Living Beyond 100 Years
Mayka Sanchez, PhD
It is not my case, but some people have grandparents that lived beyond 105 and even beyond 110 years! These people are named semi-supercentenarians and supercentenarians, respectively. Healthy aging and exceptional longevity (people who live more than 100 years) are deeply related, as clinical and biochemical data on centenarians showed that they can be considered as a paradigm of healthy aging as they avoid or largely postpone all major age-related diseases.
You (and other scientists) may ask yourself: How do they manage to live for so many years? Is it the good weather, enough exercise, good wine… is it in their GENES?
Genetic variability on human extreme longevity is supported by the fact that individuals surviving to the age of 105 have a chance to have a sibling surviving to that age of 35 times greater than the control population. Therefore, some genetic factors should contribute to this trait. However, longevity is a complex trait for which gene-environment interactions (that are population-specific) as well as the complex interplay of multiple genes and pathways play a major role. Therefore, well controlled studies should incorporate individuals with well-advanced age (more than 105 years old) and controls in a homogenous population all matched for geographical origin.
This is exactly what has been done by Italian scientists, including some belonging to our society, to have some answers to the genetic contribution on extreme longevity. They shared what they found in an e-LIFE article.
Whole-genome sequencing analysis of semi-supercentenarians. Elife. 2021 May 4;10:e57849. doi: 10.7554/eLife.57849. PMID: 33941312; PMCID: PMC8096429.
In this work, the authors generated and analyzed the first Whole Genome sequencing (WGS) data with high coverage (90X) in a cohort of 81 semi-supercentenarians and supercentenarians [105+/110+] recruited across the entire Italian peninsula together with a control cohort of 36 healthy geographically matched individuals. In addition, the use recently published data (Giuliani et al., 2018b) as a second independent cohort of 333 centenarians (>100 years) and 358 geographically matched controls to replicate their results. The aim of this study was to identify the genetic determinants of extreme longevity in humans.
The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load in semi-supercentenarians if compared to younger healthy controls).
The authors found that in their WGS association study five SNP common variants were the top association signals. Those SNPs are located in the same large block of linkage disequilibrium at chromosome 7 containing STK17A, COA1 and BLVRA genes. One of these five variants, rs10279856, may play a regulatory role in the region. The SNP rs10279856 seems to play a pleiotropic role as it is an eQTL for STK17A gene and for two other genes (COA1 and BLVRA).
The most frequent alleles in 105+/110+ people (rs10279856-G reference allele and rs3779059-A, rs849166-A, rs849175-A alternative alleles) were associated with an increase in SKT17A gene expression in heart and other tissues, reduced expression of COA1 gene in several tissues and increased expression of BLVRA in whole blood, while reduced expression in artery and esophagus.
STK17A gene, Serine/Threonine Kinase 17a (Apoptosis-Inducing), is involved in DNA damage response and positive regulation of apoptotic process (Sanjo et al., 1998) and regulation of reactive oxygen species (ROS) metabolic process. Overall, the authors’ findings indicate that aging and longevity might be due to an increase in SKT17A expression due to the presence of favorable genetic variants in supercentenarians, by a mechanism which maintains DNA damage responses, favoring healthy aging.
COA1 gene is a component of the MITRAC complex (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) that regulates cytochrome c oxidase assembly. MITRAC complexes regulate both the translation of mitochondrial-encoded components and the assembly of nuclear-translation of mitochondrial-encoded components and the assembly of nuclear-encoded components imported in mitochondrion and in particular the respiratory chain complexes I and IV. Authors do not address why the reduced expression of COA1 gene due to the most frequent alleles present in supercentenarians influences healthy aging. However, it is known that apoptosis is regulated by the redox state of cytosolic cytochrome c (a heme containing protein), that is oxidized by mitochondrial cytochrome c oxidase (COX, also referred to as complex IV).
Therefore, new exploratory roles are open to study how oxidative stress is prevented or less deleterious in supercentenarian people. Now we know that mitochondria are not only necessary for ATP generation, but it seems that mitochondrial dynamics have a crucial role for human longevity and health.
More to say about redox status and longevity…
The protein encoded by the BLVRA (Biliverdin reductase A) gene belongs to the biliverdin reductase family, members of which catalyze the conversion of biliverdin to bilirubin. Recently, it has been established that a redox cycle based on BLVRA activity provides physiologic cytoprotection as BLVRA depletion exacerbates the formation of reactive oxygen species (ROS) and increase cell death. Interestingly, BLVRA contributes significantly to modulation of the aging process by adjusting the cellular oxidative status (Kim et al., 2011). Moreover, Biliverdin reductase A was previously shown to regulate the inflammatory response to endotoxin, by inhibiting Toll-like receptor 4 (TLR4) gene expression (Wegiel et al., 2011). How low levels of BLVRA in whole blood of supercentenarians exactly contribute to longevity is a question that remains to be explored.
Finally, in this article it was also shown that supercentenarians individuals are characterized by a lower prevalence of somatic mutations in six out of seven genes involved in hematopoietic malignancies. Therefore, it seems that not only a good genetic signature in DNA repair mechanisms is needed for longevity but also clonal haematopoiesis is a crucial player for healthy aging.
Overall, living beyond 100 years seems to be a game in which our cells should escape from mutations impairing the function of genes involved in stress response and DNA repair, to avoid accumulation of DNA damage and to delay age-related decline. But if your cells cannot do that, do not worry too much as one can say in Italian: “Non c’é male che duri cent’anni” and you would be dead by that time (I mean in 100 years from now).
posted: May 25, 2021