prevention, and stimulation of the heat shock response. REMFS achieved several biological effects that modified the aging process. REMFS extended the total number of population doublings of mouse fibroblasts and contributed to youthful morphology of cells near their replicative lifespan. REMFS also enhanced cellular defenses of human T cells as reflected in lower cell mortality when compared to non-treated T cells. To determine the mechanism of REMFS-induced effects, analysis of the cellular heat shock response revealed Hsp90 release from the heat shock transcription factor (HSF1). Furthermore, REMFS increased HSF1 phosphorylation, enhanced HSF1-DNA binding, and improved Hsp70 expression relative to non-REMFS-treated cells. These results show that non-thermal REMFS activates an anti-aging hormetic effect as well as reduces cell mortality during lethal stress. Because the REMFS configuration employed in this study can potentially be applied to whole body therapy, prospects for translating these data into clinical interventions for Alzheimer's disease and other degenerative conditions with aging are discussed.

Engineered repeated electromagnetic field shock therapy for cellular senescence and age-related diseases.

A new consensus of gerontologists proposes that delay of biological senescence is the most potent public health measure for preventing chronic disease in late life. At the most fundamental level, cellular aging is characterized by a decline in repair and homeostatic systems. Thus, interventions that protect or rejuvenate these cellular systems hold significant promise for preventing or delaying the onset of age-related diseases. The most likely candidates for delaying senescence are the longevity-linked transcription factors DAF16 and HSF1. If one were to engineer negligible senescence, a key target would be the heat shock protein axis regulated by HSF1. This pathway is the preferred pathway to prevent protein damage or aggregation, whereas DAF-16/FOXO is a backup pathway activated during stress. Reduced HSF1 activity appears to accelerate tissue aging and shortens life span. Conversely, over-expression of HSF1 increases life span and decreases amyloid toxicity in animal models. This paper describes enhancement of the HSR/HSF1 pathway engineered by repeated electromagnetic field shock (REMFS). In a recent study, we demonstrated that REMFS therapy upregulates the HSR/HSF1 pathway, delays cellular senescence in young cells, and transiently reverses it in senescent cells, thus altering cellular mortality. The technology of applying certain beneficial EMF energy to the human body to stimulate the natural stress response and activate the repair and maintenance systems is a new strategy for engineered negligible senescence. We discuss the exciting clinical implications of REMFS therapy in human aging and disease.

Pathomolecular effects of homocysteine on the aging process: a new theory of aging.

Homocysteine has been associated with the most common age-related diseases but never associated with the acceleration of the aging process. This theoretical paper will try to demonstrate the pro-aging effects of homocysteine at the molecular, cellular, and organ level. High homocysteine levels in homocystinuria are associated with premature disease of the cardiovascular, skeletal, neurological, and other systems. These observations are similar to those noted in the aging process and should be considered as a progeroid syndrome. There is enough scientific evidence to support that homocysteine accelerates the aging process at the cellular and at the organism level. Most importantly, decreasing homocysteine levels by dietary or pharmacological interventions could prolong maximum life span in humans and/or delay the onset of the most common age-related diseases.

Late-onset Alzheimer's disease, heating up and foxed by several proteins: pathomolecular effects of the aging process.

Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disorder in older adults, affecting over 50% of those over age 85. Aging is the most important risk factor for the development of LOAD. Aging is associated with the decrease in the ability of cells to cope with cellular stress, especially protein aggregation. Here we describe how the process of aging affects pathways that control the processing and degradation of abnormal proteins including amyloid-ß (Aß). Genetic association studies in LOAD have successfully identified a large number of genetic variants involved in the development of the disease. However, there is a gap in understanding the interconnections between these pathomolecular events that prevent us from discovering therapeutic targets. We propose novel, pertinent links to elucidate how the biology of aging affects the sequence of events in the development of LOAD. Furthermore we analyze and synthesize the molecular-pathologic-clinical correlations of the aging process, involving the HSF1 and FOXO family pathways, Aß metabolic pathway, and the different clinical stages of LOAD. Our new model postulates that the aging process would precede Aß accumulation, and attenuation of HSF1 is an "upstream" event in the cascade that results in excess Aß and synaptic dysfunction, which may lead to cognitive impairment and/or trigger "downstream" neurodegeneration and synaptic loss. Specific host factors, such as the activity of FOXO family pathways, would mediate the response to Aß toxicity and the pace of progression toward the clinical manifestations of AD.

Longevity pathways: HSF1 and FoxO pathways, a new therapeutic target to prevent age-related diseases.

Modern medicine is directed towards the prevention, detection and cure of individual diseases. Yet, current medical models inadequately describe aging-associated diseases. We now know that failure in longevity pathways including oxidative stress, multisystem dysregulation, inflammation, sarcopenia, protein deposition and atherosclerosis are associated with age-related diseases. Such longevity pathways are potential targets for therapeutic intervention. Interventions in specific pathways have been shown to ameliorate and postpone the aging phenotype by activation of multiple genes. The strategy that we propose in this paper is to apply interventions simultaneously on complementary longevity pathways to achieve a synergistic result. For instance, aging is known to attenuate the HSF1 pathway leading to production of very toxic beta-amyloid fibrils. Consequently, the FoxO pathway is activated, resulting in the formation of less toxic high molecular weight aggregates as a defense mechanism. Thus the simultaneous upregulation of the HSF1 and FoxO pathways could potentially decrease protein deposition and proteotoxicity, thereby retarding or possibly preventing the onset of neurodegenerative diseases. Modulating these two pathways may also delay the onset of other age-related pathologies including cognitive decline, cancer, diabetes and cardiovascular disease due to its multi-gene effect. In this paper, we will discuss the role of several agents on the simultaneous modulation of these two central longevity pathways. The aging of western societies makes prevention of age-related diseases a pressing priority.