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FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, December 17, 2025

The Hallmarks of Major Chronic Diseases: A Unified Systems Biology View

Richard Z. Cheng, M.D., Ph.D.
Editor-in-Chief, Orthomolecular Medicine News Service


Abstract

Over the past decade, "hallmarks" frameworks have been used to distill the core mechanisms underlying aging and cancer. Similar hallmark-style mechanisms are now recognized across nearly all major chronic diseases, including diabetes, fatty liver disease, cardiovascular disease, neurodegeneration, autoimmune disorders, chronic kidney disease, psychiatric illness, and metabolic syndrome. Despite different clinical labels, these conditions converge on a common set of biological disruptions: mitochondrial dysfunction, metabolic dysregulation, oxidative stress, immune imbalance, hormonal disruption, microbiome disturbances, and impaired detoxification and repair.

However, these hallmarks-while mechanistically accurate-do not identify the upstream causes that trigger them. Mechanisms describe what goes wrong inside cells, but not why. For example, the somatic mutation theory of cancer does not address what causes genomic instability, and mitochondrial dysfunction theories do not explain what initiates mitochondrial injury. Without identifying and correcting root causes, disease prevention or reversal is impossible.

The Ten Root Drivers of Chronic Disease proposed in Integrative Orthomolecular Medicine (IOM)-environmental toxins, dietary and metabolic stressors, micronutrient deficiencies, chronic infections and immune dysregulation, hormonal imbalance, lifestyle factors, psychosocial stress, developmental and early-life programming, genetic/epigenetic susceptibility, and medical iatrogenesis -provide the causal foundation that the hallmark frameworks lack. These root drivers generate the hallmark mechanisms, and their differing combinations determine disease expression across tissues and organ systems.

This unified systems-biology framework explains why diverse chronic diseases share similar mechanisms, and why restoring the cellular environment-through nutrient repletion, mitochondrial support, metabolic correction, detoxification, and immune balance-can improve or reverse multiple chronic conditions simultaneously.

As argued below, these shared mechanisms arise from a finite set of upstream biological insults-the Ten Root Drivers of Chronic Disease.


Introduction

The "Hallmarks of Aging" [1, 2] and "Hallmarks of Cancer" [3, 4] frameworks are now firmly established in biomedical science. These models have helped organize complex fields around a core set of biological processes-genomic instability, mitochondrial dysfunction, disrupted proteostasis, chronic inflammation, metabolic rewiring, and more.

However, the same mechanistic themes appear repeatedly across other chronic diseases, even though they are seldom presented as such in clinical medicine.

Diabetes, fatty liver disease, cardiovascular disease, neurodegenerative conditions, autoimmune disorders, chronic kidney disease, depression, and autism-each has its own hallmark-style literature, yet the shared biological roots remain underappreciated.

This review organizes these mechanisms side-by-side, demonstrating that chronic diseases represent divergent clinical endpoints of a convergent biological disturbance.


Hallmarks of Major Chronic Diseases

Below is a concise synthesis of the key hallmark mechanisms across major diseases, with representative citations.


1. Type 2 Diabetes & Metabolic Syndrome

Hallmarks [5-8]

  • Insulin resistance and impaired glucose metabolism
  • Mitochondrial dysfunction and reduced oxidative phosphorylation
  • Lipotoxicity and ectopic fat accumulation
  • Chronic low-grade inflammation ("metaflammation")
  • Oxidative stress and impaired redox regulation
  • β-cell stress and progressive loss of insulin secretion

2. Nonalcoholic Fatty Liver Disease (NAFLD) / NASH

Hallmarks [9-12]

  • Hepatic steatosis driven by lipotoxicity
  • Mitochondrial dysfunction and impaired β-oxidation
  • Oxidative stress and lipid peroxidation
  • Kupffer cell activation & inflammation
  • ER stress and unfolded protein response
  • Fibrogenic activation of stellate cells

3. Atherosclerosis / Coronary Artery Disease

Hallmarks [13-16]

  • Endothelial dysfunction
  • Oxidized LDL accumulation and foam-cell formation
  • Mitochondrial dysfunction in vascular cells
  • Chronic vascular inflammation
  • Impaired nitric oxide signaling
  • Immune-metabolic dysregulation

4. Heart Failure

Hallmarks [17-20]

  • Mitochondrial energy deficit
  • Impaired calcium handling
  • Oxidative stress
  • Neurohormonal dysregulation (RAAS, SNS)
  • Fibrosis and extracellular matrix remodeling
  • Metabolic inflexibility of cardiomyocytes

5. Alzheimer's Disease & Neurodegeneration

Hallmarks [21-24]

  • Brain insulin resistance ("type 3 diabetes")
  • Mitochondrial failure & impaired ATP generation
  • Neuroinflammation (microglial activation)
  • Oxidative stress
  • Loss of proteostasis (Aβ, tau pathology)
  • Vascular dysfunction and BBB breakdown

6. Parkinson's Disease

Hallmarks [25-27]

  • Mitochondrial Complex I impairment
  • Accumulation of α-synuclein
  • Oxidative stress
  • Dopaminergic neuron vulnerability
  • Neuroinflammation
  • Impaired autophagy/mitophagy

7. Autoimmune Diseases (RA, Hashimoto's, SLE, etc.)

Hallmarks [28-31]

  • Loss of immune tolerance
  • Barrier dysfunction (gut, skin, lung)
  • Aberrant antigen presentation
  • Mitochondrial dysfunction and ROS-driven inflammation
  • Chronic infections as triggers (molecular mimicry)
  • Dysbiosis-driven immune imbalance

8. Chronic Kidney Disease (CKD)

Hallmarks [32-35]

  • Mitochondrial dysfunction in renal tubular cells
  • Oxidative stress and redox imbalance
  • Chronic inflammation
  • Toxin accumulation (uremic metabolites)
  • Metabolic acidosis and ammoniagenesis stress
  • Progressive fibrosis

9. Depression & Mood Disorders

Hallmarks [36-39]

  • Neuroinflammation
  • Oxidative stress
  • Mitochondrial energy impairment
  • HPA-axis dysregulation (cortisol)
  • Impaired neurogenesis
  • Gut-brain axis disruption

10. Autism Spectrum Disorder (ASD)

Hallmarks [40-42]

  • Mitochondrial dysfunction (high prevalence in ASD)
  • Oxidative stress
  • Neuroinflammation & microglial activation
  • Immune dysregulation
  • Synaptic signaling abnormalities
  • Gut dysbiosis & increased intestinal permeability

11. Obesity

Hallmarks [43-46]

  • Chronic inflammation ("adipoinflammation")
  • Hormonal dysregulation (leptin/insulin resistance)
  • Mitochondrial overload & incomplete oxidation
  • Adipose tissue hypoxia
  • Oxidative stress
  • Altered gut microbiome

12. Hypertension

Hallmarks [47-50]

  • Endothelial dysfunction
  • Vascular inflammation
  • RAAS system overactivation
  • Oxidative stress
  • Mitochondrial impairment in smooth muscle cells
  • Microbiome-mediated metabolic signals

13. Cancer (Hallmarks of Cancer)

Hallmarks [3, 4, 51]

  • Sustaining proliferative signaling
  • Evading apoptosis
  • Reprogramming cellular metabolism
  • Genome instability
  • Tumor-promoting inflammation
  • Immune evasion

14. Aging (Hallmarks of Aging)

Hallmarks [1, 2]

  • Genomic instability
  • Epigenetic alteration
  • Loss of proteostasis
  • Deregulated nutrient sensing
  • Mitochondrial dysfunction
  • Cellular senescence
  • Stem-cell exhaustion
  • Altered intercellular communication

The Ten Root Drivers of Chronic Disease: The Upstream Causes Behind All Hallmark Mechanisms

While hallmark mechanisms explain how chronic diseases develop at the cellular level, they do not reveal why these mechanisms arise. Integrative Orthomolecular Medicine (IOM) identifies Ten Root Drivers of Chronic Disease-the true upstream biological insults that generate the hallmark mechanisms observed across all major chronic illnesses [52]. These root drivers are:

  1. Environmental & Occupational Toxins
  2. Dietary and Metabolic Stressors
  3. Micronutrient Deficiencies
  4. Chronic Infections and Immune Dysregulation
  5. Hormonal Imbalance and Endocrine Disruption
  6. Lifestyle and Behavioral Factors
  7. Psychosocial and Emotional Stress
  8. Developmental and Early-Life Programming
  9. Genetic and Epigenetic Susceptibility
  10. Medical Iatrogenesis

Different combinations and intensities of these ten drivers initiate the hallmark mechanisms-mitochondrial dysfunction, oxidative stress, metabolic dysregulation, immune imbalance, impaired detoxification, and others. Thus, chronic diseases are not fundamentally separate entities but diverse expressions of the same upstream biological disturbances acting on different tissues and organ systems.


Cross-Disease Convergence: The Unifying Pattern

When the hallmark frameworks of major chronic diseases are compared side-by-side, they reveal a striking convergence at the mechanistic level. Despite different clinical diagnoses, these diseases consistently involve disruptions in the same fundamental cellular processes:

Shared Mechanistic Axes

  • Mitochondrial dysfunction
  • Metabolic dysregulation
  • Oxidative stress / redox imbalance
  • Immune dysfunction
  • Hormonal / neuroendocrine imbalance
  • Microbiome disruption
  • Impaired detoxification
  • Fibrosis & extracellular matrix pathology

Critically, every one of these convergent mechanisms can be traced back to the same upstream origins: the Ten Root Drivers of Chronic Disease [52]. These root drivers initiate the mechanistic failures, and the specific combination and intensity of root drivers in an individual determine which mechanisms dominate-and thus which disease develops.

This convergence explains why:

  • patients often have multiple chronic diseases simultaneously
  • diseases improve with root-cause interventions
  • orthomolecular therapies-nutrients, detoxification, metabolic correction-have cross-disease benefits

Implications for Integrative Orthomolecular Medicine (IOM)

This unified systems biology perspective supports the IOM principle that:

Chronic diseases are not many diseases, but different manifestations of the same underlying biological imbalances.

Addressing these imbalances-nutrients, mitochondria, inflammation, toxins, hormones, metabolism, microbiome-often leads to improvement across multiple diagnoses simultaneously.

This is why IOM frequently achieves outcomes unexplained by disease-specific medicine, such as:

  • reversal of ASCVD [53]
  • dramatic improvements in diabetes
  • stabilizing autoimmune disease
  • cognitive improvement in neurodegenerative disease
  • cancer remissions when combined with metabolic therapies [54]

Conclusion

Hallmark frameworks across chronic diseases reveal a profound truth: the biology of chronic illness is unified, not fragmented.

Instead of treating diseases as isolated entities, a root-cause approach recognizes the true upstream drivers-environmental toxins, metabolic and dietary stressors, micronutrient deficiencies, chronic infections and immune dysregulation, hormonal imbalance, lifestyle and psychosocial stress, developmental programming, genetic/epigenetic susceptibility, and medical iatrogenesis-which initiate the hallmark mechanisms that ultimately produce chronic disease. When these root drivers are identified and corrected, the downstream mechanisms they disrupt-such as mitochondrial dysfunction, metabolic instability, oxidative stress, and impaired repair-can begin to normalize, allowing the body's intrinsic healing processes to re-emerge.

This perspective forms the scientific foundation of Integrative Orthomolecular Medicine, offering a coherent, mechanistically grounded path toward genuine disease reversal and longevity.


About the Author

Richard Z. Cheng, M.D., Ph.D. - Editor-in-Chief, Orthomolecular Medicine News Service (orthomolecular.org)

Dr. Cheng is a U.S.-based, NIH-trained, board-certified physician specializing in integrative cancer therapy, orthomolecular medicine, functional & anti-aging medicine. He maintains active practices in both the United States and China.

A Hall of Fame inductee of the International Society for Orthomolecular Medicine and a Fellow of the American Academy of Anti-Aging & Regenerative Medicine (A4M), Dr. Cheng is widely recognized for his work on nutrition-based, root-cause reversal of chronic disease. He co-founded the China Low Carb Medicine Alliance and serves as an expert reviewer for the South Carolina Board of Medical Examiners.

Dr. Cheng is the author of the forthcoming book 21st Century Medicine: Integrative Orthomolecular Medicine for Chronic Disease Reversal and Longevity, which outlines a unified framework combining functional medicine, metabolic therapy, and orthomolecular nutrition.

He also offers online Integrative Orthomolecular Medicine consultation services.
📰 Follow his latest insights and book chapters on Substack: https://substack.com/@rzchengmd


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Felix I. D. Konotey-Ahulu, M.D., FRCP (Ghana)
Peter H. Lauda, M.D. (Austria)
Fabrice Leu, N.D., (Switzerland)
Alan Lien, Ph.D. (Taiwan)
Homer Lim, M.D. (Philippines)
Stuart Lindsey, Pharm.D. (USA)
Pedro Gonzalez Lombana, M.D., Ph.D. (Colombia)
Diana MacKay (Gifford-Jones), M.P.P. (Canada)
Victor A. Marcial-Vega, M.D. (Puerto Rico)
Juan Manuel Martinez, M.D. (Colombia)
Mignonne Mary, M.D. (USA)
Dr.Aarti Midha M.D., ABAARM (India)
Jorge R. Miranda-Massari, Pharm.D. (Puerto Rico)
Karin Munsterhjelm-Ahumada, M.D. (Finland)
Sarah Myhill, MB, BS (United Kingdom)
Tahar Naili, M.D. (Algeria)
Zhiwei Ning, M.D., Ph.D. (China)
Zhiyong Peng, M.D. (China)
Pawel Pludowski, M.D. (Poland)
Isabella Akyinbah Quakyi, Ph.D. (Ghana)
Selvam Rengasamy, MBBS, FRCOG (Malaysia)
Jeffrey A. Ruterbusch, D.O. (USA)
Gert E. Schuitemaker, Ph.D. (Netherlands)
Thomas N. Seyfried, Ph.D. (USA)
Han Ping Shi, M.D., Ph.D. (China)
T.E. Gabriel Stewart, M.B.B.CH. (Ireland)
Jagan Nathan Vamanan, M.D. (India)
Dr. Sunil Wimalawansa, M.D., Ph.D. (Sri Lanka)

Andrew W. Saul, Ph.D. (USA), Founding & Former Editor
Richard Cheng, M.D., Ph.D. (USA), Editor-In-Chief
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