Hem » Articles » Health » The science behind Blue Zones: genetics and molecular pathways

As we continue our journey to uncover the secrets of Blue Zones and longevity, we are reminded of the captivating appeal these regions hold. In the previous article, we laid the foundation by introducing the concept of Blue Zones– extraordinary destinations in the world where people live remarkably longer, healthier lives than the global average. From the picturesque landscapes of Sardinia, Italy, to the serene shores of Okinawa, Japan, and the idyllic island of Ikaria, Greece, these regions invite us to explore their secrets.

Now, we look deeper into the science behind Blue Zones, focusing on the complex relationship between genetics, molecular pathways, and aging. By doing so, we hope to uncover more about the factors influencing longevity, leading us to new ways to measure and improve health as we age. 

Genetics and longevity

Longevity is a complex phenomenon influenced by a combination of genetic and environmental factors. While leading a healthy lifestyle can contribute to reaching one’s early 90s without major chronic diseases, genetics plays a significant role in achieving supercentenarian age (beyond 110 years) (1). 

Studies conducted in Blue Zones, regions known for their high prevalence of centenarians and supercentenarians, have shed light on the genetic aspects of longevity. Among the genes strongly associated with longevity are FOXO3A and the Apolipoprotein E2 (ApoE2) genotype (2). The ApoE2 genotype, which is protective against Alzheimer’s disease, is more prevalent in certain Blue Zones populations, such as Ikarians and Sardinian females. Conversely, the presence of the ApoE4 genotype increases the risk of Alzheimer’s disease, although at a higher frequency among Okinawan supercentenarians.

Human Leukocyte Antigen (HLA) haplotypes and genetic variants of the bitter taste receptor TAS2R38 have also shown correlations with longevity, further highlighting the intricate genetic landscape of long-life (3). Moreover, family history plays a crucial role, with siblings of centenarians demonstrating an increased probability of longevity, especially among Okinawans and Sardinians (4).

Mental function, a vital aspect of quality of life in the elderly, is also influenced by genetics. Studies have linked specific gene polymorphisms, such as Tumor Necrosis Factor Alpha (TNF-α) and Angiotensin Converting Enzyme (ACE) variants, to cognitive function and Alzheimer’s disease risk (5). Notably, individuals with certain genotypes have an elevated risk of dementia, emphasizing the genetic underpinnings of cognitive decline in aging populations.

By uncovering the genetic factors that contribute to longevity, we can gain valuable insights into aging and develop targeted interventions to promote healthy aging and longevity. 

With the genetic testing at NEM, you gain insights into your unique genetic blueprint and potential for longevity. Your longevity physician then utilizes this information to tailor your personalized action plan even further, ensuring optimal health. This bespoke approach empowers you with targeted strategies and interventions, enabling you to make informed decisions about your health journey and achieve your highest potential for a vibrant, healthy life.


Genetics and molecular pathways are closely related because genetics influences the composition and functioning of molecules within cells, which in turn form the basis of molecular pathways. Genetic information encoded in DNA determines the structure of proteins and other molecules involved in cellular processes. These molecules interact in specific sequences and patterns, forming complex pathways that regulate various biological functions such as metabolism, growth, and response to stimuli. Changes or variations in genes can alter the structure or function of these molecules, leading to disruptions in molecular pathways and potentially affecting cellular processes and overall health. Therefore, genetics plays a fundamental role in shaping molecular pathways and their functions within biological systems.  

Molecular Pathways: Insights into Cellular Aging

Studies conducted in Blue Zones have explored the molecular pathways implicated in the aging process. From a molecular perspective, aging is characterized by chronic cellular hyperfunction, resulting in the accumulation of damage to essential macromolecules such as DNA, proteins, and lipids  (1). This disruption of normal cellular function contributes to age-related diseases like cardiovascular disease (CVD) and cancer. Researchers have identified several molecular pathways and processes associated with cellular hyperfunction and aging, including chronic inflammation, reactive oxygen species (ROS), telomere length, DNA methylation, the IGF-1 and mTOR pathways, AMPK, and various microRNAs. By investigating these pathways in Blue Zones populations, scientists aim to uncover insights into the mechanisms underlying longevity and healthy aging in these regions. 

A molecular pathway is a series of actions among molecules in a cell that leads to a certain product or a change in the cell. It can trigger the assembly of new molecules, such as a fat or protein, turn genes on and off, or spur a cell to move (6).  

The molecular pathways associated with aging:

Chronic Inflammation

As we age, our bodies often experience chronic, low-grade inflammation, which can contribute to the development of age-related diseases like heart disease, Alzheimer’s, and diabetes. Studies in regions known for longevity, such as Blue Zones, have shown lower levels of inflammation among older adults, suggesting that managing inflammation could play a role in healthy aging (1).

Reactive oxygen species

Reactive oxygen species can directly damage cellular macromolecules, leading to cellular dysfunction and age-related diseases. Studies have shown that the plasma levels of lipid peroxide, an index of oxidative stress, in Okinawan centenarians are significantly lower compared to younger controls, suggesting that protective mechanisms against oxidative stress may contribute to longevity (7).

Epigenetic changes

Epigenetic changes, such as DNA methylation, can influence how genes are expressed without altering the underlying DNA sequence. Researchers studying centenarians in Blue Zones have discovered distinct patterns of DNA methylation associated with longevity, providing insights into the epigenetic factors that contribute to healthy aging (8).

The IGF-1 and mTOR Pathways

The IGF-1 and mTOR pathways are involved in regulating cellular growth and metabolism. Caloric restriction, a dietary intervention known to extend lifespan in various organisms, may influence these pathways. In Blue Zones, where plant-based diets and moderate caloric intake are common, researchers have observed potential connections between dietary habits and the regulation of aging-related pathways (1).


MicroRNAs (miRNA) are small molecules that help regulate gene expression. Studies have identified unique patterns of miRNA expression in centenarians from Blue Zones, suggesting that miRNAs may play a role in modulating aging-related processes (9).

Connecting Molecular Insights to Practical Strategies

The molecular pathways of aging offer a fascinating glimpse into the complex interplay of genetics, lifestyle, and environmental factors that shape our health and longevity.

At NEM, we understand the critical impact that these molecular insights can have on your health. By harnessing cutting-edge advances in epigenetics, we provide a comprehensive biological age test that analyzes the molecular mechanisms of aging. This personalized assessment reveals your unique aging processes. By integrating epigenetics, genetics, gut microbiome, and hormone assessments, we develop targeted interventions to promote your health and longevity.

Imagine harnessing these insights to enhance your health, wherever your journey takes you. That’s where membership at NEM, your digital longevity clinic, comes into play. With personalized guidance, virtual consultations, and evidence-based strategies tailored to your individual needs, we are dedicated to supporting you on your path toward a longer and healthier life. From nutritional advice to stress management techniques, we’re here to empower your performance, no matter where your adventures may take you.


Silviya Demerzhan, Ph.D.

Chief Scientific Officer, Nordic Executive Medicine
Medical review by: Dr. Mahir Vazda MD



  1. Kreouzi M, Theodorakis N, Constantinou C. Lessons Learned From BZ, Lifestyle Medicine Pillars and Beyond: An Update on the Contributions of Behavior and Genetics to Wellbeing and Longevity. Am J Lifestyle Med. 2022 Aug 20;15598276221118494. 
  2. Willcox BJ, Willcox DC, Suzuki M. Demographic, phenotypic, and genetic characteristics of centenarians in Okinawa and Japan: Part 1—centenarians in Okinawa. Mech Ageing Dev. 2017 Jul 1;165:75–9. 
  3. Melis M, Errigo A, Crnjar R, Pes GM, Tomassini Barbarossa I. TAS2R38 bitter taste receptor and attainment of exceptional longevity. Sci Rep. 2019 Dec 2;9:18047. 
  4. Willcox DC, Willcox BJ, Hsueh WC, Suzuki M. Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study. Age. 2006 Dec;28(4):313–32. 
  5. Georgiopoulos G, Chrysohoou C, Errigo A, Pes G, Metaxa V, Zaromytidou M, et al. Arterial aging mediates the effect of TNF-α and ACE polymorphisms on mental health in elderly individuals: insights from IKARIA study. QJM Int J Med. 2017 Sep 1;110(9):551–7. 
  6. Biological Pathways Fact Sheet [Internet]. [cited 2024 Apr 15]. Available from: https://www.genome.gov/about-genomics/fact-sheets/Biological-Pathways-Fact-Sheet
  7. Phillips EM, Frates EP, Park DJ. Lifestyle Medicine. Phys Med Rehabil Clin N Am. 2020 Nov;31(4):515–26. 
  8. McEwen LM, Morin AM, Edgar RD, MacIsaac JL, Jones MJ, Dow WH, et al. Differential DNA methylation and lymphocyte proportions in a Costa Rican high longevity region. Epigenetics Chromatin. 2017 Apr 27;10:21. 
  9. Liu T, Gatto NM, Chen Z, Qiu H, Lee G, Duerksen-Hughes P, et al. Vegetarian diets, circulating miRNA expression and healthspan in subjects living in the Blue Zone. Precis Clin Med. 2020 Dec;3(4):245–59.