Dogs as a Model of Human Aging

Dogs are an interesting species when it comes to the study of aging. Firstly they are much closer to human metabolism and cellular biochemistry than mice, and secondly selective breeding has generated lineages with a very wide range of sizes and life spans. Thirdly, they occupy a good compromise position in the range of life spans, study cost, and similarity to humans. Mice live short lives, so studies are rapid and comparatively cheap, but there are sizable, important differences between mouse and human biochemistry. Humans live so long that most studies of aging are simply out of the question. Even in non-human primates that live half or less as long as we do, a study of aging and calorie restriction has lasted for decades, and few organizations can or will commit to that sort of effort.

Interest has picked up in recent years in the dog as a model of aging, to be used in the development of therapies to slow or reverse progression of aging. This is illustrated by the activities of the Dog Aging Project, for example, which seeks to obtain data on mTOR inhibitor therapies via their use in companion animals. Given this increased interest, researchers have started to catalog the holes in present knowledge. Even though dogs are very well studied, there is plenty to room to improve the understanding of how the mechanisms of aging progress and are influenced by genetics in this species.

Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging

Several genes have been shown to affect the body size variability of dogs, which is unmatched by any other mammalian species. Importantly, dogs also show marked differences in their expected lifespan in connection with body mass. On average, giant sized breeds (above 50 kg) have an expected lifespan of 6-8 years, while small sized breeds (below 10 kg) can live up to 14-16 years. This wide range of expected lifespans, together with other aspects, has made dogs promising as model organisms for aging research. Despite the huge progress in understanding the genetic basis of morphological variability of dogs, still very little is known about the functional relevance of canine homologs of conserved longevity genes. Currently, this may stand as an obstacle in the way of effectively utilizing dogs as aging models. As dogs can provide unique insights into many aspects of human aging, the current lack of detailed information about the canine genetic pathways of aging should be overcome by future research approaches. In this review, we provide an overview of the evolutionary conserved biological mechanisms that contribute to aging, following the Hallmarks of Aging classification, and we summarize current knowledge about these pathways in dogs.

Genomic Instability

The DNA repair machinery involves divergent pathways, each aimed to correct certain forms of DNA damage. These protective mechanisms have been in the focus of cancer and aging research for a long time. Polymorphisms in several genes of the DNA damage response machinery have been linked to longevity in humans. Intriguingly, no canine progeria syndrome, resulting from DNA repair deficiency, has been documented in the scientific literature. On the other hand, several studies that investigated various forms of canine cancer revealed alterations in the DNA repair machinery, which corresponded to findings in human cancers. While these findings clearly promote the dog as a natural model of human cancers, it is still unclear how exactly variations in DNA repair capacity contribute to the expected lifespan of dogs.

Telomere Attrition

Telomere shortening is a characteristic only of somatic cells, while in germ line cells, telomere sequences are constantly restored by telomerase enzymes. The limited proliferative potential of somatic cells may seem disadvantageous for an individual, yet it may increase fitness by limiting the growth of malignant cells. Contrary to mice, dogs were reported to have low or no telomerase expression in normal somatic tissues, a pattern similar to that in humans. Tumors in dogs often showed high levels of telomerase expression, similarly to human malignancies. Although very little is known about the molecular mechanisms regulating telomere maintenance and cell cycle arrest in dogs, such findings indicate that dogs may also share basic telomere biology with humans. Importantly, telomere length was shown to be variable across different dog breeds and was in correlation with expected lifespan. Also, telomere length in individual dogs was found to decrease with age, similarly as described in humans.

Epigenetic Alterations

Although age associated changes in chromatin structure and DNA methylation patterns have been reported in several model animals, there can be major differences between species. For example, epigenetic regulation in C. elegans seems to be limited to chromatin remodeling by histone modifications, limiting its utilization as a model to study epigenetic changes in aging. In dogs, an increasing body of evidence has suggested epigenetic regulation is behind species and breed-specific traits. Importantly, a recent study demonstrated that changes in methylation status in DNA regions, which were homologous to regions with known age-sensitive methylation patterns in humans, were in strong correlation with chronological age in dogs and wolves. This finding supported the applicability of the dog as a model of age-related epigenetic changes, while it also provided a molecular approach to determine the biological age of individual canines.

Disruption of Proteostasis

Chaperone proteins play an important role in the post-translational maturation of nascent proteins by facilitating their folding. They also function as protectors of mature proteins under various stressful conditions, by helping to maintain their natural conformation and by preventing aggregation. In dogs, the few studies that investigated chaperone proteins in relation to aging reported similar age-related changes as in humans. For example, blood levels of the Hsp70 chaperone were shown to decrease with age in dogs, similarly to what had been previously reported in humans.

Deregulation of Nutrient Sensing

Cellular metabolism, protein synthesis, and autophagy are strictly regulated by various signaling pathways. Most of these have evolved to synchronize cell growth and metabolism with nutrient availability; hence, they are often referred to as nutrient sensing pathways. Many of them converge on the target of rapamycin (TOR) kinase. Importantly, the function of mTOR can be efficiently inhibited by rapamycin, which is an already approved immunosuppressant in human medicine, and therefore has been proposed as a promising anti-aging compound to be used in humans. However, it was reported to cause severe side effects in medical dosages. Therefore, optimal dosages, which do not cause undesirable syndromes, yet still exert longevity promoting effects should be carefully determined in preclinical studies. Actually, pharmaceutical studies have already been initiated to investigate the effects of rapamycin on the lifespan of dogs.

Mitochondrial Dysfunction

Nutrient sensing pathways converge on the regulation of mitochondrial activity, as these organelles are the main sources of energy (in the form of adenosine triphosphate, ATP) in eukaryotic cells under normal circumstances, when enough oxygen is present. The availability of nutrients determines the rate of mitochondrial respiration, which, however, generates not only ATP but also chemical by-products, including reactive oxygen species. The oxidative burden created by mitochondria may be especially high in neurons, which solely depend on aerobic mitochondrial respiration as energy source. The role of mitochondrial dysfunction and increased oxidative burden in neural aging has been investigated in dogs. In general, dog brains were shown to accumulate oxidative damage with age. Several mitochondrial diseases are known in dogs, which have human homologs, such as the sensory ataxic neuropathy found in Golden Retriever dogs or the familial dilated cardiomyopathy in Doberman Pinschers. As several promising anti-aging drugs are likely to be tested in dogs in preclinical studies, looking into their effects on mitochondrial function and testing their possible interactions with mitochondrial genotypes can be highly relevant for humans.

Cellular Senescence

A marked elevation of senescent cell numbers was reported in old mice, although not in all tissues. Importantly, this accumulation process can result from both the increased generation of senescent cells and a decreased activity of macrophages that are able to eliminate aged or apoptotic cells from tissues. Little is known about the accumulation of senescent cells in canine tissues, although this phenomenon is also likely to show fundamental similarities with other mammalian species. As there is a growing interest toward pharmacological approaches to deplete senescent cells in tissues by specific apoptosis inducing agents (senolytic drugs), dogs may eventually be involved in testing these types of anti-aging interventions.

Stem Cell Exhaustion

Tissue renewal depends on the abundance and replicative capacity of tissue-specific stem cells. Hematopoietic stem cells (HSCs) were reported to have reduced replicative capacity in both aged mice and humans, mainly because of accumulating DNA damage. This reduction can explain the old age anemia of elderly people. Importantly, similar forms of age-associated changes in blood parameters, including anemia, were reported in dogs. Besides pharmacological interventions, stem cell therapy has also been suggested as a possible anti-aging intervention, with highlighted promises to treat certain forms of neurodegeneration. In this regard, stem cell therapy trials conducted on dogs affected by forms of neurodegeneration could represent a crucial step before progressing to human trials. In the case of the Golden Retriever model for Duchenne muscular dystrophy, successful stem cell-based interventions had actually preceded human clinical trials

Altered Intercellular Communication

In addition to hormones and metabolites, extracellular vesicles released by cells into the blood, called exosomes and ectosomes, have emerged as important transducers of various cellular signals. Consequently, exosomes may also modulate aging and neurodegeneration. Exosome research in dogs have been limited until recently. However, blood miRNA levels - which were hypothesized to be mainly found in exosomes - were reported to correlate with disease phenotypes in canine Duchenne muscular dystrophy. Similarly, miRNA content in circulating exosomes was shown to correlate with progression of secondary heart failure in cases of myxomatous mitral valve disease in dogs. Altogether, investigations about the connections between exosome content and aging or age-related pathologies in dogs may lead to the identification of diagnostic markers with potential translational prospects into human studies.

Comments

Hey there, just a 2 cents.

''Importantly, telomere length was shown to be variable across different dog breeds and was in correlation with expected lifespan. Also, telomere length in individual dogs was found to decrease with age, similarly as described in humans.''

Dog model is definitely one we have to check out. Dogs lose 500 bp/year in their telomeres vs humans 50 bp/year; it is an indicator (and cause) why they live around 15 years. It is the speed/rate of telomere attrition to a human with progeria (HGPS accelerated/premature aging people who live 15 years old) that show a 500 bp/year average (compared to a human living to 100 years old (with avg 50 bp/y loss). This means HGPS people and dogs have a forma of accelerated aging that make them live a small life by losing 10 times more DNA content/telomeric DNA per year. When you lose this much content in telomeres this is a surrogate of what is going on in the epigenome/methylome.

''Importantly, a recent study demonstrated that changes in methylation status in DNA regions, which were homologous to regions with known age-sensitive methylation patterns in humans, were in strong correlation with chronological age in dogs and wolves.''

If they lose this much telomeric DNA, then they lose just as much epigenomic content and have roughly ten times faster global demethylation (and have hypermethylation of genes that cause inflammation/oxidative stress/immune Attack - all this leads to depletion of telomeres, formation of oxidized DNA/DSBs/telomere breakage and loss of epigenomic DNA/loss of epistasis and epigenome stability (which causes epigenetic drifting, loss of transcription and splicing; in other words, accelerates the bio 'age signature' of the aging of the animal (they are effectively older by epiclock and thus, simply closer to death 'of natural healthy aging')).

If we find, in the furure, a way to repair damages somehow and retard these losses; for us humans, we could translate this to our pets (dogs/cats/birds...) which would give them longer lives/longer (ac)companied; it would be like a Veterinarian PitStop;;but for your pet's aging/ailing.

Posted by: CANanonymity at November 22nd, 2019 1:14 AM

There is something interesting about animals close to humans suffering from aging in a similar way to us - for example dogs, cats, horses, pigs - all have relatively short telomeres that can conceivably erode away in the normal lifespan of that animal. I wonder if selective breeding has anything to do with it. What do you think, CANanonymity?

Posted by: Mark at November 22nd, 2019 8:30 AM

Hi Mark! Thank you for asking, just a 2 cents.

It is a possibility, for careful selective breeding and also careful domestication have yielded different animals (such the difference between wild-caught animals and lab-raised animals; most of the time, if raised in a 'resource-rich' environment, the animal lives a longer lifespan/more oftently to their theoritical specie maximum lifespan; and, most of the animals, live longer Average lifespans; wild/in nature animals, oftenly, live shorter lives because of pure resource competition and predation (Which take a serious toll on the body, manifested as oxidative stress which accelerates loss of health homeostasis and the aging process (it's why they may die suddenly in nature). But, it depends, on that environment; some wild environment 'in nature' are very stressful but not to the point of ending the animal - they gain from that ('Oxidative/'Stress Resistance') when you overcome the mild stress, it is akin to CR or hormesis (a small-to-mild stress is beneficial by priming NRF2/nuclear redox/PhaseII genes for protection from said mild-stress); it is the same as animals living longer by surviving drought/famine in an resource-empty environment (where as resource rich environment can cause glutonny/diabetes/high calories...etc)..excess is just as bad as drastic lacking. I mean, animals like icelandic clams or groenland sharks live in dire environments (live in cold frigid saline water), same thing for naked mole rats (live in Burrows/near anoxia), these animas are 'stress resistant' and have impercetible/negligible senescence - they live up from 35 to 500 years. The animals, like dogs, cats, horses and pigs are very much on the mammal order; as such, as mammals, we share a lot of the same problems/limits; the longest-living mammal (warm-blooded) is the Bowhead whale (lives up to 211 years old); they too have reduction of telomeres with age, but much life icelandic clams, they preserve telomere length much longer (this was demonstrated when they compared a temperate scallop (35 year lifespan) vs polar icelandic artica clam (500 year lifespan); the difference was there; the warm clam lived short life 'in accelerated lane'; while the polar one was 'slow lane' (its metabolic growth was (very) slow but steady; while the temperate one was Fast growth (fast growth = accelerated cell growth dynamic = accelerated cell senescence/cells reach a certain size 'large flattened B-galactosidase-staining cells' = senescence (approx. 17 micron size max)); the telomeres of the short living one saw a faster decrease (over time) than the polar one; thus the rate of attrition was much quicker in the short lived one. When you look at outliers like albatros birds that ahve an Increase in telomeres with age and they die at 35 or so...it's Something else (and not telomere origin...they die because of another reason; they are 'snuffed out' in the nature - and do not reach their theoritical maximum; most likely, they face predators which éliminâtes their numbers 'in nature'...if they were lab-raised tehy might live Much longer (they would deplete their telomeres fully (because their telomeres Lenghten with age (just like the sperm of men...father's sperm telomere Lengthen with age (to increase chance of birthing in old men (old men sperm has more DNA defects but has an elongation of telomeres to give them the possibility of having children in 'whole life'/fertility..while women ahve a 'Set' number of eggs/ovules and must work with that (and why there is just 'pressure' on the woman because has only these many eggs and pregnancy takes 9 months (and why, men (from evolutionary perspective) are less important than women; the bottleneck is the woman/because only she births (not men)/number of kids she can make per portée)) And it'S why women have XX chromsomes while men are stuck with Xy (tiny y has less content and it unstable/makes compromised genome vs a full 2-X/it is the reason why men die yougner than women; if men had doubleXX they would be women and live longer lives/just as long as women/or longer. Evolution made so that men would more into sexual reproduction (can have children whole life) while women would be 'pressurized/selected' for 'having a few times'/making it count, because they birth; but they can't birth if they are dead (hence why evolution made doubleXX and allowed women to have more resource relocation towarsd 'lifespan elongation' (it's not just the 'grand-mother theory (parenting in old age/is beneficial/grand-ma lives longer/gives her long lifespan genes so everyoe lives longer); it's the 'mother theory'; they mother must survive the longest to allow specie to continue because only she births/one birth at a time/9 months at a time; that is the imperative for evolution). Just a 2 cents.

PS: Anecdote: Myself I am a twin, from an evolutionary perspective, it is oftenly chosen/selected because the mother would birth twins - in one shot (or triplets, quadruplets...etc); this would mean higher specie survival - because in one time she gave 2 (vs a woman birthing one child in 1 gestation). There have been studies on twins, and certain twins have live very long lives (not all of course, I had health problems, which my twin sister does not have...yet she had problems I don'T have; demonstrating not 100% clones (obviously we are not identical twins, she's girl, I'm boy); but even in identical twins, it is not 100% clone, it is 98-99% similar DNA makeup; I have identical twin nieces and with age they differentiated ( I have no difficulty distinguinshing them now..certain morphological difference in the faces, make them different from the other and their behaviors are different; the environment helps to 'shape/differentiate' to same identical twin people (this has been demonstrated with twins that were separated at birth and lived far away in different homes; there were changes that make them quite different (biologically) even if they ressemble each other and for most people on the street they tink they are identical 'twins/clones'; when the Truth is they Never lived in the same house since birth and as such, had very different environments which 'remolded' each twin into a different person; especially, at the epigenomic level; epigenetically the identical twin is different that their other twin)).

Posted by: CANanonymity at November 22nd, 2019 3:32 PM

PPS: The mother theory (in contrast/and resemblance to the grand-mother theory) is akin to what happens with Queen bees vs regular worker/nurse bees; the Queen bees live Years (up to 3 years) while the worker bees live 5weeks or less (are highly disposable from evolution perspective; the Queen is not; she birth All the children/the populace; thus she must Survive Live Long life..hence she lives 3 years and procures bee specie survival; for humans, the woman living longer procures/assures humanity specie survival). Same thing with Queen Ants; queen ants live up to 30 years; some of the Longest living Insect ever...as long as naked mole rats (35 year lifespan); they live 10 times longer than Queen bees; queen ants are the Crucial element to the surival of ant colony; and them living decades (vs worker/nurse ants) is a big reason for colony/specie survival; because in that long time they can birth millions of ants and offset colony popular loss (increase demographs). With humans, the grand-mother theory simply added' to the mother one.

Posted by: CANanonymity at November 22nd, 2019 4:06 PM

PPPS: Here is a great new 2019 study showing that:

1.Long-lived Temnothorax ant queens switch from investment in immunity to antioxidant production with age
https://www.nature.com/articles/s41598-019-43796-1

Posted by: CANanonymity at November 22nd, 2019 4:15 PM

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