Frontiers | Revealing the secrets of Blue Zones
Aging is influenced by cellular senescence mechanisms that are associated with oxidative stress. Oxidative stress is the imbalance between antioxidants and free radicals. This imbalance affects enzyme activities and causes mitochondrial dysfunction. It also slows down cellular energy production and disrupts cellular homeostasis. Additionally, oxidative stress stimulates inflammation, increases the number of point mutations, and alters intercellular communication. It can lead to epigenetic alterations, genomic instability, telomere attrition, and loss of proteostasis. Ultimately, these factors contribute to aging and the development of chronic diseases. Glucose-6-phosphate dehydrogenase (G6PD) is an antioxidant enzyme that protects cells from oxidative and nitrosative damage. It helps restore redox balance, preserve macromolecule function, and rescue cells from cellular senescence, autophagy, and stress-induced apoptosis. G6PD is considered an anti-senescence enzyme. The World Health Organization classifies G6PD variants into five groups based on the enzyme’s residual activity. The first four classes are categorized according to the degree of G6PD deficiency, while the fifth class includes variants with enzyme activities greater than normal. Increased G6PD activity does not exhibit clinical manifestations. Consequently, the full spectrum of mutations and the prevalence of increased G6PD activity in the population remain unknown. The world’s oldest and healthiest people live in Blue Zones. These comprise isolated populations, and there may be a geographic prevalence of high-activity G6PD variants that protect against oxidative stress-induced senescence. To uncover the secret of centenarians’ longevity, additional research is needed to determine whether the hidden factor is the increased activity of the G6PD enzyme.
Senescence is the process that causes aging and results from a lifetime of exposure to various stresses, including reactive oxygen and nitrogen species (RONS) (Calcinotto et al., 2019). Oxidative stress is the imbalance between the production and elimination of RONS that can induce senescence and age-related pathologies (Nousis et al., 2023). Aging and senescence are associated with multiple biological changes. These include loss of protein homeostasis, DNA damage, lysosomal dysfunction, and epigenetic alterations (Wyss-Coray, 2016). Chronic inflammation, increased genomic instability, altered metabolism, and cellular waste accumulation also play crucial roles (Daniele et al., 2018). Additional factors include changes in microbiota composition, increased gut permeability (Ferrucci and Fabbri, 2018), and dysfunctional mitochondria, leading to decreased energy production (Guo et al., 2023). Other key aspects are the deregulation of nutrient-sensing and damaged telomeres. Moreover, decreased NAD+ concentration, increased NAD+ consumption, and prolonged PARP activation contribute to aging (Akbari et al., 2019). Decreased enzyme activities and alterations in enzyme kinetic mechanisms have also been observed in aging (Ulusu et al., 2005; Ulusu and Tandogan, 2006; García-Domínguez et al., 2022). Furthermore, many of these molecular mechanisms are triggered by increased concentrations of RONS and decreased levels of radical scavenging molecules, such as glutathione (GSH), or by a decreased GSH/GSSG ratio (López-Navarro et al., 2020). NADP-reducing enzymes, particularly glucose-6-phosphate dehydrogenase (G6PD), and enzymes that depend on GSH metabolism play fundamental roles in preventing oxidative stress. They help maintain the redox status of cells, which is essential for cell survival and influences aging (Akbay et al., 2004; Stanton, 2012; Gök et al., 2016; Ulusu et al., 2017; Dore et al., 2021; Chen et al., 2022). G6PD-deficient cells exhibit growth retardation (Cheng et al., 2004) and increased accumulation of oxidative DNA damage. Additionally, these cells show increased sensitivity to oxidant-induced senescence (Wu et al., 2009), metabolic alterations, and cell death (Ho et al., 2013). Deficiencies in glutathione synthesis are associated with oxidative stress, as well as with normal aging and senescence (Sekhar et al., 2011; Aoyama and Nakaki, 2013). Antioxidants and radical scavenging enzymes can prevent RONS-induced cellular damage and are needed for a good healthy life, including G6PD, which protects from radicals and is one of the key factors in increasing lifespan (Nóbrega-Pereira et al., 2016; Warraich et al., 2020).
