A Preliminary Study to Investigate the Genetic Background of Longevity Based on Whole-Genome Sequence Data of Two Methuselah Dogs

Abstract

Aging is the largest risk factor in many diseases and mortality alike. As the elderly population is expected to increase at an accelerating rate in the future, these phenomena will pose a growing socioeconomic burden on societies. To successfully cope with this challenge, a deeper understanding of aging is crucial. In many aspects, the companion dog is an increasingly popular model organism to study aging, with the promise of producing results that are more applicable to humans than the findings that come from the studies of classical model organisms. In this preliminary study we used the whole-genome sequence of two extremely old dogs-age: 22 and 27 years (or 90-135% more, than the average lifespan of dogs)-in order to make the first steps to understand the genetic background of extreme longevity in dogs. We identified more than ∼80 1000 novel SNPs in the two dogs (7500 of which overlapped between them) when compared to three publicly available canine SNP databases, which included SNP information from850 dogs. Most novel mutations (∼52000 SNPs) were identified at non-coding regions, while 4.6% of the remaining SNPs (n∼1600) were at exons, including 670 missense variants-76 of which overlapped between the two animalsacross 472 genes. Based on their gene ontologies, these genes were related-among others-to gene transcription/translation and its regulation, to immune response and the nervous system in general. We also detected 12 loss-of-function mutations, although their actual effect is unclear. Several genetic pathways were also identified, which pathways may be tempting candidates to be investigated in large sample sizes in order to confirm their relevance in extreme longevity in dogs (and possibly, in humans). We hypothesize a possible link between extreme longevity and the regulation of gene transcription/translation, which hypothesis should be further investigated in the future. This phenomenon could define an interesting direction for future research aiming to better understand longevity. The presented preliminary results highlight the utility of the companion dog in the study of the genetic background of longevity and aging.

Gut Microbiome Composition is Associated with Age and Memory Performance in Pet Dogs

“…The wide range of expected lifespans, a natural risk to develop dementia, and an environment shared with humans, has also made dogs a promising model organism in aging research (for a review see [10]). Since laboratory dogs represent a limited sample of the natural genetic and environmental variability found in human populations and companion (or pet) dogs, the latter has gained more popularity in aging research recently [11][12][13][14][15][16][17][18]. Their behavior also differs from that of laboratory dogs [19] in ways that make the companion dog a more ecologically valid model of human aging.…”

Poly(A) RNA sequencing reveals age-related differences in the prefrontal cortex of dogs

“…It was previously reported, for example, that several genes experimentally linked to longevity in Caenorhabditis elegans played roles in the regulation of gene expression and were also conserved between worms and humans [ 108 ]. In addition, fine-tuning of the regulation of gene expression may also play a pivotal role in extreme longevity and determining the aging course (e.g., healthy vs. pathological aging) as was independently hypothesized by both Yanai et al (2017) and Jónás et al [ 20 ]. The current findings of the enriched representation of gene expression regulating genes in our DEG set could provide further support for this hypothesis.…”

“…Pet dogs come from a large variety of breeds and therefore show a huge natural genotypic and phenotypic variability, including a wide range of expected lifespan. The life expectancy of dogs, in general, is associated with their average body weight, as smaller dogs tend to live longer [17][18][19][20].…”

Four novel genes associated with longevity found in Cane Corso purebred dogs

“…So far, only a few studies have investigated the genetic background of the dog longevity. A whole-genome sequencing study of two extremely old dogs showed multiple potential loci that could be closely associated with longevity [12]. Another study focusing on genes associated with cancer mortality and longevity also suggests the need for further research direction in this eld [13].…”

“…In combination with arti cial selection, genetic diversity among breeds and health care comparable to humans, dogs represent an interesting model organism for longevity research.So far, only a few studies have investigated the genetic background of the dog longevity. A whole-genome sequencing study of two extremely old dogs showed multiple potential loci that could be closely associated with longevity [12]. Another study focusing on genes associated with cancer mortality and longevity also suggests the need for further research direction in this eld [13].Such results are challenging for further research of genes and loci associated with longevity in dogs.…”