Unique genes of canine “centenarians”

In humans, the age of 100 years is considered special by most people. Indeed, in terms of the human lifespan, centenarians live at least 40-70% longer than the average. The corresponding age in dogs would be 17-22 years, depending on the breed, making these Methuselah dogs an exceptional model for the study of aging and longevity.

The longer an individual lives the greater the impact genetics has on its lifespan. The genome of the oldest old “methuselahs” is enriched with gene variants that can elongate lifespan and, most importantly, according to studies, contains fewer variants that can predispose the individuals to certain diseases. Most longevity genes have functions linked to cellular homeostasis, energy production, and DNA damage repair mechanisms. The identification of such genes usually requires a huge amount of data to be analyzed to search for connections between the longer lifespan of individuals and the occurrence of certain gene variants in a population. A recent paper from the Senior Family Dog Project at the Eötvös Loránd University, Hungary, has reported the identification of gene variants that could be linked to the extreme old age of some dogs. The uniqueness of the genetic analysis done in this study lies in the applied method: the researchers sequenced, analyzed and made publicly available the full genome of the two Methuselah dogs. The results could represent a main first step to open up new directions for investigations that search for the key factors behind healthy aging and longevity in dogs.

Buksi (left) and Kedves (right, with Sara Sandor, geneticist)

Buksi, an intact male mixed-breed lived 27 years in a farm in Sárrétudvari (Pegazus Lovarda, Hungary), and Kedves, a spayed female mixed-breed lived 22 years in an animal shelter at Ócsa (Szent Ferenc Animal Shelter Foundation; Hungary). The researchers have become aware of the two extremely old dogs thanks to local veterinarians and shelter volunteers who wanted to introduce these really special dogs to a wider audience through the media. Usually, genetic investigations can be performed from buccal swabs, which are easy to collect from the animals and won’t cause any inconvenience – apart from a minor tickling. However, the researchers wanted to make sure that they can unfold the full potential their genome could hold, so they also collected a small amount of blood with the consent of the owners and with the help of experienced veterinarians. Blood is a reliable source of genomic DNA and could be superior to buccal swabs in quality, when high-throughput genomic techniques, like genome-sequencing, are to be used.

DNA collecting from Buksi

Sadly, both Kedves (†22) and Buksi (†27) have already passed away, but they left a truly unique legacy, since their complete DNA was extracted from their samples and then sequenced by the scientists. The genome of the dog contains approximately 2.5 billion genetic letters (so-called base pairs) – and every one of them twice, because each chromosome (i. e. the compact form of the DNA) is present twice in every individual, save the sex chromosome of males, who have X-Y chromosomes, instead of the X-X chromosomes of females. This results in a total of 5 billion genetic letters per individual, and its reading and the complete reconstruction of the genetic code requires enormous computational capacities. One file containing the raw sequence data of a single individual requires more than 100 GB of storage space on any computer’s hard drive.

“We analyzed this data using one of the Hungarian supercomputers, searching for the gene variants in the Methuselah dogs and investigating the overlaps of gene variants between the 2 individuals.” – said Dávid Jónás bioinformatician, the first author of the article published in the Frontiers in Genetics journal. Four out of the most promising genes were related to the regulation of gene expression and therefore might be related to the fine-tuning of basic cellular functions, which is in line with the most recent scientific findings related to aging and establishes an interesting direction for future research. Another analysis, based on a study of human centenarians, found 24 gene variants, which are specifically hypothesized to be related to aging and longevity.

“When we examined the approximately twenty thousand canine genes, we found some so-called start- and stop-codon mutations, which might result in disrupted gene functions. It is worth further examining these genes: first to verify that these mutations are true positives, then to investigate their biological effects as well” – said Sára Sándor, a geneticist.

Buksi with researchers

Ethologist Eniko Kubinyi, the leading scientist of the research said that the environment has also a very important role in the development of an extremely long lifespan. “We visited both Buksi and Kedves (see video below or available here). Both of them lived in the countryside, they could roam freely and both of them had contact with a lot of other dogs and humans alike. In this regard, they were similar to the world-recorder dog, Bluey (a cattle dog), who lived 29.5 years in Australia. However, the two Methuselah dogs in this study had very different diets. Buksi was fed with raw chicken and household leftover and used to hunt for small rodents in his younger age. Kedves, on the other hand, was fed with the same dog food as the other dogs at the animal shelter.”

The scientists would like to confirm their findings by analyzing more dogs of extreme age and therefore ask those owners, who have a dog aged 20 years or more and who are willing to participate in the study to contact them at their website.
New research identified gene variants unique to two Methuselah dogs (aged 22 and 27 years) which could not be found in 850 dogs of average age. The genome of the oldest old “Methuselahs” is enriched with gene variants that can elongate lifespan.

In humans, the age of 100 years is considered special by most people. Indeed, in terms of the human lifespan, centenarians live at least 40-70% longer than the average. The corresponding age in dogs would be 17-22 years, depending on the breed, making these Methuselah dogs an exceptional model for the study of aging and longevity.

The longer an individual lives the greater the impact genetics has on its lifespan. The genome of the oldest old “methuselahs” is enriched with gene variants that can elongate lifespan and, most importantly, according to studies, contains fewer variants that can predispose the individuals to certain diseases. Most longevity genes have functions linked to cellular homeostasis, energy production, and DNA damage repair mechanisms. The identification of such genes usually requires a huge amount of data to be analyzed to search for connections between the longer lifespan of individuals and the occurrence of certain gene variants in a population. A recent paper from the Senior Family Dog Project at the Eötvös Loránd University, Hungary, has reported the identification of gene variants that could be linked to the extreme old age of some dogs. The uniqueness of the genetic analysis done in this study lies in the applied method: the researchers sequenced, analyzed and made publicly available the full genome of the two Methuselah dogs. The results could represent a main first step to open up new directions for investigations that search for the key factors behind healthy aging and longevity in dogs.

Buksi, an intact male mixed-breed lived 27 years in a farm in Sárrétudvari (Pegazus Lovarda, Hungary), and Kedves, a spayed female mixed-breed lived 22 years in an animal shelter at Ócsa (Szent Ferenc Animal Shelter Foundation; Hungary). The researchers have become aware of the two extremely old dogs thanks to local veterinarians and shelter volunteers who wanted to introduce these really special dogs to a wider audience through the media. Usually, genetic investigations can be performed from buccal swabs, which are easy to collect from the animals and won’t cause any inconvenience – apart from a minor tickling. However, the researchers wanted to make sure that they can unfold the full potential their genome could hold, so they also collected a small amount of blood with the consent of the owners and with the help of experienced veterinarians. Blood is a reliable source of genomic DNA and could be superior to buccal swabs in quality, when high-throughput genomic techniques, like genome-sequencing, are to be used.

Sadly, both Kedves (†22) and Buksi (†27) have already passed away, but they left a truly unique legacy, since their complete DNA was extracted from their samples and then sequenced by the scientists. The genome of the dog contains approximately 2.5 billion genetic letters (so-called base pairs) – and every one of them twice, because each chromosome (i. e. the compact form of the DNA) is present twice in every individual, save the sex chromosome of males, who have X-Y chromosomes, instead of the X-X chromosomes of females. This results in a total of 5 billion genetic letters per individual, and its reading and the complete reconstruction of the genetic code requires enormous computational capacities. One file containing the raw sequence data of a single individual requires more than 100 GB of storage space on any computer’s hard drive.

“We analyzed this data using one of the Hungarian supercomputers, searching for the gene variants in the Methuselah dogs and investigating the overlaps of gene variants between the 2 individuals.” – said Dávid Jónás bioinformatician, the first author of the article published in the Frontiers in Genetics journal. Four out of the most promising genes were related to the regulation of gene expression and therefore might be related to the fine-tuning of basic cellular functions, which is in line with the most recent scientific findings related to aging and establishes an interesting direction for future research. Another analysis, based on a study of human centenarians, found 24 gene variants, which are specifically hypothesized to be related to aging and longevity.

“When we examined the approximately twenty thousand canine genes, we found some so-called start- and stop-codon mutations, which might result in disrupted gene functions. It is worth further examining these genes: first to verify that these mutations are true positives, then to investigate their biological effects as well” – said Sára Sándor, a geneticist.

Ethologist Eniko Kubinyi, the leading scientist of the research said that the environment has also a very important role in the development of an extremely long lifespan. “We visited both Buksi and Kedves (video is available here). Both of them lived in the countryside, they could roam freely and both of them had contact with a lot of other dogs and humans alike. In this regard, they were similar to the world-recorder dog, Bluey (a cattle dog), who lived 29.5 years in Australia. However, the two Methuselah dogs in this study had very different diets. Buksi was fed with raw chicken and household leftover and used to hunt for small rodents in his younger age. Kedves, on the other hand, was fed with the same dog food as the other dogs at the animal shelter.”

The scientists would like to confirm their findings by analyzing more dogs of extreme age and therefore ask those owners, who have a dog aged 20 years or more and who are willing to participate in the study to contact them at their website.

Interview with David Jonas, bioinformatician (first author of the study):

• What motivated you to investigate the genomes of extremely elderly dogs?

• What age of dogs is considered a Methuselah dog?

• What did the research find? Are you surprised by any of the findings?

• What do the findings mean for the average dog owner?

• What does it add to our understanding of aging for dogs (and possibly humans)?

• What does the study tell us that we did not already know?

• Why is it important to understand how dogs age?

• Which similarities did you find in Buksi and Kedves’ DNA compared to a regular one?

• Reference: Jónás, D., Sándor, S., Tátrai K., Egyed, B., Kubinyi, E. (2020) A preliminary study to investigate the genetic background of longevity based on whole-genome sequence data of two Methuselah dogs. Frontiers in Genetics, 11:315. doi: 10.3389/fgene.2020.00315.

More pictures here: https://drive.google.com/drive/folders/11H9nLuJ1E_OuX88l-U2epoy7Zq9FzvTd?usp=sharing