A pathological convergence theory for non‐communicable diseases

Abstract

The current paradigm considers the study of non‐communicable diseases (NCDs), which are the main causes of mortality, as individual disorders. Nevertheless, this conception is being solidly challenged by numerous remarkable studies. The clear fact that the mortality, by virtually all NCDs, tends to cluster at old ages (with the exception of congenital malformations and certain types of cancer, among a few others); makes us intuitive to assume that the common convergence mechanism that exponentially increases mortality by almost all NCDs in older ages is cell aging. Moreover, when we study NCDs, we are not analyzing which disorders cause the mortality of the populations, rather that which disorders kill us before others do, because the aging of the individuals causes inevitably their death by one cause or another. This is not a defeatist perspective, but a challenging and efficient one. These intuitive assumptions have been supported by studies from the pathophysiologic, epidemiologic, and genetic fields, leading to the affirmation that, as NCDs share genetic and pathophysiological mechanisms (derived from mostly the same risk factors), they should no longer be considered independently. Those studies should make us reconsider our current conceptions of studying NCDs as individual disorders, and to hypothesize about a paradigm that would consider most NCDs (cancer, neurological pathologies, cardiovascular diseases, type II diabetes mellitus, chronic respiratory diseases, osteoarthritis, and osteoporosis, among others) different manifestations of the same process: the cell aging.

Aggressions from main risk factors converge in limited pathophysiological pathways (eventually inflammation/oxidative stress). Genetic, pathophysiologic, and epidemiologic evidences suggest that most non‐communicable diseases (NCDs) are different facets of cell aging. Cell aging as common convergence mechanism that exponentially increases mortality by most NCDs in older ages.

1. THE PATOPHYSIOLOGIC PERSPECTIVE

We commonly consider age as proxy of aging, but depending on our genetic background and the type and amount of risk factors at which we have been exposed throughout life, that finally determined our metabolic history, these two concepts could differ substantially. ¹ , ² In fact, some biomarkers could assess our biological age that may differ from our chronological one. ² , ³

Aging is considered a multifactorial process characterized by a loss of integrity and efficiency of physiological and biochemical processes that occur after the reproductive age, ⁴ , ⁵ leading to functional alterations and the development of diseases related to aging, that include most non‐communicable diseases (NCDs), ⁵ , ⁶ , ⁷ and ultimately to cell death. ⁴

Moreover, the fact that main risk factors are shared mostly by the main age‐related NCDs ⁸ , ⁹ ; could suggest the convergence of its pathogenesis on limited pathophysiological ² , ⁷ , ¹⁰ , ¹¹ , ¹² and genetic ⁷ , ¹³ mechanisms that could be related to cell aging and be mediators between risk factors and NCDs (Figure 1). Specifically, it has been suggested that NCDs could be considered the consequence of the same molecular alterations, eventually oxidative stress (OS) and inflammation, that are additionally interconnected with each other ¹² , ¹⁴ , ¹⁵ and determine aging in different tissues and organs. ² , ³ , ¹⁴ , ¹⁶ , ¹⁷

FIGURE 1.

Convergence of non‐communicable diseases pathogenesis on a summary of pathophysiological pathways related to cell aging. T2DM, type 2 diabetes mellitus.

In this line, it has been described that inflammaging, (age‐associated inflammation) ² , ¹⁸ , ¹⁹ is one of the main pillars of aging ² that additionally increases OS. ³ , ⁴ , ¹⁰ , ¹² , ¹⁵ , ¹⁷ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ In turn, OS has proven to increase inflammation. ³ , ¹² , ¹⁵ , ¹⁹ , ²⁰ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ Thus, inflammation and OS maintain a vicious cycle and this media of inflammation/oxidation damages proteins, lipids, and DNA ¹⁰ , ¹² , ²⁰ and are related to most NCDs. ¹⁰ , ¹² , ¹⁵ , ²³

Additionally, and conjoined to inflammaging, other sources, if sustained, may increase chronic inflammatory levels and thus accelerate the aging process. These factors include persistent microbial infections, ² , ¹⁹ , ²³ cell debris, ² alterations in gut microbiota, ² altered/misplaced proteins, ² toxic chemicals, ²³ radiation, ²³ pollutants, ¹⁰ , ²⁸ , ²⁹ , ³⁰ allergens, ²³ alcohol consumption, ²³ tobacco consumption, ¹⁸ , ²³ , ³¹ , ³² stress, ¹⁸ depression, ¹⁸ sedentary lifestyle, ⁹ decrease of sex hormones, ¹⁸ unhealthy and/or high calorie diet, ⁹ , ¹⁸ , ²³ , ³² , ³³ and obesity. ¹⁰ , ²¹ , ²³ , ²⁴ , ³² , ³⁴ , ³⁵ Moreover, obesity is related to metaflammation and shares same mechanisms than inflammaging. ² This could be explained by the fact that obesity produces inflammatory molecules and cytokines ²⁴ , ³² , ³⁵ and is related to adipose tissue macrophage infiltration. ¹⁸ , ²⁴ , ³⁵ Interestingly, the relation between obesity and inflammation is suggested to be due to visceral fat, that increases with aging, rather than to subcutaneous fat. ¹⁸ , ²⁴ , ³² , ³⁶ Additionally, the excess of energy could increase glucose and fatty acid metabolisms that in turn increase chronic low‐grade inflammation, whereas caloric restriction reduces inflammatory levels. ¹⁰ , ²⁴ Those aforementioned factors, by increasing chronic sterile inflammation that alters organ and tissues homeostasis, ² are suggested to be among the main risk factors for age‐related NCDs (Figure 1). ² , ¹⁸ , ²³

On the other hand, the theory of aging based on free radical OS ³ , ⁴ , ¹⁷ describes the physiological basis of the aging process mainly related to the production of reactive species, which its most important representatives are the ones derived from oxygen, called reactive oxygen species (ROS). ⁴

To survive, we need energy as ATP that is produced, in a greater extent, in a process called oxidative phosphorylation, carried out inside the mitochondria through the electron transport chain (ETC) with the fundamental participation of oxygen in the aerobic metabolism. Oxygen is acceptor of electrons at the end of the ETC, and mostly ends reacting with hydrogen to produce water. This process is basic for the survival of our cells; thus, its alteration affects all organs and systems. During aerobic metabolism, in normal circumstances, a small percentage of electrons (0.1–3% depending on the source) are inefficiently transported to oxygen and end up forming ROS. ³ , ⁴ , ²⁶ , ²⁹ , ³⁷ ROS have an unpaired electron in their molecular outer orbit which makes them prone to react with adjacent molecules. ³ , ⁵ ROS can also be produced by numerous sources ⁵ like responses to: (a) external stimuli (air pollutants, ⁷ , ¹⁷ , ¹⁹ , ²⁸ , ²⁹ , ³⁸ chemotherapeutics, ³⁸ ultraviolet light, ³⁸ ionizing radiation, ⁷ , ¹⁷ , ³⁸ cigarette smoke, ⁷ , ¹⁷ , ²⁹ , ³² unhealthy/hyper caloric diet, ²⁹ , ³³ , ³⁹ obesity ²⁹ , ⁴⁰ (that appears to increase OS independently of hypergycemia ⁴¹ ), chronic infections, ¹⁰ (and in general by any stressor causing tissue damage ¹⁷ ; Figure 1); (b) and by other endogenous sources (NADPH oxidases, cytochrome P450s, ³⁸ xanthine oxidases, and nitric oxide synthases, among others ¹² , ²⁹ ).

Anyhow, mitochondrial ETC is the major origin of ROS generation ⁵ , ¹⁷ , ²⁹ by producing 92% of free radicals. ¹

Small levels of ROS are needed for processes related to energy metabolism, defense against infections, and cell signaling. ⁴ , ⁵ , ¹² , ²⁰ , ²³ , ²⁶ , ³⁸ Although, the increase of ROS to levels that damage cell physiology and structure, is disruptive and it is called OS. ³ , ⁵ , ¹⁷ , ²³ , ²⁶ , ²⁹ ROS lesions DNA, lipids, and proteins and accumulates over time. ³ , ⁴ , ⁵ , ¹⁷ , ³⁷ Moreover, ROS formation in the mitochondria increases with age ³⁷ until normal repair mechanisms are overwhelmed, ³ , ⁵ it induces cell senescence ⁴ and, altogether with chronic inflammation, ² , ⁴² it becomes a main determinant of age‐associated diseases. ⁴ , ⁵ , ¹⁵

It is interesting to highlight that in humans, by measuring urinary markers, it has been quantified by the oxidative DNA damage, which is inversely associated to longevity. ⁴ Moreover, oxidative DNA damage does not only depend on the basal metabolic rate ⁴ but also on its repair mechanisms (that appear to decrease with age ¹ , ⁴ ). Additionally, decreased levels of oxidative markers are associated to some behavioral factors, like caloric restriction without malnutrition ⁴ , ¹⁰ and possibly to dietary antioxidants. ³ , ⁵ Nevertheless, antioxidant supplementation has not provided successful remarkable results in health outcomes, ²⁹ , ⁴³ what has been called the antioxidant paradox. ¹² A possible hypothesis for the antioxidant paradox could be the entangled relation and coexistence between OS and chronic inflammation, that fuel each other and may require treatments that target both pathways simultaneously. ¹²

Both nuclear and mitochondrial DNA control the ETC that is essential for energy matabolism. ³⁷ The DNA most affected by ROS is the mitochondrial DNA ³ , ⁷ , ²⁹ and the ROS related mitochondrial damages accumulate over time and they are associated to mitochondrial dysfunction (MD). ³ , ¹⁷ , ⁴⁴ Thus, mitochondria is both a producer ⁴² , ⁴⁵ , ⁴⁶ , ⁴⁷ and a target of ROS ³ , ²⁰ , ²⁹ , ⁴³ , ⁴⁶ , ⁴⁸ and inflammation, ⁶ , ¹⁶ , ⁴⁶ , ⁴⁹ in a self‐perpetuating vicious circle. ²⁹ , ⁴³ , ⁴⁶ , ⁴⁹ , ⁵⁰ Additionally, obesity is associated to inflammation, ² , ³⁴ , ³⁵ , ³⁶ OS, ²⁹ , ⁴⁰ , ⁴¹ , ⁴⁴ mitochondrial damage and dysfunction, ²⁵ , ²⁹ , ⁴⁰ and premature aging. ⁴⁰ Moreover, a hyper caloric diet overloads the mitochondria resulting in MD ²⁵ , ²⁹ and increases the accumulation of ROS ²⁹ , ³⁴ and chronic inflammation ² , ³⁶ that perpetuate MD. ²⁰ , ²⁹ , ⁴⁶

In turn, MD does not only increase ROS and inflammation levels, ⁴² , ⁴⁵ , ⁴⁶ , ⁴⁷ but it is also associated to calcium and glucose homeostasis ³⁷ and alterations in apoptosis. ⁴⁰ Finally, MD is related to numerous NCDs (neurodegenerative pathologies, type II diabetes mellitus [T2DM] and cancer, ³⁷ among others). Interestingly, T2DM is three times more frequently transmitted by the mother (the parent that transmits her mitochondria to the off springs) than by the father ⁵¹ and in centenarians longevity appears to be transmitted from the maternal branch of the family. ⁵²

It is important to highlight that MD is considered a major mechanism for insulin resistance (IR) ⁴⁴ , ⁵⁰ altogether with inflammation ²⁴ , ³⁴ , ³⁶ , ⁴⁴ , ⁵⁰ and ROS. ⁴¹ , ⁵⁰ The subsequent IR, and the following increased levels of insulin and insulin‐like growth factor (IGF) are associated with numerous NCDs (T2DM, cardiovascular diseases, neurodegenerative disorders, cancer, and autoimmune diseases, among others) ⁵³ ; thus, they could be considered relevant mediators of the former physiological pathways.

As closure, there is physiological evidence of the role of ROS and chronic inflammation in the etiopathogenesis of NCDs, and both mechanisms usually coexist. ³ , ¹² , ²⁰ , ²³ , ⁴⁸ ROS (or related OS) is associated to the pathogenesis of: cancer, ⁴ , ⁵ , ¹⁷ , ²² , ²³ , ²⁶ cardiovascular diseases, ⁴ , ⁵ , ⁷ , ¹⁷ , ²¹ , ²⁹ chronic pulmonary disorders, ⁷ , ²³ , ⁵⁴ T2DM, ⁴ , ⁷ , ¹⁷ , ⁵⁰ increased aging, ⁴ , ¹⁷ , ²³ , ²⁶ osteoporosis, ³⁸ neurodegenerative diseases, ⁴ , ⁵ , ⁷ , ¹⁷ , ⁴⁶ certain mental disorders, ⁵⁵ and eventually to cell death. ¹⁷

On the other hand, chronic inflammation has also been associated to the pathogenesis of most NCDs, ¹⁸ , ⁴² including cancer, ¹⁸ , ²³ , ³² , ⁵⁶ , ⁵⁷ cardiovascular diseases, ⁵ , ¹⁸ , ²¹ , ³² , ³⁶ , ⁴⁴ , ⁵⁸ , ⁵⁹ , ⁶⁰ chronic pulmonary diseases, ⁶¹ T2DM, ²⁴ , ³² , ³⁴ , ³⁵ , ³⁶ , ⁴⁴ neurological diseases, ¹⁸ , ¹⁹ , ³² , ⁴⁶ certain mental disorders, ³² , ⁵⁹ , ⁶² osteoporosis, ¹⁸ , ⁵⁸ rheumatoid arthritis, ¹⁸ and also to frailty, ¹⁸ and an increased risk of mortality. ¹⁸

In summary, inflammation and oxidative stress are mostly interconnected through a vicious self‐perpetuating circle, ³ , ¹² , ²² , ²³ both are closely related to MD, ³ , ¹⁴ , ¹⁶ , ⁴³ , ⁴⁶ , ⁴⁹ , ⁵⁰ and contribute to the development of most NCDs (Figure 2). ¹¹ , ¹⁵ , ³³

FIGURE 2.

Summary of pathophysiological pathways between risk factors and NCDs. Prevention levels. ETC, electron transport chain; NCDs, non‐communicable diseases; ROS, reactive oxygen species.

2. THE GENETIC PERSPECTIVE

The pathological convergence theory is coherent with the following genetic data:

First, altogether with chronic inflammation and OS, the shortening of telomeres is considered a basic underlying mechanism of cell aging. ⁷ , ⁶³ , ⁶⁴ These factors are interdependent and synergistic. ⁴² , ⁶⁴

It has also been assessed that cell aging is determined by the modification of genes expression as we get older. ¹ However, even though gene expression can be modified by numerous endogenous and exogenous factors, its major determinant is the telomere ¹ that can modify the expression of nearby and distal genes. ⁶⁵

Telomeres maintain genomic integrity, but they decrease with each cell division that also alters proteins around them. ¹ This decreased telomere length plays a critical role in aging ⁶⁴ , ⁶⁵ and it appears to be associated with age‐related NCDs ⁷ , ⁶⁵ , ⁶⁶ , ⁶⁷ (cancer, ⁶⁵ cardiovascular diseases, ⁷ , ²⁸ , ⁶³ , ⁶⁵ , ⁶⁷ and neurodegeneration ⁷ , ⁶⁵ ), including mental disorders ⁶⁸ and life expectancy. ⁶⁵ , ⁶⁶ , ⁶⁹

Nevertheless, telomere length has not always had a straight linear association with chronological age. ⁷⁰ In fact, physical activity ⁹ , ⁶⁵ and antioxidant diet ⁹ , ⁶⁵ are associated with preserved telomere length. On the other hand, risk factors, such as obesity ⁴⁰ and chronic stress, ⁴² , ⁶⁴ , ⁷¹ among other environmental factors, ²⁸ , ⁶¹ , ⁶⁶ are associated to shorter telomere length. Moreover, pathologies that cause chronic inflammation, like periodontitis, are also associated with shorter telomere length. ⁷² Likewise, inflammation markers and OS have been associated with a shortening of telomeres ¹⁹ , ⁴² , ⁶⁴ and they appear to generate a vicious circle that leads to an increased aging and age‐related NCDs. ⁴²

Second, low‐grade inflammation through IGF1/insulin signaling could downregulate the expression of genes that appear to increase life expectancy and decrease age‐related NCDs. ¹⁰ Additionally, it has been assessed that some genes related to inflammatory and OS responses and IGF1/insulin signaling, appear to present different polymorphisms in centenarians compared to younger individuals. ⁷³ Interestingly, the genetic polymorphism of those genes may produce different health outcomes at younger than in older ages. ⁵² , ⁷³ , ⁷⁴

Third, as epigenetic mechanisms may produce metabolic memory, ²⁹ , ⁷⁵ , ⁷⁶ the long‐term expression of genes can vary depending on our lifestyle ²⁹ (including environmental exposures and diet, among other factors ²² ). Specifically, hyperglycemia can activate the inflammatory and OS metabolic pathways in the long term ⁷⁵ through epigenetic mechanisms. Interestingly, caloric restriction (30–50% reduction of normal amount of calories intake) inhibits GHRH‐GH‐IGF/insulin ⁷⁷ (a possible inflammatory pathway ¹⁰ ) and appears to reduce the incidence of age‐related NCDs in mammals. ¹⁰ Moreover, Catalase‐NAD⁺–Sirtuin overexpression by caloric restriction could increase longevity in mammals ⁷⁷ by regulating cell processes related to inflammation and ROS. ⁷⁶ Additionally, the OS and a proinflammatory state can induce aberrant epigenetic regulation linked to NCDs. ²² Finally, as some detrimental epigenetic changes may be irreversible over time, ⁷⁵ it would be interesting to assess the timing in which they become irreversible; which detrimental epigenetic modifications could be reversible, and to further analyze the external and modifiable factors that may increase the long‐term expression of genes that benefit our survival and health.

Fourth, different diseases are highly connected genetically. Goh et al. ⁷⁸ suggested that disease nodes are related with gene nodes and this network of NCDs tends to cluster in groups sharing the same pathophysiology. ⁷⁸ In addition, Yang et al. assessed that nearly 80% of different disease pairs significantly share the same coexpression of genes, like T2DM with allergic asthma and chronic kidney disease, ¹³ and they suggested that the relation between different diseases could be explained by common dysfunctional regulation mechanisms that may determine a common etiology and pathophysiology. ¹³

3. THE PERSPECTIVE OF THE THEORY OF EVOLUTION

Human biology has always had an efficient purpose, because the evolution selected the best options for survival. Then, why do our bodies develop metaflammation, high ROS production, and IR if they accelerate cell aging and are associated to the pathogenesis of NCDs?

The Homo Sapiens, that we know as human being, exists since 315,000 years ago. All this time, it evolved to select those individuals more fitted to the environmental conditions they were living in. Those conditions included: high exposure to infectious diseases, limited food resources, high risk of mortality at delivery and by predators, and lack of proper medical assistance. For the survival of the species, the evolution focused on selecting those individuals more fitted to survive until they reached the reproductive stage (the one that matters in evolutionary terms). Thus, the physiology of our cells has prepared to face the almost always permanent exposure to infectious diseases and shortage of food. ² , ³⁴

During the last century, in most of our planet, we changed abruptly the external conditions in which our cells learned to function. The protection from communicable diseases (CDs) and the more than sufficient access to food resources, have reduced our mortality by CDs and starvation, but have placed the physiology of our cells in conditions that they never faced before. Thus, they manage this situation poorly and, with the increase of life expectancy, their evolutionary learned physiologic behavior, make us more prone to die from NCDs.

The physiology of our cells, that has adapted to the external conditions present during 315,000 years, functions by: (1) increasing the immune response after the ingestion of any nourishment (postprandial inflammation) ² because of the high prevalence of infectious microorganisms in food and water; as it has been assessed that gut inflammations can activate and imprint specific neurons that, when later stimulated, can trigger inflammatory responses ⁷⁹ , ⁸⁰ ; (2) increasing the immune response to face any healing process and/or infection, even though it becomes chronic and leads to OS, ¹⁰ , ¹⁴ because a deficient healing process was a more urgent and hazardous health problem than a future NCD after the reproductive age (a life period not relevant in evolutionary terms); (3) increasing IR either after a sustained overstimulation of the insulin pathway, presumably by pathogens in its need to take up glucose, ³⁴ or after any chronic inflammation, ² with the possible objective of decreasing intracellular glucose levels, so the infectious microorganisms will not have energy resources for its replication ² , ³⁴ ; (4) producing ROS that help our defense cells to kill pathogenic microorganisms ⁴ , ⁵ , ¹⁴ ; and (5) and to increase energy storage (as adipose tissue) for the individual to be prepared for the, more than likely, periods of starvation, ² probably in the same way that low birth weight newborns develop higher IGF‐1 levels in adolescence to compensate and catch up with growth; however, the subsequent IGF‐1 axis long‐term programming leads to T2DM and hypertension. ⁵³ If the fats stored are not used because of a sustained hypercaloric diet, the subsequent obesity might cause IR, ²¹ , ²⁴ , ³⁵ , ³⁶ , ⁴⁴ MD, ²⁹ , ⁴⁰ inflammation, ²¹ , ²⁴ , ³⁵ , ³⁶ , ⁴⁴ and OS ⁴⁰ , ⁴¹ , ⁴⁴ ; that are related to cell aging and to most NCDs. One possible reason for the generation of metaflammation by adipose tissue could be that if the body has enough resources to prevent starvation to be an urgent hazard, it can afford to dedicate some resources to be prepared for the high risk of infections. This hypothesis is supported by the fact that malnourishment states are associated to immunosuppression ³⁴ (possibly caused by a decreased production of leptin by adypocites ³⁴ ). Moreover, activation of acute phase response (APR) against infections, depends on the mobilization of energy sources (mainly lipoid ones) ³⁴ for an increased lipidic delivery to immune cells, and a direct neutralization of microorganisms by lipoproteins. ⁸¹ The APR may protect from acute injuries/infections but, if maintained, there is a suppression of the insulin signaling anabolic pathway ³⁴ and an increase in atherogenesis, ⁸¹ inflammation, ³⁴ and oxidation. ³⁴ Additionally, the close relation between metabolic and immune pathways, ³⁴ in line with our hypothesis, is also supported by the fact that adipocytes and immune cells, like macrophags, ³⁵ share properties, functions, ² , ³⁴ , ³⁵ genetic transcription factors, ³⁴ , ³⁵ and, in some cases, a same cellular origin (macrophages from white adipose tissue could derive from preadipocytes). ³⁴ , ³⁵ Moreover, macrophages can accumulate lipids and become foam cells in the atherosclerotic plaque. ³⁴

In summary, knowing the physiologic evolution of our cells may be relevant in NCDs research. It would be of interest to consider the field of human evolutionary biology ⁸² ; within a Darwinian‐evolutionary framework, for an evolutionary theory of aging in NCDs research. ⁷³ Thus, by comprehending the past evolution of our cells, we could understand its current functioning and try to predict its future adaptation to the foreseeable changes in the environment.

4. THE EPIDEMIOLOGIC PERSPECTIVE

The pathological convergence theory is coherent with the following epidemiological data:

First, as it is generally known, mortality increases exponentially with age until the point that all individuals die. According to the records, the person that lived longer was Jeanne Louise Calment that died at 122 years old. ¹⁴ The uneven distribution of mortality with the roughly asymptotic relation between age and mortality until an apparent age limit for the human race (in the current environmental circumstances), it is in line with our hypothesis that age (as a rough proxy of cell aging) is the main convergence mechanism that leads to most NCDs and ultimately and inevitably to death.

Second, NCDs aggregate in older people. ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ , ⁸⁸ It has been described that roughly half of the population 50 years and older has between ≥ 2 ⁸⁹ and ≥ 5 NCDs ⁸⁴ and the probability of NCDs multimorbidity increases remarkably with age ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ and obesity. ⁸³ , ⁸⁶ These data are consistent with the hypothesis that NCDs share pathophysiological mechanisms ⁸⁵ , ⁸⁷ that appear to be related to aging. Additionally, the aggregation of NCDs has been associated to an increased risk of mortality. ⁹⁰

Third, one risk factor is usually related to more than one NCD (stress, ⁹¹ unhealthy and/or hypercaloric diet, ⁸ , ⁹ , ⁵³ obesity, ⁸ , ¹⁰ , ⁴⁰ , ⁹² tobacco, ⁸ , ³¹ , ⁵³ alcohol consumption, ⁹³ environmental pollutants, ¹⁰ , ²⁸ , ⁹⁴ radiation, ⁹⁵ and sedentary lifestyle ⁸ , ⁹ ). Likewise, an NCD is usually related to more than one risk factor ⁸ (cancer, ⁸ , ³¹ , ⁹² , ⁹³ , ⁹⁶ cardiovascular diseases, ⁸ , ²⁹ , ³¹ , ⁹³ chronic pulmonary diseases, ⁹ , ³¹ , ⁹² , ⁹⁶ neurological disorders, ⁹³ , ⁹⁷ T2DM, ⁸ , ⁵³ , ⁹² , ⁹⁶ arthritis, ⁹² , ⁹⁸ and premature senescence, ⁹ among others). Moreover, usually there is a mid to long latency period between the exposure to risk factors and the development of NCDs (for example, the average lag time between smoking and the development of lung cancer is 30–40 years ⁹⁶ ). According to our hypothesis, this latency period corresponds to the increased cell aging caused by the risk factor that ends up with the development of NCDs at a younger chronological age than a person not exposed to the risk factor. This hypothesis is in line with the life course approach to chronic disease epidemiology. ⁹⁶ The fact that some risk factors have higher impact in specific NCDs (for example, tobacco and lung cancer, and alcohol consumption and digestive diseases), it is reasonable to assume that it could be related to multiple factors, like the stage of life when they occurred (including intra utero exposures), ⁹⁶ the sex, ⁹⁶ the clustering of different risk factors, ⁹⁶ the accumulation, ⁹⁶ the lag time for the development of the disease, ⁹⁶ and possibly to other factors like a direct exposure of the risk factor to the specific tissue, the dose, the bioavailability, the aggressivity, and the tissue specific susceptibility among others; in a similar way as a same pathophysiologic mechanism ⁶⁰ and/or a same genetic alteration ⁹⁹ may have different pathogenic responses depending on the organ in which they arise. ⁶⁰ , ⁹⁹

Fourth, it has been assessed that the main NCDs are associated between them. ¹⁰ , ²² , ⁵⁴ , ¹⁰⁰ , ¹⁰¹ This fact is in line with our hypothesis that NCDs share common pathophysiologic pathways. ⁶⁰ For example, it has been shown that there is an association between cardiovascular risk and osteoporosis even after adjusting for age. ⁵⁸ Additionally, both share the same risk factors (tobacco, low physical activity, and vitamin D deficiency) and same pathophysiological mechanisms (OS, inflammation, and dyslipidemia). ⁵⁸ Nevertheless, it has been suggested that the associations between some NCDs could be related to shared physiological pathways (like inflammatory changes and/or OS) independently of some of their shared risk factors. ⁵⁴ , ⁵⁸ , ¹⁰¹ , ¹⁰² There have also been assessed associations between cardiovascular and respiratory diseases, ¹⁰⁰ , ¹⁰¹ , ¹⁰² rheumatoid arthritis and cardiovascular diseases, ¹⁰³ chronic obstructive pulmonary disease (COPD) and lung cancer, ⁵⁴ and T2DM and cancer, ²² , ¹⁰⁴ among other NCDs.

Fifth, it has been assessed that primary prevention of risk factors is beneficial for improving health outcomes in studies in different age groups ⁶ ; although it is recommended to initiate it at an early age. ⁶ For example, in the case of smoking, some health benefits could be most significant if quitting before 50 years old, ¹⁰⁵ the impact of its amount on the risk of COPD appears to be higher at younger ages ¹⁰⁶ and also the excess of risk for some NCDs appears to remain higher a long time after quiting, ¹⁰⁷ , ¹⁰⁸ although it is lower than for current smokers. ¹⁰⁶ Thus, future studies should further analyze whether the clear benefit on health outcomes of the primary prevention of modifiable risk factors may have different impact depending on the age group, among other factors. Additionally, NCDs generally have mid to long latency periods ⁹⁶ and a long prodromal stage (with changes in inflammatory and oxidative activity) ³³ ; moreover, some epigenetic modifications that contribute to the initiation of an NCD could be irreversible. ⁷⁵ Furthermore, in older populations, the association between inflammatory and/or oxidative markers and cardiovascular disease appears to be independent of some traditional risk factors. ¹⁸ , ¹⁰⁹ , ¹¹⁰ Thus, for older people, it could be of interest to analyze the combination of necessary and effective primary and secondary classical prevention programs ⁶ , ⁸ with the development of additional prevention programs that could be beneficial on reducing or curbing the physiological decline related to aging ¹⁸ , ¹¹¹ on an individual basis ³³ ; because it has been suggested that combining interventions targeting cell aging mechanisms with disease‐specific approaches may result in more than additive health benefits. ¹¹²

5. CONCLUSIONS

Evidence obtained from the genetic, pathophysiologic, and epidemiologic approaches allow us to conceive and understand the nature of NCDs on an integral way as different facets of the same process: cell aging, and the convergence of the aggressions that represent the main risk factors in some limited pathophysiologic pathways (eventually related to inflammation and oxidative stress). Future studies should provide more evidence about the potential health benefits of combining the effective measures of addressing each risk factor and each NCD, with interventions targeting cell aging mechanisms, on an individual basis.

AUTHOR CONTRIBUTIONS

A.P.M. formulated the research question and conceived the study design, analyzed the data, wrote the manuscript, and critically reviewed and approved the final manuscript.

FUNDING INFORMATION

This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.

CONFLICT OF INTEREST STATEMENT

The author declares no relevant financial or non‐financial interests to disclose.

ETHICS STATEMENT AND PATIENT CONSENT TO PARTICIPATE

Not applicable.

CONSENT FOR PUBLICATION

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Padrón‐Monedero A. A pathological convergence theory for non‐communicable diseases. Aging Med. 2023;6:328‐337. doi: 10.1002/agm2.12273

DATA AVAILABILITY STATEMENT

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