Whole Genome Sequencing of Supercentenarians in Search of Genetic Contributions to Longevity

Researchers here report on DNA sequencing carried out in a (necessarily small) number of supercentenarians (age 110 and over) and semi-supercentenarians (age 105 to 109), and identification of genetic variants associated with DNA repair and clonal hematopoiesis that are more common in these survivors to late old age. We should treat this all as being highly speculative, however.

Firstly, near all genetic variants that have been found to correlate with age in one study population fail to replicate in other study populations, and this is true of studies with cohorts consisting of thousands of individuals. The study here used a primary cohort of less than 100 individuals over the age of 100. This is ever the challenge in research focused on extreme old age: very few people make it that far. There was a secondary validation cohort of a few hundred centenarians, but I'm not sure that should increase our confidence in the data, given the existence of other studies that did much the same thing and still failed to replicate.

Secondly, given the identification of a genetic variant, near everything one can say about it is quite speculative in advance of much more detailed research into how exactly that variant changes cell behavior. Lastly, the most robust data established to date on the contributions of genetic variants to human longevity, with studies pulling from very large national databases such as the UK Biobank, suggests that genetics has only a minor role to play. Lifestyle choices and exposure to pathogens are the dominant factors. In the case of long-lived families, cultural transmission of lifestyle choices relating to longevity seems a more plausible explanation than genetics, given the rest of the literature as it presently stands.

Whole-genome sequencing analysis of semi-supercentenarians

The study of human extreme longevity constitutes a model useful to assess the impact of genetic variability on this trait according to the following considerations. First, researchers showed that, considering individuals surviving to age 105 years, the relative risk of sibling surviving to 105 years is 35 times the chance of living to age 105 of the control population. These data suggest a more potent genetic contributions if samples are recruited in the last percentile of survival - the power to detect association with longevity is greater for centenarians versus nonagenarians samples of the same birth cohort. Second, despite different definitions and opinion regarding the concept of healthy aging, the 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. Thus, healthy aging and exceptional longevity (people who live more than 100 years) are deeply related.

Cardiovascular diseases (CVDs) constitute the first cause of death globally and many studies highlighted the intersection between CVDs and aging as cardiac and vascular aging are considered the major risk factor for CVDs. Many molecular mechanisms have been described as hallmarks of this process such as cellular senescence, genomic instability, chromatin remodeling macromolecular damage, and mitochondrial oxidative stress, perturbed proteostasis, vascular and systemic chronic inflammation, among others. An emerging common mechanism between aging and CVD is the accumulation with age of somatic mutations. An age-related expansion of hematopoietic clones characterized by disruptive somatic mutations in few recurrent genes (such as DNMT3A, TET2, ASXL1, PPM1D, TP53), conferring to the mutated cells a selective proliferative advantage. The expansion of such mutated clones ('clonal hematopoiesis of indeterminate potential', CHIP), has been associated to an acceleration of the atherosclerotic process, an increased risk of haematological malignancies, ischemic stroke, coronary heart disease, and all-cause mortality.

In this study, we generated and analyzed the first whole genome sequencing data with high coverage (90X) in a cohort of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) recruited across the entire Italian peninsula together with a control cohort of 36 healthy geographically matched individuals (Northern, Central, and Southern Italy) (mean age 68.0 ± 5.9). Data recently published with a second independent cohort of 333 centenarians (100+ years) and 358 geographically matched controls (Northern, Central, and Southern Italy) were used to replicate our results.

We identified five common variants (rs7456688, rs10257700, rs10279856, rs69685881, and rs7805969), all in the same region located between COA1 gene and STK17A gene. The gene-based analysis of sequencing data identified STK17A gene as the most significant gene that is validated in the second cohort.

STK17A is involved in DNA damage response and positive regulation of apoptotic process and regulation of reactive oxygen species (ROS) metabolic process. Moreover, it has been suggested that STK17A can be activated in response to external stimuli such as UV radiation and drugs. Data suggests a possible role of this gene in DNA damage response as the variants associated to an increase of SKT17A expression (in-silico prediction) were found more frequent in 105+/110+ than controls. Researchers have proposed the following sequence of events that occurs during aging: (i) mutation impairs function of genes involved in stress response and DNA repair; (2) DNA repair became more error-prone leading to accumulation of DNA damage; (3) this process accelerates age-related decline. In this model, genetic variants in STK17A may maintain DNA damage responses in 105+/110+, favoring healthy aging.

Comments

There very well could be a few mutations enhancing mitophagy and other repair mechanisms but will they be a good candidate for treatment, even if they were clearly identified?

Posted by: Cuberat at May 12th, 2021 5:29 PM

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