While the focus of my professional attention, and my writing, has largely shifted away from complementary and alternative veterinary medicine (CAVM) per se and towards the field of aging, I obviously cannot escape the pseudoscience and sloppy or motivated reasoning that characterizes so much of alternative medicine as it pops up often in the aging biology domain as well. Aging is both a legitimate area of scientific inquiry and fertile ground for the growth of snake oil remedies. From the plausible but unproven to the outright ridiculous, purported “anti-aging” products abound, for humans and for our pets.
I’ve already written about the use and misuse of aging science to justify alternative practices in my review of The Forever Dog, where the framework of aging is used to try and give a shiny new luster to so many tired tropes and arguments from the world of CAVM. While attending the recent VMX veterinary continuing education conference in Orlando, I saw the usual profusion of dubious practices on sale, from the traditional nonsense of the Chi Institute’s ‘Traditional” Chinese Medicine training to cold laser devices and, of course, SUPPLEMENTS!!
What’s not to love about a dietary supplement? Virtually no regulation makes creating a new product orders of magnitude cheaper than developing a drug because there is no need to prove it works or is safe. And despite the lack of meaningful evidence for the vast majority of supplements on the market, vets and pet owners just assume they are safe and are willing to use them based on even the thinnest thread of hope that they might do something useful. Billions of dollars to be made with just a little creative marketing and negligible effort or expense for research.
And, of course, aging is a prime target for such supplements since we do not yet have properly validated medicines to target the underlying mechanisms that lead to age-associated disease. I believe such medicines are coming, but the work of development and testing is a lot slower and more challenging that simply extrapolating from some mouse studies and slapping a shiny label and the Quack Miranda Warning on a bottle of some dietary supplement, so it’s a hard temptation for many companies to resist.
While there have been veterinary supplements on the market claiming to target aging in pets for a while, the latest and most visible player in the Expo Hall at VMX was Leap Years from a company called Animal Biosciences.
What is It? Animal Bioscience is a company founded by David Sinclair, his brother Nick Sinclair, and Virginia Rentko, a veterinary internist and researcher. I have written about Dr. Sinclair previously, reviewing his book, Lifespan. He is that fascinating and frustrating, but all too common, chimera- a talented scientist who produces legitimate and valuable research evidence and also a slick salesman who regularly promotes dubious or even clearly false ideas and products. He is particularly famous in the aging biology field for his research, and his business activities, in the area of sirtuins and resveratrol. I have written about resveratrol regularly since 2009, and it nicely illustrates the dangers and pitfalls of excessive hype, enthusiasm, and commercial products based on preliminary preclinical research.
Despite this controversy, Dr. Sinclair is still a prominent advocate for the dietary supplement approach to aging, and he focuses a lot of his attention now on compounds intended to boost NAD+, a ubiquitous and important element in multiple physiologic processes, including many related to aging. Dr. Sinclair has acknowledged taking one of these compounds, NMN, and recommending it to family and friends.
He is also involved in a company, Metro Biotech, that has produced a proprietary version of NMN. This company has been associated with some controversy recently when the FDA banned the sale of NMN supplements. The agency determined that NMN can no longer be classified as a dietary supplement because it is in the process of being evaluated as a possible drug through clinical studies overseen by the FDA. Some have made the claim that Metro Biotech is pursuing a strategy of using the FDA regulatory system to exclude forms of NMN other than its own from the marketplace, though this is only speculation.
In any case, Dr. Sinclair is listed as the founder of Animal Biosciences. The sole product of this company is a supplement called Leap Years. The company does not identify the specific compounds in its product, but one is claimed“ to restore cellular health by boosting NAD+ production,” and it is not much of a “leap” to suspect that the NAD booster they are using is NMN, or even the proprietary version of NMN made by Metro Biotech.
The other ingredient is also not disclosed but is claimed to be a senolytic. These are compounds intended to help with the removal of senescent cells, that is cells with abnormal replication and function that can promote age-related disease through increasing inflammation and other mechanisms. Popular examples include quercetin and fisetin.
The Claims Animal Biosciences makes a lot of claims for their product on their web site and in the materials they provided at the VMX conference. These include-
Since there are no proven medications or supplements that extend lifespan and healthspan in humans, the first claim is unsupported. Dr. Sinclair often makes such claims and then references pre-clinical or pilot studies in lab animals and humans, but this is a classic leap beyond the true probative value of these kinds of evidence that supplement manufacturers often rely on. Promising studies suggesting benefits based on basic mechanisms or animal model studies are useful for guiding us towards the most promising targets for real-world clinical trials, but they don’t make these trials unnecessary. Without real-world clinical trial evidence, claims of “proven” efficacy are unjustified.
Similarly, many things have been shown to extend lifespan in rodents and in a few other model species, but the devil is always in the details. Some interventions may work in some strains of mice but not others, in males or females but not both, or they may appear to work for one research group only to be unreplicable by other scientists, as was the case with some of Dr. Sinclair’s work with sirtuins and resveratrol. While the concepts of NAD+ boosters and senolytics are valid, and there is data supporting the potential of some specific agents, we do not have clinical trial evidence showing real-world benefits for this supplement or its ingredients in pet dogs.
Which brings us to the clinical study at NCSU. This study is still enrolling subjects, and no results have been published. Despite this, the company cites the work as evidence its product is “clinically proven,” which is inaccurate and unethical. Once the full results and methods are published, we will have a better sense of the strengths and limitations of this piece of evidence. Even if the results are encouraging, though, more will be needed to build a confident, reliable case that this product will make a real difference in dogs’ lives.
From the perspective of the basic science behind NAD+ boosters and senolytics, the existing evidence is encouraging but by no means definitive. NAD+ levels do decline with age, and this is associated with many negative health impacts that occur during aging. However, there is no consensus that NAD+ precursors or boosters are effective at slowing aging or reducing the risk of age-associated health problems, by raising NAD+ levels or by any other mechanism. Several companies sell NAD+ precursors for dogs, including NMN. None have been demonstrated safe and effective by high-quality clinical studies in dogs (or in humans).
Clearance of senescent cells using senolytic drugs is another popular area of geroscience research, and there are a number of compounds that have been investigated. Other companies also sell supplements claiming they are senolytics that will extend lifespan and healthspan in dogs (e.g. Fisetin Vet). However, as with NAD+ precursors, none of these compounds have been proven effective for this use in human or in dogs with reliable scientific evidence.
Bottom Line Leap Years is similar to most veterinary supplements on the market: It is based on some plausible ideas with limited supporting evidence, and it is marketed with claims that go well beyond anything scientifically proven or reasonable. The potential risk are as uncertain as the potential benefits. While NMN and various senolytics commonly available as supplements have not shown obvious signs of causing health risks, the limited real-world evidence doesn’t allow us to say with confidence that don’t do harm, only that we haven’t found any yet.
As always, using a product with weak evidence for both safety and benefits intended to treat a broad variety of health problems in normal dogs who are currently healthy is a roll of the dice, and the potential outcome is hard to predict. If evidence emerges this specific product truly extends healthspan and lifespan in dogs, I will be first in line to recommend it, but that evidence will need to be a good bit stronger than it is right now.
As you may have noticed, my productivity in writing blog posts has declined significantly this year. A large part of the reason is that I have been spending my time writing scientific publications and preparing continuing education talks for veterinary conferences, all on subjects related to canine aging.
This post is intended to highlight the scientific articles I have written or worked on this year. Hopefully, this will be an interesting introduction to the field of canine aging and the potential for legitimate scientific interventions which can be shown to meaningfully impact aging and the negative health outcomes associated with it.
Currently, most of the advice pet owners receive about aging is unproven or pseudoscientific and unlikely to truly improve the welfare of their pets. Real science is often more nuanced and complex and less sexy and satisfying than pseudoscience due to the frustrating limits set by fidelity to actual scientific evidence. Still, the field of geroscience is a an exciting point where there is the potential to begin translating decades of lab research into clinically useful therapies. As always, we must proportion our confidence (and excitement) to the level of evidence, and we have a long way to go before we can confidently say that Drug X or Practice y will extend your dog’s health span or lifespan. But there is a path forward to doing this, and these articles are my small part in helping to pave that path.
Aging is the leading cause of disability, disease, and death in adult dogs. One major consequence of aging is diminishing physical function. In humans, there are validated clinical assessments of physical function that can predict disability, morbidity, and mortality. There are also effective interventions to preserve and restore function and reduce the risk of death and disease in the elderly. This review evaluates the decline in physical function with age in dogs and the potential utility in this species of clinical assessment tools and interventions developed for humans.
Contrary to the common view of aging as a mysterious and inevitable natural event, it is more usefully understood as a set of complex but comprehensible biological processes that are highly conserved across species. Although the expression of these processes is variable, there are consistent patterns both within and between species. The purpose of this review is to describe the patterns currently recognized in the physical and behavioral manifestations of aging in the dog and how these impact the health and welfare of companion dogs and their human caregivers. This will set the context for future efforts to develop clinical assessments and treatments to mitigate the negative impact of aging on dogs and humans.
The purpose of this review is to describe key mechanisms of aging at the cellular and molecular level and the manifestations of these in the tissues of the musculoskeletal system, adipose, and the brain. This will highlight knowledge gaps and important targets for future research to extend lifespan and healthspan in dogs and cats.
In this paper we propose a new conceptual framework for aging in dogs, the Canine Geriatric Syndrome (CGS). CGS consists of the multiple, interrelated physical, functional, behavioral, and metabolic changes that characterize canine aging as well as the resulting clinical manifestations, including frailty, diminished quality of life, and age-associated disease. We also identify potential key components of a CGS assessment tool, a clinical instrument that would enable veterinarians to diagnose CGS and would facilitate the development and testing of interventions to prolong healthspan and lifespan in dogs by directly targeting the biological mechanisms of aging.
Developing valid tools that assess key determinants of canine healthspan such as frailty and health-related quality of life (HRQL) is essential to characterizing and understanding aging in dogs. Additionally, because the companion dog is an excellent translational model for humans, such tools can be applied to evaluate gerotherapeutics and investigate mechanisms underlying longevity in both dogs and humans. In this study, we investigated the use of a clinical questionnaire (Canine Frailty Index; CFI; Banzato et al., 2019) to assess frailty and an owner assessment tool (VetMetrica HRQL) to evaluate HRQL in adult companion dogs.
This is my last piece for Veterinary Practice News as the EBVM columnist. I chose to focus on the open veterinary hospital model, which I have been a proponent of for many years.
There is widespread recognition in veterinary medicine of the critical role clients and client communication play in patient care. Informed consent and establishing a veterinarian-client-patient relationship (VCPR) are typically legal prerequisites for providing veterinary services. On a more pragmatic level, we cannot care for our patients effectively without the understanding and engagement of their owners, as well as their consent.
Many strategies have been investigated and promoted to improve client communication,1,2 generally with the aim of improving acceptance of veterinary recommendations. In addition to specific communication strategies, establishing an effective VCPR requires building rapport and trust between pet owners and veterinarians. This is especially true for managing complex, ongoing medical problems.
One approach I have experienced and believe deserves greater study and broader adoption, is the open-hospital model.3For most of my career, I have worked in a hospital that encourages clients to be with their pet at any time while they are in our care, whether in the exam room for a routine checkup, hospitalized in the ICU, and even during dentistry, surgery, or other invasive procedures.
Some are horrified
I am no longer surprised, albeit still amused, by the horror that many of my colleagues display when I tell them about our open-hospital policy. The idea of drawing blood or vaccinating a patient with the owner present, much less allowing them to observe us performing surgery, is sometimes seen as dangerous, if not completely insane.
When exploring this response, the justifications for the horror usually involve concerns about negative client reactions, from fainting at the sight of blood to misperceiving restraint or invasive procedures as abuse and deciding to sue. Veterinarians and veterinary nurses also worry their own anxiety about being watched by owners will degrade their performance, particularly for technical procedures. Legal liability for owner injury is also a common concern.
All of these issues are, of course, real potential negative consequences of having clients accompany their pets through all stages of veterinary care. My own experience, however, suggests these are rare outcomes that are more than balanced by the benefits of an open-hospital model. Appropriate policies and safeguards can minimize the risks and maximize the benefits of this approach.
The benefits pertain to both owners and patients. There is some evidence that dogs, for example, are more relaxed and compliant during veterinary treatment when their owners are present.4,5 The fact our patients, a social species with close relationships to individual humans, should take comfort in the presence of their human caregivers is not surprising. Certainly, we take such comfort from the presence of family members when we receive medical care.
Our clients also benefit from being able to be present for all aspects of their pets’ care. This enhances their trust and confidence in our treatment of their pets by taking away the uncomfortable sense we are doing scary and painful things to their companions “in the back.” Clients can see how much we care for our patients, how we try to comfort them, and treat them well, even when they are fractious. It is also often easier to explain the nature of a health problem when the client can see the images or the lesions directly. Being a part of the process makes clients feel more like the partners they should be in the medical care given to their pets, and it helps build familiarity and relationships between clients and the veterinary team.
There are benefits to veterinary professionals, as well, from having clients accompany their pets in the hospital. Watching the veterinary team provide care illustrates the difficulty and complexity of what we do, and helps show how much skill is required and why we are justified in charging appropriately for our services. It facilitates communication and relationship building. It also helps encourage consistently compassionate and professional behavior on our part, knowing our words and actions will be seen and interpreted not just by our colleagues, but by laypeople.
As for the anxieties my colleagues often express, again, my own experience of 20 years in an open hospital does not support them. While some clients choose not to watch routine procedures, and most have no interest in seeing their pets have surgery, the vast majority do like to be with their pets during routine exams and when they are hospitalized in our ICU. Cases in which the behavior of the owner interferes with our work are extremely rare, and it is always an option to ask an owner to leave if they do so.
When serious adverse events have occurred with an owner present, from extravasation of chemotherapy drugs to unexpected bleeding during surgery, and even cardiopulmonary arrest, owners have always expressed appreciation for the effort and professionalism of the veterinary team in responding and doing everything possible to help the patient. Without exception, all of the clients I have had over the years who responded to negative outcomes by accusing the team of negligence or incompetence have been clients who were not present to see the care given for themselves.
More studies needed
Of course, anecdotal experience is never a very reliable basis for judging any medical practice. There is very little research evaluating the pros and cons of an open-hospital policy. Studies in human medicine consistently show people want to be with their family members undergoing medical care, and parents in particular see this as an obligation and a right. The limited literature available seems to support the impression that while the idea of this approach engenders some anxiety in healthcare workers, in practice it benefits patients and their family members and does not impede or degrade the care provided.6–8
Even studies of intensive medical procedures, such as family-witnessed CPR, show being present for this type of care has psychological benefits for the family, improves the relationship between family members and the healthcare team, and does not interfere with appropriate treatment of patients.6,9,10 The patient-centered model of care currently widely employed in human medicine recognizes such a policy is an important element of such care and has more benefits than risks. A few studies in veterinary medicine also show that owner-witnessed CPR has positive effects on the owners’ perception of the care given to their pets.11
During the COVID pandemic, our hospital endured the natural experiment of having to suspend our open-hospital policy and keep owners outside of the building while treating their pets. This was universally regarded as more difficult and less satisfactory by both owners and the veterinary team. Communication was more frustrating, patients were often more stressed and less cooperative, and the trust and rapport necessary for an effective functioning VCPR was weakened. While there were some minor benefits to not being constantly observed by clients, these were thoroughly outweighed by the disadvantages of this more distanced arrangement. While the processes necessary during a pandemic do not, of course, fairly represent the normal operations of a hospital without an open-access policy, they did give our team a chance to reflect on the open-hospital experience, and we unhesitatingly and enthusiastically returned to this approach as soon as we safely could.
There is limited evidence objectively evaluating the risks and benefits of allowing pet owners full access to all aspects of their animal companions’ care. Limited relevant research in both human and veterinary medicine suggests caregivers want such access; it is comforting for patients and family members, it supports stronger rapport and communication between the healthcare team and the family, and it does not impede care.
My own personal experience, and that of nearly all the veterinarians and nurses I have worked with in an open-hospital setting, is overwhelmingly positive. There are some potential risks, but these can be mitigated by appropriate policies and good communication. The benefits, to clients, patients, and staff, seem to greatly outweigh these risks. The resistance to this model is based on anxiety and unfamiliarity more than on a realistic understanding of the risks, and I strongly encourage my colleagues to consider a more client-centered care model.
And now, the news
Sadly, I must announce that I am stepping down from both of my EBVM columns here at VPNPlus+ and Veterinary Practice News. It has been my great pleasure to share my passion for evidence-based veterinary medicine and to interact with the outstanding editors and the readers of VPN. I will continue to carry the banner of EBVM into my new work studying aging in dogs, and I look forward to future opportunities to share that work with you.
Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of VPN Plus+.
PUN JKH. An integrated review of the role of communication in veterinary clinical practice. BMC Vet Res. 2020;16(1):394. doi:10.1186/s12917-020-02558-2.
Bard AM, Main DCJ, Haase AM, Whay HR, Roe EJ, Reyher KK. The future of veterinary communication: Partnership or persuasion? A qualitative investigation of veterinary communication in the pursuit of client behaviour change. Weary D, ed. PLoS One. 2017;12(3):e0171380. doi:10.1371/journal.pone.0171380.
Yagi K. The Open Practice & Client Presence During Procedures. Clin Br. 2017.
Stellato AC, Dewey CE, Widowski TM, Niel L. Evaluation of associations between owner presence and indicators of fear in dogs during routine veterinary examinations. J Am Vet Med Assoc. 2020;257(10):1031-1040. doi:10.2460/javma.2020.257.10.1031.
Girault C, Priymenko N, Helsly M, Duranton C, Gaunet F. Dog behaviours in veterinary consultations: Part 1. Effect of the owner’s presence or absence. Vet J. 2022;280:105788. doi:10.1016/j.tvjl.2022.105788.
Toronto CE, LaRocco SA. Family perception of and experience with family presence during cardiopulmonary resuscitation: An integrative review. J Clin Nurs. 2019;28(1-2):32-46. doi:10.1111/jocn.14649.
McCabe M. Impact of Family Presence in the Healthcare Setting. 2014. https://core.ac.uk/download/pdf/58825534.pdf. Accessed July 22, 2022.
Beesley SJ, Hopkins RO, Francis L, et al. Let Them In: Family Presence during Intensive Care Unit Procedures. Ann Am Thorac Soc. 2016;13(7):1155-1159. doi:10.1513/AnnalsATS.201511-754OI.
Mark K. Family presence during paediatric resuscitation and invasive procedures: the parental experience: An integrative review: An integrative review. Scand J Caring Sci. 2021;35(1):20-36. doi:10.1111/scs.12829.
Dainty KN, Atkins DL, Breckwoldt J, et al. Family presence during resuscitation in paediatric and neonatal cardiac arrest: A systematic review. Resuscitation. 2021;162:20-34. doi:10.1016/j.resuscitation.2021.01.017.
Gradilla SM, Balakrishnan A, Silverstein DC, Pratt CL, Fletcher DJ, Wolf JM. Owner experiences with and perceptions of owner?witnessed CPR in veterinary medicine. J Vet Emerg Crit Care. 2022;32(3):322-333. doi:10.1111/vec.13180.
Aging in the Dog: Foundations of Canine Geriatric Medicine
What is aging? How we define aging depends on our goals and our frame of reference. From the biomedical perspective of the veterinary clinician, the important elements are:
The passage of time
Deleterious physiologic and functional changes at the molecular, cellular, tissue, and organismal levels
A progressive increase in the risk of the three Ds
As dogs age, they lose robustness (the ability to maintain a state of baseline or optimal physiologic function in the face of external stressors) and resilience (the ability to return to this state following perturbations caused by such stressors).1 This leads to frailty and the development of many age-associated diseases which seem superficially unrelated but which are actually all consequences of the same underlying mechanisms of aging.
Is aging a disease? Because aging is a universal phenomenon, at least in mammals, and because historically there have been no effective interventions to slow or stop the aging process per se, only treatments to mitigate the clinical consequences, aging is widely seen as natural, inevitable, and immutable. However, decades of foundational research in laboratory model species, and more limited recent studies in humans and companion dogs, suggest that the core mechanisms of aging can be altered in a way that may prevent the health consequences of aging.2,3 Much debate has focused on the semantic issue of whether or not something natural and ubiquitous but also responsible for illness and death should be labeled a disease.4 There is not yet any consensus resolution to this debate.
A pragmatic approach that avoids this semantic debate is to view aging is the most important modifiable risk factor for disease in companion dogs. This is a familiar concept to veterinarians. Obesity, for example, is a risk factor for multiple specific diseases which increases the overall risk of mortality.5 Focusing on reducing this risk by targeting obesity, rather than waiting for the clinical consequences to develop and then managing each independently is a well-established practice in preventative medicine.
Age-associated changes are responsible for most of the health problems of adult dogs, and there are plausible hypotheses suggesting therapies that could directly target aging and so prevent these problems. The focus of geroscience (the study of the fundamental mechanisms of aging) is to identify these targets and therapies so the field of geriatrics (the clinical management of the aged) can move away from the reactive practice of treating the clinical consequences of aging as they arise and towards a preventative approach of delaying and preventing these consequences by modifying the fundamental processes of aging.
Why do dogs age? It is sometimes supposed that because evolution selects against deleterious traits, the fact that most animals develop disability and disease with age is a paradox. Shouldn’t we have evolved for eternal good health, since this seems obviously more “fit” than getting old and frail?6
One possible explanation for this apparent paradox is that genes and phenotypes which promote reproductive success early in life can cause health problems later in life but still be favored by natural selection.7 Intensive parental investment, for example, may improve reproductive success while simultaneously diminishing the parents reserves and capacity to maintain their own health. Genes favoring such investment would likely outcompete genes favoring parental neglect even if the latter strategy led to longer healthspan and lifespan.
Dogs are also arguably more a product of artificial than natural selection, and many aspects of their aging reflect this. Large and giant-breed dogs, for example, have much shorter lives than smaller breeds, and this is closely tied to genetic differences associated with growth and adult size.8–10
How do dogs age? The cellular and molecular processes associated with aging, and the tissue dysfunction and ultimate health problems that result from these processes, are complex and multifactorial. Research in laboratory species, and in humans and our canine companions, has elucidated many of these mechanisms, and our understanding of them is growing rapidly.1,11–13 Figure 1 illustrated just a few nodes in the complex web of aging.
Figure 1. The web of tissue aging—a partial illustration of the interactions between key tissue-aging mechanisms. GH = Growth hormone. IGF-1 = Insulin-like growth factor-1. From McKenzie (2022)1.
Despite the complexity of aging, it is ultimately just biology, a collection of physiologic processes that can be understood and manipulated like any other. There is a vibrant field of canine geroscience research investigating the processes of aging and potential targets for intervention to extend healthspan and lifespan.
When is a dog “old”? The old canard that every year in a dog’s life is equivalent to seven years for a human is a misleading oversimplification. Dogs age more rapidly than humans at the beginning and end of their life cycles, but the overall lifespan trajectory is quite similar.14 Large and small dogs often age quite differently as well, so the designation of geriatric status may be appropriate much earlier for some breeds than others. In terms of chronological age, or simply the time a dog has been alive, one has to consider size, breed, and individual characteristics. For practical purposes, this approximation is at least useful for triggering more intensive monitoring and investigation of clinical complaints, but it is merely a very rough guide to when we might call a dog “old:”
Small (under 20 lbs) > 12 years
Medium (20-50 lbs) > 10 years
Large (over 50 lbs) > 8 years
More important than chronological age, however, is biological age, defined as the degree to which aging has impacted the robustness, resilience, and state of health and function in an individual as measured by physical, functional, and biomarker assessment.1 We do not yet have reliable tools for measuring biological age, but many are being developed and tested, and ultimately this will be a much more accurate way to predict the age-associated risk of the three Ds (disability, disease, and death) than chronological age.
What can we do about canine aging? The ideal response to the burden of aging on the health and wellbeing of dogs and their caregivers is to target the core mechanisms of aging and extend lifespan by preventing the entire array of age-associated diseases and clinical problems. Figure 2 illustrates the goal of extending both lifespan (the time alive) and healthspan (the time without significant age-associated health problems).
Figure 2. Lifespan trajectories in the dog. a) standard trajectory showing gains and declines in robustness and resilience throughout the lifecycle from birth to death. b) trajectory showing the results of therapies targeting core aging mechanisms and resulting in extended lifespan and healthspan and morbidity compressed into a smaller window of time prior to death
Until we have validated therapies to accomplish this, however, we can best serve our canine patients by encouraging lifestyle habits that are known to delay age-associated disease and mortality:
A systematic approach to the geriatric canine patient Once age-associated health problems do develop, we can best care for our patients with systematic, rational, evidence-based assessment and management. There are many tools that allow us to evaluate pain, impaired mobility, frailty, and other manifestations of canine aging, and these are not yet widely and consistently used. Many of the most common age-associated diseases, such as chronic kidney disease, cardiac disease, and many types of neoplasia, have been the focus of extensive research, and there are often clinical practice guidelines and other evidence-based tools to help support high-quality therapeutic management of these conditions.18–20 And finally, despite some significant limitations, the emerging discipline of hospice and palliative care is an important element in caring for those patients most severely affected by aging.21
A systematic approach to geriatric medicine encourages proactive identification of disease and clinical problems and using the bets available evidence to guide diagnostic and treatment interventions. Too often, clinical signs of frailty and disease are dismissed as “just slowing down” or “normal aging” rather than appropriately assessed, monitored, and managed. In the future, proactive and systematic detection of such signs will be a critical element in the determination of biological age and the decision to employ therapies targeting aging directly.
1. McKenzie BA, Chen FL, Gruen ME, Olby NJ. Canine Geriatric Syndrome: A Framework for Advancing Research in Veterinary Geroscience. Front Vet Sci. 2022;0:462. doi:10.3389/FVETS.2022.853743
2. Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nat 2019 5717764. 2019;571(7764):183-192. doi:10.1038/s41586-019-1365-2
3. Lawler DF, Evans RH, Larson BT, Spitznagel EL, Ellersieck MR, Kealy RD. Influence of lifetime food restriction on causes, time, and predictors of death in dogs. J Am Vet Med Assoc. 2005;226(2):225-231. doi:10.2460/javma.2005.226.225
4. McKenzie BA. Is Aging a Disease? DVM360. 2022;53(3):25.
5. Salt C, Morris PJ, Wilson D, Lund EM, German AJ. Association between life span and body condition in neutered client-owned dogs. J Vet Intern Med. 2019;33(1):89-99. doi:10.1111/JVIM.15367
6. Johnson AA, Shokhirev MN, Shoshitaishvili B. Revamping the evolutionary theories of aging. Ageing Res Rev. 2019;55:100947. doi:10.1016/J.ARR.2019.100947
7. Austad SN, Hoffman JM. Is antagonistic pleiotropy ubiquitous in aging biology? Evol Med Public Heal. 2018;2018(1):287-294. doi:10.1093/EMPH/EOY033
8. 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
9. 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
10. 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
11. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217. doi:10.1016/j.cell.2013.05.039
12. Sándor S, Kubinyi E. Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging. Front Genet. 2019;10:948. doi:10.3389/fgene.2019.00948
13. McKenzie BA. Comparative veterinary geroscience: mechanism of molecular, cellular, and tissue aging in humans, laboratory animal models, and companion dogs and cats. Am J Vet Res. 2022;83(6). doi:10.2460/AJVR.22.02.0027
14. Wang T, Ma J, Hogan AN, et al. Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome. Cell Syst. 2020;11(2):176-185.e6. doi:10.1016/j.cels.2020.06.006
15. Salt C, Morris PJ, Wilson D, Lund EM, German AJ. Association between life span and body condition in neutered client-owned dogs. J Vet Intern Med. 2019;33(1):89-99. doi:10.1111/JVIM.15367
16. McKenzie BA. What does the evidence say about feline fitness and dog aerobics? Vet Pract News. Published online January 2022:25-26.
17. 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
18. (IRIS) IRIS. Treatment Recommendations for CKD in Dogs.; 2019.
19. Keene BW, Atkins CE, Bonagura JD, et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med. 2019;33(3):1127-1140. doi:10.1111/jvim.15488
20. Biller B, Patel M, Smith D, Bryan C. 2016 AAHA Oncology Guidelines for Dogs and Cats*. J Am Anim Hosp Assoc. 2016;52:181-204. doi:10.5326/JAAHA-MS-6570
21. Bishop G, Cooney K, Cox S, et al. 2016 AAHA/IAAHPC End-of-Life Care Guidelines. J Am Anim Hosp Assoc. 2016;52(6):341-356. doi:10.5326/JAAHA-MS-6637)
As part of my work as Director of Veterinary Medicine for Loyal, a company studying therapies to extend lifespan and delay or prevent age-associated disease in dogs, I am writing regular blog posts. Many of these concern canine aging, though there are some addressing general canine health and biology as well. This is partly responsible for the reduced frequency of my SkeptVet posts, but since many of these may be of interest to followers of this blog as well, I am collecting these posts here just as I did for my VPN column.
As always, feedback is welcome, and if you have subjects you would like to hear more about, let me know!
Should you zoom call your dog? There are now lots of devices that let us call our dogs and say “Hi!” when we aren’t at home. But are these really for our dogs, or just for us? (February, 2022)
Healthspan: the healthy prime of life Lifespan is the amount of time lived. Healthspan is the time lived with vigor and good health. Which do you think is more important? (February, 2022)
Obesity and epigenetics One of the most important health problems in veterinary medicine today is the epidemic of obesity in our pets. (April, 2022)
The reliance on a convenience sample of online owner surveys as the main source of data
The inconsistency of many of the findings with the underlying hypotheses and conclusions
Because such an article in such a prestigious journal is likely to create the false impression of strong evidence in favor of feeding a raw diet, I felt it was worthwhile to submit a letter to the editor of JVIM detailing my concerns about the report. I was joined in this by Dr. Jennifer Larson, a board-certified veterinary nutrition specialist.
The process of getting this letter printed in the journal was surprisingly prolonged and difficult. The letter was initially submitted in January, and has finally appeared today, seven months later, which is an unusually long time. The main problem appears to have been concerns on the part of the JVIM legal team that the journal might be sued over my characterization of one of the funders, Dr. Joseph Mercola. Regular readers will know that Dr. Mercola, and the leader of the veterinary side of his website, Dr. Karen Becker, are stalwart promoters of pseudoscience and alternative medicine. Dr. Mercola has been warned and sanctioned several times by the FDA and the FTC for illegal medical claims, but it was quite a struggle to get JVIM to accept this factual information as part of the letter.
The report Puppyhood diet as a factor in the development of owner-reported allergy/atopy skin signs in adult dogs in Finland, which appeared in the September/October issue of the Journal of Veterinary Internal Medicine (JVIM), suggests that “puppyhood exposure to raw animal-based foods,” “human meal leftovers” and other “real foods” might have a protective influence against canine atopic dermatitis (CAD) while “heat-processed foods” might increase later occurrence of CAD. We are concerned that the results of this study likely represent residual bias in data collection and analysis rather than the actual influence of specific dietary components on the risk of CAD.
Common recognized sources of bias in research studies include a priori beliefs on the part of researchers, recall and selection bias in survey respondents,1 funding bias,2 and a large number of researcher degrees of freedom in the design, conduct, and analysis of the study.3All of these are present in this study.
Dr. Hielm-Björkman and the Dog Risk research group have expressed strong beliefs about the health benefits of raw diets and the dangers of conventional commercial pet foods in previous research reports and popular media.4, 5
The main source of data in this study is an online survey available only in Finnish. Previous publications regarding validation of this data source have identified low response rates to validation questions and important proportions of duplicate, automated, and discordant responses.6, 7 Asking owners to remember in detail what they fed their puppy between 2 and 8 months of age and then trying to associate that with health outcomes years later is, in our view, a questionable strategy. Self-reporting of diet and health information are unreliable in humans, and we believe that it is unlikely to be more reliable among dog owners.1 Dog owners consistently misperceive even straightforward measures such as body condition score despite formal training in this assessment, so their assessment of signs of CAD is, in our view, likely to be equally unreliable.8 The survey responses are expressions of the perceptions and beliefs of the owners who participated, not necessarily the true nutritional and environmental exposures nor health outcomes experienced by the dogs.
Dr. Hielm-Björkman has previously cited funding bias as a problem in the study of raw diets, stating that raw foods are “not really researched in universities. Most universities get sponsored by these big billion-dollar companies, and you don’t really want to step on their toes, I guess.”5 In light of the recognized problem of funding bias it could be relevant that disclosed funding sources for this research include companies selling raw pet foods.
The authors also report accepting funding from Dr. Joseph Mercola. Dr. Mercola’s organization advocates for raw pet diets and argues against conventional pet foods on its web site.9–11 We believe that he is also a consistent promoter of unapproved medical practices and medical product claims, as evidenced by multiple warning letters from the Food and Drug Administration and a lawsuit by the Federal Trade Commission related to therapeutic claims that violate the U.S. Food, Drug, and Cosmetic Act.12–16 Such an affiliation is at least as relevant to assessing potential bias as accepting funding from an organization with a commercial interest in raw or conventional pet foods. Bias in scientific research is as likely to arise from ideological as financial factors.
We believe that the results of the analysis and how they are reported also suggest the influence of bias. Many comparisons are listed only in supplemental materials, and those reported in the main article tend to be those which support the authors’ hypotheses. This creates the appearance of consistency when, in fact, the associations identified are often inconsistent and do not logically support the claims in the conclusions. For example, why would raw tripe and organ meats be protective against CAD but raw red meat, eggs, and poultry not be? If cooking is the key risk factor, why would cook vegetables be protective and raw vegetables would not or why would both cooked and raw eggs be protective while neither cooked nor raw poultry is associated with the likelihood of CAD? If exposure to bacteria is the main variable, why is eating dirt, sticks or carcasses protective but eating clay and grass is not and drinking from puddles is actually associated with increased risk? If excessive processing is the issue, why was there no association with eating processed meats or canned foods and only a marginal association with dry food when it was the only food offered?
Dogs with CAD were reportedly more likely to be eating no raw food at all than controls, and dogs without CAD were more likely to be fed 20% or 90% raw, but there were no statistically significant differences at any other ratio of the 2 foods. Similarly, allergic dogs were more likely to be fed 80% dry than controls, but there was no significant difference in CAD risk if they were fed more than 80% dry. Control dogs were more likely to be fed 50% or less than 10% dry, but there was no difference at intermediate ratios. It is easier to see cherry picking and researcher degrees of freedom than a consistent dose-response in these results.
While the authors do acknowledge the potential for recall bias and misclassification, and they do state that their findings cannot prove causal relationships, the overall message of the paper is that uncooked foods and human meal leftovers likely have health benefits, and this is inconsistent with the methodological limitations and potential for residual bias of this study.
Given the importance of CAD, in terms of both prevalence and the negative impacts on pet and owner quality of life, we agree that identification of protective factors is warranted. However, considering the significant risks of illnesses and death that have been consistently associated with the feeding of raw animal products, rigorous and well-designed research methodology, objectivity, and full reporting of results are needed to explore if any benefits exist for this practice, and certainly are required before this practice can be confidently recommended.
CONFLICT OF INTEREST DECLARATION Jennifer Larsen declares the following conflicts:
Investigator in clinical trials and other research partly or fully sponsored by Royal Canin, Nature’s Variety Instinct, and Nestle Purina PetCare.
Develops educational materials for Mark Morris Institute and HealthyPet magazine.
Serves as advisory group consultant for Elanco Animal Health.
Participates in continuing education events, as a speaker & as an attendee, sponsored/organized by Royal Canin, Nestle Purina PetCare, Nature’s Variety Instinct, and Hill’s Pet Nutrition.
A resident of the Nutrition Service received funds through the Hill’s Pet Nutrition Resident Clinical Study Grants program.
The Veterinary Medical Teaching Hospital at the University of California, Davis receives funds from Nestlé Purina PetCare to partially support a nutrition technician.
Brennen McKenzie declares no conflict of interest.
As is usual and appropriate, the authors had an opportunity to provide a response to the letter. The response didn’t really contain any meaningful rebuttal of the concerns we expressed, merely a series of assertions that they weren’t valid, relevant, or important. Here is the full content of the authors’ rebuttal:
We read Drs McKenzie and Larsen letter with interest, and we thank the Editor for the opportunity to discuss the scientific questions through this forum.
Dr McKenzie (skeptvet1) and Larsen in their letter to the editor indicate that the DogRisk research group has a priori notions about the benefits of raw feeding. We want to point out that we only have three veterinarians and only three dog owners in our research group of eight, only two feeding raw, and that we take pride in discarding our hypotheses every time we prove them wrong. Regarding raw food we have time after time, through published articles and 10 university student theses in Finnish, seen that there are health benefits when owners use a raw diet for their dogs, compared to a dry. We acknowledge the variety of raw and dry dog diets available and therefore we also know that the reasons behind the health benefits are hard to estimate. We have analyzed gene-expression2 and metabolomics3 in a raw-dry diet-intervention study. We look at processing, the absence of heat, macronutrient profile (proteins, fats, and carbohydrates, content and origin), bacterial load, among other factors. We now work with 10 hypotheses of why the raw food diet repeatedly comes up as healthier in our studies. In a world where our dogs suffer increasingly from noncommunicable diseases that are similar to those of humans (atopy, allergies, IBD, diabetes, certain cancers and similar) we can also make veterinary medicine relevant for human medicine by reporting what we see in dogs, that share most of the other environmental factors with us, their human owners. To this end, diet is an excellent variable to investigate, as dog owners tend to keep their dogs on the same diets for extended periods of time, sometimes a whole lifetime. Also, because of diets being so homogenous, owners do not tend to forget or misrepresent it, as they might do about their own diet. These are our motivators, not proving a preconceived hypothesis.
The second issue that Dr McKenzie and Larsen were concerned about was survey problems. All relevant concerns are mentioned in the limitations part of the article, as they themselves point out. In contrast to what was said in the letter, we want to point out that our research is, and has been in all our papers, completely transparent. We always mention the reasons for omitting cases: for example, robot answers, dogs not reported to eat enough to stay alive, too young controls as they still could develop the disease etc. As expected from an academic research group, our survey is validated,4 including the dependent variable of this paper (allergy/atopy). We are of the same opinion with the authors of the letter that owners misperceive especially body condition score; our data show that only 13% of owners have reported that their dogs are overweight (12%) or obese (1%). But we also know that they are good at perceiving the clinical signs their dogs have: itching, ear, eye or skin infections, anal gland problems, teeth and gum problems etc., as those are the reasons that they contact their veterinarians for appointments. The owners in our survey also had the possibility to tick other skin related disorders (eg, hot spots, demodicosis, seborrhea etc.) than allergy/atopy. And as they did not, there are not so many other diagnoses than allergy/atopy they could have had, as flea allergic dermatitis is not a common entity in Finland.
Further, the authors of the letter to the editor addressed an issue we again take pride in, analysis of the data. We totally disagree with the notion of “cherry picking” data and instead again want to highlight that by putting all results in either the main article or supplemental material for other researchers to see, we can best forward this area of research. Regarding selection bias, when using backward stepwise regression, the computer starts with all variables and excludes the ones with the lowest coefficient of determination. The result is a computer-generated final model, including the significant variables. Only the machine chooses, not humans so no bias is even possible. It is common practice to discuss the significant results and trends while the pre-analyses are put into the supplemental data (S1-2). Figure 2A,B in our article show that there are more non-atopic dogs than atopic dogs when the dogs have been eating more than 10% raw food and on the contrary, more atopic dogs, when they have been eating more than 80% of their diets as dry. Not all 10% intervals will show significance between the two diets as there will not be enough cases at all intervals and it is also normal that some of 20 intervals (here one; eating 60% dry) will be out of line, for the same reason. That it is so consistent, is remarkable.
At the start of our response, we mentioned some of our hypotheses for why raw diets come up as healthy, but that we lack an answer to the “why?”. The authors to the letter also had many “If-why?” questions. At this time, we do not have the answers, but we hope that we will be able to answer them within a couple of years.
Another issue raised was funding bias. Also here, we have been completely transparent as can be seen in our long list of funders. We have been able to attract funding, for example, from state funding bodies, foundations, private people and companies by crowdfunding, raw food companies etc. and we are equally thankful to all. However, the big traditional dry feed companies have not been interested in funding our research, despite enquires. On our website, we disclose and thank all our sponsors (Moomin trolls and all) while letter author McKenzie instead has paid advertisements from Hills’ and Mars, for example, featuring the same Royal Canin advertisement on atopy diets both as “sponsored content” and in his “education center,” on his Veterinary Practice News homepage.5 Dr JA Larsen discloses her close co-operation with Mars, Hills’ and Nestle’ Purina in the Conflict of Interest section in all of her published articles.
Finally, we would like to point out that we have no “raw food agenda” but if we find that the “raw” is of value, we feel that we have an ethical obligation to the community to report it. We will therefore now recommend that people who feed dry food supplement the diet with at least 20% raw. If the health benefits come from beneficial bacteria, we will recommend that they should be added to the dry food, etc. Also, contrary to the letter authors’ comments, we have and will continue to report on raw feeding not being dangerous for neither dogs nor family. In our risk-analysis study, we found only three verified cases of food pathogen transmission from raw dog food to humans in 16?475 households feeding raw and in 98?353 pet years at risk.6 This study has been replicated with similar results.7 As a university-based independent research group, we are driven by a concern for the growing disease load in our dogs. We hope our research will benefit both canine and human health and therefore we report everything we find, as we find it.
Here is how I view these responses:
“We only have three veterinarians and only three dog owners in our research group of eight, only two feeding raw”
If I interpret this correctly that all eight members of the group own dogs and only two of them feed raw, I would say that is interesting, but not really relevant to the issue of whether the group in general has a bias in favor of raw diets that influences their work. Our personal practices don’t always perfectly mirror our beliefs.
The next point they make is that their studies have consistently found benefits to feeding raw and that they have numerous hypotheses for why, though they cannot yet claim a specific reason for these benefits. Again, the fact that their work consistently finds what they believe and expect to find doesn’t say much about whether those beliefs, of the evidence they have generated, are correct. It would be much more convincing if other research groups with other perspectives and agendas found the same results.
It is always the case in science that when much of the evidence for a claim comes from a single source, that is a reason to be skeptical of that evidence, and there is no reason not to apply that principle to the subject of raw diets or the DogRisk group.
The group next acknowledges the limitations of an owner survey as a data source while simultaneously claiming that the particular evidence and conclusions they have drawn from such a survey are correct. This is just an assertion of belief, not evidence that the limitations Dr. Larson and I raised are not influencing the findings.
They then respond to our pointing out the inconsistency of the findings and the emphasis only on those that support their claims while those that do not are relegated to the supplemental material. This response is, again, just to assert that there is nothing about these findings or reporting that is problematic or should undermine confidence in their conclusions. That is for readers of the article to decide, but simply responding to the identification of a potential problem by saying “that’s not a problem” isn’t a very compelling argument.
In particular, they acknowledged that they cannot explain some of the inconsistencies we pointed out in the findings, but they don’t see these inconsistencies as a reason to question their underlying conclusions about the benefits of raw diets. That response certainly has all the hallmarks of cognitive dissonance.
With regard to the issue of funding bias, the authors respond by arguing that it isn’t a problem since they disclose their funding sources and then move on to the tu quoque fallacy, which is the strategy of arguing that if someone else has a potential financial conflict of interest, that negates the potential significance of their own.
Apart from being irrelevant, this claim fails with regard to my own supposed financial interests. Since I receive no funding of any kind from the pet food industry, the only way they could make a claim of funding bias was by pointing out that the Veterinary Practice News puts ads for pet food on some of the pages where they print my column on evidence-based medicine.
I not only have no influence on advertisers the magazine works with and receive no income from ad in the magazine, I am actually unaware of what ads appear in the magazine since I rarely even read my own columns once they have been published. How this could possibly influence my positions on raw diets is unclear, so this is a bit of a desperate tactic.
1. Ravelli MN, Schoeller DA. Traditional Self-Reported Dietary Instruments Are Prone to Inaccuracies and New Approaches Are Needed. Front Nutr. 2020;7:90. doi:10.3389/fnut.2020.00090
2. Resnik DB, Elliott KC. Taking financial relationships into account when assessing research. Account Res. 2013;20(3):184-205. doi:10.1080/08989621.2013.788383
3. Simmons JP, Nelson LD, Simonsohn U. False-positive psychology: undisclosed flexibility in data collection and analysis allows presenting anything as significant. Psychol Sci. 2011;22(11):1359-1366. doi:10.1177/0956797611417632
4. Fredriksson-Ahomaa M, Heikkilä T, Pernu N, Kovanen S, Hielm-Björkman A, Kivistö R. Raw Meat-Based Diets in Dogs and Cats. Vet Sci. 2017;4(4):33. doi:10.3390/vetsci4030033
5. Habib R, Becker K. The Dog Cancer Series: Rethinking the Cancer Epidemic Vol. 1- Chapter 4 (Transcript).; 2018:73.
6. Hemida M, Vuori KA, Salin S, Moore R, Anturaniemi J, Hielm-Björkman A. Identification of modifiable pre- and postnatal dietary and environmental exposures associated with owner-reported canine atopic dermatitis in Finland using a web-based questionnaire. PLoS One. 2020;15(5):e0225675. doi:10.1371/journal.pone.0225675
7. Roine J, Uusitalo L, Hielm-Björkman A. Validating and reliability testing the descriptive data and three different disease diagnoses of the internet-based DOGRISK questionnaire. BMC Vet Res. 2016;12(1):30. doi:10.1186/s12917-016-0658-z
8. Eastland-Jones RC, German AJ, Holden SL, Biourge V, Pickavance LC. Owner misperception of canine body condition persists despite use of a body condition score chart. J Nutr Sci. 2014;3:e45. doi:10.1017/jns.2014.25
Dr. Nir Barzilai is a well-known researcher and advocate for longevity studies. He is an MD and the founder or driving force behind many geroscience institutes and initiatives. In 2020, he also became one of a growing number of scientific figures in the aging biology field who have written popular books on the subject for the general public.
Among the aging science books I have reviewed so far, this one is the most casual and conversational. It conveys the impression that the reader is sitting in a living room as a relaxed but enthusiastic Dr. Barzilai shares anecdotes, recollections, and opinions over a few glasses of wine. This approach has both advantages and disadvantages.
The material is easy to read and not overly technical or full of scientific jargon. It is also very loosely organized, even a bit rambling at times, and it is heavy on anecdotes and opinions and light on evidence and critical assessment. One could easily come away with the impression that every idea, every hypothesis about aging is exceptionally promising and that radical transformation of human lifespan and healthspan is just around the corner. Unfortunately, that is probably not the most accurate picture of the field, and it glosses over the complexity of aging biology and the scientific challenges of significant lifespan extension.
Dr. Barzilai does talk quite a bit about the political and financial challenges, going so far as to say “the only thing standing between [a world of healthy, productive elderly people] and the one we have is money.” Much of the book is about commercial ventures he has been involved in that hope to turn promising scientific hypotheses into readily available therapies and products at warp speed; much faster than the painstaking, laborious processes of non-profit scientific investigation and regulatory approval. Again, the reader gets a very clear impression (accurate or not) of Dr. Barzilai’s personality and views on the best way to move forward with geroscience. Though he is a well-respected scientist who has made significant contributions to aging biology, he seems a bit impatient with the speed of progress and inclined to suggest the market could do a better, or at least faster, job of capitalizing on the scientific possibilities with sufficient funding and less conservative regulatory constraints.
The book shares many anecdotes about the human experience of aging, and this fits well with one of the central stories, which is Dr. Barzilai’s work with centenarians attempting to uncover the secrets to their exceptional longevity and health. The predominant message coming from this work appears to be the importance of genetic factors in protecting some individuals against aging and age-related disease. This may disappoint some readers looking for tips to improve their own health and lifespan, but Dr. Barzilai also provides plenty of these. Despite the appropriate caveats about not blindly following his example, he shares with his friend Dr. David Sinclair a willingness to try out new treatments on himself long before the scientific evidence and the drug approval system endorse doing so, and he shares many of these in this book.
In several of these reviews, I have talked about the tricky balance of skeptical optimism. As researchers in a relatively new and rapidly changing field, we must be sufficiently hopeful and open-minded to take up and test new ideas, even with relatively little to go on at first. However, such enthusiasm can easily carry us beyond the boundaries of rigorous science and good sense if we don’t balance it with appropriate skepticism. Particularly when writing for a non-science audience, it is easy to convey the false impression that big problems are easy or on the verge of being solved or that we already have good reason to put treatments into use that, in reality, we have not yet proven are effective or safe. Striking the perfect balance, to sustain excitement and energy without giving in to wishful thinking, is a difficult and ongoing challenge in the field.
Dr. Barzilai leans a bit too far to the side of enthusiasm over skepticism for my taste. He lists many approaches as “promising” even when the evidence or scientific rationale for these is pretty weak. Reasonable advice about exercise and diet are mixed in with questionable ideas about supplements and fasting, and even some pretty fanciful stuff about the benefits of pseudoscience like reflexology or the claim that prayer can lengthen telomeres. In the long list of ideas put forward in the book, little meaningful distinction is made between science, speculation, and fantasy, and that has significant potential to create a misleading picture for many readers.
Overall, Dr. Barzilai’s book is an engaging, relaxed, and relatively personal look at the aging biology field. It skims the surface broadly with limited scientific depth and it leaves a positive, rosy picture of the state of the field. While Age Later may not be the most scientifically detailed or critical assessment of the field, it is easy to see why Dr. Barzilai has been so successful at organizing and leading geroscience research efforts and finding funding for his endeavors. These activities require the kind of exuberance and optimism that comes across quite clearly in his book.
Introduction Sepsis is currently defined as a life-threatening organ dysfunction secondary to a dysregulated physiologic response to infection. There are widely used, evidence-based guidelines for diagnosis and management of sepsis in human medicine,1but there is no single guideline or consensus statement on sepsis management in veterinary medicine. The guidelines most veterinarians follow, and those which we use at my hospital, are derived from expert opinion and the adaptation of human sepsis protocols employed at several academic veterinary institutions.
Management of sepsis is a great example of the challenge of practicing evidence-based medicine in an evidence-poor environment. Extrapolation from evidence in humans and reasoning from physiologic first principles are rational and necessary strategies, but of course they sometimes lead to practices which turn out to be ineffective or even counterproductive in veterinary patients. Such approaches should always be viewed as a starting point, a provisional strategy pending the development of better evidence in clinical studies of the target patient population.
Human medicine, though often blessed with much higher quality evidence that we can typically expect, still finds itself mired in controversies over questionable practices that become widespread despite limited or poor-quality evidence and which later turn out to have been ineffective. A condition such as sepsis, which is acutely life-threatening and for which no universal, highly-effective therapy is yet available, is fertile ground for such disputed approaches. These often spill over into veterinary medicine when we adopt new practices in human patient care, and it is important for us to keep an eye on the evolution of ideas and evidence regarding such practices. In the case of sepsis, for example, the use of Vitamin C, alone or in combination with steroids and other vitamins, is an example of a controversial practice that has been ported into our patient care protocols to some extent based on limited, and controversial, early evidence and which we may now want to rethink.
Diagnosis of Sepsis Confirming sepsis and identifying a source of infection can be challenging. However, the emphasis in sepsis management is now on early initiation of therapy since this has been associated with lower mortality in human patients, so diagnostic criteria have been developed to favor rapid diagnosis and therapy. Based on the definition of sepsis given above, a tentative diagnosis of sepsis should be made whenever there is a known or suspected infection and evidence of organ dysfunction or a systemic inflammatory response. Suspicion of infection should be based on history and physical examination findings. Suggested criteria for identifying organ dysfunction and an inflammatory response in dogs and cats, adapted from those used in humans, include:
Therapy The emphasis on early intervention for sepsis has led to the development of treatment and monitoring “bundles,” that is sets of tests and treatments to be implemented universally when sepsis is suspected. There are no validated guidelines or consensus statements to define sepsis bundles in veterinary patients, however many institutions use treatment protocols adapted from those recommended for humans. The priorities for sepsis treatment are:
Early institution of antibiotic therapy2
Identification and control of the source of infection
Supportive care and recovery
Immediate Therapy for Sepsis
Following a tentative diagnosis of sepsis, recommended immediate care should include:
Culture samples- Samples for culture should be obtained before antibiotic administration if this does not delay the use of antibiotics more than 45 minutes. Samples should be specific to the site of infection if this has been identified and can be accessed. If the site is unknown or inaccessible, blood cultures and urine cultures can be taken. Both aerobic and anaerobic cultures should be run.
Antibiotics- A de-escalation approach is currently favored in the treatment of human sepsis patients. This involves early initiation of broad-spectrum antibiotic therapy and then a reduction in antibiotic coverage as soon as possible as indicated by culture results. Recommended duration of antibiotic therapy for humans is 7-10 days unless the source of infection cannot be definitively controlled
There are no evidence-based guidelines for antibiotic use in veterinary sepsis patients. Ideally, antibiotic selection should be based on culture results, local population susceptibility patterns, and the history and condition of the individual patient. Common empiric protocols used in veterinary sepsis patients include:
Ampicillin/Unasyn + Amikacin
Ampicillin/Unasyn + Enrofloxacin
Cefazolin + Cefotaxime
Clindamycin + Enrofloxacin
Lactate Measurement- Lactate is an important biomarker for sepsis management. Values > 2.5 mmol/L should be interpreted as an indicator of inadequate perfusion.
Fluid therapy- Crystalloids are the initial fluid of choice, and aggressive fluid therapy (e.g. boluses of 20-30mL/kg over 15 minutes) should be initiated for patients with evidence of hypotension (e.g. MAP< 65mmHg) or poor perfusion (e.g. lactate > 4.0 mmol/L or consistent physical exam findings) unless there is a clear contraindication (e.g. primary cardiac disease, evidence of overhydration). Fluid therapy should be titrated to endpoints, including:
Normalization of heart rate
Normalization of respiratory rate
Normalization of blood pressure (MAP> 65mmHg, systolic > 100mmHg)
Normalization of lactate (< 2.0mmol/L)
Normalization of mentation
Normalization of urine output (UOP> 1mL/kg/hr)
Hetastarch is not recommended in human sepsis patients due to some evidence of increased mortality and risk for acute kidney injury. It is unclear the extent to which this applies to veterinary patients,3 however many experts recommend avoiding synthetic colloids if possible. Canine albumin is preferred as a colloid, though it is often unavailable or unaffordable.
Continued hemodynamic stabilization- If the targets for fluid therapy (blood pressure, lactate, etc.) are not met with initial crystalloid treatment, vasopressors should be started early because hypotension in sepsis is often due to decreased peripheral vasomotor tone. Based on guidelines for humans and limited evidence in veterinary patients, the following are common recommendations for use of vasopressors in sepsis patients:
Warning! Some vasopressors can cause ischemic necrosis due to extreme vasoconstriction. They should ideally be given through a central line, and clients should be advised of this possible complication.
Norepinephrine- 0.1-0.5mcg/kg/min Start low and titrate upwards in 0.1mcg/kg/min increments every 5-10 min until BP targets are reached (e.g. MAP>65mmHg) or 2-3mcg/kg/min is reached.
Vasopressin is often recommended as a second-line pressor or to reduce the dose of norepinephrine in humans, but it is often unavailable to veterinary patients due to cost.
Epinephrine- 0.05- 1mcg/kg/min. This can be added to norepinephrine if needed and titrated upwards every 5-10 min until BP targets are reached.
Dopamine- This drug has historically been the pressor of choice in veterinary patients, but recent practice has shifted to norepinephrine based largely on extrapolation from research in human sepsis patients.
Dobutamine- This is primarily an inotrope and is only recommended if there is evidence of poor contractility because it decreases vascular tone and can decrease BP
It is important to identify all physiologic abnormalities that can be treated in patients with sepsis and septic shock. These may include:
Coagulation- PT/PTT/platelet counts
Vital signs- HR, RR, body temperature, pulse quality, mm color, CRT
Pain Score and mental status- Analgesia should be provided if there is evidence of pain. NSAIDs should be avoided if there is hemodynamic instability or evidence of GI or renal impairments.
Urine output and renal values
Body weight- this is a key measure for assessing fluid balance
Gastroprotectants- (e.g. pantoprazole) These can be considered if there is evidence of gastrointestinal lesions or symptoms
Anti-emetics- (e.g. maropitant, ondansetron) These can be considered if there is evidence of nausea or vomiting.
Promotility drugs- (e.g. metoclopramide, low-dose erythromycin) These can be considered if there is evidence of GI hypomotility or ileus.
Blood products- There is significant controversy and uncertainty regarding the use of blood products in septic patients. Strict arbitrary cutoff values for use of blood products are now discouraged in human patients due to growing evidence of harm related to transfusion. There are no clear guidelines for veterinary patients.
Treatment of Anemia- Most critical patients become anemic at some point. Anemia should be treated when associated with significant clinical symptoms (e.g. hypoxia, tachypnea/tachycardia), ongoing losses of red blood cells, or anticipated losses associated with surgical source control procedures.. Though strict cutoffs are discouraged, a Hb of 7.0g/dL is often used as a guideline for when to transfuse in human sepsis patients.
Treatment of Thrombocytopenia- Platelet-rich plasma is given to humans when there is clinical evidence of bleeding (e.g. petechiae, ecchymoses, epistaxis), when a surgical procedure is planned and platelet count is < 50k/mm3, or prophylactically when platelet count is <10k/mm3.
Treatmwnt of Coagulopathy- It is not recommended to give fresh-frozen plasma (FFP) to correct clotting times in the absence of active bleeding. If PT/PTT are elevated and there is bleeding or a surgical procedure is planned, FFP may be beneficial.
Vitamin C Though this is, at best, an ancillary therapy to consider in patients with sepsis, without the acknowledged critical importance of many others and not necessarily widely used in veterinary patients, I want to focus a bit on it because it illustrates the challenges of an evidence-based approach to a complex medical problem.
In human medicine, as in the veterinary field, practices may be adopted based on early evidence that is both encouraging and extremely limited. Unlike veterinary medicine, however, follow-up studies are much more common and robust, and better evidence that shows the true state of affairs is often available within a few years. Unfortunately, in our profession we are more likely to adopt a practice based on a single small study and then employ it widely for a long time before subsequent studies either confirm the benefits or show them to be illusory. Vitamin C for sepsis is a cautionary tale that should encourage us to try harder to confirm our initial assessment of new therapies.
In 2017, a study of 94 human patients with sepsis was published comparing patient given standard treatment and those also given Vitamin C, thiamine, and low-dose hydrocortisone (called HAT therapy).4 This was a small by the standards of human medicine, though larger than many equally influential veterinary trials, but it appeared to show dramatic benefits. Mortality was 8.5% in the experimental group and 40.4% in the control group, and there were apparent benefits in terms of other standardized measures of disease severity.
This study had a dramatic impact in the human critical care field, with reverberations in veterinary medicine. Debate and additional research began immediately in human medicine. In the veterinary profession, there was buzz about this new treatment at conferences5 and online, and some veterinarians began adding it to their management of sepsis cases.6 It is unclear how widespread this practice became in veterinary circles, but the published research on Vitamin C in critically ill veterinary patients is pretty sparse, and there are not prospective randomized clinical trials specifically comparing HAT to standard care in veterinary sepsis cases.5–7
In contrast, the five years since the publication of the original HAT study has seen a flurry of research in humans, and there are now more than a dozen systematic reviews and meta-analyses evaluating studies in thousands of sepsis patients.4,8–17 Unfortunately, the majority of these have failed to confirm the dramatic results from the original study. Most have found no reduction in mortality from adding HAT to standard care. Some have shown modest improvement in some assessments of disease severity, but many have found no statistically significant nor clinically meaningful effect at all.
This is about as clear an example of the Decline Effect as one could ask for. Dramatic effects seen in initial studies of a new therapy get smaller and smaller as subsequent studies attempt to replicate the results until the literature settles on a far less dramatic reality, which surprisingly often turns out to be no effect at all. The explanations for this involve both intentional and, most of the time, unconscious bias on the part of enthusiastic researchers studying a new idea, as well as the limitations of small, often poorly controlled research studies in unrepresentative patient populations. This phenomenon is the main reason we should avoid enthusiastically embracing new therapies before appropriate replication of such initial studies has been done.
In the case of HAT, the controversy has grown more dramatic than usual. The primary author of the original study, Dr. Paul Marik, vehemently stands by his results despite all the failed attempts to replicate them. A recent letter to the editorof the journal in which this study was published has alleged that analysis of the results and statistics reported in the original paper is not only suggestive of data fabrication but clear proof of misconduct. An investigation by the journal is likely, especially in light of a very similar controversy involving the same investigator.
Dr. Marik has also published a study purportedly showing a different novel approach with equally dramatic benefits in COVID-19 patients. This paper has recently been retracted due to evidence of data manipulation. The author has also been reprimanded by the Virginia Medical Board for misconduct, resigned his academic position, and become involved in a lawsuit with his hospital over the use of ivermectin as a COVID-19 therapy. Like HAT, the approach Dr. Marik advocates for COVID-19 appeared promising in his early studies, but the elements of it have so far failed to show benefits in subsequent research.18,19 Dr. Marik illustrates starkly how hard the habit of excessive enthusiasm for new therapies based on preliminary evidence is to break.
Bottom Line Sepsis is a serious and complex problem with numerous possible treatment approaches and mixed, often disappointing results. An evidence-based approach involves attention to the limited and weak evidence available in veterinary patients and judicious extrapolation from the more robust, but still imperfect, evidence available in humans.
The use of Vitamin C, alone or in combination, in sepsis patients has evolved from an exciting and promising new idea to an example of failed promise, and of the dangers of unconscious bias, if not outright scientific fraud. The lesson we should draw from this is not merely that use of Vitamin C in veterinary sepsis patients is probably not warranted, but that we should proportion our acceptance of and confidence in new therapies to the strength of the evidence for them. For veterinarians, this often means a perpetual state of using treatments in which we can have very little confidence, but this is still preferable to enthusiastic commitment to practices which later prove ineffective or even dangerous for our patients.
1. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. doi:10.1097/CCM.0000000000005337
2. Abelson AL, Buckley GJ, Rozanski EA. Positive impact of an emergency department protocol on time to antimicrobial administration in dogs with septic peritonitis. J Vet Emerg Crit Care. 2013;23(5):n/a-n/a. doi:10.1111/vec.12092
3. Glover PA, Rudloff E, Kirby R. Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use. J Vet Emerg Crit Care (San Antonio). 2014;24(6):642-661. doi:10.1111/vec.12208
4. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036
5. Silverstein D. Treating Sepsis with Vitamins? The Risks, Benefits, and Evidence. In: International Veterinary Emergency and Critical Care Symposium. Washington, D.C.; 2019.
6. Taylor SD. Oranges for Horses? Exploring Vitamin C in the Fight against Equine Sepsis. Purdue Equine Heal Updat. 2019;21(2):5.
7. Gordon DS, Rudinsky AJ, Guillaumin J, Parker VJ, Creighton KJ. Vitamin C in Health and Disease: A Companion Animal Focus. Top Companion Anim Med. 2020;39:100432. doi:10.1016/j.tcam.2020.100432
8. Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock. JAMA. 2020;323(5):423. doi:10.1001/jama.2019.22176
9. Anderson MJ, Ibrahim AS, Cooper BR, Woolcock AD, Moore GE, Taylor SD. Effects of administration of ascorbic acid and low-dose hydrocortisone after infusion of sublethal doses of lipopolysaccharide to horses. J Vet Intern Med. 2020;34(6):2710-2718. doi:10.1111/jvim.15896
10. Lee YR, Vo K, Varughese JT. Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: A systematic review. Nutr Health. 2022;28(1):77-93. doi:10.1177/02601060211018371
11. Wu T, Hu C, Huang W, Xu Q, Hu B, Li J. Effect of Combined Hydrocortisone, Ascorbic Acid and Thiamine for Patients with Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Shock. 2021;56(6):880-889. doi:10.1097/SHK.0000000000001781
12. Assouline B, Faivre A, Verissimo T, et al. Thiamine, Ascorbic Acid, and Hydrocortisone As a Metabolic Resuscitation Cocktail in Sepsis: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis. Crit Care Med. 2021;49(12):2112-2120. doi:10.1097/CCM.0000000000005262
13. Patel JJ, Ortiz-Reyes A, Dhaliwal R, et al. IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2022;50(3):e304-e312. doi:10.1097/CCM.0000000000005320
14. Fujii T, Salanti G, Belletti A, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16. doi:10.1007/S00134-021-06558-0
15. Ge Z, Huang J, Liu Y, et al. Thiamine combined with vitamin C in sepsis or septic shock: a systematic review and meta-analysis. Eur J Emerg Med. 2021;28(3):189-195. doi:10.1097/MEJ.0000000000000812
16. Scholz SS, Borgstedt R, Ebeling N, Menzel LC, Jansen G, Rehberg S. Mortality in septic patients treated with vitamin C: a systematic meta-analysis. Crit Care. 2021;25(1):17. doi:10.1186/s13054-020-03438-9
17. Somagutta MKR, Pormento MKL, Khan MA, et al. The Efficacy of vitamin C, thiamine, and corticosteroid therapy in adult sepsis patients: a systematic review and meta-analysis. Acute Crit care. 2021;36(3):185-200. doi:10.4266/acc.2021.00108
18. Popp M, Stegemann M, Metzendorf M-I, et al. Ivermectin for preventing and treating COVID?19. Cochrane Database Syst Rev. 2021;(7). doi:10.1002/14651858.CD015017.PUB2
19. Lim SCL, Hor CP, Tay KH, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities. JAMA Intern Med. 2022;182(4):426. doi:10.1001/jamainternmed.2022.0189
If my posts have seemed few and far between lately, one of many reasons is I have been busily typing away producing some scientific publications in my new focus area- canine aging science. My collaborators and I have produced several recent papers which I hope will be of some interest to some of you. Since not all are readily available outside of academia, I will post them here. Enjoy!
Abstract Biological aging is the single most important risk factor for disease, disability, and ultimately death in geriatric dogs. The effects of aging in companion dogs also impose significant financial and psychological burdens on their human caregivers. The underlying physiologic processes of canine aging may be occult, or early signs of aging may be ignored because of the misconception that biological aging is natural and therefore inevitable. The ability to detect, quantify, and mitigate the deleterious processes of canine aging would greatly enhance veterinary preventative medicine and animal welfare. In this paper we propose a new conceptual framework for aging in dogs, the Canine Geriatric Syndrome (CGS). CGS consists of the multiple, interrelated physical, functional, behavioral, and metabolic changes that characterize canine aging as well as the resulting clinical manifestations, including frailty, diminished quality of life, and age-associated disease. We also identify potential key components of a CGS assessment tool, a clinical instrument that would enable veterinarians to diagnose CGS and would facilitate the development and testing of interventions to prolong healthspan and lifespan in dogs by directly targeting the biological mechanisms of aging. There are many gaps in our knowledge of the mechanisms and phenotype of aging in dogs that must be bridged before a CGS assessment tool can be deployed. The conceptual framework of CGS should facilitate identifying these gaps and should stimulate research to better characterize the processes and effects of aging in dogs and to identify themost promising preventative strategies to target these.
Abstract Aging is the single most important cause of disease, disability, and death in companion animal species. Contrary to the common view of aging as mysterious and inevitable, it is more usefully understood as a set of complex but comprehensible and modifiable biological processes that are highly conserved across species. The purpose of this Currents in One Health manuscript is to describe key mechanisms of aging at the cellular and molecular level and the manifestations of these in the tissues of the musculoskeletal system, adipose, and the brain. The characteristics of these processes as identified in common laboratory animal models and in humans will be described and compared with the much more limited information available concerning aging in dogs and cats. This will highlight important targets for future research in these species. The consistent patterns across species in the hallmarks of aging and their manifestations at the level of tissues, organ systems, and individual animals signify potential targets for interventions to mitigate the negative health impacts of aging and extend both life span and health span (the period of life free of significant disease or disability). Further research to elucidate aging mechanisms in companion dogs and cats will eventually support development, testing, and implementation of clinical therapies to prevent and ameliorate age-related dysfunction, disease, and death.
Abstract Aging is the single most important cause of disease, disability, and death in adult dogs. Contrary to the common view of aging as a mysterious and inevitable natural event, it is more usefully understood as a set of complex but comprehensible biological processes that are highly conserved across species. Although the phenotypic expression of these processes is variable, there are consistent patterns both within and between species. The purpose of this feature is to describe the patterns currently recognized in the physical and behavioral manifestations of aging in the dog and how these impact the health and welfare of companion dogs and their human caregivers. Important gaps in our knowledge of the canine aging phenotype will be identified, and current research efforts to better characterize aging in the dog will be discussed. This will help set the context for future efforts to develop clinical assessments and treatments to mitigate the negative impact of aging on dogs and humans.