One of the most common medicines used by veterinarians is metronidazole. Though labeled as an antibiotic, like most drugs metronidazole has multiple effects. In addition to killing some bacteria, it can be used to treat the protozoal parasite Giardia, and it has a variety of anti-inflammatory and immunomodulatory effects. However, it is primarily used to treat diarrhea.
Like many alternative therapies I write about, metronidazole is widely used on the basis of primarily anecdotal experience. Most vets will tell you they have given it to dogs with diarrhea and seen the diarrhea stop, convincing them that the drug is beneficial. However, while it is certainly a more plausible remedy than some (e.g. homeopathy), the exact mechanism by which metronidazole should resolve diarrhea isn’t clear. The impact of the drug on the microbial flora of the gastrointestinal tract or effects on immune function might explain any benefits, but this is pretty theoretical.
Despite the fact that most vets should know better, anecdotal clinical experience is pretty persuasive. Of course, we all realize that most cases of diarrhea in which a specific cause, such as a parasite or underlying disease, is not found are cases that are going to get better no matter what we do. The use of metronidazole is very often mostly to placate pet owners tired of dealing with diarrhea and unwilling to wait a week or so for it to go away on its own, which it most often will.
Ideally, we would use metronidazole and all our other therapies on the basis of reliable controlled research evidence, but we don’t live in an ideal world. Such evidence is unavailable for many veterinary therapies, so we make the best judgement we can based on the evidence we have. Since self-limiting diarrheas in otherwise healthy dogs is not a cutting-edge medical research topic, for decades we have had to take our best guess about this treatment without good evidence.
A couple of years ago, I was excited to see a study looking at metronidazole for acute diarrhea in dogs. I wrote about the study, and summarized the other evidence for and against the use of metronidazole in diarrhea cases, in a Veterinary Practice News (VPN) column. The study found no difference in the time to resolution of diarrhea symptoms between metronidazole (4.6 days) and placebo (4.8 days). Dogs given a probiotic got better a little faster (3.5 days), but the difference was not statistically significant. This study suggested that metronidazole has little effect on the kind of mild, self-limiting diarrhea it is most often used to treat.
The finding for the probiotic was interesting, but also worth taking with a grain of salt. The overall evidence for probioticsin treating diarrhea is mixed, and it has proven much more difficult than proponents will admit to clearly prove they work. It is also interesting that the first two authors of this study are proponents of so-called “integrative medicine,” and there is a significant potential for bias here against pharmaceutical therapies and in favor of supposedly “natural” treatments like a probiotic.
After I wrote my VPN summary (but before it was published), another study of metronidazole for acute diarrhea in dogswas published. Since I only revisit recurring topics periodically, I hadn’t had a chance to look at it until recently. This study followed a broadly similar design, but with differences in the specific population of dogs studied and how they were included or excluded from the study groups. The results differed from the prior study in finding a marginally significant difference between the groups in the duration of diarrhea (metronidazole= 2.1 days, placebo= 3.6 days, p=0.04). Once again, the vast majority (about 89%) of dogs got better with no treatment, and the groups were quite small.
Overall, this study is more supportive of a benefit, but this is still pretty weak evidence, with fewer than 20 dogs treated and both statistically and clinically marginal effects for a condition that almost always goes away by itself. Undoubtedly, many owners would be happy to have a treatment that cut short the duration of their dogs’ diarrhea by a day and a half, assuming it was affordable (which metronidazole is) and safe (which it seems to be, though there is not extensive evidence for this either). The authors, as far as I can find, have conventional, science-based views of medicine.
So where does that leave vets in making decisions about the use of metronidazole for diarrhea? My own view is that the evidence for benefits is weak and inconsistent, that it is a plausible treatment but one for which we have to specific mechanism of action we can confidently credit for the supposed benefits, and it is used predominantly because of anecdotal experience, not strong research evidence. The drug is also used, in this context, for treating a mild and self-limiting condition. It has no obvious risks of harm to patients with the doses and time it is typically given, but the evidence for safety is no stronger than the evidence for efficacy.
As such, it shares a lot of characteristics with many alternative treatments.
If vets feel obliged to give owners something to try and relieve the symptoms of acute diarrhea in otherwise healthy dogs without parasites or another proven cause of diarrhea, using metronidazole may be reasonable so long as the lack of good evidence is disclosed to clients. Using probiotics is probably just as reasonable, with little to distinguish the two approaches from an evidence-based medicine perspective. Not treating at all once appropriate evaluation is done to rule out potential causes or more serious problems is probably the most reasonable thing to do, but it is unlikely many vets will be able to justify this to owners upset about their dogs’ symptoms.
I have written about Jean Dodds many, many times. She is one of those controversial figures who did some legitimate, even trailblazing work early in her career and then went off the deep end, not only embracing many forms of pseudoscience but apparently becoming convinced that she could never be mistaken regardless of the evidence against her ideas. She promotes speculative, inaccurate, and even clearly false claims about thyroid disease, pet nutrition, and vaccines. She has become especially blatant in selling proprietary diagnostic tests that, at best, are unproven and that, in some cases, have been clearly shown not to work. She has an undeserved reputation for being an “expert” in fields in which she is actually simply an outlier, promoting views that clash not only with the assessments of true experts but with basic science and research evidence.
Despite all of this, she has continued to practice and promote her unscientific approaches openly and with impunity for many years. Vets throughout the country, myself included, regularly have to try and explain to misinformed clients why her tests and recommendations are not reliable and shouldn’t be followed. And while holding this role as an iconoclastic sage for the alternative veterinary medicine movement, she has not held an actual license to practice in any state.
However, I have also discussed in the past the impotence of most legal and regulatory restraints on unscientific veterinary practice, with examples of figures such as Gloria Dodd and Al Plechner, arguably even more dangerous in their views and actions than Dr. Dodds, practicing openly without effective sanction for decades. With or without a medical license, many individuals are able to promote and sell pseudoscientific products and practices freely despite misleading and endangering the public because the political will does not exist to restrain them.
I was pleasantly surprised, then, to read in The Canine Review that the California Veterinary Medical Board has issued a cease-and-desist order and levied a fine on Dr. Dodds for practicing veterinary medicine without a license. The details of the citation involve Dr. Dodds being listed as the veterinarian of record on both electronic medical records and on results from her bogus Nutriscan allergy test and other laboratory tests.
Given the evidence of history, I am not sanguine that there will be any significant consequences for Dr. Dodds stemming from this action. Dr. Gloria Dodd was cited for malpractice and also issued a warning by the FDA for her quackery, and neither prevented her from continuing her actions. Dr. Plechner was being investigated by the veterinary medical board for a malpractice claim when he died, after decades of dangerous and unscientific practice, making the claim moot. I will not be at all surprised if Dr. Dodds manages to evade responsibility and continue her practices regardless of this action.
Nevertheless, at a minimum it is worthwhile to have an official regulatory body confirm what so many of us have known and discussed for years– that Dr. Dodds is not a trustworthy representative of the veterinary profession but an outlier whose views and conduct do not reflect the values or practices of the vast majority of her colleagues.
Today’s review is of my favorite book about aging so far, Steven Austad’s Why We Age: What science is discovering about the body’s journey through life. Dr. Austad’s style is clear and approachable, even a bit folksy. He creates the kind of engaging, personal narrative that Dr. Sinclair often achieved in Lifespan, but with none of the self-promotion. His explanations are easily understood without sacrificing accuracy or an acknowledgement of uncertainty.
Dr. Austad also takes an approach beloved by skeptics, explicitly stating his goal is to separate “substance and reasonable speculation from myth and wishful thinking.” He begins with ideas that are popular but not as accurate or powerful a representation of reality as often thought and then shows their limitations and the evidence against them. But he does an unusally effective job of this in that he creates authentically compelling stories for these ideas even when he ultimately debunks them. Often, he finds the useful bits of outdated theories and illustrates how they form part of a chain of reasoning and experimentation that leads forward, rather than reinforcing the narrative of science as a series of failures or flip-flops.
One of the myths he punctures is the notion of “special” populations of humans with unusually long lives. Often such populations are studies with an eye to understanding what makes them live so much longer than the rest of us. Austad shows that these pockets of exceptional longevity are based mostly on a combination of poor record keeping and excessive credulity. A strong correlation with lifespan turns out to be the literacy rate, since people who can’t read or keep accurate vital records can easily misremember or misrepresent their longevity.
The book also does a good job of challenging common assumptions and practices in the aging field. There is an interesting discussion of why lifespan itself isn’t a great measure of aging. We have extended average lifespan significantly by reducing causes of illness and death in children, but that hasn’t really changed the rate at which we age or affected maximum lifespan much. Lifespan and disease incidence may both be confounded by factors other than biological aging per se.
The age-specific mortality doubling time might be a better measure of the impact of specific interventions on the rate of aging, even if extended lifespan and healthspan are the real-world outcomes we are seeking. And given that reduction of specific causes of mortality individually have fairly small effects on lifespan, focusing on the rate of aging and measuring it accurately is critical.
Dr. Austad also introduced me to my new favorite phrase: “testosterone dementia.” In a cogent discussion of the evolution of aging, he touches on sex differences in mortality and longevity. One feature of this that readily appears is the increased non-disease-related mortality of young males, in humans, certainly, but in many other mammals as well. Often this involves behavioral risk factors, and as someone who cringes at memories of my youthful risk-taking, I appreciate the humorous but apt description of this particular sex-associated behavioral pattern.
Why We Age ends with a review of popular proposed methods for retarding aging and the state of the evidence for these. The book was written in 1997, so this is not entirely up to date, but it is still an excellent example of skeptical optimism—evaluating proposed interventions in a critical, evidence-based way even when one is personally hopeful about them.
The age of the book is one of its few weaknesses. Additionally, there is a rather long chapter on the subject of menopause, which includes some conclusions not consistent with current evidence-based guidelines. While the subject of reproductive senescence is an interesting and important one, this section hasn’t aged as well as the rest of the book.
On the whole, however, this is an excellent introduction to aging biology for the general reader: readable and engaging, accurate without being excessively detailed, skeptical yet positive, and much less focused on the personality and achievements of the author than the others I have reviewed.
Today’s review involves another influential book by a prominent figure in the anti-aging field. This one is considerably more problematic than my review of David Sinclair’s book Lifespan. While Dr. Sinclair is somewhat controversial for his salesmanship and for claims and practices that aren’t always consistent with accepted scientific methods or evidence, he is still widely respected as a scientist and advocate for longevity research. Though I occasionally found myself gritting my teeth or rolling my eyes while reading Lifespan, I admired the quality of the writing and still found it an enjoyable and informative book. I found it much more difficult to read Ending Aging: The rejuvenation breakthroughs that could reverse human aging in our lifetime by Aubrey de Grey.
I must admit, some of the difficulty was personal. Dr. de Grey has a demonstrated history of sexually harassing women, and he appears entirely unrepentant for his inexcusable behavior. As a feminist and a man of about the same age as Dr. De Grey, I am both encouraged to see the fruits of the #MeToo movement in the growing intolerance for such behavior and infuriated that so many men still act this way. Such excuses as De Grey offers were unconvincing forty years ago, and they are absurd and delusional now.
I admit to some ambivalence about posting a review that draws attention to a such an individual. However, the aging field is a complex mix of sound science and pseudoscience, rational optimism and pure delusion, and, like most fields of human endeavor, admirable and unpleasant individuals. Part of the process of separating wheat from chaff is to look closely and critically at the most prominent ideas and arguments and, when necessary, at relevant characteristics of the individuals who promote them.
A major hurdle geroscience faces is the reputation of the field, which is inevitably dominated by the most visible figures rather than the most productive or wise. Dr. de Grey is unquestionably a highly visible figure promoting longevity, and I suspect ignoring him and his work is ultimately more enabling than looking at it directly and critically like that of other, less problematic individuals in the field.**
Apart from these considerations, most of the difficulty in reading Ending Aging, however, was purely due to the content and style. Where Sinclair is exuberantly optimistic and his tone is redolent of salesmanship, De Grey’s writing style is very much centered on himself and convincing the reader of the obvious truth of his insights. He also sees the battle against aging very much in martial terms, a war that would be easy to win were it not for the wrongheadedness of most everyone but him.
Most of us are in what he calls the “pro-aging trance,” mistakenly accepting aging as a natural feature of life to be approached with graceful acceptance rather than as a horrid disease to be cured. He characterizes this view as an understandable but inherently irrational psychological coping mechanism that we should be able to easily leave behind once we see, as he does, that aging is easily defeated.
This is a dominant theme running through the book. De Grey blames much of the lack of progress in retarding aging not on the inherent difficulty of the scientific task but on a lack of clear understanding of the problem and its importance. He frequently walks the reader through his thought processes in developing, and in his own mind confirming, theories that neatly wrap up all the complexities and loose ends about aging biology that other scientists struggle with.
Ending Aging shares a characteristic of many books written about alternative medicine in that it explains purported insights that the author has which promise to upend all previous thinking about a subject yet which somehow no one else has come across before. There is a dismissiveness towards objections or other points of view that obviates dealing with the substance and merits of those objections.
The central idea De Grey is proposing is that ending aging requires only a commitment, financial and intellectual, to his “engineering” approach. Instead of investigating the complexities of aging biology in order to prevent aging at its roots, or treating the negative impact of aging as it manifests clinically, he proposes interrupting the link between the core metabolic processes and the damage they cause. He suggests that the damage which aging creates, and which manifests as age-related disease, is due to a limited set of processes. Fixing each of these should be, in his view, relatively easy, so a few interventions should take care of pretty much all the harm caused by aging, leading to significant life extension.
After a clear discussion of the evolutionary roots of aging and an explication of De Grey’s core thesis and how it came to him, Ending Aging runs through each of the types of damage he believes form the majority of the effects of aging on health and discusses ideas for how these can be mitigated.
Many of these are subjects of intensive study in geroscience, including protein cross-linking, accumulation of senescent cells, mitochondrial dysfunction, loss of stem cells, and others. Most of the solutions he sees as forthcoming involve the use of processes or techniques already being developed, for these applications or for other purposes. He is unfailingly confident that each of these tools will be safe and effective and ready soon enough to make a huge impact on the health of most people alive today.
This confidence is a critical component of his approach to aging, which again is to characterize it as a war in which we must make intensive investments in a short time in order to definitively win. This war metaphor, and the promise of a clear victory, is used to support his call for funding, for alteration of the ethical and regulatory systems that he believes impede aging research, and for a change in the mindset of scientists, policymakers, and the public. It is also a major flaw of the book.
While many of us studying aging hope to bring about change in how the problem and routes to solutions are viewed, de Grey goes well beyond what most others in the field would advocate. For example, he calls for a “root-and-branch revision of laws and regulations governing clinical trials and approval of drugs.” He even goes so far as to suggest that because the effort to defeat aging is a war, we should view harm done to individuals in pursuit of this goal as an acceptable sacrifice. De Grey argues that the protections currently in place to minimize harm and even death during drug development go too far; losing more lives in faster, less careful drug development is ultimately worth it to save lives in the long run by defeating aging:
“People will die as a result…And people will be happy about this change, because they’ll know that it’s wartime, and the first priority—even justifying considerable loss of life in the short term—is to end the slaughter as soon as humanly possible.”
He employs the same logic in his “defense” of his sexual harassment of women, with the bizarre claim that it would be perfectly appropriate to suggest female associates sleep with potential doners to further the cause of fighting aging:
“It is at the same level of women in World War II sleeping with Nazis to get information. It is a war against aging here. You have to persuade people to give money. That is honestly who I am. I am the general.”
Many of the ideas and aging mechanisms discussed in Ending Aging are well-established and central to mainstream thinking in the field. The concept of an “engineering” approach to combating the effects of aging has some appeal, and it is worth continued exploration. Overall, however, the book represents a viewpoint inconsistent with the values and perspectives of many geroscientists and others working on the problem of aging.
The martial metaphors, the unqualified confidence and predictions of radical short-term progress, the reduction of hard scientific challenges to simple problems of faulty thinking, and the extremist views of how we should test longevity-promoting therapies seem to me unhelpful and counterproductive. This is the book of a zealot, and as such it isn’t a good representation of or introduction to the field of aging and longevity science.
**In the interest of transparency, I will also say that I work at a company headed by someone who has exposed de Grey’s harassment of her and other women. However, we have never discussed these events, and I have no information about it other than what is publicly available.
As part of my efforts to learn as much as I can about both aging biology and also the effective communication of geroscience research, I have been reading popular books on the subject by influential figures in the field. While the details of the science are more accurately and thoroughly expounded in the scientific literature, the philosophy, history, and ethos of the aging biology field is often best explicated in books for the general public. And while I have been communicating to many different audiences about science for many years, this experience has centered on veterinary medicine, evidence-based medicine, and alternative medicine. Being relatively new to the aging biology field, I am enjoying learning the metaphors and techniques various authors use to communicate about the field to those who are not specialists in the subject.
As always, I endeavor to share what I learn through this blog, so I will be posting a series of reviews of the aging biology books I have read. I am starting today with Dr. David Sinclair’s book Lifespan: Why we age-and why we don’t have to.
Dr. David Sinclair is a bit of a controversial figure in the geroscience community. He is recognized as a talented and productive scientist. He is also an eloquent and persuasive advocate for aging biology research. Yet he is prone to hyperbole and enthusiasm that goes beyond what can be supported by reliable data. He is known for using, and at least tacitly or indirectly recommending, anti-aging interventions that have not yet been appropriately tested for safety and efficacy in humans. The ambivalence Dr. Sinclair inspires has been well-characterized by his friend, and fellow renowned aging biology researcher and author, Dr. Steven Austad:
“He’s a superb scientist, as well as a superb salesman. You talk to him about science and you won’t find many more knowledgeable, incisive experimentalists as David. And then you can listen to the stuff he says on TV and be like, What the hell is he talking about??”
Dr. Sinclair’s book is an excellent example of both the good and the bad in the popularization of science. He makes extensive and effective use of personal stories and anecdotes, and he humanizes even the minor characters in his story, offering engaging personal tidbits or colorful characterizations of scientists whose work he references. The writing is clear and entertaining, and the analogies and similes he chooses to explain scientific concepts are usually quite effective. He summarizes complex biology succinctly and accurately. Nuance and uncertainty are sometimes smoothed over, but not usually to the point of misleading the reader.
Lifespan also does a thorough and respectable job of covering not just the science of longevity but some of the history of the field as even some of the philosophical and ethical implications of efforts to extend human lifespan. Much of the book goes beyond the science and research evidence, but that is often an important part of popular science literature—to put the evidence in context and explore the ideas and implications beyond the data. From the perspective of science communication, this is an enjoyable and effective book.
Unfortunately, Dr. Sinclair’s book also contains examples of many of the flaws and foibles of popular science. He makes free with exuberant speculation, promises to the reader, extrapolation and exaggeration. He emphasizes his own credentials in a way that invokes an argument from authority, at least indirectly implying his speculations and beliefs should hold more credibility than can be justified by actual evidence simply because of who he is. Similarly, while he is careful to employ qualifiers and caveats, his use of anecdote and personal experience often goes beyond illustration to at least suggest that these anecdotes are evidence supporting his beliefs and practices.
Like many accomplished scientists, Dr. Sinclair undoubtedly believes his perspective on a complex topic is the “right” one in most respects. Popular science literature allows him a freedom to promote his views and agenda that the strictures of the scientific literature do not. The picture he creates of the field is clear and not grossly distorted, but it very much takes his perspective, and there are plenty of elements other experts in the field would take issue with.
As far as specifics, the review of the aging field and some of the main theories of aging is clear and readable. Dr. Sinclair is reasonably fair in his summaries, though he does editorialize and pass judgement on many of the ideas he covers. The review is clearly intended to lead inexorably to his personal ideas about aging, which is fair enough for a popular science book. He also makes an eloquent defense of the position that aging should be conceived and treated as a disease, and that the alternative view of it as a natural feature of the life cycle impedes efforts to understand and combat it.
The book then reviews some of the longevity-promoting interventions that have been studied in animal models, such as caloric restriction and drugs like rapamycin and metformin. This section tends to emphasize the positive and gloss over the limitations and uncertainties of many of these interventions, and the general reader is likely to come away with an erroneous sense that we already have clearly effective anti-aging therapies that we should reasonably be using in humans.
This is exacerbated by Dr. Sinclair’s descriptions of using various interventions himself and for his family members. While he makes appropriate caveats about anecdote and evidence, there is no question that he believes he and his relatives have benefitted from using treatments not adequately tested in humans. His enthusiasm and credentials are very likely to convince some readers that they should follow his example regardless of the lack of evidence.
It is understandable that when someone believes they have found a powerful health-promoting practice that they would want to share it with others, but this sort of promotion of insufficiently tested practices is a hallmark of pseudoscience. It is problematic for a legitimate scientist to promote untested therapies using tactics associated with the promotion of pseudoscience, not only because it may lead people to adopt unproven and potentially unsafe practices but because it makes the demarcation problem worse and diminishes the standing of science and scientists as sources of reliable guidance.
The latter sections of the book lay out a very optimistic view of the potential for geroscience research to extend healthspan and lifespan. There is always a tension between hope for the potential of scientific research in a particular field and recognition that many hard problems are truly hard to solve, and that a surprising proportion of good ideas turn out to be wrong. Dr. Sinclair errs, if it can be characterized as an error, on the side of exuberance and optimism. This seems a natural feature of his temperament, and it certainly fits with the desire of any researcher to present their area of expertise as likely to be fruitful, even world-changing.
A different balance between creative and critical thinking, skepticism and hopefulness, can be struck in this domain, as in any other area of rapidly growing and changing scientific knowledge. I would be inclined to be more cautious about my speculations than Dr. Sinclair chooses to be. The future, and the data, will be the final arbiter of how much optimism about the field as a whole, or specific hypotheses in it, was justified. It is easy to see, however, why some of Dr. Sinclair’s colleagues feel his enthusiasm sometimes goes too far.
I appreciated Dr. Sinclair’s discussion of the potential negative impact of pursuing increased longevity for humans. It is an issue everyone in the field should give serious thought to. Again, his answers are exceedingly optimistic and rely on a confidence in technology and human behavior to save us from the potential consequences of our discoveries that I find hard to support with the evidence of history. Still, a popular science book is most often an opportunity to make a case for one’s own perspective on a subject, and I cannot fault him for doing so even if I am not entirely convinced by the case he makes.
Overall, Lifespan is an enjoyable read and contains a lot of effective and accurate explication of key concepts and findings in longevity science. It often promotes a distinctive perspective that may well not be shared by other experts in the field, but not usually in a way that involves gross misrepresentation of the facts. Dr. Sinclair clearly prefers optimism to skepticism, and his portrayal of the state of geroscience is likely to lead many readers to see our ability to alter human health and lifespan as far more advanced than it actually is.
Dr,. Sinclair is entitled to shape the narrative of geroscience in his book to fit his own optimism and enthusiasm. However, when he uses anecdotes and references to his credentials, rather than reliable, relevant scientific evidence, to influence readers to accept this view, I think he does edge into the territory of snake oil salesmen, at least in his methods. The line between genuine and fair optimism and misleading salesmanship is a narrow one, and Dr. Sinclair treads right along it, wobbling to either side throughout the book. I would still recommend reading Lifespan, but as always I would encourage a skeptical, critical reading balanced with other sources, some of which I will review in the future.
While rigorous scientific research is the best way to evaluate most proposed medical treatments, there are circumstances in which scientific study can actually be quite misleading. Studies of implausible therapies using unreliable methods rife with uncontrolled bias serve only to create the false impression of scientific legitimacy for useless practices. The bulk of the research literature concerning homeopathy illustrates this phenomenon quite well.
One of the clearest characterizations of this problem is Dr. Harriet Hall’s description of the phenomenon of Tooth Fairy Science. Extensive controlled research can be done to evaluate the behavior of the Tooth Fairy. The relative monetary value of different teeth from children of different ages or genders, the geographic distribution of Tooth Fairy activity, and many other related variables can be analyzed, complete with complex statistics. At the end of the day, however, all this data proves nothing because the underling phenomenon being studied is imaginary. The same is often true of research into alternative medical therapies
The latest example of such Tooth fairy science is a study purporting to show that chiropractic manipulation prevents spinal spondylosis deformans in dogs.
Halle KS, Granhus A. Veterinary Chiropractic Treatment as a Measure to Prevent the Occurrence of Spondylosis in Boxers. Vet Sci. 2021 Sep 17;8(9):199. doi: 10.3390/vetsci8090199. PMID: 34564593; PMCID: PMC8473340.
Spondylosis deformans is a condition in which new bone forms gradually in the spinal column of dogs over years. It is very common in dogs, and does not appear to cause pain or other clinical symptoms, though it can reduce the flexibility of the spine in advanced cases. Spondylosis is believed to occur due to small tears in the cartilage disks between vertebrae that, which cause inflammation and perhaps excess movement, leading to reactive bone formation. There are also genetic influences, and the condition is moderately heritable in some breeds, such as Boxers.
The theory presented in this paper is that spondylosis is caused by decreased flexibility in the spine, and that chiropractic assessment and treatment can detect this excess rigidity and correct it. The study was conducted to prove this by comparing pairs of littermates evaluated and treated by a veterinary chiropractor monthly from 8 weeks to 1 year of age. The authors reported that spondylosis was less common in the treated dogs.
There are many, many issues with this study that make its conclusions unreliable and not useful for evaluating the effects of chiropractic treatment in dogs. The most obvious, which I’ve already mentioned, is that the study is testing an imaginary method of diagnosis and treatment. Chiropractors have never been able to demonstrate that the abnormalities they claim to treat exist or that they are able to reliably detect them by physical examination.1–3 Finding supposed differences in the flexibility of specific spots in the spine is an entirely subjective process, and historically chiropractors haven’t been able to convincingly demonstrate that what they claim to identify is real.
Similarly, the physical manipulation employed by chiropractors, thee low-amplitude, high-velocity thrust, hasn’t been shown to have meaningful beneficial effects despite decades of trying to prove this. The best we can say about chiropractic in humans is that it might have some small subjective benefits for back pain, no better than many other therapies, and even this rests on weak evidence.4 There is even less reason to believe there are meaningful effects in veterinary species. The idea that a short, hard shove against the bones of the spine once a month based on an unreliable subjective assessment of how flexible they are is going to have meaningful effects on health is pretty far-fetched, and it would take an extraordinary body of evidence to validate such a claim.
This paper clearly does not constitute such a body of evidence. Despite plenty of opportunities for residual bias in the study design the ultimate findings only barely reached statistical significance for one dubious measure of effect. The authors report that occurrence of spondylosis was lower in treated dogs with a p-value of 0.0478, with 0.05 being the cutoff for statistical significance. None of the other statistical analyses showed any significant results.
While a thorough explication of the methodological issues with the study is unlikely to be of interest to anyone without an unusual love of epidemiology, I will list the most significant so that the limitations of this piece of evidence can be seen. Ultimately, the fact that an imaginary diagnosis and treatment narrowly showed an effect in a study specifically designed to do so and run by investigators with a deep ideological commitment to the value of chiropractic is a classic example of how Tooth Fairy Science serves primarily to create the illusion of scientific legitimacy for therapies that are instead fundamentally pseudoscientific.
Placebo Control, Blinding, Randomization
One way of trying to minimize the impact of variables other than the treatment being tested on the outcome is to have patients randomly assigned to get either the treatment or an indistinguishable placebo, and to make sure that no one knows which patient is getting which so that our beliefs and expectations are less likely to influence how we evaluate or treat patients in each group. This control group in this study were littermates of the treated dogs who received no chiropractic treatment. There was no placebo control, and clearly the investigator knew which puppies were treated and which weren’t. It is likely that the owners also knew, and while the people reading the x-rays to look for spondylosis were apparently blinded to the treatment, it doesn’t appear the individuals doing the statistical analysis were (it isn’t made clear who this was or what potential biases they might have had). And while the study is described as “randomized,” there is no discussion of how this was done. Overall, then, it isn’t clear that most of the core, routine methods for controlling bias and error in a scientific study were used, and one of the most important, blinding to treatment, was not.
The subjects were recruited by convenience over an 11-year period. This too opens the door to lots of small decisions which, in aggregate, could influence which dogs are chosen and which group they are placed in, all of which can add up over such a long time to influence the ultimate outcome of the study. This is not at all standard scientific methodology.
Spondylosis was not found to be associated with sex or the presence or absence of the condition in parents. This is in conflict with most previous studies of this condition, which find both an influence of sex and a relatively high heritability. This suggests this study either looked at an unusual population or the methods led to atypical findings.
The dogs were assessed for spondylosis at 1 year of age. However, this condition is progressive over time and frequently emerges later in life, so whether the findings at one year were representative of the actual emergence of the condition in these dogs over the majority of their lifetime is unclear.
The likelihood of spondylosis varies at different sites in the spinal column. Rather than picking a particular site to treat and evaluate, the owners lumped all spondylosis at any site into “Yes” or “No” categories. This can easily misrepresent the extent and severity of the condition. In fact, the authors note that not doing this led to a statistically non-significant result. Given that the statistical analysis was not apparently done blinded, this is a perfect example of how manipulation and statistical testing of data after a study can create a significant result even if the data don’t clearly support a real difference between the groups.
The study was described as a “randomized case-control” study. There is actually no such thing, and this is more properly described as a randomized clinical trial with a variation of block randomization by litter. The terminology itself is not relevant to the outcome or conclusions, of course, but it does suggest that the authors may not have extensive familiarity with designing and conducting clinical research studies.
Most importantly, spondylosis is not a cause of significant clinical problems in a majority of dogs, and nearly all dogs will have it to some extent as they age. The very best possible outcome of this study would have been a decrease in the occurrence of something that isn’t a real problem. Chiropractors, of course, would still consider that a success since it would support their claims that what they are doing has real effects on patients. However, this study does not provide reliable evidence that this is true. It certainly does not warrant ignoring the decades of research that have failed to find that chiropractic is a real treatment for any real physical problem.
References
1. Mirtz TA, Morgan L, Wyatt LH, Greene L. An epidemiological examination of the subluxation construct using Hill’s criteria of causation. Chiropr Osteopat. 2009;17(1):13. doi:10.1186/1746-1340-17-13
2. Hestbaek L, Leboeuf-Yde C. Are chiropractic tests for the lumbo-pelvic spine reliable and valid? A systematic critical literature review. J Manipulative Physiol Ther. 2000;23(4):258-275. http://www.ncbi.nlm.nih.gov/pubmed/10820299. Accessed November 18, 2018.
3. French SD, Green S, Forbes A. Reliability of chiropractic methods commonly used to detect manipulable lesions in patients with chronic low-back pain. J Manipulative Physiol Ther. 2000;23(4):231-238. http://www.ncbi.nlm.nih.gov/pubmed/10820295. Accessed November 18, 2018.
4. McKenzie B. Placebos for Pets: The Truth About Alternative Medicine for Animals. Ockham Publishing; 2019.
I recently had another chance to visit my friends Dr. Andy Roark on his Cone of Shame podcast. We talked about my favorite subject–aging in dogs and what we can do about it. Enjoy!
It is well established that exercise has health benefits in humans. Regular physical activity can significantly reduce the occurrence of age-associated diseases and help maintain function. Exercise is also a powerful anti-aging tool which can extend both healthspan and lifespan. But what about dogs? Is it time to start a chain of canine fitness centers?
Just as in humans, one of the biggest risk factors for illness and premature death in dogs is obesity. Surveys of dog owners have found that low levels of exercise are associated with an increased risk of obesity, so it is possible that regular physical activity may be protective against becoming overweight.
A few studies have investigated exercise as an adjunct to caloric restriction for weight loss in dogs. Some have found benefits, but not all, and it is clear that exercise without caloric restriction is unlikely to be an effective treatment for obesity. However, overweight dogs may still benefit from exercise during dieting in other ways, such as preserving lean body mass.
Exercise also improves comfort and function in dogs with osteoarthritis, and it appears to trigger the activation of metabolic pathways associated with glucose regulation. These same pathways are implicated in the effects of caloric restriction on health and longevity, which suggests that exercise could extend healthspan and lifespan in dogs by mechanisms similar to those demonstrated in other species.
More research is needed, but there it is highly likely that increased physical exercise will be beneficial for dogs in maintaining health and slowing aging. There’s also plenty of evidence that exercising with our dogs is good for our health. So take your for a walk right now!
Dogs’ lives are too short. Their only fault, really. Agnes Sligh Turnbull
How long should a dog live? The obvious answer for any dog lover, of course, is “Forever!” Unfortunately, since this does not appear possible, we must settle for trying to understand the current patterns of longevity in dogs, including lifespan, causes of death, and the variables that may influence these. There is a substantial body of research investigating longevity and mortality in dogs, and we are beginning to develop sufficient knowledge to enable us to understand, and even influence, how long dogs live.
The optimal way to assess longevity and risk factors for mortality is a prospective cohort study, in which a large number of individuals are followed from early in life until death and extensive data is collected on lifestyle and environmental exposures, clinical laboratory values, disease occurrence, and the circumstances associated with their deaths. Such studies are standard in human epidemiology, but nearly non-existent in veterinary medicine. The first canine study of this kind is the Golden Retriever Lifetime Study (GRLS),1 run by the Morris Animal Foundation, which promises to be an invaluable source of data about longevity, morbidity, and mortality in this breed. Other efforts, such as the Dog Aging Project are also under way.2
Most of the data we currently have about canine longevity is derived from retrospective analyses of a variety of data sets. Data sources have included veterinary medical college patient data,3–7 medical records from private practice,8–10 and pet insurance company records.11–15 Owner surveys have also been used to investigate mortality and longevity in companion dogs.16–18 Some studies have even used records from pet cemeteries to investigate lifespan in dogs.19,20 Each of these sources has their own strengths and limitations.
Veterinary medical school datasets are often large and contain extensive diagnostic test results. They are also likely to have complete and accurate diagnoses. However, the population of dogs seen at such tertiary care institutions is not representative of the general owned dog population. Patients in such settings may have more severe and more uncommon disease and owners who provide different husbandry and medical care and make different decisions regarding treatment and euthanasia than canine patients in primary care settings. Generalizations based on data derived in this setting can be unreliable.
Primary care records are likely to be much more representative of owned dogs in general, and the types of health issues, husbandry, and owners they have. However, such records can be difficult to access due to the variety of medical record systems in use and the lack of standardization in record keeping practices. Primary care patients also may not receive as extensive a diagnostic evaluation as those seen in academic centers, so the information available may be more limited and potentially inaccurate. The benefits of such “real-world” data sources are somewhat offset by the lack of standardization and quality control.
Surveys of owners are the most convenient and least expensive type of morbidity and mortality to collect. They are also likely the least reliable, with numerous potential sources of uncontrolled bias and error not seen in medical records. Likewise, pet cemetery data rely primarily on information from a small subset of pet owners unlikely to be representative of the general population or consistently accurate.
Considering the variety of data sources used to study canine longevity, the general findings are remarkably consistent. Overall median lifespans for all breeds have been reported between about 8 and 15 years, with most estimates falling between 10 and 12 years, though given the differences in study populations and methods, these figures are not strictly comparable.8–10,12,16–22 (Table 1)
Different data sets also show similar lifespan distributions, typically with a dip in mortality in young adulthood followed by a steady increase in deaths peaking at about 10-14 years of age and then a sharp decline after age 15. (Figure 1) The truncation of the right end of these distributions may reflect some limitations in the data collection as well as a sharp decline in survival past the early to mid-teens.
Little effort has been made to assess changes in global canine life expectancy over time. Many owners and veterinarians believe dogs are living longer than they used to due to improvements in preventative and therapeutic interventions, nutrition, husbandry, and other factors. There is not much evidence to confirm this suspicion. Periodic analyses of the medical record systems at Banfield have been cited to show that dog life expectancy is increasing. Comparisons of life expectancy estimates from different years have also suggested increased longevity in dogs. Analysis of cemetery and insurance records in Japan, for example, have estimated higher life expectancy in recent decades compared with earlier studies.19,20,23 However, these are not results from prospective studies specifically designed to evaluate changes in canine life expectancy over time, and studies done at different times are not truly comparable due to changes in sample populations and methods.
Similar questionable comparisons between surveys at different times have been used to make the opposite argument, that dogs are dying younger than they used to do to purported harm from environmental toxins and contemporary husbandry, nutrition, and healthcare practices. Surveys conducted by the U.K. Kennel Club in 2004 and 2014 show different results for lifespan in specific breeds. Some breeds have a longer lifespan in the earlier study and others have a longer reported life expectancy in the more recent study. There is no clear overall pattern showing a change in lifespan, but even if such a pattern were evident, comparison between the two studies would not be appropriate due to differences between them. As the authors point out:
“Given the difference in methodologies between the surveys, the data from each is not fully comparable and differences observed do not definitively imply changes in population parameters. Furthermore, there were 5,864 deaths reported in the 2014 survey compared to 15,881 deaths reported in the 2004 survey. This significant drop reduces the likelihood of the sample accurately representing the wider dog population, and so would likely have an impact on median longevity figures if the two sets of data were compared, which would not be reliable.”
Of course, assessments of overall longevity and mortality aren’t particularly useful since there is significant variation in lifespan by breed, size, neuter status, and other factors. The one datum owners are most interested in, of course, is “How long will my dog live?” That is, sadly, not something we are likely to ever be able to predict with great accuracy. However, in terms of setting reasonable expectations and thinking about what we and owners can do to maximize the chances of as long and healthy a life as possible for each dog, it is helpful to understand some of the variables that influence lifespan on a population level.
One of the most complex factors is neuter status. I have written previously about the health effects and overall risks and benefits of neutering,24 as well as considerations for what age is optimal for neutering dogs. The general conclusions we can draw from the extensive literature is that neutering has both risks and benefits, and these will vary by breed in complex and often unpredictable ways. Neutering increases the risk of some health conditions in some breeds and lowers the risks of others. However, with respect to lifespan, the evidence is pretty consistent that neutered dogs tend to live longer than intact dogs.5,9,10,24–27
Typically, this effect is more pronounced in females, which may be due to the high incidence of diseases such as mammary neoplasia and pyometra, which are much more common in intact females. However, neutering has been associated with increased longevity in both males and females of other species as well.28 The relationship between sex hormones, environmental conditions, and lifespan is complex, and we do not yet have a complete understanding of it. It is reasonable to tell dog owners that neutering appears to increase lifespan in dogs, especially female dogs, but there are risks as well as benefits, and there is still significant uncertainty about the impact on the life of any individual dog.Body size is another factor that clearly impacts longevity. Once aspect of this is largely beyond the control of owners, which is the size of a dog determined by its breed. There is a roughly linear inverse relationship between body size and lifespan, with giant breed dogs often living half as long as small breeds.3,6,9,10,16,17,20,21,25,27 (Figure 2) This relationship holds even when breed is factored in, showing that it is not simply genetic risk factors for specific diseases in specific breeds causing the apparent association but a true causal relationship between body size and overall mortality.
There are a number of possible mechanisms for negative effect of body size on longevity. Several researchers argue that large and giant breed dogs age at a faster rate, and this accelerated aging is responsible for their shorter lifespan.6,7,29Body size is determined by a small number of genes in dogs,30,31 and one hypothesis is that the shortened life expectancy for larger breeds is an example of antagonistic pleiotropy. This is an evolutionary explanation for age-associated disease that argues genes which convey fitness advantages during the early, reproductive period of life will be retained by natural selection even if they cause harm or shorten overall lifespan through effects later in life, when reproductive output is less. Dogs, of course, have been the subject of very intensive artificial selection, and it is possible that the selection for large body size has preserved genes which contribute to accelerated aging and shorter overall lifespan.
All studies evaluating lifespan in dogs show significant breed variation in longevity. Some of this variation may be attributed to body size, but when that is controlled for in analysis, some breeds do still live longer on average than others. These differences sometimes have straightforward explanations in terms of the incidence of specific diseases, but some breeds may have consistently shorter lives that cannot be explained by obvious genetic predisposition to particular maladies. It is likely that there are differences in the underlying mechanisms of aging between breeds, but this is not a subject that has been extensively investigated in enough breeds to allow confident explanations for many breeds.
One interesting finding concerns telomeres. Telomeres are repetitive non-coding base sequences at the ends of chromosomes that allow for complete replication of the coding portion of the DNA. These shorten with each replication event in the absence of the reparative enzyme telomerase, which is not usually present in somatic cells. When telomeres become too short to protect the coding section of a chromosome, replication is impeded, and cells become dysfunctional. Telomere shortening accompanies aging, and accelerated aging is associated with telomerase deficiency or induced telomere attrition.
Research has shown that telomeres shorten with age in dogs much more rapidly than in humans at a ratio roughly corresponding to the difference in average lifespan between the species. The length of telomeres also differs between breeds, and those breeds with longer telomeres tend to have longer lifespan than breeds with shorter telomeres. These findings support the importance of telomere attrition in canine aging and suggest that one of the fundamental underlying mechanisms of aging may explain some of the difference in longevity between breeds.32,33
Another breed-related variable that does seem consistently related to longevity is purebred versus mixed-breed status. Mixed breeds appear to have greater lifespans in most7,10,16,19,25,34,35, though not all9 studies. Genetic analyses suggest that there is some relationship between the degree of inbreeding and lifespan, both between and within breeds, but this relationship is not simple or straightforward, and it is complicated by confounding variables such as body size.7
When considering longevity in dogs, it is of course necessary to look at what causes of death limit lifespan. Patterns in cause of death can be informative for understanding variability in lifespan and for formulating strategies to extend canine lifespan (the number of years lived) and healthspan (the number of years without significant disease or disability). Once again, differences in study populations and methods limit direct comparisons, but research has identified some apparent patterns in the causes of death seen in dogs. Table 2 lists the most common causes of death reported in various epidemiologic studies.
Overall, neoplasia is almost always a leading cause of death. Diseases of the nervous, musculoskeletal, urinary, and respiratory systems are also very commonly listed. The order in which these appear, and the specific diagnoses identified as leading to death, vary between studies, again due to differences in the populations studied, the methods used to acquire data, and the definitions employed of various causes of death.
The specific diseases leading to death and the organ systems involved also vary in association with several key patient variables. Old dogs tend to die of neoplasia and degenerative diseases more often than young dogs, who experience more mortality related to trauma and infectious disease. Differences are also seen associated with sex, neuter status, and breed. The details are complex and not always consistent between studies, but again the patterns are useful in targeting interventions. Reduction in infectious disease through vaccination, for example, has much. More impact on mortality early in life than interventions targeting neoplasia. Treatments for degenerative musculoskeletal diseases may prolong healthspan and lifespan significantly for dogs in the latter phases of the life cycle, while they are less likely to be useful or to justify potential adverse effects in younger dogs.
Many studies include a generic category of “old age” in asking owners about cause of death. While this is not a very specific nor clearly defined diagnosis, it represents the deleterious functional impact aging can have on dogs even in the absence of specific diagnoses. In humans, frailty is a recognized phenomenon of aging that has significant effects on quality of life and mortality rates, and while such a syndrome is not yet well-characterized in dogs, it is likely also present and relevant to end-of-life decisions for dog owners.42,43
The proximate cause of death for the majority of owned dogs is almost always euthanasia.25,35,44 Though there is usually some underlying ultimate disease or dysfunction precipitating the decision to euthanize, it is important to recognize that death in dogs is most often the result of a human decision-making process. This has significant implications for any efforts to prolong lifespan and healthspan and mitigate the impact of specific causes of mortality, and understanding the reasons owners choose to euthanize their dogs, and the clinical presentations that drive such decisions, is vital to such efforts.
While specific clinical diagnoses are often part of owners’ decisions to euthanize their canine companions, more commonly people cite symptoms or perceived deficits in comfort and quality of life.45–49 Dogs without a clearly fatal disease will often be euthanized when they exhibit symptoms that suggest to owners they are in pain or in some other way uncomfortable, or when they exhibit behaviors that are unacceptable for companion dogs. Loss of mobility, change sin social behavior, housesoiling, and many other symptoms that are not inherently life-threatening or associated with fatal disease can still be life-limiting in dogs due to their impact on owners.
Finally, we cannot hope to understand longevity patterns in dogs without understanding canine aging. For a phenomenon we all experience, aging is challenging to define precisely. It involves changes that occur over time, but time is not necessarily the primary driver of those changes.
A useful general definition in this frame is that aging is “the progressive accumulation of changes with time associated with or responsible for the ever-increasing susceptibility to disease and death.”36 Individual dogs experience progressive loss of function, greater risk of certain types of disease, and a greater likelihood of death as they get older.
Aging involves many different processes at multiple levels, from changes in molecules and genes at the microscopic scale to changes in appearance and function identifiable to dog owners and veterinarians. There are recognizable patterns to these changes that are seen in most dogs, and even in humans and other animals. However, aging is also a variable and individual process. Biologically, some individuals age faster than others. Biological age is related to, but not synonymous with, chronological age. This is especially clear in the dog, in which larger dogs typically experience deleterious consequences of aging earlier and die younger than smaller breeds.6,37,38
Decades of research into the mechanisms of aging, in laboratory models, humans, and dogs, have revealed both variation and complexity as well as recognizable patterns and evolutionarily conserved processes involved in aging. Research efforts are ongoing, and rapidly expanding, to use our understanding of how aging happens to develop preventative and therapeutic interventions to delay age-associated disease, disability, and death. In addition to prevention and treatment of specific diseases, overall improvement in health, comfort, and function in older dogs and compression of frailty and illness into a shorter period preceding death (i.e., an extension of healthspan) may be possible, which would be a fundamental shift in the perspective and practice of veterinary preventative medicine.
The patterns so far identified in longevity and mortality give us some very limited ability to offer general prognoses for lifespan and causes of death to individual dog owners. They also offer a baseline against which to measure our efforts to improve canine health and give our clients and their dogs more quality time together.
References
1. Guy MK, Page RL, Jensen WA, et al. The golden retriever lifetime study: Establishing an observational cohort study with translational relevance for human health. Philos Trans R Soc B Biol Sci. 2015;370(1673). doi:10.1098/rstb.2014.0230
2. Kaeberlein M, Creevy KE, Promislow DEL. The dog aging project: translational geroscience in companion animals. Mamm Genome. 2016;27(7-8):279-288. doi:10.1007/s00335-016-9638-7
3. Galis F, Van der Sluijs I, Van Dooren TJM, Metz JAJ, Nussbaumer M. Do large dogs die young? J Exp Zool B Mol Dev Evol. 2007;308(2):119-126. doi:10.1002/jez.b.21116
4. Fleming JM, Creevy KE, Promislow DEL. Mortality in North American Dogs from 1984 to 2004: An Investigation into Age-, Size-, and Breed-Related Causes of Death. J Vet Intern Med. 2011;25(2):187-198. doi:10.1111/j.1939-1676.2011.0695.x
5. Hoffman JM, Creevy KE, Promislow DEL. Reproductive capability is associated with lifespan and cause of death in companion dogs. PLoS One. 2013;8(4):e61082. doi:10.1371/journal.pone.0061082
6. Kraus C, Pavard S, Promislow DEL. The size-life span trade-off decomposed: Why large dogs die young. Am Nat. 2013;181(4):492-505. doi:10.1086/669665
7. Yordy J, Kraus C, Hayward JJ, et al. Body size, inbreeding, and lifespan in domestic dogs. Conserv Genet. 2020;21(1):137-148. doi:10.1007/s10592-019-01240-x
8. O’Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC. Longevity and mortality of owned dogs in England. Vet J. 2013;198(3):638-643. doi:10.1016/J.TVJL.2013.09.020
9. Urfer SR, Kaeberlein M, Promislow DEL, Creevy KE. Lifespan of companion dogs seen in three independent primary care veterinary clinics in the United States. Canine Med Genet. 2020;7(1):7. doi:10.1186/s40575-020-00086-8
10. Urfer SR, Wang M, Yang M, Lund EM, Lefebvre SL. Risk Factors Associated with Lifespan in Pet Dogs Evaluated in Primary Care Veterinary Hospitals. J Am Anim Hosp Assoc. 2019;55(3):130-137. doi:10.5326/JAAHA-MS-6763
11. Bonnett BN, Egenvall A, Olson P, Hedhammar Å. Mortality in insured Swedish dogs: rates and causes of death in various breeds. Vet Rec. 1997;141(2):40-44. doi:10.1136/vr.141.2.40
12. Michell AR. Longevity of British breeds of dog and its relationships with-sex, size, cardiovascular variables and disease. Vet Rec. 1999;145(22):625-629. doi:10.1136/vr.145.22.625
13. Bonnett BN, Egenvall A. Age patterns of disease and death in insured Swedish dogs, cats and horses. J Comp Pathol. 2010;142 Suppl 1:S33-8. doi:10.1016/j.jcpa.2009.10.008
14. Bonnett BN, Egenvall A, Hedhammar A, Olson P. Mortality in over 350,000 insured Swedish dogs from 1995-2000: I. Breed-, gender-, age- and cause-specific rates. Acta Vet Scand. 2005;46(3):105-120. doi:10.1186/1751-0147-46-105
15. Inoue M, Hasegawa A, Hosoi Y, Sugiura K. A current life table and causes of death for insured dogs in Japan. Prev Vet Med. 2015;120(2):210-218. doi:10.1016/j.prevetmed.2015.03.018
16. Proschowsky HF, Rugbjerg H, Ersbøll AK. Mortality of purebred and mixed-breed dogs in Denmark. Prev Vet Med. 2003;58(1-2):63-74. doi:10.1016/S0167-5877(03)00010-2
17. Adams VJ, Evans KM, Sampson J, Wood JLN. Methods and mortality results of a health survey of purebred dogs in the UK. J Small Anim Pract. 2010;51(10):512-524. doi:10.1111/j.1748-5827.2010.00974.x
18. Lewis TW, Wiles BM, Llewellyn-Zaidi AM, Evans KM, O’Neill DG. Longevity and mortality in Kennel Club registered dog breeds in the UK in 2014. Canine Genet Epidemiol. 2018;5(1). doi:10.1186/s40575-018-0066-8
19. Hayashidani H, Omi Y, Ogawa M, Fukutomi K. Epidemiological studies on the expectation of life for dogs computed from animal cemetery records. Nihon Juigaku Zasshi. 1988;50(5):1003-1008. doi:10.1292/jvms1939.50.1003
20. Inoue M, Kwan NCL, Sugiura K. Estimating the life expectancy of companion dogs in Japan using pet cemetery data. J Vet Med Sci. 2018;80(7):1153-1158. doi:10.1292/jvms.17-0384
21. Inoue M, Hasegawa A, Hosoi Y, Sugiura K. A current life table and causes of death for insured dogs in Japan. Prev Vet Med. 2015;120(2):210-218. doi:10.1016/J.PREVETMED.2015.03.018
22. Hoffman JM, Creevy KE, Promislow DEL. Reproductive Capability Is Associated with Lifespan and Cause of Death in Companion Dogs. Helle S, ed. PLoS One. 2013;8(4):e61082. doi:10.1371/journal.pone.0061082
23. Inoue M, Hasegawa A, Hosoi Y, Sugiura K. A current life table and causes of death for insured dogs in Japan. Prev Vet Med. 2015;120(2):210-218. doi:10.1016/J.PREVETMED.2015.03.018
24. Mckenzie B. Evaluating the benefits and risks of neutering dogs and cats. doi:10.1079/PAVSNNR20105045
25. Michell AR. Longevity of British breeds of dog and its relationships with sex, size, cardiovascular variables and disease. Vet Rec. 1999;145(22):625-629. doi:10.1136/vr.145.22.625
26. Moore GE, Burkman KD, Carter MN, Peterson MR. Causes of death or reasons for euthanasia in military working dogs: 927 cases (1993-1996). J Am Vet Med Assoc. 2001;219(2):209-214. doi:10.2460/javma.2001.219.209
27. DG O, DB C, PD M, PC T, DC B. Longevity and mortality of owned dogs in England. Vet J. 2013;198(3). doi:10.1016/J.TVJL.2013.09.020
28. Austad SN. Sex differences in health and aging: a dialog between the brain and gonad? GeroScience. 2019;41(3):267-273. doi:10.1007/s11357-019-00081-3
29. Selman C, Nussey DH, Monaghan P. Ageing: It’s a Dog’s Life. Curr Biol. 2013;23(10):R451-R453. doi:10.1016/J.CUB.2013.04.005
30. Plassais J, Rimbault M, Williams FJ, Davis BW, Schoenebeck JJ, Ostrander EA. Analysis of large versus small dogs reveals three genes on the canine X chromosome associated with body weight, muscling and back fat thickness. Clark LA, ed. PLOS Genet. 2017;13(3):e1006661. doi:10.1371/journal.pgen.1006661
31. Rimbault M, Beale HC, Schoenebeck JJ, et al. Derived variants at six genes explain nearly half of size reduction in dog breeds. Genome Res. 2013;23(12):1985-1995. doi:10.1101/gr.157339.113
32. Sándor S, Kubinyi E. Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging. Front Genet. 2019;10. doi:10.3389/fgene.2019.00948
33. Fick LJ, Fick GH, Li Z, et al. Telomere Length Correlates with Life Span of Dog Breeds. Cell Rep. 2012;2(6):1530-1536. doi:10.1016/j.celrep.2012.11.021
34. Patronek GJ, Waters DJ, Glickman LT. Comparative longevity of pet dogs and humans: implications for gerontology research. J Gerontol A Biol Sci Med Sci. 1997;52(3):B171-8. doi:10.1093/gerona/52a.3.b171
35. O’Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC. Longevity and mortality of owned dogs in England. Vet J. 2013;198(3):638-643. doi:10.1016/j.tvjl.2013.09.020
36. Harman D. The aging process. Proc Natl Acad Sci U S A. 1981;78(11):7124-7128. doi:10.1073/pnas.78.11.7124
37. Egenvall A, Bonnett BN, Hedhammar Å, Olson P. Mortality in over 350,000 insured Swedish dogs from 1995-2000: II. Breed-specific age and survival patterns and relative risk for causes of death. Acta Vet Scand. 2005;46(3):121-136. doi:10.1186/1751-0147-46-121
38. Miller RA, Austad SN. Growth and Aging. Why Do Big Dogs Die Young? In: Handbook of the Biology of Aging. Elsevier Inc.; 2005:512-533. doi:10.1016/B978-012088387-5/50022-4
39. BN B, A E, A H, P O. Mortality in over 350,000 insured Swedish dogs from 1995-2000: I. Breed-, gender-, age- and cause-specific rates. Acta Vet Scand. 2005;46(3). doi:10.1186/1751-0147-46-105
40. O’Neill DG, Elliott J, Church DB, McGreevy PD, Thomson PC, Brodbelt DC. Chronic kidney disease in dogs in UK veterinary practices: prevalence, risk factors, and survival. J Vet Intern Med. 2013;27(4):814-821. doi:10.1111/jvim.12090
41. Lewis TW, Wiles BM, Llewellyn-Zaidi AM, Evans KM, O’Neill DG. Longevity and mortality in Kennel Club registered dog breeds in the UK in 2014. Canine Genet Epidemiol. 2018;5(1):10. doi:10.1186/s40575-018-0066-8
42. Hua J, Hoummady S, Muller C, et al. Assessment of frailty in aged dogs. Am J Vet Res. 2016;77(12). doi:10.2460/AJVR.77.12.1357
43. Banzato T, Franzo G, Di Maggio R, et al. A Frailty Index based on clinical data to quantify mortality risk in dogs. Sci Rep. 2019;9(1):16749. doi:10.1038/s41598-019-52585-9
44. Pegram C, Gray C, Packer RMA, et al. Proportion and risk factors for death by euthanasia in dogs in the UK. Sci Rep. 2021;11(1):9145. doi:10.1038/s41598-021-88342-0
45. Mallery KF, Freeman LM, Harpster NK, Rush JE. Factors contributing to the decision for euthanasia of dogs with congestive heart failure. J Am Vet Med Assoc. 1999;214(8):1201-1204. http://europepmc.org/article/med/10212683. Accessed April 6, 2021.
46. Edney ATB. Reasons for the euthanasia of dogs and cats. Vet Rec. 1998;143(4):114. doi:10.1136/vr.143.4.114
47. McMullen, S.L., Clark, W.T. , Robertson I. Reasons for the euthanasia of dogs and cats in veterinary practices. Aust Vet Pract. 2001;31(2):80-84.
48. Bussolari CJ, Habarth J, Katz R, Phillips S, Carmack B, Packman W. The euthanasia decision-making process: A qualitative exploration of bereaved companion animal owners. Bereave Care. 2018;37(3):101-108. doi:10.1080/02682621.2018.1542571
49. Marchitelli B, Shearer T, Cook N. Factors Contributing to the Decision to Euthanize: Diagnosis, Clinical Signs, and Triggers. Vet Clin North Am – Small Anim Pract. 2020;50(3):573-589. doi:10.1016/j.cvsm.2019.12.007
