The emergence of chronic diseases of adulthood and middle age in the young: the COIDS (chronic inflammation, obesity, insulin resistance/type 2 diabetes, and depressive syndromes) noxious quartet of pro-inflammatory stress outcomes

Abstract

Major depression, type 2 diabetes, and essential (primary) hypertension are chronic medical and psychiatric disorders that have traditionally affected primarily adults and middle-aged individuals. However, recent decades have witnessed an increasing prevalence of these conditions among children and adolescents. For diseases that typically require prolonged exposure to risk factors to emerge in childhood and adolescence, the amount of exposure to a single risk factor would have to be exceptionally high. We advance the alternative hypothesis of multiple factors acting synergistically. Biological mechanisms underlying the response to ongoing (chronic) stress are logical candidates for being a shared pathway. In the context of persistent and synergistic psychological, social, and economic pressures, unremitting stress can lead to such disease outcomes, exerting a direct influence on the emergence of chronic disorders, and it can also contribute to obesity. Depression follows the same trajectory; therefore, we should examine it as an entity whose consequences are directly reflected in behavioral outcomes, including (over-) eating. Other contributing pathways include chronic sleep deprivation, epigenetic modifications, telomere shortening, the physical environment, pathogens, and the microbiome. We introduce here the concept of the Chronic inflammation, Obesity, Insulin resistance/type 2 diabetes, and Depressive Syndromes (COIDS) noxious quartet of pro-inflammatory stress outcomes, as an increasingly common pathophysiologic state, representing a distinct presentation of type 2 allostatic overload, with direct implications for the current chronic disease epidemic. The compounded effects of a pro-inflammatory state that is fueled by four different and co-existing sources may contribute to explain the emergence of chronic diseases of adulthood and middle age in the young. PPARγ might represent a potential translational therapeutic target for those with COIDS. We propose that highly adverse environments sustain sufficient chronic stress to bring about in the young diseases that had been previously confined to adults.

INTRODUCTION

There are medical and psychiatric disorders that used to occur most commonly in adulthood and middle age. Those include major depressive disorder (MDD), type 2 diabetes (T2D), and essential (primary) hypertension. In the last 20 years, those disorders have been increasingly diagnosed in children and adolescents. This trend has been following obesity rates, which have been regarded as the sole explanation for this phenomenon. While it is undeniable that obesity has attained epidemic proportions, we question whether obesity alone has the potential to precipitate a significant increase in the prevalence of chronic disorders of middle age in the young.

In order to have diseases that require protracted exposure to a single risk factor emerging in infancy and adolescence, the amount of such exposure has to be exceptional. This article advances the alternative hypothesis that multiple factors acting synergistically are more likely to explain this unusual scenario. Risk factors that act through different routes are attractive candidates, and the biological mechanisms underlying the response to chronic stress are logical candidates for being a shared pathway. The interpretation of the available evidence seems to have overlooked the fact that unremitting stress, particularly in the context of prolonged economic, racial, psychological, and social stressors, can lead to these chronic disease outcomes, exerting a direct influence on the emergence of chronic disorders, and that it can also contribute to obesity. Depression follows the same trajectory; therefore, we should examine it as an entity whose consequences are directly reflected in behavioral outcomes, namely (over-) eating. Here we propose that the environment sustains a sufficient concentration of adversity, hostility, and consequently chronic stress, which could foster the development in the young of diseases previously confined to adulthood or middle age.

RATIONALE FOR THE COIDS FRAMEWORK

We have selected Chronic inflammation, Obesity, Insulin resistance/type 2 diabetes, and Depressive Syndromes (COIDS) as the core components of this framework for several essential reasons. First, these four conditions represent a nexus of mental health (depression), metabolic health (obesity and diabetes), and immune function (chronic inflammation) that collectively form a particularly noxious combination. Second, all four have shown alarming increases in prevalence among young populations over recent decades. Third, they share common biological pathways, particularly involving inflammatory processes and stress response systems. Fourth, they demonstrate strong bidirectional relationships with each other, creating enduring vicious cycles of worsening health outcomes. Finally, together they represent a distinct type of allostatic overload that may explain the emergence of diseases traditionally seen only in older adults.

These components interact in multiple ways: depression can lead to behavioral changes that promote obesity; obesity creates a proinflammatory state that contributes to insulin resistance and diabetes; diabetes further exacerbates inflammatory processes; and chronic inflammation feeds back to worsen depressive symptoms. This self-reinforcing cycle creates a pathophysiological state greater than the sum of its parts.

While the COVID-19 pandemic provided a particularly salient example of an inflammatory trigger with both direct (infection) and indirect (social isolation, economic stress) effects, our COIDS framework encompasses a broader range of chronic inflammatory processes from various sources, including other infections, environmental exposures, and lifestyle factors.

SOCIO-ECONOMIC STATUS AND WEIGHT GAIN

A reasonable body of evidence has now demonstrated a significantly higher prevalence of obesity among the poor [1, 2]. In the United States BMI¹ values are inversely proportional to annual income, particularly in women. Old notions that developing countries suffered a scarcity of food supplies and thus were less prone to have obesity as a significant public health problem are now outdated. When plotted against the GDP² of different countries, the mean BMI of the population increases sharply and attains a plateau very early. This data shows that other than the nations under extreme economic hardship, a marginal financial performance is able to produce average population BMIs comparable to those of the wealthiest economies [3].

Data from the United States NHANES³ study provides strong links between obesity and groups of lower socio-economic status. Children from minority groups have higher BMIs than their counterparts, and this difference shows statistical significance from age six onwards. At the same time, one can see trends in this direction as early as the second year of life. Moreover, this study shows that Mexican-Americans (who have replaced Non-Hispanic Blacks as the ethnic group with the highest prevalence of overweight children) have the highest prevalence of overweight children [4]. Among the ethnic groups evaluated by NHANES, Mexican-Americans have also replaced Non-Hispanic Blacks as the ones with the lowest average income [5]. Hemmingsson et al. have proposed a cascading sequence: (A) social adversity within the family (parents having low education, a low social position, poverty, and financial insecurity; offspring being exposed to gestational stress, unmet social and emotional needs, abuse, maltreatment and other adverse life events, social deprivation, and relationship discord); (B) increasing levels of insecurity, negative emotions, chronic stress, and a disruption of energy homeostasis; and (C) weight gain and obesity, eliciting further social stress and weight stigma in both generations [6].

WEIGHT GAIN, OBESITY, AND DIABETES: THE GLOBAL PANDEMIC OF DIABESITY

Despite earlier and flawed apocalyptic predictions that by now, the world would be facing significant famines with hundreds of millions dying of starvation, obesity has become a pandemic, and the prevention of the metabolic syndrome has been recognized as a global challenge [7–9]. T2D and obesity have such an interdependent relationship that the term “diabesity,” originally coined by Shafrir, is now widely used, sadly without proper attribution [10].

In their expert review, Reed et al. state that in recent decades, the number of people with T2D has more than doubled, and the increased global burden of T2D is thought to be due primarily to an increase in obesity over recent decades [11]. They continue to say that T2D is the most common and clinically crucial metabolic disorder, representing a significant healthcare burden worldwide. The most prevalent form of diabetes is T2D, as an estimated 90% of diabetes patients are diagnosed with this form, and the majority of the remaining 10% have type 1 diabetes (T1D). In addition, post-diagnosis complications, especially long-term complications, are prevalent globally. Consequently, diabetes remains a leading cause of blindness, end-stage renal disease, lower limb amputation, and cardiovascular disease [12, 13].

STRESS: A CHRONIC AND PERVASIVE FACTOR IN MODERN SOCIETY

Numerous studies have evaluated the life conditions of the poor in America. Several possible scenarios capable of generating stress can be identified among them. As expected, the increased rates of violence have been restricting lifestyle in ways that aim to protect children from the violence of the streets but that at the same time confines them to small home quarters [14]. Television watching becomes a vital entertainment option under these circumstances and has been associated with an increased risk of lowering hysical activity and becoming overweight [4].

Several markers of violence and social stress are concentrated among lower-income groups. Compared to the upper classes, the poor have an up to a fourfold increase in the prevalence of divorced parents. Separation is associated with poor marital quality, defined as marriages marked by conflict and lack of warmth and support. The severity of its consequences on children is robust. Research evidence has shown that permanent parental separation is a risk factor for developing MDD in adulthood. As a risk factor for depression, early parental separation is more detrimental than parental death [15]. Marital conflict has also been associated with punitive and harsh parenting styles and corporal punishment. Children undergoing early loss also lack the constancy and predictability in the environment required for ideal development, as evidenced by an increased likelihood of residential changes and eviction [16]. Drake and Pandey demonstrated an increase in child maltreatment, defined by neglect, and physical-sexual abuse, as the neighborhood’s average income decreases [17]. A study that interviewed 9–15-year-old African-Americans in a housing development showed that more than half of the children had been asked to traffic drugs or had seen someone being asked. Furthermore, a significant association between these two variables and witnessing or being victimized by other violent events was observed [18].

Hobson and colleagues have provided a theoretical framework describing how racism is a potent stressor that affects the health and well-being of racialized minorities [19]. Additionally, ethnic groups vary in the genetic basis of pharmacological treatment response due in part to interethnic differences in cytochrome P450 polymorphisms [20]. Refugee status is another important contributing factor to chronic stress. Daniel-Calveras et al. conducted a systematic review of the mental health of unaccompanied refugee minors in Europe [21]. Nearly half of Europe’s refugee and asylum-seeking population is under 18, and many of these individuals are unaccompanied children and adolescents. They explained findings from 23 studies conducted in 9 countries which examined 80,651 child and adolescent underrepresented minorities (URMs). Their findings included a high prevalence of mental health disorders among URM children and adolescents, which varied considerably between studies, ranging from 4.6–43% for (PTSD), 2.9–61.6% for depression, 32.6–38.2% for anxiety and 4–14.3% for behavioral problems. Two studies looking at suicide attempts and deaths also observed higher rates in URM compared to the host population of the same age.

While these stressors may be particularly acute in under-privileged populations, it is important to note that chronic stress affects individuals across all demographic groups. Economic pressures, work demands, social media influences, and other modern stressors create environments that foster chronic inflammation and stress response activation across society, contributing to the rising prevalence of the COIDS components in the general population.

STRESS: TYPE 2 ALLOSTATIC OVERLOAD AS A DIRECT RISK FACTOR FOR CHRONIC DISEASES

The neurobiology, neuroendocrinology, and neuroimmunology of the stress response have been extensively reviewed elsewhere, and a stress-related continuum of chronic disease development has been proposed by Agorastos & Chrousos [22–26]. In 1993 McEwen and Stellar coined the term “allostatic load” as “the wear and tear on the body” which accumulates as an individual is exposed to repeated or chronic stress [27]. Later, McEwen & Wingfield differentiated type 1 allostatic overload, which occurs when energy demand exceeds supply (famine, starvation, critical illness) from type 2 allostatic overload that begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction [28]. As we examine unremitting stress in this article, we are conceptualizing a new and distinct presentation of type 2 allostatic overload.

Because of the potentially pathogenic outcomes of unremitting stress, the relationship between stress and chronic diseases has been a significant issue for epidemiological studies. Stimulated by the growing rates of these illnesses in an aging and urbanizing society, researchers have been compelled to find ways to measure psychological stress and its consequences. Studies examining its impact on chronic disease endpoints are widespread in adult populations, and pathophysiologic mechanisms have also been proposed. The rationale for these associations is equally applicable to the emergence of the same outcomes among infants and adolescents.

The relationship between cardiovascular diseases and stress has been extensively studied. Psychological factors were found to elevate the risk of “soft” cardiac endpoints, such as angina and coronary angiography findings and “hard” events represented by myocardial infarction and cardiac death [29, 30]. An increased sympathetic tone induced by stressful situations has been suggested as the trigger for these acute events. Chronic stress is consistently associated with atherosclerosis. Evidence suggests that individuals with higher basal levels of cortisol are at an increased risk for coronary calcification, a finding that can be demonstrated even among relatively young subjects [31].

Among the lay public, hypertension has been the prototypical physical malady with a psychological background. In this case, the folkloric assumption is in line with scientific evidence. Simple mental stress tasks like arithmetic calculations can increase diastolic and systolic blood pressures [32]. Following this path, the next step would be to analyze whether central nervous system-mediated increases in adrenergic activity can lead to hypertension-related endpoints. The exciting work of Matthews et al. measured blood pressure reactivity among female adults undergoing simple, stress-inducing psychological tasks. Thirteen years later computed tomography scans revealed that participants with the highest blood pressure changes were at increased risk of presenting with carotid artery calcifications.

The involvement of stress as a mediator of insulin resistance and T2D also stands on compelling grounds. These entities develop during acute, repeated acute and prolonged stress. Stress hormones actions are generally opposed to those of insulin, and maintaining them constantly above ideal levels may lead to both disorders. Among patients with manifest T2D, some studies point out that those under higher loads of psychological stress have more difficulty in attaining proper glycemic control [33, 34]. Demonstrating that a similar psychological burden can lead previously healthy individuals to T2D needs to be more well-documented. However, considering the hurdles in delineating epidemiological studies powered and designed to assess this issue and the evidence from different fronts demonstrating the capacity of stress hormones to worsen the course of established disease, assuming that stress can be causally implicated in T2D is far from lacking plausibility.

DEPRESSION: ONE MORE TILT TOWARD DISRUPTING A FRAGILE BALANCE

MDD is a chronic disorder that has been recognized as among the most burdensome for society. Like obesity, this disease has also seen its prevalence rise among children and adolescents [35], and like obesity, depression bears the mark of a health disorder related to urbanization. As a mental disorder, depression represents a complex intertwining of genetic factors and psychological stress, and the boundaries between the two certainly overlap [36]. Thapar and colleagues have reviewed depression in young people and noted that depression rates in young people had risen sharply in the past decade, especially in females, which is of concern because adolescence is a period of rapid social, emotional, and cognitive development and critical life transitions. They comment that young people who have a family history of depression, exposure to social stressors (e.g., bullying, discordant relationships, or stressful life events), and belong to specific subgroups (e.g., having a chronic physical health problem or being a sexual minority) are at exceptionally high risk of depression [37]. Strong evidence from replicated research supports the notion that the rates of depression have indeed been rising de facto and that these increasing rates cannot be explained by more intensive screening efforts or a higher level of awareness about the disorder. Indeed, the increase in depression incidence was noted before the emergence of the current obesity epidemic. This temporal synchronicity would be compatible with the causative role of psychological stress in the emergence of obesity. Epidemiologic data support the notion that a depression epidemic antedated the obesity one [38, 39]. This reasoning allows a look at the weight-gaining outbreak from a much-needed behavioral perspective.

The conditions existing in the early 1980s, when the population weight started climbing, were fertile for the appearance of this highly social epidemic. On top of endemic levels of mental disorders, an unprecedented level of freedom to commercialize food products as if they were commodities whose consumption did not have a significant impact on public health offered an avenue of opportunity to brand and market these items under traditional economic tenets. The formula for more significant profit lies in increasing caloric content and portion size while decreasing prices [40]. A large segment of the population, particularly the underprivileged, has proven unfit to resist this seductive combination. Let us consider that these environmental changes were able to lure an expressive number of individuals into a lifestyle of increased calorie consumption. We must also consider the apparent conclusion that the failure to cope with the seductive appeal of calorie intake must involve higher cognitive processes. Thus, parts of the current epidemic’s biological pathways are probably related to weaknesses in our psychological defense mechanisms to resist the external stimuli promoting calorie consumption, in opposition to imbalances in our physiological systems that regulate calorie intake and expenditure.

Psychological symptoms, including those of depression, may easily account for the slight changes necessary to shift the equilibrium of a regular weight diet into one that sustains weight in the overweight and obese ranges. An increase of 10% in the average daily caloric consumption can do that. Increased anxiety or stress-related depression can explain at least partially a change in eating behavior of this magnitude. A light stressor such as an exam period can increase food consumption and elevate university students’ urinary cortisol and insulin levels [41]. The comfort food concept fits well with the findings from this study. These foods are characterized by a high caloric content, primarily due to increased amounts of fat and carbohydrates, and are the ones individuals tend to overindulge in when stressed. The foodstuffs most commonly blamed for the increased obesity rates are the same. Therefore, it is reasonable to accept that the intensity and chronicity of psychological stress exposed to underprivileged populations can produce such changes in food consumption.

Depression and diabetes: a bidirectional relationship

While the relationship between depression and obesity has been well-documented, the bidirectional relationship between depression and diabetes is equally important in the COIDS framework. Depression increases the risk of developing T2D through multiple pathways, including neuroendocrine dysregulation (HPA axis hyperactivity leading to increased cortisol), behavioral changes (reduced physical activity, poor diet, medication non-adherence), and medication effects (some antidepressants can contribute to weight gain and insulin resistance).

Conversely, diabetes significantly increases the risk of depression. This relationship stems from the psychological burden of managing a chronic illness, direct effects of hyperglycemia on brain function, and shared inflammatory mechanisms. Studies have demonstrated that individuals with diabetes have a 24–38% increased risk of developing depression compared to those without diabetes. The resulting depression can worsen diabetes self-management and glycemic control, creating a vicious cycle.

The shared inflammatory pathways between depression and diabetes are particularly notable. Both conditions are associated with elevated pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, which can cross the blood-brain barrier and affect neurotransmitter metabolism, neuroendocrine function, and neural plasticity. This common inflammatory mechanism helps explain why these conditions so frequently co-occur and mutually exacerbate each other.

CHRONIC INFLAMMATORY TRIGGERS: RISK FACTORS FOR CHRONIC DISEASES

Chronic inflammation represents a central component of the COIDS framework. While the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic provided a dramatic example of both direct (infection) and indirect (social isolation, economic disruption) inflammatory triggers, numerous other sources of chronic inflammation contribute to the pathogenesis of chronic diseases in modern society.

Not only are patients with metabolic dysfunction (e.g., obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing inflammation-driven conditions, but chronic inflammatory states might lead to new-onset metabolic disorders or aggravation of pre-existing metabolic conditions [42]. Steenblock and colleagues have postulated that diabetes, MDD, and inflammatory processes are bidirectionally connected, forming a vicious cycle [43]. They suggest that, firstly, depressed individuals show a higher risk of developing diabetes, and patients with diabetes have a higher risk of developing symptoms of depression. Secondly, patients with metabolic disorders have a higher risk of developing severe inflammatory responses. Thirdly, in both patients with T2D and those recovering from acute inflammatory conditions, the prevalence of depression seems to be increased. Steenblock et al. have also recently suggested that post-acute infectious syndromes require multimodal assessment and treatment approaches targeting multiple pathophysiological mechanisms rather than single biomarkers or interventions [44] Moreover, it is not unreasonable to suggest that the addition of lockdown-related stressors and SARS-CoV-2 infection, which disproportionately affected the disadvantaged groups [45, 46], may have contributed to further exacerbate chronic morbidity in young individuals.

Beyond infectious agents, environmental factors such as air pollution, endocrine-disrupting chemicals, and microplastics represent significant sources of chronic inflammation [47, 48]. Dietary factors, including ultra-processed foods, advanced glycation end products, and excess saturated fats, similarly trigger persistent inflammatory responses [49–51]. Physical inactivity, sleep disruption, and psychological stress further amplify these inflammatory signals. In vulnerable individuals, this state of persistent inflammation can contribute to all elements of COIDS, creating a self-reinforcing cycle that accelerates biological aging and promotes the premature onset of diseases typically associated with advanced age.

Together, these diverse inflammatory triggers create an unprecedented inflammatory burden that, when combined with the other components of COIDS, helps explain the concerning trend of adult-onset diseases emerging in younger populations. This represents a public health challenge requiring multilevel interventions addressing both the sources of inflammation and their metabolic and psychological consequences.

INFLAMMATION: THE SHARED PATHOPHYSIOLOGIC PATHWAY OF THE COIDS NOXIOUS QUARTET

What is the shared pathophysiology of the four components of the chronic inflammation, obesity, insulin resistance/type 2 diabetes, and depressive syndromes (COIDS) noxious quartet of chronic stress outcomes? Elevated cortisol and norepinephrine are hallmarks of the stress response [24]. They can be elevated in states of type 2 allostatic overload, such as depression, obesity, diabetes, and COVID-19, with potentially deleterious effects on health outcomes, including cardiac implications [52–56]. New approaches have been proposed for the treatment of “long Covid” [57]. It remains to be determined if such treatments will affect the course of COIDS.

There is ample evidence that all four elements of the COIDS noxious quartet represent chronic pro-inflammatory states [58–60]. In each of the COIDS quartet constituents there is evidence for involvement of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which then via caspase-1 activation leads to the release of the mature forms of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL18 [61–64]. Wang et al. have suggested that P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes [65]. Additionally, IL-6 has been shown to be elevated in major depression, obesity, diabetes, and various chronic inflammatory conditions [60, 66, 67]. If each of the four parts of this quartet can by themselves cause an unremitting pro-inflammatory state, the co-existence of all four COIDS constituents in the same person would be at the very least additive, or possibly even synergistic. The compounded effects of an ongoing pro-inflammatory state that is fueled by four different and co-existing sources may contribute to explain the emergence of chronic diseases of adulthood and middle age in the young.

ADDITIONAL CONTRIBUTORY FACTORS

Epidemiological studies indicate that sleep disturbances are increasingly common across the population, with certain groups experiencing particularly high rates of insufficient sleep [68]. Moreover, insufficient sleep has been associated with MDD and T2D, an outcome of obesity [69, 70].

The human body hosts abundant and diverse microbes, which perform various essential and beneficial functions but are also involved in disease pathophysiology. Interactions between intestinal microbiology and host regulatory systems have now been implicated both in developing psychiatric conditions, including depression and in the efficacy of many standard therapies [71–73]. In addition, it has been shown that altered gut microbial composition in obesity is associated with increased energy extraction from dietary carbohydrates, increased gut permeability, and enhanced production of proinflammatory metabolites, resulting in systemic inflammation and insulin resistance [74]. The effects of gut microbes on eating patterns appear to be regulated by the communication pathways between gut microbiota and the host central nervous system, the microbiota-gut-brain (MGB) axis, a potential new therapeutic target in the treatment of obesity [75]. Current treatments are being designed for engineering the gut microbiome as an innovative therapeutic strategy to prevent or reverse obesity [76, 77]. There are differences in gut microbiome composition that have been ascribed by Borrello et al. to overall diet quality and component food intakes, which vary across different populations [78].

There is increasing evidence that childhood maltreatment and abuse are associated with epigenetic changes that may subsequently serve as disease mechanisms [79]. Those changes include methylation of the glucocorticoid receptor (hGR) and oxytocin receptor (OXTR) genes [80, 81]. Such epigenetic changes have been correlated with the severity and type of trauma [82]. As exposure to childhood abuse is associated with human sperm DNA methylation, such changes may be transmitted across generations [83].

Diverse demographic groups in the U.S. have differing characteristics [20] and show varying life expectancies [84]. Elizabeth Blackburn, Carol Greider, and Jack Szostak received the 2009 Nobel Prize in Physiology or Medicine “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase” [85]. Telomere length decreases with age and may predict lifespan in individuals and species [86–88]. Prolonged psychosocial stress, chronic mental illness, and drug and alcohol abuse have been associated with the shortening of telomere length [89–94]. This could have profound implications for morbidity and life expectancy across the population.

The physical environment continues to impact individuals adversely. Historically, low hygiene standards were the marker of diseases of poverty. Developed countries were able to eradicate several infectious and potentially fatal diseases through the universal establishment of basic sanitation. Nevertheless, residual pathogens are still present among many households of wealthy nations [95]. Roughly 40% of the cases of asthma in certain studies can be attributable to residual levels such as these [96], and the resulting hyperactive immune state has inflammatory consequences that may well play a role in the emergence of chronic disorders.

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARγ): A TRANSLATIONAL THERAPEUTIC TARGET?

PPARγ is a type II nuclear receptor that functions as a transcription factor, and which has been found to be dysregulated in T2D and obesity. Among multiple actions, PPARγ regulates lipid uptake, adipogenesis, increases insulin sensitivity, and increases brain-derived neurotrophic factor (BDNF) levels and activity [97, 98]. PPARγ agonists, such as pioglitazone and rosiglitazone, have been widely used in the treatment of T2D [99]. PPARγ has been thought to be involved in depression, with pathophysiologic and therapeutic implications [98]. Interestingly, it has been suggested that telomere length might be a predictor of response to pioglitazone in patients with unremitted depression [100].

The entrance of infectious agents into host’s cells triggers an array of multiple molecular signaling pathways; those signals include dysregulation of PPARγ [101]. A question that remains to be answered is: As each constituent of the COIDS noxious quartet dysregulates PPARγ, would this be a potential translational therapeutic target for those with COIDS?

PROTECTIVE FACTORS AGAINST COIDS-ASSOCIATED DISEASE PROGRESSION

While this article focuses primarily on the pathogenic mechanisms of COIDS, it is important to acknowledge the protective factors that can mitigate its effects and potentially prevent the premature development of chronic diseases. These protective factors operate at multiple levels, from individual behaviors to societal systems.

At the individual level, regular physical activity has been shown to reduce inflammation, improve insulin sensitivity, and exert antidepressant effects. Healthy dietary patterns, particularly those rich in anti-inflammatory components like omega-3 fatty acids, polyphenols, and fiber, can counteract the inflammatory processes central to COIDS. Adequate sleep hygiene and stress management techniques, including mindfulness-based interventions, have demonstrated efficacy in reducing the physiological burden of chronic stress.

Social support systems represent another crucial protective factor. Strong social connections buffer against the negative health effects of stress and provide practical and emotional resources for managing health challenges. Educational achievement and health literacy empower individuals to make informed health decisions and navigate healthcare systems effectively.

At the societal level, improved access to healthcare, particularly preventive services and mental health resources, can interrupt the progression of COIDS. Public health initiatives targeting early identification and intervention for at-risk youth show promise in preventing the cascade of metabolic and psychological consequences. Policy approaches addressing social determinants of health, including poverty, food insecurity, and environmental hazards, may have the broadest impact on reducing the burden of COIDS across populations.

These protective factors do not operate in isolation but interact with risk factors and with each other to determine individual disease trajectories. Understanding both risk and protective factors is essential for developing comprehensive prevention and treatment strategies for COIDS and the premature chronic diseases it promotes.

THE MULTIPLE-HIT HYPOTHESIS

The ubiquity of the effects of stress is undeniable. In the major COIDS noxious quartet of chronic stress outcomes delineated here, stress is readily blamable for the deleterious endpoints of the quartet’s health consequences. Features of elevated psychological stress and increases in mental disorders were widely debated in the past decades, but attempts to measure their consequences were much less noticeable, and efforts to change the behaviors of the affected populations were almost negligible. The obesity epidemic is an easy-to-measure and undeniable facet of this combination of morbidities. Nevertheless, the whole picture will almost certainly include several other factors that have not yet been fully identified but which have been present for a long time and that may also be significantly responsible for the emergence of these disorders among the young while posing increased risks to weight gain. Such factors could include environmental toxins, emerging pathogens, changes in what we eat, and alterations in our microbiomes, and chronic inflammation, which coexists with the stress response [25, 102], to name a few. In a sense, the surprised reaction to the surge in obesity rates is equivalent to being impressed by the arrival of a long-awaited guest.

Still, the puzzling emergence of diseases of adulthood and middle age among children and adolescents is a phenomenon of such magnitude that simplistic explanations for it will certainly not survive unchallenged. In our view, a significant body of evidence allows these severe outcomes to be traced to the presence of multiple adverse factors. The emergence of chronic stress, depression, obesity, and its metabolic and cardiovascular consequences (T2D and hypertension), and more recently, the added aftermath of chronic inflammation in children and adolescents is possibly the result of the synergistic sum of factors that are strongly related to chronic disease endpoints and that are increasingly common in modern society, with the young being particularly vulnerable to such unremitting conditions (Fig. 1).

Fig. 1.

The COIDS (Chronic inflammatory disease syndrome) noxious quartet conceptual framework. The diagram illustrates how chronic stressors (environmental, physical, psychological, and social) lead to ongoing stress, which contributes to the development of four interconnected conditions: chronic inflammation, obesity, insulin resistance/type 2 diabetes, and depressive syndromes (COIDS). These four elements form a self-reinforcing network with bidirectional relationships (indicated by arrows), ultimately leading to chronic diseases of adulthood/middle age emerging in young individuals. Key pathophysiological mechanisms are highlighted in yellow boxes: 1) sleep deprivation, epigenetic modifications, telomere shortening, physical environment effects, pathogens, microbiome alterations, and inflammation; 2) distinct presentation of type 2 allostatic overload; 3) continually elevated cortisol, norepinephrine, PPARγ, and inflammatory mediators, including the NLRP3 inflammasome (caspase 1) and IL-6; and 4) PPARγ as a potential translational therapeutic target. The blue hexagon identifies this interconnected pathophysiologic state as “The COIDS noxious quartet”.

CONCLUSIONS

Future preventive and translational therapeutic strategies [103], for obesity and its complications in children and adolescents must examine the co-occurrence of chronic inflammation, obesity, insulin resistance/type 2 diabetes, and depressive syndromes, resulting in a distinct presentation of type 2 allostatic overload for which we have coined the term “COIDS noxious quartet.” It is unlikely that treatments focused exclusively on obesity, which is just one element of COIDS, can be fully successful unless they also approach the burden of the underlying chronic psychosocial stress.

Obesity treatments also need to address the quartet’s other elements, such as chronic inflammation and MDD, the latter being often unrecognized and untreated, or inadequately treated, in the young [104]. Furthermore, other factors may also come into play, such as chronic sleep deprivation, epigenetic modifications due to early life stress, telomere shortening, adverse physical environment, pathogens, and the microbiome. We also suggest that shared pathways for COIDS include not only classic stress mediators, such as continually elevated cortisol and norepinephrine, but also PPARγ as well as components of the inflammatory response, including the NLRP3 inflammasome that causes caspase 1 activation and IL-6. PPARγ might represent a potential translational therapeutic target for those with COIDS.

We suggest that COIDS represents an increasingly common pathophysiologic state that contributes significantly to the current epidemic of chronic diseases across the lifespan. The COIDS noxious quartet has direct implications for the emergence of chronic diseases of adulthood and middle age in the young. Addressing this complex syndrome will require coordinated efforts across multiple disciplines and may hold the key to reversing concerning trends in population health.