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.
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.
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
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).
