Hallmarks of health: Understanding the factors that contribute to health and wellness

 Highlights:

• Health is a collective term that extends beyond physical well-being
• Health is influenced by several elements that can be grouped into a number of categories, namely environmental factors, genetics and biology, access to health care, and social factors
• Hallmarks of health include factors like the integrity of barriers, response to stressors, hormetic regulation, repair and regeneration, and other elements

Introduction

The World Health Organization (WHO) defines health as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”. This means that health is a holistic collection of dynamic features. Characteristics of biological health can be viewed in the context of maintaining homeostasis over time. This is reflected through the capacity to maintain the integrity of biological barriers, respond to stressful situations, and regulate the internal body environment. Mental health is viewed in the context of learning, interacting with others, and coping with and managing uncertainties in life.

Determinants of health

Today, multiple definitions of health exist. For example, the field of biomedical science defines health as the absence of a disease (abnormalities pertaining to physiological, anatomical, and cellular aspects) (1, 2). To better understand health, we need to consider all the aspects that contribute to it.

According to the WHO and the United States Office of Disease Prevention and Health Promotion (ODPHP), there are many factors that potentially influence health and usually fall within several broad categories (3, 4). These categories involve environmental factors, genetics and biology, access to health care, and social factors. When it comes to health, there is a general belief that the genetic factor is the major determinant in well-being; however, it only contributes partially to the process (5). This has been validated across studies, highlighting that even monozygotic twins can have different disease outcomes, despite sharing the same genes and epigenetic markers (5, 6). This means that changes in epigenetic markers, in addition to other factors, play a major role in determining the health of individuals, which has been validated in studies conducted on the aforementioned twin population. 

Another determinant of health is the environmental factor. Examples of these factors include air pollution, drinking water contamination, heavy metal poisoning, mold and mycotoxin, and places that discourage physical activities (7, 8). It is important to note that all the stated factors are modifiable, yet they account for 16.3% of global disability-adjusted life years according to WHO estimates (7). Additional environmental factors that negatively influence health include radiation exposure, noise, tobacco smoke, and ambient temperatures (8). It is important to note that one environmental factor can cause several diseases. For example, a meta-analysis assessing 103 studies found that 14 air pollutants, like carbon monoxide, desert dust, and solid fuel, are linked to 34 conditions, ranging from respiratory disorders to cancer (8). These pollutants produce their effect through various mechanisms, such as inducing inflammatory responses through mediators like tumor necrosis factor-α and interleukin-6 (9). Additionally, they can cause oxidative damage that affects the respiratory tract with a downstream effect extending to other body systems. These pollutants also affect the gut microbiome, where they have been found to cause dysbiosis (reduction in the diversity of gut bacteria) (10). This impact is significant because the literature suggests that disruption of the gut microbiota could lead to diseases like diabetes, mental disorders, inflammatory conditions like irritable bowel syndrome, and others (10, 11).

The social factor is another contributor and determinant of health and well-being. This represents an important pillar in health that is easily overlooked. Examples of social factors include income, support network, education, gender, employment, and others (12). This factor is interconnected with other elements that influence health. For example, lower socioeconomic status leads people to work and live in a more degraded environment that puts them in contact with harmful environmental factors and exerts adverse effects on their mental health (12). Additionally, such living conditions make people more liable to making poor dietary choices. Consequently, this increases the risk of chronic disorders and decreases the lifespan.

The integrity of barriers and health

Humans and other beings have external layers that protect them from the surrounding environment. Additionally, the body’s internal components also have defensive barriers (2). Maintaining the integrity of the external and internal barriers like skin and cell membrane, respectively, is a hallmark of health. For example, disruption of the mitochondrial membrane results in releasing its content in the cellular medium leading to inflammation (2, 13). This process, in turn, fuels the process associated with aging. Other examples include disturbance of the nuclear membrane, resulting in genomic instability, senescence, and skin disruption, causing infection and dehydration (2). The blood-brain barrier (BBB) is important in regulating the flow of fluids and nutrients from and into the brain. Disruptions in cells making up the BBB, like astrocytes and glial cells, lead to the accumulation of neurotoxic substances, neurodegenerative proteins, and iron in the brain (2). This leads to conditions like Alzheimer's disease.   

Health and the capacity to respond to internal and external stressors

One of the hallmarks of health is the capacity to maintain the integrity of the internal body environment in the face of internal and external stressors (2). Examples of external stressors include physical trauma, foreign bodies, and pathogens. These factors could lead to outcomes like infections or disruption of bodily processes through blockage of critical blood vessels. Internal stressors arise from a variety of faulty processes, such as failed repair of the genetic material, accumulation of damaged organelles, improper cell division, and others (2). Internal and external stressors play a role in inflammation. Under normal circumstances, inflammation resolves after removing the causative agent (14). However, when there is a defect in any of the aforementioned processes, it could become chronically activated (continuous activation of the inflammatory process, as opposed to acute (short-term). This could have negative implications on all body systems and play a major role in speeding up the aging process (2). Chronic, sterile, low-grade inflammation associated with aging results in a process called “inflammaging”, which is a significant contributor to morbidity and mortality in the elderly population.

Removal of aged and dysfunctional bodily elements and how it relates to health

Cellular and internal body organelles are affected by various internal and external stress factors that could lead to their damage, prompting activation of repair or remove mechanisms (2). One of these mechanisms is called autophagy (a self-degenerative process that helps the body remove damaged organelles and proteins using lysosomes). Under normal circumstances, this process operates optimally. However, if disrupted due to mutations in autophagy genes, damaged organelle and misfolded proteins, and other dysfunctional components will accumulate (15). The outcome of the process is the accumulation of reactive oxygen species (ROS) and other damaging molecules that contribute to a number of disease conditions, including accelerated aging (2, 15). Research has highlighted that autophagy can be positively influenced by interventions like fasting, caloric restriction, ketogenic diet, and others; therefore, beneficially influencing health (2, 16). It is important to note that fasting has been attributed as one of the most influential factors involved in the upregulation of autophagy, highlighting its importance as an intervention.

Maintenance of internal communications between different body circuitries

Maintaining health requires cross-talk between different body cells, organs, and systems to remain intact. One such example is intracellular communication and cross-talk between different cells, which occurs via metabolites or secondary messengers (2). An example is acetyl coenzyme A (Acetyl-CoA), which influences the activity of metabolic enzymes and autophagy-related proteins. Another example is the cross-talk between the gut microbiota and various body systems and organs like the immune system and brain, respectively (17, 18).

Rhythmic oscillations and their role in health

The circadian clock is another hallmark of age and is involved in many bodily functions. The master clock exerts its effects through neural projections from the suprachiasmatic nucleus (SCN) in the hypothalamus, in addition to other peripheral regulators (19). Literature highlights that damaged SCN lead to sleep problems and disturbance of oscillatory rhythms. The circadian clock has been implicated in disease and health and has been found to influence the aging process (20). In this context, disruptions in the circadian rhythm have been associated with negative outcomes on the immune system, leading to increased susceptibility to diseases. Additionally, literature has highlighted that disruption in the gene coding brain and muscle ARNT-like protein (BMAL1) in mice is associated with premature aging and reduced lifespan (21).  

Maintenance of the internal environment (homeostasis)

One of the hallmarks of good health is the capacity to maintain the equilibrium of the internal body environment. This can be measured by various parameters like blood pH, blood pressure, oxygen saturation, and others (2). To achieve this, dynamic orchestration between regulation, resilience, repair, and regeneration mechanisms is required. These mechanisms are controlled by neural, genetic, and metabolic elements (2). Examples include the autonomic regulation of the internal milieu and DNA repair mechanisms, both of which can influence disease and aging states (2, 22). An example of a DNA repair mechanism is mismatch repair (a system that detects and corrects errors created during/after DNA replication), which, if defective, could negatively affect the mitochondria, telomeres, and epigenetics, therefore, accelerate the aging process (23).

Hormetic regulation as a hallmark of health

The term hormesis refers to the situation in which low doses of stressors induce an adaptive mechanism that enhances biological response to stimuli (2). Examples of this process include mitohormesis, where mild and transient mitochondrial stress produces beneficial effects. There are different methods by which this transient stress can be created; examples include caloric restriction, exercise, and intermittent fasting (2). This stress leads to the production of low levels of ROS, which induces the activation of protective genes like BCL2 and SOD2; this, in turn, produces cytoprotective effects and enhanced stress resistance.

Repair and regeneration response and their effect on health

These mechanisms are activated in response to a specific type of damage that needs to be repaired and regenerated to achieve a full recovery and retain functionality (2). Regeneration occurring at the tissue level is an example of this process. Another example is the self-renewal capacity of neural stem cells that generate glial cells and differentiated neurons (2). With aging, many regenerative and repair mechanisms decline and lose their efficiency due to causes like mutations (24). For example, genetic disruption of Tertc, a gene that encodes the RNA component of telomerase, leads to stem cell depletion coupled with impaired capacity to respond and repair damage (24). Additionally, disruption of the said gene also leads to a condition named clonal hematopoiesis of indeterminate potential (CHIP) (25). The latter is characterized by an increase in the numbers of a genetically distinct subpopulation of blood cells with somatic mutations. This leads to a higher risk of developing hematological cancer and atherosclerosis. CHIP is commonly observed in the elderly population (25).

Conclusions

Many factors contribute to health. They extend beyond physical wellness and to social and mental integrity. Health is a collective dynamic state that comprises several hallmarks, like repair and regeneration, regulation of rhythmic oscillations, and others. Disruption associated with any of the hallmarks of health by any external or internal factors could lead to a progressive state of stress that could lead to diseases or accelerated aging.

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