Cover Photo By Zac Durant

At its simplest health is the absence of a disease or disorder — that is a negative definition — and scientists have spent decades trying to study and define “the disease” i.e. The Hallmarks of Cancer, or even The Hallmarks of Aging the product of accumulating disorders. At the end, this negative definition of health has led all of us to believe, so far, that health is just a consequence of being young and without any sing of a disease. 

But is it really like this? Is health just the absence of a disease? After all, healthy people can have an accident, get an infection but then recover and be healthy. And most importantly, young people can be unhealthy, and old people can be healthy. 

Accordingly, in order to address this issue, two biologists Carlos López Otín and Guido Kroemer have decided to define health in positive terms. That is not any more as the absence of a disease but as the presence of the Hallmarks of Health. In their paper, published in Cell on January 2021, they are telling us that health resides in the overall organization of the meta-organism that integrates the host and the microbiota”, transcending in this way the boundaries of the minimal definition “absences of a disease”.

Let’s see now the hallmarks of health by Carlos and Guido.

Hallmark 1: Integrity of Barriers

None of us would exist 

  • without the “barriers” (i.e. intestinal, respiratory and cutaneous) that shield us from our environment, and 
  • without the subcellular, cellular and inter-cellular compartments, that allow for vital electrophysiological and chemical gradients to form at the levels of organelles (i.e. mitochondria and nuclei), cell membranes and internal barriers (i.e. blood-brain). 

This compartmentalization in every living organism, as a consequence of the reduction of entropy associated with a state of disorder or randomness, is actually what allows the maintenance of health. 

For example, your skin is the largest organ of your body and has many roles that are essential for your health, since: 

  • is protecting you against microbial pathogens, physical/chemical damage and excessive water loss,  
  • is providing you with thermal regulation, 
  • is selectively absorbing specific ultraviolet wavelengths for your vitamin D synthesis, 
  • is playing a critical role in sensory perception and immunologic surveillance, and
  • is hosting a multitude of friendly bacterial species that provide health benefits by boosting multiple aspects of skin’s barrier function. 

Any alteration or deficiency in the different regulatory and structural components of the molecular network of your skin, just described, can cause severe pathologies. 

Hallmark 2: Containment of Local Perturbations

Your skin, as well as your entire body, is constantly subjected to “perturbations” that can originate from:

  • intrinsic ‘‘accidents’’ occurring during incomplete and asymmetric cellular division (failed DNA repair and accumulation of dysfunctional organelles or proteins), and from 
  • external agents including invading pathogens, chemical or physical trauma. 

All these “perturbations” can compromise your barriers; therefore in order to maintain a “healthy state” it is essential to confine the perturbation, avoiding its spread to a systemic level. 

For example, a local trauma such as cut or burn in your skin normally gives rise to a rapid wound healing response designed to repair the trauma, activating also responses like local inflammation, capillary angiogenesis and compensatory proliferation of fibroblasts and epithelial cells (barrier healing). When the wound healing capacity is reduced, as it occurs in the elderly, this increases the susceptibility to chronic and systemic complications. 

Additionally, the skin has also the capacity to delimitate foreign bodies and protect you from invading pathogens, while conferring at the same time innate immune responses, self-limited inflammation and anticancer immune-surveillance.

Hallmark 3: Recycling and Turnover

But apart the maintenance of barrier functions and containment of their local perturbations, each of your subcellular/cellular components undergoes modifications due to endogenous damage (i.e. oxidative modifications or spontaneous denaturation and degradation of macromolecules). So, in order to avoid degeneration most cell types and their cellular components must be constantly recycled and replaced without errors.

For example, the keratinocytes located at the surface of your skin undergo desquamation and they are replaced with proliferating cells in the basal level that move upward while going through terminal differentiation and keratinization (Cell Death, Removal, and Replacement). Overall, a healthy skin must maintain its barrier, contain any local perturbations and recycle itself.  

So, let’s move know to the meta-organism and its ability to be healthy.     

Hallmark 4: Integration of Circuitries

All multicellular organisms are “meta-organisms” encompassing the host and the bacteria, archaea, fungi, phages, viruses and parasites that inhabit them, all build in a way that facilitates the integration of circuitries (Intracellular Circuitries, Inside-Outside Communication and Outside-Inside Communication), within and between the different layers of this meta-organization, in order to maintain the stability of the whole system all the time.

For example, your gut’s microbiota (an ecological community of commensal, symbiotic and pathogenic microorganisms) influences 

  • digestion and absorption of nutrients, local synthesis of vitamins, gut motility, clearance of pathogens, elimination of xenobiotics, inflammation and colon carcinogenesis, and exerts
  • long-distance effects via neuroendocrine circuitries, by determining the response of the inflammatory and immune system, to prevent overt inflammation, autoimmunity, allergy and oncogenesis. 

So, it is not a surprise that major diseases including obesity, cardio-metabolic disorders, cancer and even psychiatric conditions have all been linked to “modifications” in the composition of the gut microbiota. After all, we are what we eat.

Hallmark 5: Rhythmic Oscillations

Moreover, the timing and the precise order of all molecular and cellular events (i.e. embryonic development, regeneration) are essential for life and for maintenance of health. Ultradian, circadian and infradian oscillations provide rhythmicity to all your physiological functions, thus contributing to your health.

Any alterations of your utradian rhythms (with a periodicity shorter than 24 h), infradian rhythms (with a periodicity well above 1 day) and circadian rhythms —namely the evolutionarily conserved and most studied circadian clocks— are associated with an increased risk of pathologies ranging from cancer and depression to diabetes and dysbiosis (when the gut bacteria become imbalanced).

For example, non-salutary dietary habits and eating schedules disturb the alignment of the feeding-fasting cycles to the circadian cycle and cause metabolic perturbations. But hopefully, nutritional interventions, such as time-restricted feeding, intermittent fasting and ketogenic diets can improve metabolic health in part by restoring the temporal orchestration of our circadian clocks. 

Hallmark 6: Homeostatic Resilience

Health is also about maintaining myriads of biological parameters (blood pH, serum osmolarity, arterial oxygen and carbon dioxide, glycaemia, blood pressure, body temperature, body weight, or the concentrations of hormones) at homeostatic resilience, which is close to a constant level. Homeostatic resilience involves genetic, neural, metabolic, immunological and microbiome-based mechanisms.

Hallmark 7: Hormetic Regulation

Hormesis, the 7thhallmark, a biphasic response to exposure to increasing amounts of a substance or condition — namely low doses of toxins elicit a protective response that prevent the organism from experiencing harm on exposure to a higher dose of the same toxins — is also affecting your health. 

For example, a mild/transient mitochondrial stress (exercise, caloric restriction, intermittent fasting and dietary phytochemicals) induces beneficial responses in the brain, by causing the production of low levels of mitochondrial oxidants (ROS) that promote the expression of protective genes in neurons safeguarding them against more severe oxidative stress, while diminishing the risk of oxidative and ischemic injuries. 

Hallmark 8: Repair and Regeneration

Finally, in contrast to cell turnover (3rdhallmark) that occurs without specific stimulation, repair and regeneration are stimulated responses that occur in response to a precise type of damage inflicted to the system. In particular, cells have developed intricate signaling networks like DNA Damage and Repair, Protein Damage and ProteostasisER/Mitochondrial/ Lysosomal Stress Responses, Tissue-Level Regeneration and Cell Identity Reprogramming that systematically sense and react to specific types of damage in all strata of the body.

Clearly, all these hallmarks do not exist in isolation since they are highly interconnected at multiple levels; therefore the manifestation of a disease is usually connected to the loss of more than one of the hallmarks of health. 

That means that health is a state of perfect balance between all hallmarks and your ability to bounce back from adversity, or as the authors put it “health is the integration of many, if not all, of the eight hallmarks” in a complicated world where your cells and their microbiome have learned to co-exist billions of years ago  

Thanks for reading.

*Disclaimer: This information is for educational purposes only.



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