Using whole-genome sequencing, researchers have explored the link between genetic variation and extreme longevity in people aged 105 and over.
The study of healthy ageing is critical to understand age-associated diseases, such as cardiovascular disease, cancer or dementia. The geroscience perspective, considers ageing as the major common risk factor for several diseases. However, to date, very few genetic studies have explored this theory to find a common mechanism between ageing and age-related diseases.
The study of extreme longevity is a useful model to determine the impact of genetic variability on this trait. However, in the last decade, many of the approaches that researchers have applied to study human longevity have fallen short. Nonetheless, with the declining costs of sequencing technologies, whole-genome sequencing represents an important approach to study genomic variability within individuals. To date, there have only been a few studies of human longevity that have harnessed whole-genome sequencing. These studies however did not consider a group of controls from the general population.
Analysing people aged 105 and over
In a recent study, published in eLife, researchers generated and analysed whole-genome sequencing data from a cohort of 81 semi-supercentenarians (105+) and supercentenarians (110+) in Italy. They also recruited a control cohort of 36 healthy geographically matched individuals with a mean age of 68. They then cross-checked their results with genetic data from a previous study. This previous study analysed 333 Italian people aged over 100 years old and 358 people aged around 60 years old.
The team found five common genetic changes that were more frequent in the 105+/110+ age groups. These changes were also found in the individuals over 100 years from the published data. Some of the most frequent genetic changes found were linked to increased activity in the STK17A gene. This gene is involved in maintaining the health of cells. Furthermore, other frequent genetic changes were linked to reduced activity in the COA1 gene. This gene is important in the crosstalk between the nucleus and mitochondria (whose dysfunction is a key factor in ageing). The gene, BLVRA, was also found to be linked to increased expression in some tissues and is important in eliminating dangerous reactive oxygen species. The researchers also measured naturally occurring somatic mutations, revealing that people aged over 105 generally had a low burden of mutations.
Overall, the results showed that individuals over 105 have a unique genetic background that makes their bodies more efficient at repairing DNA. These findings were seen in both germline data and somatic patterns. The results were also replicated in a second independent cohort.
Senior author Claudio Franceschi, concluded:
“Our results suggest that DNA repair mechanisms and a low burden of mutations in specific genes are two central mechanisms that have protected people who have reached extreme longevity from age-related diseases.”
Image credit: By Andrii Zastrozhnov – canva