Heritability of MDD is approximately 35% [56, 57]. The specific genes that are causal or increase the risk for the development of depression remain unknown. Numerous susceptibility genes have also been implicated, but none has yet been definitively established as a bona fide depression gene. Most of the known genes interact extensively with the gene pathways associated with aging, stress, inflammation, and nutrition sensing pathways. Risk of MDD is highly polygenic and multifactorial, and it is possible that virtually all genetic risk factors have individually small effects [58].

The biological and environmental factors together determine the events that happen in one’s life, and the impact varies depending on the life stage of the person. The peak prevalence of MDD is seen in adulthood. Environmental and social conditions are increasingly stressful, and susceptibility to stress varies across the population. Events during early life and childhood also contribute to the events in adulthood. Stress, in its various forms, is a major determinant in the causation of MDD.

Unhealthy lifestyles are associated with MDD. The key factors associated with unhealthy lifestyle are often referred to as “anthropogens” (or “…man-made environments, their by-products and/or lifestyles encouraged by these, some of which may be detrimental to human health”) and include high-calorie diet, lack of exercise, abnormal sleep patterns and sexual behavior, unhealthy habits like smoking, alcohol consumption, and abuse of drugs, medication, and modern technologies [59]. These factors predispose to stressful events.

Early epidemiological research centered on traumatic events such as such as loss of employment, financial insecurity, chronic or life-threatening health problems, and exposure to violence, separation which might be temporally associated with MDD. More recent research, however, has centred on childhood exposure as a precedent for MDD later in life [60]. These incidents include physical and sexual assault, psychological deprivation, and exposure as a result of death or separation to domestic violence or early separation from parents, with strong evidence of a dose-response interaction between the intensity of adverse life events and the risk, severity, and chronicity of MDD [5].

DNA damage may represent a common pathophysiological mechanism in depression that increases the vulnerability to accelerated aging in MDD. Accumulation of genetic damage throughout life is one the common denominators of aging [62, 63]. Genetic lesions resulting from extrinsic or intrinsic damage are extremely complex and include point mutations, translocations, chromosomal gains and losses, shortening of telomeres, and gene destruction induced by virus or transposon integration. These lesions are associated with errors in the complex network of DNA repair mechanisms [69]. The specific mechanisms for maintaining the appropriate length and functionality of telomeres, and those for ensuring the integrity of mitochondrial DNA (mtDNA) are found to be disrupted [65, 66]. The literature provides evidence for accelerated biological aging in major depressive disorder, as indicated by shorter telomere length [67, 68].

Several papers have documented connections between depression and oxidative stress (OS). Increases in oxidative damage and modifications in the ETC complex I in the prefrontal cortex of depressed patients were documented by Ben-Shachar and Karry [69]. Other researchers noted decreased levels of antioxidants and antioxidant enzymes in MDD [70]. The primary source of ROS is mitochondria, which play important roles in cell signaling and homeostasis under normal conditions. In the oxidative phosphorylation pathway, ROS is produced; however, mitochondria generate protective factors in normal physiological conditions that can neutralize harmful free radicals [71, 72]. Endogenous and exogenous causes such as smoking, excess alcohol intake, electromagnetic radiation exposure, cancer, xenobiotic exposure and psychological stress are attributable to supraphysiological ROS levels [73]. Even ROS levels below physiological limits are detrimental to normal cellular activity, and it is necessary for cell survival to preserve OS at physiological levels. Macromolecular damage, including harm to DNA and telomeres, is caused by increased OS. Signal transduction and gene transcription are both impaired by genome-wide hypomethylation and gene-specific hypermethylation, inducing epigenome-specific changes [74].

Oxidative stress-induced mitochondrial dysfunction changes intracellular metabolism and can damage both nuclear and mtDNA. The level of resistance to stress or “physiological reserve” of mitochondria may explain the difference in the clinical appearance and seriousness of the disease. Mitochondria reproduce the energy requirements of particular intracellular microenvironments and react to them [75].

One major characteristic of MDD is the uncoupling of circadian rhythms [76]. This leads to disruptions in the incorporation of melatonin levels that control the circadian rhythms in relation to Zeitgeber, a normal rhythmic mechanism that serves as a guideline in the modulation of circadian rhythms of the body such as light/dark cycle, seasons in a year, and social experiences. Circadian rhythms are related to the increase in endogenous melatonin secretion at night. Melatonin modulates circadian rhythms through signalling pathways linked to the MT1 and MT2 melatonin receptors [61, 77]. Melatonin has recently been reported to increase the expression of the clock genes Per1 and Per2, which play a crucial role in resetting the circadian clock [78]. There is a decrease in plasma levels of melatonin in MDD patients [70]. Depressed patients show disruptions in the rhythm of melatonin secretion, and melatonin may increase the quality of sleep in these patients. The suprachiasmatic nucleus (SCN) regulates melatonin secretion, and elevated melatonin receptor concentrations exist in the SCN. Its suitability as a medication is limited because of the low half-life of melatonin [79]. Pharmacological treatments with agomelatine, a prolonged-release melatonin, have shown antidepressant benefits with a distinct 5-HT2C receptor and melatonin receptor agonist (MT1/MT2) selective antagonist profile [80]. In addition, in brain regions such as the hippocampus and prefrontal cortex, agomelatine is able to strengthen neuroplasticity processes and adult neurogenesis [80]. Mind-Body Interventions (MBIs) have also shown improvement in melatonin and circadian rhythms in clinical settings [81]. These findings highlight the importance of circadian rhythms in neuroplasticity and depression therapy.

Many studies have found that stress-related improvements in inflammatory and glucocorticoid signaling are connected to sufficient functional changes in several brain networks [82]. Indeed, MDD neuroimaging experiments have reported anomalies within the affective-salience circuit, the medial prefrontal-medial parietal default mode network and the fronto-parietal cognitive function system in either stimulation or communication.

The HPA axis is among the most researched biological systems in MDD [83]. Several researches concluded that cortisol levels were raised, with a moderate effect size in patients with MDD [84]. In these patients, HPA variations are related to diminished cognitive performance [85]. In addition, multiple experiments have prospectively demonstrated that elevated cortisol levels are a contributing factor in at-risk populations for subsequent MDD [86]. Meta-analyses in the past have confirmed that cortisol levels have risen in patients with MDD [87]. Higher levels of cortisol are correlated with reduction in the size of the hippocampus [88]. Finally, a review using evidence from a survey in primary care involving $>$ 370,000 persons found that synthetic glucocorticoid medication is correlated with an elevated risk of suicide (approximately sevenfold), MDD (approximately twofold) and other significant neuropsychiatric conditions, even though the underlying medical condition is regulated.

Same authors have also reported the occurrence of severe neuropsychiatric outcomes including depression following discontinuation of long-term glucocorticoid therapy [89]. Moreover, the central hormones regulating cortisol levels are also shown to be dysregulated in MDD. For example, increased levels of corticotropin-releasing hormone in the cerebrospinal fluid (CSF) have been shown in patients with MDD.

The immune system is an essential part of the mechanisms of physiological stress-sensing and interacts directly with the major integrative systems of the body [90]. A large body of evidence from animal studies has supported the role of peripheral immune dysfunction and neuro-immunological mechanisms in MDD. These models have also provided intriguing insights into how peripheral cytokines can affect brain circuits, behaviour, and mood, directly and indirectly. Through the blood-brain barrier, peripheral cytokines can be transported to act directly on CNS-resident cells, including astrocytes, microglia, and neurons [90]. In addition, inflammatory signals can be transmitted to the CNS through cellular mechanisms (peripheral immune cell infiltration of the CNS) or via vagus nerve (‘inflammatory reflex’) signalling. Animal models have shown that these pathways converge to modify molecular programmes (such as receptor expression), neurogenesis and plasticity in the CNS [90]. Clinical observations indicate that similar inflammation mechanisms may also be relevant to patient development of MDD. A population-based study, has shown that both previous serious infections and autoimmune diseases increase the risk of subsequent MDD development [91]. Finally, MDD patients display elevated serum cytokine levels, such as TNF-alpha and IL-6, as confirmed by meta-analysis [92]. There was an increased gene expression of IL-6 signalling in MDD patients relative to healthy controls [93]. A few prospective studies have also shown that increased IL-6 levels in childhood dramatically increase the likelihood of developing MDD in adulthood [94]. Neuro-inflammation and microglial activity in the CNS of patients with MDD have been documented in recent research using PET imaging as well as post-mortem brain tissue analysis [95]. Finally, a potential role for inflammation in MDD is also supported by clinical trials of non-steroidal anti-inflammatory drugs (NSAIDs), reviewed in a meta-analysis [96].

The effects of food consumption and metabolism on depression were studied. Previous research has shown that appetite and satiety can reward exposure to gauze, and diet plays a role in controlling actions [97]. The melanin-concentrating hormone (MCH) nerve cells spread from the lateral hypothalamus to the limb system, including the NAcc. They predominantly carry out signal transduction that encourages appetite [98]. Mice lacking melanin-concentrating hormone receptor 1 demonstrate increased heart rate associated with altered autonomic activity [99]. Antidepressant effects in mice demonstrated a complete decline in MCH-induced signal propagation and MCH antagonism in the NAc [100].

Ghrelin can produce antidepressant effects in depressed patients with poor appetite, in contrast to the depression-inducing effects of MCH [101]. In animals, metabolic status significantly influences mood and motivation. Therefore, a new perspective on depression may be suggested by understanding the correlation between peripheral metabolic signal transmission and the regulators secreted from the central nervous system, which affect food intake and wakefulness.

Lower levels of leptin and higher levels of ghrelin may be linked to a higher prevalence of depression [102]. Leptin, a hormone for satiety, is secreted from white fat cells and is involved in regulating food intake. Considering that poor appetite and decreased food intake are common symptoms of depression, studies have been carried out on the role of leptin in depression. Depression was associated with low levels of leptin, and patients who attempted suicide demonstrated significantly low levels of leptin in their cerebrospinal fluid [103]. Other studies, however, reported that depressed patients showed high levels of leptin [104]. It is possible to explain these high levels of leptin as leptin resistance. In type 2 diabetic patients, this could be close to insulin resistance. It has been documented that obese people suffer depression more frequently than normal-weight subjects [105]. In obesity, elevated leptin levels and tolerance to leptin are frequently observed.

In order to promote optimal neuroplasticity, cellular health of all CNS and peripheral organ systems and their long-term preservation over the life cycle is necessary, which will guarantee continued remission of MDD, avoid complications and maintain somatic health. Achieving and maintaining optimum cellular health depend on genomic stability, oxidative eustress, and telomere length maintenance.

MDD is associated with oxidative DNA damage and consequent genomic instability [133]. This predisposes to mutations and aberrant methylations. The results may be attributed to increased oxidative stress. Psychological stress, sedentary lifestyle, intake of processed and nutritionally depleted food, unhealthy social habits (smoking, excess alcohol intake, etc.), and exposure to environmental pollutants have taken a toll on human health with the onset of MDD at a much younger age [16, 129]. These environmental and lifestyle factors are responsible for genomic instability [128]. DNA damage to mitochondrial and nuclear genome results in the accumulation of genetic and epigenetic aberrations [27, 131].

Genomic stability is essential to cellular survival, youthful cancer free, healthy life, and persistent health issues such as MDD prevention and care. Recent studies suggest the reduction of genomic instability (decreased levels of 8-OHdG) after YBLI in MDD. Previous studies have shown that active interventions like psychotherapy reversed DNA strand break accumulation originating from traumatic stress [132]. Commonly used drugs for MDD including SSRIs have shown adverse effects on genomic stability with increased complications like male infertility by causing sperm DNA damage [133].

DNA damage is mostly due to the aberrant pathway of the DNA damage response, which is important for DNA repair and genomic integrity monitoring. In order to facilitate irreversible ageing, inadequate DNA repair causes structural consequences [130]. DNA damage reduction by YBLI suggests that yoga has the capacity to optimize the DDR pathway to repair genomic damage and improve genomic stability. Improved oxidative stress and telomere stability along with changes in mind-body communicative and neural markers by YBLI contribute to stabilizing the genetic-make-up [11].

Several research and meta-analyses have documented a systematic decrease in telomere duration in both depressed and MDD individuals [134]. Recent studies have also documented dysregulations in telomere metabolism within the brain of rat model of depression and post mortem brain of MDD patients [135]. OS is a crucial player in the maintenance of telomere length, and there is an inverse relation between OS and telomere length. Studies have shown that OS can decrease telomere length by causing telomerase deficiency. ODD is significant among the factors which adversely affects telomere length [136]. Telomere attrition, due to DNA damage at the ends of chromosomes, has been traditionally associated with senescence and related disease conditions [137]. Obviously, enhanced oxidative stress may result in impairment in telomere metabolism and accelerated cellular aging and decrease cellular longevity in patients with depressive disorder.

It has recently been shown that optimum oxidative stress may increase induction of the expression of several genes involved in genomic stability and telomere maintenance, leading to improved cellular processes like autophagy, intercellular communication, stem cell renewal, and neuroplasticity. Study data shows that frequent yoga participants have increased telomere length relative to controls, and yoga exercise may enhance telomere metabolism by seemingly stable individuals [10]. The potential molecular pathways for increasing telomere protection after exercise were also established in recent studies [138]. The function of telomerase is understood to mediate cell survival through the promotion of BDNF actions [139]. Recent studies from our lab have shown significant increase in telomerase activity after yoga in MDD and that telomere length was maintained in them [11]. Although the impact of SSRI treatment on telomere metabolism is not known, a recent study suggests that short leucocyte telomere length may serve as a vulnerability index of poorer response to SSRI treatment in MDD [139, 140]. More research is needed to investigate the processes of how telomere metabolism can be positively changed by yoga and other therapies.

Increased ROS, and decreased TAC and cytochrome c oxidase (COX2) activity in MDD patients is suggested by several studies that have reported mitochondrial dysfunction and unregulated oxidative stress in the pathogenesis of MDD [10, 11]. At the cellular level, environmental influences such as perinatal insults, childhood maltreatment, and other adverse pathophysiological or psychosocial life events may activate oxidative stress pathways, thereby altering neuronal plasticity and function [141]. Mitochondria are the main energy metabolism organelles that are highly essential for adaptation to OS. Interestingly, OS process has also been observed in the frontal cortex of patients with recurrent depressive disorder [142].

Oxidative eustress variance is associated with macromolecular injury, turnover of telomeres, epigenetic changes and altered gene expressions. It is strongly associated altered neuroprotection, neurogenesis, and neuroplasticity in the brain [143]. HPA hyperactivity predisposes to increased cellular oxidative stress [144]. Szebeni et al., have even documented the elevated expression of DNA oxidation and DNA repair enzymes in brain white matter in MDD [135].

Achieving maximum oxidative eustress is a highly responsive activity, even under extremes of stress related to lifestyle and environmental challenges. A number of methods are followed to minimize or prevent the OS [145]. A meta-analysis by Liu et al. confirms the fact that antioxidant levels are raised and that after antidepressant treatment, the levels of oxidative damage products are reduced [61]. Passive interventions such as drugs and anti-oxidants can change the status of OS. In chronic lifestyle conditions, successful strategies such as daily physical activity are also helpful in minimising OS [148]. Asanas and pranayama contribute to voluntary exercise may improve mitochondrial health [149]. Findings from our recent study have shown that MDD therapy with YBLI contributes significantly to achieve oxidative eustress (homeostatic balance) and decrease DNA damage (Fig. 3). Another study of YBLI in apparently healthy also reports that yoga and meditation could re-establish oxidative eustress [10]. COX2 is an important component of cytochrome c oxidase (complex IV), and increased COX2 levels by YBLI stabilize the cytochrome c oxidase super complex organization. Cytochrome c oxidase regulates the functions of cytochrome c that maintains mitochondrial transmembrane potential and ATP generation. Its activity is an indicator of the oxidative capacity of the cells. Moreover, the activation of apoptotic mechanisms are suggested for the mediation of psychosocial stress in inducing depression-like behavior, and ceramides that mediate apoptosis have been suggested as targets for therapies in depression [148]. YBLI mediated increase in COX2 activity may further improve mitochondrial function by decreasing the levels of the pro-apoptotic C16 : 0 ceramide mediated by inhibition of ceramide synthase 6. The modulation of cellular OS within physiological limits after YBLI suggests the ability of this intervention to defend cells from DNA disruption and telomere attrition triggered by oxidative stress and to reverse epigenetic modifications accumulated by unhealthy behaviours and unfavourable environmental conditions. Previous studies have reported conflicting findings for the impact of MDD drug treatment on oxidative stress and mitochondrial dysfunction, some of the adverse effects may be due to disruptions in these mechanisms [61]. A recent study in our laboratory has documented that Yoga improves mitochondrial integrity and functionality. This is seen by increased expression of genes which maintain mitochondrial integrity and increase in mitochondrial copy number. There is also increase in mitochondrial membrane potential and COXII activity. Thus improvement in mitochondrial health is critical as it results in higher ATP and less free radical production and thus is able to meet the metabolic demand of the brain and also improves neuronal health along with various neurotrophins and factors which promote neuroplasticity like BDNF and DHEA. This improvement in mitochondrial DNA integrity has implications in various mitochondrial diseases like Leber hereditary optic neuropathy (LHON) and various skeletal, cardiac and liver diseases.

Fig. 3.

Yoga based lifestyle intervention is designed to activate signaling pathways of cellular longevity.

Yoga, a premier MBI, has been increasingly accepted as a cost-effective strategy for promoting health, including brain health. This is evident from the reduced age associated decline in gray matter of yogis and regular meditators [149]. Recent studies and meta-analysis of neuroimaging in meditation practitioners, found consistent alterations and activations of brain areas involved in processing of higher mental functions [150]. BDNF plays an important role in neuroplasticity and neurogenesis, and is a cardinal biomarker, which positively correlate with the improved neuroplasticity seen at morphometric, neural network, and molecular levels [151, 152]. There is even growing interest to translate BDNF biology into therapies for depression. Passive interventions, although modify neuroplasticity and related processes in the brain, they fail to provide long term remissions, and are associated with complications [153]. In a recent study exercise increased BDNF levels in MDD patients [154]. In another study, Taekwondo, a form sport and exercise, improved neuroplasticity-related growth factors, including BDNF, in healthy children [155]. Yoga has also been shown to improve levels of BDNF in MDD [186]. Our recent study further confirmed that in MDD subjects 12 weeks of YBLI could significantly increase systemic BDNF level, in association with improvement in biomarkers of mind-body communications and cellular health (Fig. 4). We observed that levels of BDNF were 42% higher (P 0.001) post YBLI in MDD patients in yoga group compared to baseline values; on the other hand MDD patients in the control group did not show significant post-intervention change in BDNF levels [11].

Fig. 4.

Hallmarks of cellular aging in major depressive disorder.

A recent review has analyzed how peripheral somatic stimulation by acupuncture may increase neurotrophic factors like BDNF, and improves neuroplasticity [156]. Asanas (postures) and pranayama (breathing exercise) in YBLI may provide similar peripheral stimulation to CNS. In this regard, increased BDNF levels and improved clinical outcomes by YBLI, suggest that it may be an intervention to improve neuroplasticity, reverse pathobiology of MDD, and provide long-term remission [11].

Although drug treatment can improve neuroplasticity, they do so through the “GPCR-cAMP” pathway that is commonly seen in other organs or tissues, but is not the major pathway regulating the function of cAMP response element binding protein in the brain that is activated by BDNF [157]. BDNF also promotes neuroplasticity and neurogenesis in the amygdala, ventral tegmental area and NAc, which is believed to cause depressive-like behaviors or exacerbate depressive symptoms [158, 159]. Therefore, the effectiveness of the antidepressant is not completely contradictory to the site-specific neurophysiological and neurochemical efficacy of tension in various areas of the brain, which prevents neuroplasticity, causes atrophy in the hippocampus and prefrontal cortex, encourages maladaptive neuroplasticity and induces amygdala hypertrophy. The hypertrophy and increased activation of amygdala may underline the heightened risk of relapse in chronic MDD.

Adult neurogenesis facilitates resistance to stress at a cellular level by strengthening glucocorticoid-mediated negative feedback on the HPA axis [50]. Lower levels of BDNF have been reported in depression patients [152]. Decreased BDNF in association with altered regulatory systems of mind-body communication like stress and immune response, along with accelerated cellular aging support the neuroplasticity theory of MDD [61, 160]. In particular, during chronic stress response, elevation of endogenous cortisol will exert a neurotoxic impact on hippocampal neurons through the glucocorticoid receptor and its downstream effects, resulting in reduced neurogenesis, synaptogenesis and dendritic spines and increased neuronal apoptosis [161]. In addition, stress will decrease cell proliferation and facilitate glial cell apoptosis, which is the primary cell responsible for glutamate clearance in the brain and may be responsible for hippocampal atrophy in MDD [162]. Recent studies suggest that disruption of microglia’s normal structure and function, triggered either by extreme inflammatory activation or by the decline and senescence of these cells, may lead to depression and related impairment of neuroplasticity and neurogenesis [163].

Improved homeostasis of other neurotransmitters, including serotonin, dopamine, norepinephrine, acetylcholine, GABA, and glutamate, may be associated with increased neuroplasticity in after YBLI in MDD [164]. Crosstalk between improvements in other hallmarks of cellular aging mediates this neurotransmitter homeostasis. Lower concentrations of serotonin in MDD patients have been reported previously. Serotonin is thought to be implicated in multiple MDD-dysregulated physiological and behavioural mechanisms, including mood, appetite, sleep, exercise, suicide, sexual behaviour and cognition. In tandem with the mood-lowering effects of tryptophan depletion and the effectiveness of serotonin-modulating antidepressants, reduced serotonin metabolite levels in CSF have supported the hypothesis that serotonin system dysfunctions are implicated in the pathogenesis of MDD [165].

Recent studies show that YBLI-optimized serotonin homeostasis in MDD patients and is associated with significantly improved crosstalk with others hallmarks of cellular aging, which may contribute to increased remission and response. YBLI-optimized neurotransmitter homeostasis, including serotonin, in MDD patients is associated with improved neuroplasticity by the optimization of the dynamic multi-directional regulatory feedback systems that are discussed in relevant places for other biomarkers of cellular aging in this thesis. Crosstalk between these biomarkers provides the necessary explanations for the combined mechanisms because of the changes in the biomarkers assessed. Further discussion on the mechanism of YBLI is provided in a separate section below.

Melatonin is decreased in MDD patients that highlight the importance of the biological clock in the pathogenesis of MDD [166]. Biological clocks at the molecular level have been observed in almost every body organ and tissue so far examined, and these clocks are synchronized by the suprachiasmatic nucleus directly (via neural connections) or indirectly via hormonal inputs (e.g., cortisol, melatonin) or behavioral outputs (e.g., feeding). The clock also monitors the timing of sleep and, as such, communicates with sleep and circadian processes to monitor periods of rest-activity and maintain an individual in harmony with the natural world. Disruption of certain main homeostatic mechanisms could clearly lead to allostatic overload and depression [166]. This is partially due to a sustained inflammatory brain response mediated by immune cell penetration across the blood brain barrier and elevated levels of pro-inflammatory soluble proteins [70]. Recently studies have identified several circadian rhythm genes that are dysregulated in depression [167]. Several transcriptomics analysis show the association of MDD patients with pathways related to circadian rhythms.

Diverse strategies aimed at counteracting circadian misalignment, and thereby decrease allostatic load, have been proved to be beneficial for the clinical management of MDD. Sleep constraints have been shown to raise blood pressure, decrease parasympathetic tone, increase levels of cortisol, pro-inflammatory cytokines and insulin, and encourage increased appetite, likely by raising the pro-appetitive hormone ghrelin, along with decreased levels of leptin [168]. Therefore, improved sleep and melatonin levels by YBLI may optimize biomarkers of cellular aging including cortisol and inflammatory markers.

It is hypothesised that melatonin’s anti-stress and antidepressant-like activities interfere with many neurotransmitter processes, including GABAergic, serotoninergic, glutamatergic and nitrergic, as well as hypothalamic-pituitary-adrenal axis regulation [169]. Moreover, melatonin is also shown to protect cells from oxidative stress and improve mitochondrial function [170]. A recent study suggests that antidepressant effects of melatonin are by inhibition of acid-sphingomyelinase/ceramide system [171]. YBLI induced antidepressant action may be due to improved melatonin and mitochondrial function, thereby inhibiting acid-sphingomyelinase/ceramide system.

Improved melatonin homeostasis and circadian rhythms optimize neuroplasticity, and evidence in rodents has shown that it stimulates all stages of neuroplasticity [172]. Preclinical experiments have found that improvements in neuroplasticity in the adult brain follow a circadian pattern and are often caused by the light/dark cycle, with neuroplasticity during the dark period achieving its highest levels. Electrophysiological experiments have shown that long-term hippocampal potentiation was greater in magnitude and had improved flexibility during the dark period, which is indicative of synaptic strength. Drug therapies with SSRIs have been associated with decreased melatonin levels and disruption of sleep [140]. Therefore, while drug therapy is associated with relapses and complications, YBLI may optimize the circadian rhythms of neuroplasticity in MDD, which may contribute to long-term remission.

Previous findings confirm the correlation of elevated cortisol with reduction in BDNF and increased incidence of depression. Through repressing glucocorticoid receptors, increased cortisol is known to inhibit BDNF secretion throughout the brain, and decreasing activity-dependent expression of BDNF mRNA in hippocampal neurons, and thereby contribute to neurodegeneration [174].

Decreasing cortisol levels has been shown to reverse the reduced hippocampus volume [175]. A research by Taren et al. reveals that instruction in mindfulness meditation facilitates physiological neuroplastic improvements and includes decoupling of the amygdala and subgenital anterior cingulate cortex as a possible neurobiological process influencing the intervention results of mindfulness training [176]. Yoga-related cortisol reduction in MDD was associated with a rise in blood BDNF levels. Our research confirms that YBLI reduces the amount of cortisol and enhances contact between the mind and body that controls MDD neuroplasticity [11].

YBLI increased stress resilience in association with reduced depression severity and optimized stress response in MDD patients. Previous findings have demonstrated that cortisol concentrations were not impaired by a particular type of antidepressant medication in patients with MDD, so stress physiology was unlikely to be a contributing factor in MDD drug therapy results [177].

Several studies suggested the role of various inflammatory processes and mediators in the pathobiology of MDD [178]. The inflammatory biomarkers that were significantly altered in MDD patients in comparison to healthy population included increase in the levels of IL-6, and LL-37, and decrease in the levels of CX3CL1 gene expression. In a previous study, patients with MDD displayed elevated levels of IL-1$\beta$, TNF-alpha, and IL-6 with elevated levels of neopterin, chemokines, and soluble IL-2 receptors, suggesting improved cell-mediated immunity and macrophage activity [179]. The neuroimmunological pathways of peripheral immune dysfunction in MDD have been documented in previous studies and have shown that these routes intersect in the CNS to modify molecular programmes, neurogenesis and plasticity [92]. Frodl et al. have reported that increased cortisol and decreased hippocampal volumes in MDD are correlated with elevated IL-6 levels [180]. Previously, LL-37 is shown to be increased in elderly patients with depression [181]. Our recent study has shown the increase in blood LL-37 in adults with depression.

Crosstalk between different hallmarks of cellular aging is important for the improved clinical outcomes mediated by optimized inflammatory responses in MDD. Emerging research has indicated that in patients with MDD, many inflammatory cytokines such as IL-6 and TNF-alpha are associated with OS [178]. Latest research indicates that microglial SIRT1 deficiency contributes to a cognitive impairment in ageing and neurodegeneration by epigenetic modulation of immune molecules such as IL-1$\beta$[182]. Moreover, by inhibiting nuclear factor kappa B signaling, SIRT1 defends against microglia-dependent amyloid-$\beta$-toxicity [183]. Therefore, optimization of oxidative stress and nutrition sensing by YBLI may contribute to optimization of immune response and improve brain health. A meta-analysis found data linking blood chemokine defects to human depression [184].

Preclinical study has demonstrated that chemokines are associated with peripheral-central crosstalk and may be essential to mediate suicidal behaviors. In both physiological and pathological settings, crosstalk between CX3CR1 and CX3CL1 tends to be an essential means of coordination between microglia and neurons [185]. Future studies should investigate the putative processes driving this relationship, strive to reproduce current outcomes in broader communities and seek to establish novel diagnostic and therapeutic strategies.

A recent trial investigating differential antidepressant treatment response by proteomic approach, has reported that several cytokines (IL-5, IFN-$\gamma$, IL-13), two chemokines (Eotaxin-1/CCL11, RANTES) and an acute-phase reactant (serum amyloid P component) showed change from baseline to week 12 [186]. However, they found increase of chemokine Eotaxin-1/CCL11 correlated with remission, whereas decrease of IFN-$\gamma$ correlated with non-remission. Difference between YBLI and drug therapy in inflammatory biomarkers of differential remission response may be related to respectively active and passive actions on the body. A systematic review of gene expression changes by Buric et al., indicate that MBI practices are linked to downregulation of NF$\kappa$B pathway, an effect opposite to that of chronic stress on gene expression [119]. Meditation decreases inflammatory marker IL-6 and increase neuroplasticity, as shown in a study using imaging [187]. These findings suggest that YBLI slows the rate of aging by decreasing stress and inflammatory response and improves cellular health (Fig. 5).

Fig. 5.

Schematic representation of improved cellular health by yoga and meditation and its association with molecular and clinical parameters.

Nutrition and energy sensing pathways are important among the factors that promote longevity, and Sirtuin 1 plays a prominent role. Literature available with respect to blood sirtuin-1 levels in patients with MDD is limited, but most have shown decreased levels of sirtuin 1 in MDD [188]. In support of this observation, lower sirtuin-1 concentration was associated with MDD in a recent study from our lab. Latest research indicates that microglial SIRT1 deficiency contributes to a cognitive impairment in ageing and neurodegeneration by epigenetic modulation of immune molecules such as IL-1$\beta$[182]. Sirtuin 1 deficiency may contribute to neuroinflammation in MDD through microglial activation.

SIRT1, a mammalian class III member of histone deacetylases dependent on nicotinamide adenine dinucleotide (NAD+) and a nutrient and energy sensor, has been a target for longevity and aging-related disease interventions [187]. Recent evidence suggests that caloric limitation and resveratrol may increase the levels of circulating sirtuin 1 [190]. Our recent study is the first to document an increase in levels of sirtuin-1 independent of caloric restriction after yoga practice [10, 11].

These improved processes may result in delaying onset and slowing down progression of diseases associated with accelerated cellular aging. Sirtuin 1 strongly contributes to the correlation between BDNF and BDI-II scores. A research in rats indicated that therapy exercise and resveratrol increased the regeneration of neurological and motor activity via the SIRT1 signalling pathway following cerebral ischemic injury [191]. Potential underlying molecular mechanisms for decrease in MDD severity by increased sirtuin 1 include: (1) increasing cell survival and neurogenesis through mTOR signaling, (2) promoting synaptic plasticity by increasing BDNF transcription, mediated by inhibition of miR-134 expression that inhibit binding of cAMP response element-binding protein to several BDNF promoters, (3) regulating circadian rhythm mediated by inhibiting the central circadian timer protein CLOCK, a histone acetyltransferase, (4) by powerful antioxidant mechanisms [192]. SIRT1 provides cells with tolerance against OS. By modulating forkhead transcription factors, SIRT1 may offer protection against oxidative stress in some cells [193]. In addition, SIRT1 defends cells against OS by increasing catalase activity [194]. Sirtuin-1 provides resistance to OS, anti-inflammation and immunosuppression [195]. SIRT1 over-expression enhances tolerance to free radical toxicity in neuronal cells and through microRNA-regulated DNA repair and genomic stability pathways. A previous research revealed that SIRT1 modulates synaptic plasticity and memory development through a pathway mediated by microRNA [196]. SIRT1 stimulation promotes synaptic plasticity, although its lack of action impairs. Appropriately, these effects were mediated by a brain-specific microRNA, miR-1344 miR, through post-transcriptional regulation of cAMP reaction binding protein expression. SIRT1 usually acts to restrict miR-134 expression through a transcription factor YY1 repressor complex. It also unchecks miR-134 expression following SIRT1 deficiency which results in downregulated cAMP reaction element-binding protein and BDNF expression, thereby impairing synaptic plasticity. The results of our research indicate a role for the increase in SIRT1 caused by YBLI in correcting MDD pathology via a microRNA-based mechanism.