Epigenetic Modulation of Neuro-Immuno-Endocrine Axis in Mind-Body Practices

Mental well-being and physical health when interlinked can have a direct impact on the other, affecting overall health and wellbeing. Mind-Body Practices (MBPs), also referred to as Mind-Body Interventions (MBIs) or Mind-Body Training (MBT), are health and fitness activities designed to enhance this interaction for holistic wellness. MBPs are administered or taught by trained practitioners or teachers and are focused on the interactions between the brain, mind, body, and behaviour [1,2]. These practices include yoga, tai chi, Qigong, acupuncture, Pilates, guided imagery, meditation, aromatherapy, hypnosis, art therapy, music therapy, and dance therapy. Some of these procedures or techniques focus on strong physical activities while others engage in relaxation responses and are mainly sedentary. Even though mind and body practices include diverse techniques they appear to benefit both healthy and clinical populations providing a broad range of physiological benefits like alleviating stress, reducing anxiety, and improving conditions and symptoms related to chronic diseases [3,4]. In past decades, Mind and body practices have gained a lot of recognition and support from health specialists due to their clinical relevance as well as potential applications in alternate health care and integrative medicine giving them widespread acceptance. Besides this, these practices have also proven beneficial alongside conventional treatments and as preventive therapy [5]. 

To realize the full potential of MPBs research to decipher the potential mechanisms has soared. Accumulating evidence suggests MBPs regulate neurological, immune, and endocrine systems through various effectors [6,7]. However, a comprehensive and extensive understanding of the mechanisms through which MBPs modulate these effectors is still unclear and thus needs to be further developed for innovative alternative approaches to treating or preventing diseases and disorders that are currently resistant to conventional medical treatments [5]. Additionally, evidence suggests the existence of a dense and intricate relationship between the immune, nervous system, and endocrine systems [6]. Thus, it would be interesting to understand if the MBPs can also influence effectors that mediate crosstalk. 

Gene expression analysis techniques have served as an important tool to measure, evaluate, and compare the effectiveness of MBPs, thus revealing the underlying mechanisms of the psychological and physical effects of such practices [7]. Consequently, epigenetics and functional genomics methods to analyse the genomic outcomes and mechanisms of MBPs have increased [8]. Various MBPs including Tai-chi, Mindfulness meditation, and Yoga have been analysed in recent years to determine epigenetic determinants. The findings indicate epigenome modulation influencing inflammation markers, immunomodulators, age-related DNA methylation, immune cell metabolism, and global histone modifications leading to stress healing in practitioners [9-14].

Thus, understanding the intersection of epigenetics and the neuroendocrine-immune axis in the regulation of gene expression, physiological responses, and mental well-being becomes imperative to identify novel mechanisms of action for mind-body practices. The need for this approach has been established through clinical research that demonstrates how an individual’s genetic variability can be used for diagnosis, disease prediction and prevention, and care. 

In the current review, we will investigate how MBPs impact epigenetic mechanisms, neuroimmune regulation, and hormonal balance and underline their clinical implications for health promotion, wellness, and precision medicine.

The neuroimmunoendocrine axis, including the nervous, immune, and endocrine systems, influences the physiological functions significantly, therefore impacting the quality of life and longevity [15]. The complex interactions between the nervous-endocrine-immune systems are mediated by diverse factors and multiple pathways that integrate the functions of major organs including the hypothalamus, pituitary, adrenal, thyroid glands, gonads, and autonomic nervous system. This neuroimmunoendocrine axis regulates a variety of biological functions, and its normal interaction is crucial to prevent the onset of certain clinical implications and pathologies [16,17]. These systems can interact either as the neuroendocrine system that regulates immune responses or as neuroimmune systems that modify the functional aspects of the endocrine system [18]. 

The intricate interplay between the nervous and endocrine systems, known as neuroendocrine regulation, holds profound significance for both health and disease. The neuroendocrine system mediates the communication between the Central Nervous System (CNS) and endocrine glands, coordinating hormone secretion, and regulating functions. Dysregulation of neuroendocrine pathways can lead to altering hormone secretion and receptor expression [19]. Notably, the disruptions mainly impact hypothalamus-pituitary-thyroid and hypothalamus-pituitary-adrenal axes potentially contributing to complications such as cognitive impairment and depression. The changes in neuroendocrine activity therefore become a crucial factor in increasing the complexity of recovery as well as health and disease prevention [19]. 

Neurotransmitters and neuropeptides constitute the complex interaction between the nervous and immune systems, modulating inflammatory responses and maintaining tissue homeostasis. Recent advances have unveiled neuroimmune synapses as discrete regions where neurons exert precise control over immune cell activity, emphasizing their critical role in health and disease [20]. Disruption in this dynamic interaction leads to the pathogenesis of a diverse array of disorders. Neuroimmune signalling not only participates in cognitive processes but orchestrates inflammatory processes and tissue regeneration, yielding multifaceted effects on physiological processes [21,22]. Neurotransmitters and neuropeptides constitute the complex interaction between the nervous and immune systems, modulating inflammatory responses and maintaining tissue homeostasis. 

The neuroendocrine-immune interaction is an exchange between the nervous-endocrine, and immune systems and is crucial for homeostasis and for responding to environmental challenges. Neurotransmitters, hormones, cytokines, and their receptors form part of this dynamic communication through bidirectional crosstalk that includes responses of immune cells to neural and hormonal signals and responses of endocrine cells to cytokines. Immune and neuroendocrine factors function in the regulation of various physiological processes, such as immunity, behaviour, and reproduction [23]. The endocrine and immune systems have bidirectional communication through hormones and cytokines. Cytokines influence the hypothalamic-pituitary-adrenal axis on immune responses and neuroendocrine dynamics, important for maintaining balance and having effects on inflammation, stress, and susceptibility to diseases. This dysregulation may lead to autoimmune disorders and inflammation [23]. 

Establishing brain development requires the interplay of the immunological and neuroendocrine systems. Neurotransmitters, hormones, cytokines, affect several aspects of brain maturation, including neurogenesis, synapse formation, and programmed death of cells [24,25]. To regulate both innate immunity and acquired immunity, cytokines and their receptors are constitutively produced in the brain. Further demonstrating the interdependence of these systems is the innervation of primary and secondary lymphoid organs by nerve fibers [25]. 

Studies on neuroimmunoendocrine axis therapy have tested several interventions toward the ability to modulate this complex network. Practices such as yoga, meditation, acupuncture, and mindfulness have shown promising effects on stress hormones and inflammatory markers for a range of health conditions, such as cancer, HIV, depression, and cardiovascular diseases. These interventions point out the bidirectional interactions between the nervous, immune, and endocrine systems that play a critical role in physiological homeostasis and disease pathology [26,27].

Epigenetic mechanisms are responsible for mediating spatial and temporal gene expression while functioning to regulate gene-gene and gene–environmental interactions. Primarily epigenetic mechanisms include DNA methylation and hydroxymethylation; histone modifications, chromatin reorganization; and noncoding RNA regulation. These mechanisms are closely knit processes that execute vital genomic functions like replication, transcription, posttranscriptional modifications, translation, genomic imprinting, DNA repair, and genomic stability maintenance [28]. 

The epigenetics field has focused extensively on DNA methylation due to its crucial role in mammalian development and gene silencing. Many human diseases are linked to imbalances in DNA methylation. In mammalian genomes, this epigenetic modification primarily occurs at cytosines in promoters, enhancers, repetitive regions, and gene bodies [29]. Genetic and acquired genomic alterations can cause aberrant CpG island methylation when recombined into active transcriptional regions, suggesting CGI methylation results from, rather than causes, transcriptional activity. Histone modification H3K36me3 is linked to gene body methylation by recruiting DNA methyltransferase 3B (DNMT3B), with its distribution correlating to the extent of gene body methylation [30]. This seems to indicate that the methylation of CGI would be dependent on the transcriptional machinery driven by the promoter. Conversely, in ES cells, the CGIs that are transcribed remain unmethylated due to CpG-binding factors such as CFP1 [31]. The strength of transcriptional initiation at different CGIs within a gene influences their methylation status, suggesting a functional role for longer CGIs with higher CpG density. Additionally, histone modifications such as H3K4me3, H3K9me3, H3K27me3, and H4K20me3 interact complexly with DNA methylation, affecting its dynamics and gene expression regulation [31,32]. 

Epigenetics profoundly alters cellular function by modifying gene expression and structurally affecting chromatin through DNA repair mechanisms. These complex processes allow cells to adapt and respond dynamically to environmental cues. In obesity and metabolic disorders, epigenetic changes significantly influence the plasticity and function of adipose tissue. The interaction between epigenetics and metabolic pathways provides valuable insights into disease etiology and potential therapies. Additionally, epigenetic mechanisms reveal how environmental factors impact human health and well-being [33-36]. 

Histone Post-Translational Modifications (PTMs), such as methylation, acetylation, phosphorylation, ubiquitination, sumoylation, and biotinylation, intricately regulate gene transcription by altering chromatin structure. These modifications predominantly occur at specific amino acid residues on histone proteins H3 (e.g., H3K4, H3K9, H3K27) and histone H4 (e.g., H4K16), significantly impacting gene expression. During cellular differentiation and disease progression, these modifications change dynamically, creating specific histone modification signatures that predict gene expression patterns. Additionally, crosstalk between PTMs, such as H3S10ph inhibiting H3K9me3 formation, orchestrates gene expression programs [4,33]. Table 1 summarizes common epigenetic mechanisms, their effects on gene expression, and associated health benefits. 

 Non-coding RNAs modulate histone marks by regulating their deposition, modification, and erasure, impacting gene expression in both physiological and pathological conditions. Among these non-coding RNAs, microRNAs (miRNAs) are key epigenetic regulators that recognize specific sequences, primarily through the "seed sequence," to influence mRNA. [37]. MiRNAs can target mRNAs encoding histone methyltransferases, histone deacetylases, and polycomb proteins. Long non-coding RNAs (lncRNAs) act as "scaffolds" for histone modifiers, recruiting writers, erasers, and readers to specific chromatin loci to orchestrate chromatin structure. Furthermore, histone modifications reciprocally regulate the expression of both miRNAs and lncRNAs, creating complex regulatory loops that fine-tune gene expression programs [38]. 

Environmental factors such as diet, smoking, and psychological stress significantly impact the epigenome [39]. Epigenetic mechanisms intricately regulate gene expression and disease, involving heritable and reversible processes that modulate gene activity without altering the DNA sequence. Altered DNA methylation serves as a biomarker for diseases like cancer, while dynamic histone modifications influence genes involved in conditions such as cardiovascular diseases and cancer. Non-coding RNAs also play a key role in epigenetic regulation, with their misregulation linked to disease onset and progression. Additionally, DNA and histone methyltransferases and demethylases are critical in conditions like cardiovascular diseases, cancer, and aging, offering potential targets for therapeutic interventions [1,4,40]. Physical activity, environmental factors, diet, and stressors significantly influence epigenetics and human health and disease. Understanding these mechanisms is essential for developing safer and more effective treatments. Additionally, knowledge of such interactions offers potential pathways for disease prevention and cellular health enhancement [41].

Table 1: Epigenetic Mechanisms, Their Effects on Gene Expression, and Associated Health Benefits [36-40].

Mind and body practices (MBPs) modulate both psychological and physiological changes and can act either directly or indirectly at the level of the epigenome. While some of these approaches initiate their effects at the psychological level, ultimately modifying the epigenome, others can directly influence the epigenome, initially leading to physiological and psychological outcomes [5]. Although MBPs have diverse effects, the most well studied interface has been through interactions with the neuroendocrine-immune axis [6,7]. Thus, understanding the molecular mechanisms, starting from gene expression and epigenomic levels, is necessary. Preliminary studies have indicated a probable connection between various MBPs and epigenetic alterations, leading to positive health outcomes [5]. A comprehensive understanding of this connection might prove beneficial in realizing the full potential of such practices and exploring applications in integrative or complementary approaches to conventional therapies, thus improving quality of life. 

• Tai Chi: Randomized controlled trials have reported that MBPs like Tai Chi have improved inflammatory regulation through decreases in the expression of genes regulated by the transcription factor NFκB [42].
• Qigong: In a study of Qigong adepts, gene expression analysis was carried out on neutrophils, the most prevalent type of white blood cells and crucial in fighting infection. Using a microarray of 12,000 genes, they found that Qigong practitioners had 132 downregulated and 118 upregulated genes in comparison with controls [43]. Some of the differentially expressed genes have common functions, suggesting that Qigong enhances immunity, downregulates cellular metabolism, and delays cell death.
• Meditation: IL-6 and C-reactive protein, both markers of inflammation, are reduced after meditation, and the magnitude of the reduction correlates with the amount of meditation experience [44]. Research has show receptor-interacting serine-threonine kinase 2 (RIPK2), which promotes the generation of NF-κB and COX2 genes being downregulated in meditators, while are also downregulated in meditators [45].
• Mindfulness-Based Stress Reduction (MBSR): Research exploring inflammation, longevity, and loneliness conducted genome-wide transcriptional profiling using peripheral blood mononuclear cells (PBMCs), controlling for variables such as sex, age, ethnicity, BMI, sleep quality, and exercise with a bioinformatics analysis of differentially expressed genes to determine how many of them are targeted by NF-κB transcription factors using the TELiS transcription factor search. After participating in MBSR, participants reported reduced loneliness, and gene analysis showed a reversal of the pro-inflammatory gene expression pattern [46]. Further analysis indicated that the genes with changed expression originated mostly from monocytes and B lymphocytes.
• Yoga: A clinical study found rapid changes in global gene expression profiles in the peripheral blood mononuclear cells (PBMCs) in healthy people that practiced yoga programs, with the study recommending the study of MBP as accessible, quickly effective interventions for improving health [47]. Research into systems dynamics found yoga’s interactions with the HPA axis, PNS, and nociceptive neurological networks (all systems that interact with epigenetic expression) constitute a complex adaptive system with disproportionate health benefits [48].
• Pranayama: A study with a sample consisting of eight patients with chronic lymphocytic leukemia examined the effects of several kinds of pranayama breathing practices. The notable results showed that 4,428 genes of 28,000 analyzed were upregulated up to 200% in leukemia patients who practiced breathing techniques. Of the 4,428 differentially expressed genes, only a set of upregulated stress-related genes is reported, along with a pair of upregulated genes that delay cell death, suggesting improved immune regulation. The published report lacks further details about the methods and procedures used [49].
• Altered States of Consciousness: Researchers explored gene expression changes in adepts who claimed to enter a higher state of consciousness (a state of “pure awareness” without thoughts, feelings, or perceptions), drawing from Zen, Kriya yoga, Kundalini yoga, and pranayama traditions [50]. Genes that changed expression by 30% or more after entering into higher consciousness were considered significant. For one participant, 1,688 genes changed expression (1,559 downregulated and 109 upregulated), and for the other, 608 genes changed expression (338 upregulated and 270 downregulated). The genes that changed in both meditators suggest a downregulation of metabolism and cell cycle processes, while genes related to the immune system, cell death, and the stress response were downregulated. 

Table 2 shows the various mind-body practices, summarizing the epigenetic modifications, their effect on the neuroendocrine-immune axis, and also mentioning their health benefits.

Table 2: Various types of MBP summarizing the key epigenetic modifications, effect on the Neuro-Endo-Immune Axis, and corresponding health benefits [51,52].

Epigenetics is critical in regulating brain development, cognitive and behavioral functions, aging, and neural plasticity, with these effects potentially being inherited transgenerationally [28]. Additionally, numerous epigenetic processes have been reported to play a central role in neurological disorders and pathologies [28], making epigenetics a promising target to halt or reverse neurological diseases and aging while promoting longevity and health [53]. Mind-Body Practices (MBPs) have shown a promising influence on neurobiological mechanisms, addressing brain function from illness to wellness [54,55]. Such practices have been found to impact neural networks both structurally and functionally, thereby regulating neuromodulatory activities [54,56]. Clinical studies have demonstrated that MBPs are effective in improving cognitive function, depression, anxiety, and symptoms of other chronic neurological health conditions [57,58]. A systematic review and meta-analysis of mindfulness meditation programs, including 47 randomized clinical trials with 3,515 participants, concluded that mindfulness meditation programs provided significant evidence of improvements in anxiety, depression, and pain [59]. 

A randomized study exploring the effects of a mindfulness-based program on elderly individuals revealed significant improvements in cognitive function. Interestingly, these individuals demonstrated increased expression of microRNA-29c present in neuron-derived exosomes in blood. Additionally, DNA methyltransferase 3 alpha, DNA methyltransferase 3 beta, and signal transducer and activator of transcription 3 expressions were significantly decreased in neuron-derived exosomes of the practitioner group. This implies that mindfulness-based practices (MBPs) have the potential to prevent neuronal loss and cognitive decline in the elderly by regulating neuronal miR-29c expression [60]. A pilot study on the effects of mindfulness-based interventions (MBIs) for patients with early-stage Alzheimer’s disease concluded that MBI training is effective in increasing the quality of life and preventing the worsening of symptoms in patients with early-stage Alzheimer’s dementia [61]. Another study following patients at risk for Alzheimer’s disease measured trait mindfulness, longitudinal cognitive assessments, and amyloid-beta and tau positron emission tomography scans. It concluded that trait mindfulness is associated with less cognitive decline and reduced amyloid-beta and tau in the brain in older adults at risk for Alzheimer’s dementia [62]. A randomized, controlled clinical trial on the effects of lifestyle changes, including the daily practice of meditation and yoga on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease, concluded that lifestyle changes may significantly improve cognition and function in patients with mild cognitive impairment or early dementia due to Alzheimer’s disease [63].

Moreover, lower expression of histone deacetylase genes (HDAC 2, 3, and 9) in peripheral blood mononuclear cells (PBMCs), as well as alterations in global histone H4 acetylation levels, were found in another study on mindfulness-based program subjects, representing a potential therapeutic effect in depression [14]. Another MBP, known as Quadrato Motor Training (QMT), which is a specifically structured walking meditation [64,65], was reported to influence neuroplasticity processes and modulate neurotrophins proBDNF and proNGF levels in saliva [66]. This was found to be associated with improved cognitive functions in practitioners [67]. Recently, a significant correlation between proBDNF and proNGF was also found post 3 months of QMT practice [68]. This likely represents a link between the cognitive and psychological outcomes of QMT-mediated increased neuroplasticity. 

It is noteworthy that BDNF, a widely expressed neuromodulator, is a critical epigenetic regulator in the brain [69]. It mediates neuronal survival, neuronal development, growth, and neural plasticity [51]. Epigenetic regulation, such as the modulation of histone deacetylase (HDAC) activity and microRNA expression, is crucial in maintaining neuronal health and function, and changes in epigenetic markers like DNA methylation and histone acetylation can influence gene expression patterns critical for cognitive processes and neuroplasticity. This emphasizes the potential value of MBP-derived epigenetic therapies in treating neurodegenerative diseases and enhancing brain health. 

Besides Quadrato Motor Training (QMT), multiple meditation approaches have been studied at the molecular levels [52,70-72]. A comparative study involving experienced long-term meditators and meditation-naïve subjects, using the methylation profiles obtained from circulating lymphocytes, identified differentially methylated regions, including those involved in neurotransmission. Among these, 14% methylation was observed in genes linked to neurodegenerative diseases [73]. Nuclear receptor family 4 group A member 2 (Nr4a2), which encodes a nuclear transcriptional regulator, was the most differentially methylated gene. Nr4a2 is known to be a critical regulator of neuronal differentiation, survival, and maintenance. Moreover, Nr4a2 is essential for neuronal development and maintenance of the dopaminergic (DA) system [74]. It would be interesting to examine the effect of meditation-promoted methylation of this gene in DA dysfunction-related disorders like Parkinson’s disease and other neurodegenerative disorders. Analysis of Nr4a2 methylation patterns may also serve as a valuable diagnostic marker for MBP-based therapies. 

In addition to meditation practices, MBPs like acupuncture have also been shown to influence the epigenome. A preclinical study on spontaneous hypertensive rats treated with manual acupuncture at the liver acupuncture point confirmed miRNA-339 upregulation in the medulla region of the brain [75]. MiR-339 has been reported to regulate Sirtuin 2 (SIRT2) gene expression in human and rat neurons. Since SIRT2 is involved in deacetylating histones, thereby influencing chromatin structure and gene expression, which plays a role in cellular aging and stress resistance, the data suggest that acupuncture may influence epigenetic changes [75]. It would be valuable to validate these findings further in human subjects. 

Collectively, these preclinical and clinical research studies indicate a promising interrelation between the neurological impact of MBPs and epigenomic modifications.

MBPs are also found to act through significant epigenetic mechanisms with immunological effects using epigenetic and functional genomics methods [76]. Using DNA microarray technology, the role of stress response pathways has been reported in various studies for disease, stress, and in the response to MBPs. In a study by [8], DNA samples from 20 individuals participating in an MBP protocol were evaluated with an epigenetic marker using an MSAP molecular tool to determine methylation status. The comparison of samples taken before, one hour post-, and 24 hours post-administration demonstrated significant changes from heterogeneous to homogeneous epigenetic profiles after treatment [77]. Other studies have found MBPs linked to pervasive effect sizes for immune function and inflammatory regulation alike, supporting the concept of systemic neuroendocrine-immune interactions [78] (Figure 1). 

Figure 1 (adapted from PMID:34588793, DOI:10.2147/JIR.S323356) Data point map of catalysts, inflammatory markers, and effect size of connection. Color of the circles identifies whether an inflammatory marker, anti-inflammatory marker, adjunct intervention, medication, or COVID-19 is being referenced. Blue connecting lines indicate a regulating effect from the catalyst to the marker. Brown connecting lines indicate a regulating effect from the catalyst to the marker. The thickness of the connecting line represents the relative effect size of the catalyst on the marker.

Similarly, the study by Marson et al., examines the impact of the movement meditation practice QMT on the psychophysical well-being and DNA methylation of repetitive sequences in healthy women aged 40 to 60. Improved search for meaning, reduced presence of meaning, and increased positive relations in QMT participants compared to controls revealed a reduction in automatic cognitive patterns. Significant methylation alterations in LINE-1 repeats and ribosomal changes linked to QMT suggest that such practices can enhance genomic stability, which is crucial for preventing genomic instability-related diseases like cancer, neurodegeneration, and premature aging. QMT may be useful in enhancing psychophysical health and DNA methylation patterns since correlations between methylation changes and psychological indices suggest a relationship between epigenetic and psychological changes [79]. 

Mindfulness and meditation practices have proven to be efficacious in reducing stress and improving general health, with wide-ranging implications for longevity and telomere length as a marker of human aging [80]. It is notable that long-term meditation results in changes in DNA methylation in certain sub-telomeric regions, especially within genes such as GPR31 and SERPINB9, which are related to telomere length. The age in this population did not significantly correlate with telomere length, which could explain a putative relationship between long-term meditation, epigenetic mechanisms, and changes in gene-specific DNA methylation of selected sub-telomeric regions [80]. 

A study examined the effect of a month-long meditation retreat on gene expression related to epigenetic regulation and immune function. Experienced meditators attending the retreat uniquely demonstrated altered gene expression, particularly downregulating the TNF pathway, which was not observed in the controls. These findings indicate that meditation retreats may impact inflammatory mechanisms that contribute to chronic diseases, suggesting therapeutic potential for experienced practitioners [76]. 

Skeletal muscles exhibit extreme adaptability to metabolic changes, with a strong capacity for regeneration driven by satellite cells. Locally, factors such as IL-6, produced during muscle contraction, could play a major role in mediating the benefits of exercise via stimulation of anti-inflammatory responses [81]. IL-6, produced during muscle contraction, can act as both a pro-inflammatory and anti-inflammatory cytokine, influencing muscle regeneration and adaptation, highlighting the dual role of exercise-induced epigenetic changes in muscle health. Exercise also induces changes in protein and mRNA patterns, DNA methylation, histone modifications, and microRNA content. Such epigenetic modifications play a key role in regulating gene expression and controlling muscle adaptation and function in response to physical activity [82]. 

Upon measurement of miRNA concentrations in the vastus lateralis muscle tissue of men after intense resistance training, a modulation of a panel of 30 miRNAs, including miR-133a, miR-206, miR-486, miR-378b, miR-146a, and miR-23a, was observed [82]. The most marked effects were observed two hours after exercise, with increased expression of miR-133a and miR-206 and decreased expression of miR-378b. Four hours after exercise, increased expression of miR-486 and miR-146a and decreased expression of miR-23a were observed [82]. Specific miRNAs, such as miR-133a and miR-206, are known to be involved in muscle differentiation and regeneration, while others like miR-378b, miR-486, and miR-146a play roles in muscle metabolism and inflammatory responses, showcasing the complex epigenetic regulation of muscle adaptation to exercise.

The endocrine system involves critical physiological processes through hormone-mediated signaling pathways that govern growth, metabolism, and reproductive functions [83]. Epigenetics forms an important bridge between genetic predispositions and environmental cues in regulating the responsiveness of the endocrine axis to both intrinsic and extrinsic stimuli [84]. Epigenetic changes exert long-lasting effects on endocrine function, although a decline in sensitivity is observed with advancing age [84]. 

Evidence indicates MBPs modulate hormone levels, but studies are currently limited. One systematic review and meta-analysis on MBPs for patients with type 2 diabetes concluded that MBPs are strongly associated with improvements in glycemic control in patients with type 2 diabetes [85]. Meditation has been reported to exert its positive effects through the endocrine system, mainly influencing the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-thyroid axis, the renin-angiotensin-aldosterone system, and energy homeostasis [86]. The most well researched of these dynamics is the influence of MBPs on Hypothalamic-Pituitary-Adrenal (HPA) axis, especially through meditation, which is known to affect stress response through epigenetic regulation of glucocorticoid receptor genes. 

A cross-sectional Chinese study reported that 10 years of Tai Chi practice might widely affect endocrine function, including the pituitary-thyroid system and the pituitary-gonad system, and may strengthen pituitary metabolic reaction among elderly men. However, the conclusion of this study lacked proper validations [87]. This preliminary evidence holds promise but warrants a detailed investigation into the epigenome connection. 

Besides conventional endocrine organs, the gut microbiome can also be considered an endocrine organ due to its metabolic capacity to create and modulate multiple complexes that influence distal organ functions [88]. MBPs are well known to impact metabolism and gut functions. Aerobic exercises such as yoga elevate parasympathetic tone and may affect gut-brain connectivity. While there are positive effects of yoga on gut microbiota diversity and psychological health, empirical research on the benefits of yoga to vagal transmission and microbiome regulation is scarce [89,90]. The vagus nerve, a key component of the gut-brain axis, can be influenced by both epigenetic expression and directly through MBPs, with potential implications for how MBPs like yoga and meditation influence gut health and systemic well-being. Additionally, the modification of gut flora by yoga and exercise may contribute to stress management and mental health. Traditional yoga cleansing techniques, such as Dhauti and Vasti, might have physiological benefits in maintaining gastrointestinal homeostasis and controlling oxygen dynamics [91]. 

In a randomized controlled experiment, simplified Tai Chi practitioners had higher levels of high-density lipoprotein cholesterol and lower triglyceride levels compared to collegiate basketball players. The results of the Tai Chi intervention were significant, showing increased diversity of gut flora, suggesting an association between exercise and improved digestive ambiance. Additionally, diastolic blood pressure in the Tai Chi group was reduced compared to controls. These results indicate how Tai Chi can enhance metabolic and cardiovascular health indices and increase gut flora diversity [90].

Recent research has shown how the gut-brain axis can be influenced by gut microbiota in its effects on mental health. One study examined changes in gut microbiota and metabolite profiles following a serious meditation program known as Samyama, combined with a diet rich in raw foods and vegan components. Participants underwent metabolomics analysis and sequencing before, during, and after the program. Beta diversity showed remarkable changes after Samyama, reflecting changes in microbial composition, although there were no changes in alpha diversity. Changes in short-chain fatty acids and increased amounts of beneficial bacteria were observed, indicating possible positive effects of the intervention on gut health and psychological well-being [91]. A summary of the impacts on gut microbiome symbiosis on physiological effectors is provided in table 3. 

Taken together, MBPs hold promise for regulating the endocrine system as well as the gut microbiome axis. However, increased research evidence on the inter-relationship between epigenetic mechanisms and the endocrine effects of MBPs would be valuable for developing therapies most beneficial for the health and well-being of diverse clinical populations.

Table 3: Summary of effects of Mind-Body Practices on Gut Microbiome Symbiosis causing physiological and health benefits.

Epigenetic impact of mind-body practices on neuroendocrine-immune crosstalk and integration 

As mentioned in the above sections, MBPs altering epigenetic marks have a significant impact on neurological, endocrine, and immunological functions, and together these interactions have the potential to affect epigenetic factors of longevity and quality of life. Since the neuro, endocrine, and immune systems are interconnected and work mutually, an intriguing notion arises regarding the effect of MBPs in modulating such crosstalk. Common regulatory molecules, such as steroids, neuropeptides, cytokines, and neurotransmitters, elaborate on the complex interplay between the nervous, endocrine, and immune systems.

The neuroendocrine-immune axis primarily operates through the Hypothalamic-Pituitary-Adrenal (HPA) axis, the Autonomic Nervous System (ANS), inflammatory pathways, and neurotransmitter systems. These pathways are related to cellular senescence, neurotransmission, lipid and glucose metabolism, immunology, and inflammation [11]. 

Recent research in Nature Cell Biology show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via the downregulation of its ubiquitin-dependent degradation [92]. While p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment, which can contribute to an increased burden of senescent cells, treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors leads to the elimination of PD-L1 and p16-positive cells. This highlights the potential for influence of p16 regulation of PD-L1 protein stability to improve immunosurveillance of senescent cells and improve the age-inflammation cycle. Critically, meditation and other MBPs have been linked to improved p16 regulation, heart rate variability, and telomere health, all major factors of longevity and mortality [93].

The activation of the HPA axis, under the control of Corticotropin-Releasing Hormone (CRH), plays a crucial role in maintaining homeostasis during inflammation or infection, and epigenetic modifications such as methylation and histone modifications can regulate key expressions involved in the HPA axis, influencing stress responses and neuroendocrine functions [94]. These mechanisms affect the brain through several pathways: binding to receptors at the blood-brain barrier, active transport, penetration through circumventricular organs, central synthesis, and signaling via peripheral nerves. The central expression of cytokines and their receptors in the hypothalamus and anterior pituitary modulates neuroendocrine responses, showing a complex interplay between immune and hormonal signaling [95-97]. Several pieces of evidence suggest that MBPs like yoga and meditation reduce stress by modulating the HPA axis, although advanced research on the epigenetic correlation remains to be addressed [98,99]. Further, cytokines and their receptors are subject to epigenetic regulation, which can impact their expression in the hypothalamus and pituitary, thus modulating immune and hormonal signaling.

Thus, the effectors of this neuroendocrine-immune axis can serve as promising targets for advanced treatments. Identifying MBPs that affect this axis by modulating the epigenome would aid in providing comprehensive health benefits. These impacts can be brought about independently or synergistically to enhance health and well-being.

Mind-body interventions could have a significant clinical and public health benefit; however, several outstanding questions require further research and legislative support. Clarity in foundational understanding is critical for developing more targeted and effective interventions. There is an urgent need for studies with larger and more diverse sample sizes. Variability in study designs, including differences in MBP techniques, duration, and intensity of the interventions, complicates the synthesis of findings across studies. There is also a lack of longitudinal research that can track the stability and long-term effects of epigenetic changes induced by MBPs. Utilizing advanced bioinformatics tools to analyze epigenetic data can help in distinguishing subtle changes. Moreover, there is a lack of collaboration across multidisciplinary teams, including experts in neurobiology, immunology, endocrinology, and psychology, which is essential for standardizing the research design of future studies. 

As there may be multiple mechanisms of change underlying efficacious treatments for mental health conditions of various etiologies, identifying the effects of various treatment components could help refine, optimize, and individualize mind-body interventions to maximize affordability, time, and accessibility. Studies integrating neuroimaging, biological, or physiological measures are needed to identify the psychobiological mechanisms through which mind-body interventions improve mental health.

Technological constraints impede a comprehensive analysis of histone changes, DNA modifications, and the participation of non-coding RNAs in epigenetic research. Most of the current work is descriptive, which does not offer a comprehensive understanding of epigenetic mechanisms and their impact on gene regulation [100]. Epigenome editing instruments pose significant challenges in the accuracy, accessibility, and dependability needed to comprehend the dynamic interactions among chromatin architecture, gene expression, and epigenetic states. Overcoming these challenges is critical to bringing epigenetic technology closer to clinical application. 

Future research should focus on less explored practices such as Tai Chi and Qigong. Meditation practices other than mindfulness should be studied more extensively, and their corresponding epigenetic mechanisms on the neuro-immuno-endocrine axis should be investigated. The use of objective biomarkers may also prove feasible in identifying the subjects who may benefit most from specific interventions in line with precision medicine and identifying mechanisms of treatment. Findings from a meta-analysis of exercise interventions suggest that moderate-intensity exercise results in greater augmentation of endocannabinoid concentrations, which is a suggested biomarker of anxiolytic and antidepressant effects. 

Many mind and body therapies have both physical and psychological components. There is also an overlap between the psychological and nutritional categories in the form of mindful eating. Additionally, integrating MBPs with herbal products, which have their own potential epigenetic effects, offers a promising area for investigation. It is important to evaluate how these therapies in multicomponent interventions formulate a “super integrative approach” for synergistically enhanced therapeutic benefits. 

Novel expressions, such as "gut-brain axis" and "Ayurnutrigenomics," emphasizing the link between physiological and psychological components, symbolize this integration and lay the basis for Phytoneuroendocrinology, which studies the possible influence of phytochemicals on neuroendocrine responses.

In this section we provide an integrative framework that can serve as a quantitative analysis of the state of health of an individual in real time and a potential for following its evolution over time, especially in the context of aging. 

The human gene pool accounts for roughly 30% of disease risk while the environment accounts for the other 70%. Environment impacts health and disease through the effects vitalizing and toxic stressors respectively that act through the allostatic stress response, comprising the hormonal and autonomic branches of the stress response and their intersection with the immune system. Resilience to stress is mediated by this response. Moderate intensity physical, mental (cognitive and emotional) and social stressors to which we are resilient allow our physiology to restore balance and stability in the sense of maintaining metabolic homeostasis (energy, oxidation/redox and acid base within narrow physiological ranges).  

Homeostasis means resistance through change, while allostasis means stability through change. We maintain homeostasis through allostasis, that is, the allostatic stress response. When the intensity and duration of the stress exceeds our metabolic resilience (in the sense of oxidation stress overwhelming the antioxidant systems thus impairing the capacity to meet the high energy demands of the stress) and pushes through an energy barrier, our physiology goes through a period of instability and metabolic decline before eventually coming to a new physiological stability. This newly arrived balance of metabolic interactions represents an incremental advancement in biological age which reduces the ability of resilience to subsequent stressors (physical, mental and social), which in all cases intersects in and amplifying the emotional fear centers of the brain, predominantly the amygdala, while diminishing the executive functions of the prefrontal cortex as well as human qualities of humility, gratitude, empathy and compassion. 

The mind, body, brain and behaviors in response to stress, mediated by the hormonal endocrine, autonomic nervous system and immune systems are indeed intricately, deeply and inextricably interwoven. As a system they become bidirectionally subsumed into a self-amplifying matrix including the gut microbiota composition, diversity and circadian biology that, taken together, dictate the states of physical health or disease. Behaviors, most prominently, diet, exercise and sleep dictate the health of our microbiota, and in turn us, the host of the microbial residents in our gut. The epigenetic modifications of our host genes may be induced by ancient Ayurvedic and Traditional Chinese Medicine (TCM) practices including yoga, tai chi, qigong, meditation, music, dance, aroma and art therapies, guided imagery, pilates, hypnosis and other mind body coordination training exercises can have robustly favorable effects on psychological, physiological and physical wellbeing as well as metabolic and chronic disease as elaborated on above in this paper. 

While the oldest, dating back as far as 5,000 years, and present widely practiced medical system is Ayurveda (ayus meaning “lifespan”, and veda meaning “knowledge”), Traditional Chinese Medicine remains another ancient medical system that remains popular today. Central to TCM is the notion of “Qi” , a vital life force of energy flow through the body that is necessary for a healthy lifespan. Another central concept of Qi is balance, or yin yang, to represent the opposing and complementary forces that maintain the body’s life force. 

Modern day equivalents of the yin yang idea of Qi, opposing and complementary vital forces of energy flow and the state of health, are applicable to the notion of ‘redox’ in the context of metabolism, including energy production itself. 

Redox is a foundational metabolic parameter of biology and IS the most fundamental circadian function demonstrated in ancient Cyanobacteria. Redox refers to oxidation and reduction of chemical reactions in and between cells involving the transfer of electrons between atoms of molecules in tissues of the body. The molecule that receives an electron is reduced while that which loses one is oxidized. In fact, extraction of electrons from macronutrient dietary sugar and fats become the energy source that allows the transfer of energy harnessed in food to the biological currency of energy, or ATP, that can be utilized to power the work of physiology. The final pathway of the ATP energy producing machinery in the powerplant mitochondria present in our cells is the electron transport system embedded in the Inner Mitochondrial Membrane (IMM). Here, electrons transferred sequentially across a horizontal conveyor belt type arrangement of molecular complexes is made possible by opposing complementary forces creating redox potentials, the relative difference in electron binding and transfer (accepting and donating) affinities from one complex to the next. This process of electron flow generates a perpendicular proton-motive force that drives protons vertically across the IMM, thus generating the electrochemical gradient that is released at the end of the system of redox chain reactions where the energy is captured in the formation of molecules of ATP. 

Molecular oxygen indeed is the ultimate electron acceptor where it also combines with the protons as they move back across the IMM, hence to form water. The complete metabolism of sugars and fats in their conversion to ATP releases CO₂ and H₂O as the biological exhaust products. Hence, critical to all terrestrial beings, O₂ is essential for energy production that makes life on land possible. 

Redox and energy as foundational metabolic pillars of all living systems are inextricably interwoven and synchronized. This is illustrated with an amazing level of similarity between the long logarithmic Nernst (quantifying redox) and Gibbs free energy (quantifying energy) equations, respectively. While the flow of redox drives energy production, it also drives its utilization as well as the coupling of energy production and utilization. This is the modern day explanation of qi, the sine qua non of health, wellness and life. 

It is well known that bacteria and other microbes cause infections that can get quite serious and even be life taking. However, like perhaps all things this instantiates pleiotropic effects of nature as being both toxic and beneficial. It’s ironic that ancient Proteobacteria became subsumed into the cells of fish to become the major energy-producing machinery carrying mitochondria, which allowed the evolution of land animals and ultimately human beings. Moreover, it’s the microbial composition and their gene pool in the human large intestine that lies at the core of human health and disease. This is briefly described below. The other pinnacle electron transferring example of what makes human life and wellbeing possible yet also takes it away, is oxygen.  

Another example of the inseparable relationship of energy and redox, or oxidation-reduction balance, is exemplified in the generation of oxygen derived highly reactive free radicals in the deeply interwoven process of energy production. These free radicals promote cell signaling, such as the 1700 insulin signaling processes that in turn for example promote the processes of energy production, cell growth and replication. However, when dietary intake exceeds the function and robustness of energy producing machinery, electrons spill off the metaphorical conveyer belt of the electron transport chain, combining with oxygen to generate an accumulation of free radicals.  

Central to the ideas of Qi and yin yang is balance, for example balance of dietary energy intake and its utilization, and balance of the totality of oxidative free radical burden to the antioxidant capacity to neutralize it. Perfect balance would be the metaphor of a perpetual motion machine or an ageless being. The imbalance of oxidants and antioxidant systems is the very basis for the aging and accelerated aging process as it degrades the body’s exquisite and beautiful organizational perfection. In point of fact, the oxidation of tissues is like the rusting of iron. 

The epigenetic mechanisms induced by ancient Ayurvedic and Traditional Chinese Medicine practices may be direct or indirect, the latter by influencing the allostasis components of the stress response, circadian and microbiota biology. It should be underscored that woefully under recognized is the role of the composite microbiome with a 3.3 million gene pool capacity to produce proteins that express or silence with enormous dynamic complexity, the rudimentary human genome of only 19,000 genes (compared to a worm w 90,000 genes (30,000 genes if we omit redundant genes), or a kernel or rice w 250,000 genes (40,000 genes if we omit redundant genes)). Our microbiome produced proteins play our host genome like a piano, allowing us to adapt to short term stressors favorably by turning on or silence genes via its interactions on micro (non-coding) RNAs embedded in the DNA, histone modifications and DNA methylation in a way that would protect against vulnerable gene traits (e.g. susceptibility to heart disease or diabetes) in the face of atherogenic challenges/stressors such as low HDL and high triglycerides that are key contributors to atherogenic LDL as well as to endothelial dysfunction evolving to hypertension impairing delivery of glucose to skeletal muscle causing a key tissue insulin resistance and compensatory hyperinsulinemia which are well known but under-recognized powerful drivers of cardiovascular disease, cancers and Alzheimer’s, as well as diabetes itself. 

Underpinning imbalance of redox, i.e. oxygen derived free radicals predominantly generated in the process of energy production (exaggerated production of ROSs due to mitochondrial dysfunction as a result of insulin resistance and impaired peroxisome proliferator receptor (PPAR) gamma that impairs mitochondrial biogenesis and its robustness and capacity to produce energy efficiently (i.e. consuming high volumes of oxygen to produce a given amount of biological energy currency of ATP), ultimately overwhelming the antioxidant potential, thus resulting in oxidative stress; this in turn promotes inflammation through a feedforward self-amplification of central hub transcription factor (NFkB) acting on genes to produce many inflammatory cytokines that interfere with insulin signaling. Noteworthy is that agonists of PPAR gamma include the currently available insulin sensitizing pharmaceutical, pioglitazone, approved for the treatment of diabetes. This drug, and agents of the same class will undoubtedly in the future have many indications for chronic disease prevention and treatment not yet formally studied. 

While human beings evolve traits over generations and many years, our microbiome can adapt much quicker (bacteria reproduce in 20 minutes). Thus, the microbiome induced proteomics indeed is fertile and promising fodder for elucidating mechanisms for how ancient Ayurvedic and TCM practices promote psychological and physical health and well being. 

We maintain genes with predispositions which we inherit from our parents that persist over generations despite their vulnerabilities to heart disease, diabetes, etc, because these same genes inextricably code for many favorable adaptive effects, depending on how they are expressed, whichever is more adaptive for the challenges faced at a given time. Hence, only a richly diverse and robust healthy symbioses of gut microbiota can do this. Thus personalized healthcare strategies targeting the epigenetic landscape will be powerful, and our MFL provides the blueprint to optimize the tools of AI and bioinformatics to achieve this epochal watershed entelechy. 

The human body, as any biological system, is intrinsically and uniquely nonlinear and unpredictable, leaving only a very small component of medical practice relegated to science. 

The “core 4” weaknesses of current medical practice include: 1) over reliance on the art of empirical observation; and 3 ways of masquerading art as science: 2) over reliance on population studies rooted in the ‘art’ of statistical analysis; 3) compartmentalization of medical specialties and diagnostic labels with band aid solutions; 4) nature of hypothesis in medicine which seeks to be correct at all costs vs in the century older more mature discipline of physics which seeks to find flaws that can be used to asymptotically move the hypothesis closer to absolute truth. Taken together, the 3 weaknesses masquerading as science explain why ~50% of standards of care are wrong, in the sense of being unconfirmable by repeated proof of concept studies. The future of medicine should aim to advance a more bolstered science beyond reductionism to better predict biological emergence.

To this end, we introduce the Metabolic Fitness Landscape model (MFL) [101-103], a precision, personalized and dynamic scale of medicine that integrates insights from all disciplines of science and Medicine, and is a blueprint for algorithms of AI. It uses evolving fields of both bioinformatics (or big data) and healthcare AI to open the door to health- and life-spans approaching 120 years for the majority of the world’s population. Inspired by its hugely successful analogue in physics, the Fitness Landscape, a Nobel Prize worthy concept that’s already been applied to physiological systems in the context of genetics and evolution, where it predicts animal survival in changing environments. Analogously, the MFL uses metabolic data, 100’s of thousands of them. The combinatorial space of all their possible interactions also with an immense number beyond the computational barrier, however computer systems are capable of simplifying complexity to a manageable few simple rules, patterns of data, that predicts biological phase transitions between health and disease. These patterns may be considered vital signs, not just in the sense of BP, HR or T, but in the sense of any pattern that predicts a biological phase transition. 

Imagine a metaphorical mountainous terrain of connecting peaks and valleys that describe metabolic decline over the lifetime of an individual whereby maximum human health occurs by the age of thirty when biological and chronological age are the same and the fitness terrain is at its highest altitude. On the other end of the landscape maximum human lifespan approaches a biological age of 120, which is always the biological age of a vital organ system at the time of death, whether that occurs at a chronological age e.g. of 60, 80, 100 or 120. As the terrain dynamically plots an individual’s metabolic fitness over a lifetime, the altitude declines with biological age until it reaches ground level which is tantamount to death.  

The way it could work in practice is as follows. A patient would have a chip that contains their prior updated MFL data. The physician would obtain a fresh standardized profile of a high volume personalized metabolic biomarkers including proteins, lipids, genes, hormones, microbiota signature, transcriptional regulators, immune system, inflammatory and protein, lipid and DNA markers of oxidative stress and other products of metabolism obtained from mucosal scrapings, blood, urine, sputum and fecal specimens. This data would be integrated into an AI algorithm using the MFL as a blueprint juxtaposed to metabolic data of 100’s millions even billions of personalized metabolic profiles worldwide with healthy states and every conceivable subtype of disease to plot the trajectory of their newly updated fitness terrain. It also integrates therapeutic and preventative interventions that had proved successful with similar metabolic profiles as theirs. The physician would take this information and, use the intuitive intelligence based on experience, together with a balanced understanding of the interventions and how they match the unique qualities of the patient, their fears, expectations, hopes, biases, etc. to navigate a semi empirical management of the patient’s condition. 

Here’s what an application of the MFL looks like using a single physiological parameter of bodyweight for simplicity and overeating as a control parameter. This is a relatable way to understand some key features of the mountainous terrain. The valley between mountains is a stability zone that may be a bodyweight set point. There exists a threshold of criticality just before reaching the top of the mountain, a predictive feature of the PFL, whereby up to that threshold simply stopping the driving stress of overeating is all that is required to restore the baseline stable state. If overeating however persists, and the mountaintop is reached, this is an instability zone where you cannot get proper footing and continue to gain weight even after overeating stops, until you fall off the cliff on the other side of the mountain into a new valley at a lower fitness altitude with a higher body weight set point and e.g. new onset of high blood lipids and other markers of insulin resistance (e.g. blood pressure, plaque buildup in the blood vessels that feed the heart). 

While the mathematical precision, personalized and dynamic scale of medicine will require a scientifically integrated cultural shift and therefore a longer time horizon, there is also a qualitative lifestyle version of the model that empower people in the immediate term to maintain a more energetically vitalizing life with abounding wellness, health and greater longevity. Society has long recognized that poor lifestyle behaviors can promote the premature onset of many chronic diseases while healthy and more socially integrated lifestyles, albeit unique to the individual, prolongs health- and life- spans. Yet to date there has never been a formalized model that puts this into place. The MFL model provides a 5x5 Rubik’s cube of lifestyle medicine. It’s a quintet of quintets of lifestyle behaviors that, like the quantitative model, invokes the notion of building metabolic resilience to toxic stress. It does this by employing and pairing the optimal quantity, quality and timing (the time of the day, the frequency and duration) of diet, sleep, physical, mental and social activities.

The attitudes of the West (in US /Europe/Canada) are individualistic motivated by goal oriented accomplishments and pride, while attitudes of the East is a sense of collective belonging with strong social bonding and support systems, families, communities and networking, that spreads stress over a wider mass, reducing toxic stress and increasing resilience. The alternative philosophies of the East and the West are in truth complementary and synergistic. On the one hand the West encourages vitalizing stressors of individuals, including emotionally, cognitively. socially and physically, that evolve strength and resilience in the different aspects of character. This pushes through energy barriers that allow reaching mountaintops where a dynamic balance of metabolic interactions form new healthier symmetries to replace the broken less resilient and healthy symmetries along the prior metaphorical mountainside. Taken together, this symbolically equates to a reversal of the biological aging process, narrowing the gap to chronological age.  

This pattern contrasts with the typical metabolic decline that occurs over a lifetime with each successive mountain we climb is fueled by toxic chronic exaggerated stress that pushes through energy barriers of a higher slope and greater resilience than the next mountain we encounter at a lower altitude trough with a shallower slope. The landscape is shaped by dynamic balances of metabolic interactions that occur on mountaintops from new but weaker symmetries than the previously more resilient broken ones. This represents the aging process with each successive trough we hit at lower altitudes equating to advancing biological age and greater distance from the younger chronological age. On the other hand, the Eastern philosophical culture of social and physiological integration invoking the Ayurvedic and TCM strategies emphasize maintaining balance within the body to minimize stress. 

It follows that the integration of two very different but complementary cultural philosophies of the East and West, by symbiotically joining life forces represent a synergistic, interwoven and optimal strategy for finding new mountains to climb, to slow the arrow of time. Through the MFL model, we can change the future of medicine and medical training to predict and prevent disease before it is too late. We wish to invite the global scientific and medical communities to join me on this transformative journey of wellness as a next evolution of, and scientifically integrated cultural shift in medical practice and healthcare delivery. 

A fundamental molecular level sine qua non of metabolic decline and chronic disease is the uncoupling of the initial stage of glucose metabolism from its complete combustion inside the power-plants, or mitochondria, of cells. Since the mitochondrial phase of energy production accounts for the vast majority of the energy produced per unit time, defining metabolic rate and is a measure of mitochondrial health. This is the basis for the prototypical exercise stress test employed in cardiology, as an indirect measure of metabolic rate which is compromised in the setting of coronary artery blockage, obstructing oxygen flow to the heart. In the future of medicine stress testing techniques in all specialties will be developed to assess tissue specific measurements of metabolic rate and metabolic efficiency (the ratio of oxygen consumed to energy produced, the P/O ratio). While a higher metabolic rate is not tantamount with metabolic health, i.e. of mitochondria and the function of the metabolic machinery carried in it, it is when accompanied by high metabolic efficiency with a high P/O ratio. We encourage the smart and creative people in the audience to join this transformative journey and use this mechanism to patent unique stress testing applicable to other diseases. A positive stress test in this sense is illustrated on the MFL by a reduced slope of the mountainside while chronic activated branches of the stress response accelerate the pace of biological aging relative to chronological age translating to a MFL terrain with a declining altitude of the terrain.  

The light/dark cycle provides an organizing framework for our metabolism and physiology, orchestrated by molecular clocks, which are astonishing evolutionary microcosms of the earth’s rotation around its own axis. These molecular clocks synchronize the light dark cycle with circadian behavioral patterns including fasting-feeding and sleep-wake around which the metabolism of energy production and utilization fuels cognition, hormonal, nervous system and immune system activity, and digestive processes, and ultimately synchronization with microbiota reproduction and metabolism. Desynchronized circadian physiology within and between tissues, accompanying chronically activated branches of the stress response, along with disturbed Microbiota composition and diversity inextricably together lies at the core of metabolic decline, with important links not only obesity and diabetes, but to all the chronic diseases of aging including heart, vascular, Alzheimer’s diseases and cancer.

The integration of epigenetics with mind-body practices (MBPs) could offer exciting new routes for improving general health and well-being. The neuroimmunoendocrine axis is positively influenced by MBPs through the mediation of epigenetic marks, impacting gene expression, brain function, immunoregulation, and hormonal balance. The interaction between MBPs and epigenetic processes underscores the practical importance of these interventions for fostering mental and physical well-being. Moving forward, there is a need for more investigation to fill the gaps and address the complexities in understanding epigenetics within the context of MBPs, particularly by exploring less-studied methods. Ultimately, there is potential for improving individualized MBP therapies and optimizing personalized healthcare procedures through the use of epigenetics. 

MBPs like yoga and Tai Chi help in improving gut flora diversity, ultimately leading to better mental and physical health. The modulation of the gut-brain axis through these practices positively impacts physiological and psychological health. However, there are several challenges in establishing causality and understanding the long-term effects of MBPs on epigenetic changes. Future studies should focus on rigorous, standardized study designs with varied samples and must investigate less explored MBPs. The integration of MBPs should be investigated for synergistic therapeutic benefits. Overall, advancing our understanding of the epigenetic impacts of MBPs could lead to innovative, personalized interventions for a range of health conditions. The introduction and implementation of the MFL in the context of general healthcare promises to lead to major improvements not only in the average lifespan, but perhaps more importantly, the healthspan in our modern society.

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