Gabapentin: Is it useful for pain control in dogs and cats?

Veterinary medicine suffers from a chronic lack of scientific evidence to identify safe and effective treatments. We are authorized to used medicines approved for human or animal use on an off-label basis in other species or conditions because the Food and Drug Administration (FDA) recognizes that there are so few properly tested and approved medications for our patients. Without this off-label authority, our ability to treat serious health problems would be crippled.1 Unfortunately, this means therapies are often widely used on the basis of low-quality or unreliable evidence, including in vitro or lab animal studies, extrapolation from human studies, clinical experience and anecdote, or weak clinical evidence. 

One of the most critical unmet needs in companion animal medicine is for oral analgesics other than non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are the mainstay of our treatment for acute and chronic pain in dogs and cats. While they are safe and effective in many cases, sometimes they are contraindicated or the risks of NSAID use may outweigh the benefits.2–6 There is also an inappropriate level of anxiety among pet owners and veterinarians about using these drugs, especially in cats, that further limits their utility.

Many alternative oral analgesics are recommended and commonly used, but these typically lack the robust evidence regarding safety and efficacy we have for the NSIADs.7–11 In some cases, such therapies have been widely employed and then eventually found to be ineffective. Tramadol is perhaps the most well-known example of this.12 Despite promising evidence from human and preclinical research, the extensive use of this drug as a treatment for acute and chronic pain in dogs likely resulted in significant undertreatment and unnecessary suffering. Though the evidence for CBD is slightly better, the ubiquity of this remedy as an analgesic is also out of proportion to the strength of this evidence, and it remains to be seen if we will come to regret rapid and widespread adoption of this as an oral analgesic.13,14

The current leading non-NSAID oral analgesic appears to be gabapentin. I often encounter pet owners and veterinarians firmly convinced that this is a proven therapy for acute and chronic pain in dogs and cats. A recent survey of veterinarians found it the most popular prescription for chronic musculoskeletal pain in cats, ahead of much more extensively studied treatments such as meloxicam.8 Is this confidence justified? Let’s take a look at the evidence.

What is Gabapentin?
Gabapentin is a structurally similar to gamma-aminobutyric acid (GABA), though it is not a GABA receptor agonist.10It’s mechanisms of action are not well-understood, but it appears to operate by affecting pre-synaptic calcium channels in neurons.10,11 It is licensed as an anti-seizure medication in humans and for treatment of herpesvirus-associated neuralgia.10,11

Studies in Humans
Apart from its validated uses for seizures and herpetic neuralgia, gabapentin has been studies for many types of acute and chronic pain in humans. The evidence is mixed, low-quality, and inconclusive.15–23 Studies of perioperative gabapentin use in patients undergoing knee replacement19, hip replacement17, Cesarian section22, breast cancer23, and other surgical procedures16,18,20 are inconsistent. Some show reduction of opioid use and various measures of pain and others do not. In many of these reviews, some assessment tools for pain or discomfort may show beneficial effects from gabapentin while others do not. Even studies examining neuropathic pain in humans, which is considered the most reliable indication for gabapentin, find that many patients experience no benefit.21 Nearly all literature reviews emphasize that the evidence is of poor quality and that better quality research is needed to support firm conclusions.

Veterinary Evidence
Basic pharmacology and pharmacokinetic research indicates gabapentin given orally can be absorbed and achieve plasma levels associated with analgesia in humans.10 Because the drug has a very short half-life, it likely needs to be given every eight hours to achieve these levels.10

A few preclinical studies have been done in dogs and cats. Gabapentin did not affect thermal nociceptive response when given orally in cats. It also did not lower the minimum alveolar concentration (MAC) of isoflurane when given intravenously in this species.24,25 The MAC for isoflurane in dogs was decreased by oral gabapentin, though whether this reflects analgesia or some other effect, such as sedation, is unclear.26

Some case series, and the usual mountain of less formal anecdotal evidence, have suggested analgesic benefits from oral gabapentin in dogs and cats.27–30 However, these uncontrolled observations are at high risk of bias and error, and they frequently do not reflect the findings of better controlled clinical studies.

There are some clinical trial studies of oral gabapentin as an analgesic in dogs and cats. These have generally not been very encouraging, though they all have some methodological limitations, from ineffective blinding or other bias-control measures to administration of gabapentin every 12 hours, which is less than pharmacokinetic studies suggest is needed to achieve an effect. 

In dogs, adding gabapentin to opioid or NSAID analgesia provided no additional pain benefit by most measures in dogs undergoing intervertebral disk surgery,31 mastectomy32, and forelimb amputation33. Studies involving dogs with neuropathic34,35 pain have also failed to find robust evidence of any benefit. One study in cats undergoing ovariohysterectomy found no analgesic benefit of oral gabapentin added to buprenorphine or meloxicam compared with a placebo.36 Reviews of the evidence uniformly conclude that the widespread use of gabapentin for acute and chronic pain in dogs and cats is not based on high-quality, robust scientific research.9–11

Is it Safe?
The potential risks of gabapentin are based almost entirely on anecdotal reports. Sedation, ataxia, and vomiting or diarrhea are commonly listed as potential adverse effects and have been reported in clinical trials, but there is virtually no research specifically investigating the potential risks of this drug in dogs or cats.37

Bottom Line
The widespread acceptance and use of gabapentin as a safe and effective treatment for acute and chronic pain in cats and dogs is not based on reliable scientific evidence. Extrapolation from preclinical research and the limited evidence available in humans is a common but poor foundation for clinical use of the drug in veterinary patients. The few studies so far published in dogs and cats have not been encouraging. It may turn out that gabapentin is a useful non-NSAID oral analgesic, but it seems equally likely that we will eventually realize we have been relying on yet another ineffective pain therapy. While we inevitably have to make the best effort we can to treat our patients in the information-poor context of veterinary medicine, we have ample reason to be wary of trusting therapies with such weak evidence behind them. Our patients deserve better than treatments we only hope will effectively treat their pain. Until better more definitive evidence is available, gabapentin should be regarded as no more than theoretically beneficial as an adjunctive treatment, and it should not be relied on as a sole therapy or an alternative to treatments with better evidence of real benefits, such as opioids and NSAIDs.

References

1.        American Veterinary Medical Association. Extralabel Drug Use and AMDUCA: FAQ. https://www.avma.org/extralabel-drug-use-and-amduca-faq. Published 2021. Accessed January 7, 2021.

2.        Monteiro B, Steagall P, Lascelles B, et al. Long-term use of non-steroidal anti-inflammatory drugs in cats with chronic kidney disease: from controversy to optimism. J Small Anim Pract. 2019;60(8). doi:10.1111/JSAP.13012

3.        Sparkes A, Heiene R, Lascelles B, et al. ISFM and AAFP consensus guidelines: long-term use of NSAIDs in cats. J Feline Med Surg. 2010;12(7). doi:10.1016/J.JFMS.2010.05.004

4.        Innes J, Clayton J, Lascelles B. Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Vet Rec. 2010;166(8). doi:10.1136/VR.C97

5.        Luna S, Basílio A, Steagall P, et al. Evaluation of adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs. Am J Vet Res. 2007;68(3). doi:10.2460/AJVR.68.3.258

6.        Monteiro-Steagall B, Steagall P, Lascelles B. Systematic review of nonsteroidal anti-inflammatory drug-induced adverse effects in dogs. J Vet Intern Med. 2013;27(5). doi:10.1111/JVIM.12127

7.        Epstein ME, Rodan I, Griffenhagen G, et al. 2015 AAHA/AAFP Pain Management Guidelines for Dogs and Cats. J Feline Med Surg. 2015;17(3):251-272. doi:10.1177/1098612X15572062

8.        Adrian DE, Rishniw M, Scherk M, Lascelles BDX. Prescribing practices of veterinarians in the treatment of chronic musculoskeletal pain in cats. J Feline Med Surg. 2019;21(6):495-506. doi:10.1177/1098612X18787910

9.        Ruel H, Steagall P. Adjuvant Analgesics in Acute Pain Management. Vet Clin North Am Small Anim Pract. 2019;49(6). doi:10.1016/J.CVSM.2019.07.005

10.      KuKanich B. Outpatient oral analgesics in dogs and cats beyond nonsteroidal antiinflammatory drugs: an evidence-based approach. Vet Clin North Am Small Anim Pract. 2013;43(5). doi:10.1016/J.CVSM.2013.04.007

11.      Moore S. Managing Neuropathic Pain in Dogs. Front Vet Sci. 2016;3. doi:10.3389/FVETS.2016.00012

12.      McKenzie BA. Is tramadol an effective analgesic for dogs and cats? Vet Pract News. June 2018:32-33.

13.      McKenzie B. A conclusion on cannabis? Vet Pract News. July 2019:26-27.

14.      McKenzie BA. Cannabis-based remebdies: No reliable clinical research evidence. Vet Pract News. August 2017:38.

15.      Fabritius M, Wetterslev J, Mathiesen O, Dahl J. Dose-related beneficial and harmful effects of gabapentin in postoperative pain management – post hoc analyses from a systematic review with meta-analyses and trial sequential analyses. J Pain Res. 2017;10. doi:10.2147/JPR.S138519

16.      Fabritius M, Geisler A, Petersen P, Wetterslev J, Mathiesen O, Dahl J. Gabapentin in procedure-specific postoperative pain management – preplanned subgroup analyses from a systematic review with meta-analyses and trial sequential analyses. BMC Anesthesiol. 2017;17(1). doi:10.1186/S12871-017-0373-8

17.      Mao Y, Wu L, Ding W. The efficacy of preoperative administration of gabapentin/pregabalin in improving pain after total hip arthroplasty: a meta-analysis. BMC Musculoskelet Disord. 2016;17(1). doi:10.1186/S12891-016-1231-4

18.      Egunsola O, Wylie C, Chitty K, Buckley N. Systematic Review of the Efficacy and Safety of Gabapentin and Pregabalin for Pain in Children and Adolescents. Anesth Analg. 2019;128(4). doi:10.1213/ANE.0000000000003936

19.      Han C, Li X, Jiang H, Ma J, Ma X. The use of gabapentin in the management of postoperative pain after total knee arthroplasty: A PRISMA-compliant meta-analysis of randomized controlled trials. Medicine (Baltimore). 2016;95(23). doi:10.1097/MD.0000000000003883

20.      Fabritius M, Geisler A, Petersen P, et al. Gabapentin for post-operative pain management – a systematic review with meta-analyses and trial sequential analyses. Acta Anaesthesiol Scand. 2016;60(9). doi:10.1111/AAS.12766

21.      Wiffen P, Derry S, Bell R, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane database Syst Rev. 2017;6(6). doi:10.1002/14651858.CD007938.PUB4

22.      Felder L, Saccone G, Scuotto S, et al. Perioperative gabapentin and post cesarean pain control: A systematic review and meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol. 2019;233. doi:10.1016/J.EJOGRB.2018.11.026

23.      Rai A, Khan J, Dhaliwal J, et al. Preoperative pregabalin or gabapentin for acute and chronic postoperative pain among patients undergoing breast cancer surgery: A systematic review and meta-analysis of randomized controlled trials. J Plast Reconstr Aesthet Surg. 2017;70(10). doi:10.1016/J.BJPS.2017.05.054

24.      Pypendop B, Siao K, Lkiw J. Thermal antinociceptive effect of orally administered gabapentin in healthy cats. Am J Vet Res. 2010;71(9). doi:10.2460/AJVR.71.9.1027

25.      Reid P, Pypendop B, Ilkiw J. The effects of intravenous gabapentin administration on the minimum alveolar concentration of isoflurane in cats. Anesth Analg. 2010;111(3). doi:10.1213/ANE.0B013E3181E51245

26.      Johnson B, Aarnes T, Wanstrath A, et al. Effect of oral administration of gabapentin on the minimum alveolar concentration of isoflurane in dogs. Am J Vet Res. 2019;80(11). doi:10.2460/AJVR.80.11.1007

27.      Davis L V, Hellyer PW, Downing RA, Kogan LR. Retrospective Study of 240 Dogs Receiving Gabapentin for Chronic Pain Relief. J Vet Med Res. 2020;7(4):1194. https://www.jscimedcentral.com/VeterinaryMedicine/veterinarymedicine-7-1194.pdf. Accessed January 7, 2021.

28.      Steagall P, Monteiro-Steagall B. Multimodal analgesia for perioperative pain in three cats. J Feline Med Surg. 2013;15(8). doi:10.1177/1098612X13476033

29.      Vettorato E, Corletto F. Gabapentin as part of multi-modal analgesia in two cats suffering multiple injuries. Vet Anaesth Analg. 2011;38(5). doi:10.1111/J.1467-2995.2011.00638.X

30.      Lorenz N, Comerford E, Iff I. Long-term use of gabapentin for musculoskeletal disease and trauma in three cats. J Feline Med Surg. 2013;15(6). doi:10.1177/1098612X12470828

31.      Aghighi S, Tipold A, Piechotta M, Lewczuk P, Kästner S. Assessment of the effects of adjunctive gabapentin on postoperative pain after intervertebral disc surgery in dogs. Vet Anaesth Analg. 2012;39(6). doi:10.1111/J.1467-2995.2012.00769.X

32.      Crociolli G, Cassu R, Barbero R, Rocha T, Gomes D, Nicácio G. Gabapentin as an adjuvant for postoperative pain management in dogs undergoing mastectomy. J Vet Med Sci. 2015;77(8). doi:10.1292/JVMS.14-0602

33.      Wagner A, Mich P, Uhrig S, Hellyer P. Clinical evaluation of perioperative administration of gabapentin as an adjunct for postoperative analgesia in dogs undergoing amputation of a forelimb. J Am Vet Med Assoc. 2010;236(7). doi:10.2460/JAVMA.236.7.751

34.      Plessas I, Volk H, Rusbridge C, Vanhaesebrouck A, Jeffery N. Comparison of gabapentin versus topiramate on clinically affected dogs with Chiari-like malformation and syringomyelia. Vet Rec. 2015;177(11). doi:10.1136/VR.103234

35.      Ruel H, Watanabe R, Evangelista M, et al. Pain burden, sensory profile and inflammatory cytokines of dogs with naturally-occurring neuropathic pain treated with gabapentin alone or with meloxicam. PLoS One. 2020;15(11). doi:10.1371/JOURNAL.PONE.0237121

36.      Steagall P V, Benito J, Monteiro BP, Doodnaught GM, Beauchamp G, Evangelista MC. Analgesic effects of gabapentin and buprenorphine in cats undergoing ovariohysterectomy using two pain-scoring systems: a randomized clinical trial. J Feline Med Surg. 2018;20(8):741-748. doi:10.1177/1098612X17730173

37.      Peck C. The adverse effect profile of gabapentin in dogs – a retrospective questionnaire study. 2017.

Posted in Science-Based Veterinary Medicine | 5 Comments

Lifespan & Body Size- Big Animals Live Longer, Except When They Don’t

One of the earliest recorded assertions that large animals live longer than small ones comes from Aristotle in 350 BC. Such unstructured observations have subsequently been supported by more rigorous scientific study. As this graph shows, there is a positive correlation between body size and lifespan in many different groups of mammals. A similar relationship holds for other classes of animals as well, such as birds. 

Chart, diagram, scatter chart

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The question of why bigger is better for lifespan, however, is less clear. Aristotle’s notion that larger animals live longer because they contain more fluid and more heat hasn’t held up very well to scientific scrutiny. More specific hypotheses about the relationship between metabolic rate, production of damaging free radicals, or ecological niche and longevity have proven more robust, but there is no single universal explanation for the relationship between body size and lifespan. 

It is likely that the average and maximum lifespan of a species is influenced by many factors, some intrinsic and some extrinsic, and the general relationship between longevity and size can be exaggerated or weakened by the net effect of many variables and how they interact for each species. As a broad generalization, though, it is safe to say than there is an underlying tendency for larger species to live longer than smaller ones.

This relationship often gets turned on its head, however, when we look at the effect of size on lifespan within species. For dogs, in particular, it is well established that larger dogs age faster and have shorter lives than smaller dogs. One study showed that body size alone explained almost 50% of the variance in life expectancy between breeds. 

Chart, scatter chart

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So why do big dogs age faster and die younger than small dogs? Again, there is likely no single, simple answer. However, genetic differences are likely the key. When the degree of inbreeding is added to body weight, these variables explain almost 95% of the difference in lifespan between breeds. The enormous variation in body size across breeds is due to differences in only a few genes, and these genes likely contribute to shorter lifespans as well as larger size.

Posted in Aging Science | 6 Comments

Stem Cell Therapies in Veterinary Medicine: Where are We Now?

I’ve written about stem cell therapies numerous times over the years, though not for quite a while. My conclusions were always along the lines of “promising but unproven.” This is one of those perfectly plausible therapies that I expect will be beneficial at some point but which has, like so many conventional and alternative treatments, has been rushed into use well before we have sufficient evidence to know what it can really do and what it can’t.

I have recently written an update on the topic, and not a great deal has changed since I first covered it over a decade ago. There is much more research evidence, but the variety of types of treatments tested and the different conditions and measures of effect used make it difficult to confidently asses the effectiveness of any specific stem cell treatment on the market for any specific problem. Overall, the evidence is still promising but unproven, though it has gotten at least a little better for the most common use, osteoarthritis. Despite this, there is a long way to go before we can recommend stem cell treatments without a lot of caveats about the uncertainty for their benefits and for long-term safety.

Leaping Before Looking
Science can be frustrating. There is always a gap between having a great idea and having a new tool to change things in the real world. Ideally, that gap is bridged by robust, rigorous scientific research which tells us whether the original idea is really as great as it seems and what it will actually let us accomplish. Even in the best case, filling the gap between inspiration and real-world change takes time. And all too often, seemingly good ideas crack under the pressure of scientific investigation and fail to live up to their promise. 

Our natural human tendency is to let our excitement over a new discovery or hypothesis to carry us away, and to start implementing our new ideas as quickly as possible. If we’re lucky, that lets us achieve the change we want to make in the world more quickly. Unfortunately, in most cases the result is less positive. Skipping past the process of interrogating new hypotheses scientifically commonly leaves us with tools that don’t work, or that have harmful effects we didn’t anticipate. Nature is inevitably more complex that our ideas about it, and enthusiasm can’t overcome the gap between what we think we understand and the reality of the natural world.

In veterinary medicine, we are always seeking new understandings and new tools to better care for our patients. Compared to our colleagues in human medicine, we are relatively unconstrained in trying out our ideas. As I discussed in my last essay, regulatory oversight of veterinary medicine is light, and we are accustomed to therapies with little supporting evidence and to leaping into new practices well before they have built the kind of supportive evidence required in human medicine. 

This is a necessary evil given the limited resources available to build better evidence in veterinary medicine. When our ideas turn out to be right, we have the advantage of getting effective treatments to our patients faster and with less cost than in human medicine. When we are wrong, of course, we end up exposing our patients to therapies that seem like they should work but are actually ineffective (e.g. tramadolglucosaminehomeopathy) or harmful (e.g. high-dose steroids for spinal cord injurytreatment of asymptomatic bacteriuria with antibiotics).

One of the most exciting ideas I have watched develop over my twenty years as a veterinarian is the hypothesis that stem cell therapies can be used to treat a great variety of different health problems in veterinary patients. Stem cells have been a subject of intense enthusiasm, controversy, and research in human medicine for several decades, and this has spilled over into veterinary medicine, with the usual time delay and lower level of available evidence. In an example of the potential benefits from the looser regulatory burden in our field, stem cell therapies are being also explored in our patients as a springboard for more rapid development and approval of treatments for humans. 

As often happens, preliminary research in laboratory animals and in human medicine led to relatively rapid commercialization and clinical use of stem cell treatments in veterinary medicine well before robust clinical trial evidence in companion animals with natural disease had been developed. Fortunately, as better evidence has been slowly accumulated, it is looking more and more like we may have “guessed right” in this case, and that the risks to our patients are minimal (though not negligible) and there may well be meaningful benefits. Regulatory approval of commercial veterinary stem cell therapies is just beginning, and I am hopeful that despite our cart-before-the-horse approach to this treatment, therapies which are demonstrably safe and effective may be available soon. However, as a recent review of the science in this field concluded, “despite considerable advancements in veterinary regenerative

medicine in recent years, this field is still in its infancy and much more work is needed to resolve many questions before proven, standardized therapies [can] be offered to the clinical patients.”1

What Are Stem Cells?
Stem cells possess the ability to differentiate into a variety of cell types.1 The degree of differentiation present in a stem cell and the potential for further replication and differentiation varies among different kinds of stem cells. Pluripotent trophoblasts present in the early embryo can give rise to a complete organism, while stem cells present in adults have considerably less potential to differentiate.2 Early stem cell research focused on embryonic cells derived from fetal tissue, but social and political controversy around this led to the predominance of mesenchymal stem cells (MSC) derived from adult tissues as the focus of research into potential stem-cell therapies.3 It is also possible to induce fully-differentiated adult cells to become pluripotent stem cells through genetic manipulation, though there are potential safety concerns to such methods which are still being investigated.1,2,4

Early hypotheses about the medical benefits of stem cell use centered on the idea that these cells could be introduced into diseases tissue where they would differentiate into needed cell types. For example, if a dog has a damaged cranial cruciate ligament or degraded articular cartilage, intra-articular stem cell injection could produce new connective tissue or cartilage to replace the damaged tissues. This is now understood to be incorrect, and the mechanisms by which exogenous stem cells influence disease are more complex and indirect.

Stem cells have significant immunomodulatory effects, exerting paracrine influence on a variety of cells via cytokines and mediators of inflammation and growth. MSCs can also influence apoptosis of other cells, and they appear to be able to exchange extracellular vesicles and even mitochondria with endogenous cells.1,2 There is a great deal still to be learned about how exogenous stem cells function and what physiologic effects they have when administered to veterinary patients. These details are critical to rational use of these cells as clinical treatments, and failing to appreciate this complexity is likely to lead to ineffective therapy.

Finally, stem cell therapies can be categorized based on their origins. As already mentioned, they may be embryonic, induced pluripotent adult cells, or mesenchymal stem cells, which are most commonly used in veterinary medicine. MSCs can also be taken from the patient we intend to treat (autologous), from another donor individual of the same species (allogenic), or even from a donor of a different species (xenogenic). Each of these sources has different potential risks and benefits. 

Autologous stem cells are most commonly used in commercial treatments available today. This is largely due to regulatory constraints. The Food and Drug Administration (FDA) has indicated that while the agency considers stem cell therapies to be animal drugs under the law, and therefore theoretically an FDA license is required for their use, they choose to employ discretion in enforcement. Specifically, the FDA allows use of autologous stem cell products under a set of specific conditions:

  1. The product is minimally manipulated.
  2. The product is for homologous use. 
  3. The product is for use in nonfood-producing animals. 
  4. The manufacture of the product does not involve the combination of the cells with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new safety concerns with respect to the product. 
  5. The finished product is not combined with or modified by the addition of any component that is a drug or device.

Allogenic stem cells do not meet these criteria and so require FDA licensing for use, which is a significant burden in terms of time and cost, and this has encouraged regenerative medicine companies to focus on autologous products.

In theory, autologous stem cells should have  minimal risk since they are derived from the patient in which they are used. However, the complexity of stem cell behavior and the potential for changes in these cells with isolation and handling after harvesting means there is still some potential for adverse effects.1

One disadvantage to autologous stem cell therapies is the need for harvesting of tissue (usually fat) from the patient under sedation or anesthesia. This is followed by isolation of MSCs and then administration of these cells to the patient, often with another procedure under sedation or anesthesia depending on the route of administration. Patients who are ill or cachectic or who cannot tolerate the delay between harvesting and administration of the therapy may not be good candidates for this process.

Commercial, ready-to-use allogenic stem cell therapies would obviate the need for harvesting MSC form the patient and allow faster, more standardized treatments. Because of their capacity to multiply, stem cells harvested from a single healthy donor could be used to produce therapies for many patients. The major impediments to this approach are the regulatory requirements for demonstrating safety and efficacy and the inherently greater potential for harm in giving tissue from one individual to another. However, the benefits of allogenic tissue donations can outweigh the risks, as is often the case for common practices such as blood transfusion. If this proves true for allogenic MSC therapies, there would be significant advantages compared to the currently more common autologous products. 

What Can Stem Cells Be Used For?
The potential benefits of stem cell therapies are many.1,2,5 The most commonly studied involves  administering stem cells to support tissue healing and regeneration. Stem cells may be useful in reducing pain and disability associated with osteoarthritis, promoting healing of wounds, and even supporting development of nervous system tissues to restore function lost after nerve damage. Typically, MSCs are delivered directly to the site of injury to support healing and regeneration. However, our growing understanding of stem cell activities and effects has raised the possibility of less intuitive uses.

For example, MSCs have also been shown to exhibit homing, a chemotactic behavior in which they migrate to sites of tissue injury.1 This opens the possibility of treating diseases through systemic administration of MSCs rather than local delivery. This is a significant advantage when local administration is not safe or practical, as in patients unable to tolerate anesthesia or in organs it may be difficult to administer stem cells to directly, such as the heart or kidneys. The paracrine and other effects of MSCs on endogenous cell activity may allow for treatment of inflammatory and autoimmune diseases and other indications beyond straightforward tissue regeneration. 

There are, of course, technical challenges to such applications, such as the difficulty ensuring MSCs get to the target tissue and the complex and the sometimes unpredictable interactions between such exogenous cells and the body of the recipient. It is also important to bear in mind that many specific uses for stem cell therapies are largely hypothetical, will little or no reliable evidence to validate them. 

What is the Evidence?
As I suggested earlier, stem cell therapies are an example of a promising idea that was turned into commercial products and rushed into clinical use in veterinary patients use well before adequate research evidence was available to establish the true risks and benefits. I have been quite critical of this field in the past, and while better supporting evidence is gradually accumulating, it is still disappointing that so many veterinary patients have received largely unproven stem cell therapies.

The International Society for Stem Cell Research (ISSCR) has warned human patients for many years that most stem cell therapies marketed to them are not scientifically validated. Apart from bone marrow transplantation and the use of stem cells in some tissue grafting procedures, there are no stem cell therapies approved for use in humans. While the FDA applies similar standards to regulation of veterinary and human stem cell therapies, including a relatively permissive attitude towards autologous treatments, it has warned manufacturers of stem cell therapies for both animal and human patients against marketing products or making claims that are not consistent with the regulatory limits the agency has set. Unapproved stem cell treatments have cause serious injury to human patients6, and while there are few reports of harm in veterinary patients,7 this is likely due as much to a lack of reporting and surveillance as to a lack of actual harm.

The veterinary stem cell industry has proven profitable, with estimates in the tens of millions of dollars and projections for growth into the hundreds of millions in the near future. One of the major companies in the field, VetStem, reports first using its stem cell therapy in dogs in 2004. By 2020, the company claimed 30,000 of its treatments had been given. FDA approval for this therapy, however, is still “expected” sometime in 2022. Though manufacturers of veterinary stem cell therapies and others have conducted some studies, it is difficult to justify such extensive use of multiple different stem cell treatments without even the minimum standard of FDA approval, much less a robust base of replicable clinical trial evidence showing the safety and efficacy of specific therapies. Only one veterinary stem cell therapy has received official regulatory licensure, a product for use in horses in the European Union.

The research literature concerning stem cell therapies is large and varied. There are in vitro and lab animal studies, studies in humans, and clinical trials in veterinary species, mostly horses and dogs. These studies cover many different types of both autologous and allogenic treatments for numerous medical conditions.1,2,5 Each type of evidence, and every specific study, has particular strengths and limitations, and a comprehensive review is beyond the scope of this article. The most robust evidence, and the most common use for stem cell therapies in small animals, involves osteoarthritis in dogs, so I will focus on that subject. This is a fair representation of the best companion animal stem cell research has to offer as well as the still significant gaps in the evidence.

There have been some relatively good quality studies, with randomization, blinding, and control groups, for both autologous and allogenic stem cell therapies for arthritis in dogs.8–10 The strongest of these compared intra-articular injection of an allogenic stem cell product and saline in 74 dogs using subjective measures of pain and function from both owners and veterinarians.8 The study found an expected placebo effect but also significantly greater improvement in most outcome measures for the treatment group.

A smaller study of 21 dogs compared an autologous adipose-derived product with saline injected into the hip joints of arthritic dogs.9 In general, blinded subjective assessments by veterinarians showed improvement in measures of pain and lameness for both groups, with the treatment group improving more than the control. Owner assessments also showed more improvement in treated dogs than in the placebo group, though the differences were not statistically significant. Another study by the same group using the same product in 14 dogs with elbow arthritis also reported improvement in both veterinary and owner assessments, but no control group or blinding was reported.11

Other studies have had less robust methodology. One, for example, showed improvement with autologous MSC treatment in 8 dogs with severe hip arthritis on some objective measures of weight bearing, but the control dogs were healthy and were not treated with a placebo.10 Another study evaluated an allogenic stem cell therapy in over 200 dogs and reported dramatic improvements.12 However, there was no control group or other control for bias in this study, which render the results potentially unreliable.

A study of an autologous adipose-derived MSC treatment in 10 dogs with osteoarthritis of the knee show some clinical improvement but no change in radiographic appearance or synovial fluid composition compared with a saline placebo.13However, there is no reported information about blinding or other important bias control methods and no statistical analysis, making the reliability of the findings difficult to assess.

A trial investigating allogenic adipose-derived MSCs given as an intra-articjular injection to 30 dogs with elbow arthritis followed the dogs for a year and reported significant improvements. Again, unfortunately, the results of an uncontrolled and unblinded study such as this cannot support confident statements about efficacy.14

In addition to placebos, stem cell therapies have been compared to other regenerative treatments such as platelet rich plasma (PRP, which I have discussed previously).15 In one study, 31 dogs were randomized to an adipose-derived autologous MSC treatment or PRP and evaluated on a number of measures of pain and function by veterinarians and owners. There were statistically significant improvements in both groups, though the changes were sometimes small in magnitude, and the MSC group appeared to improve more than the PRP-treated dogs. The lack of a placebo control is a limitation in this study.

Far less plausible uses for stem cell therapies in arthritic dogs have been studied, such as the injection of MSCs at acupuncture points to treat hip arthritis.16 Apart from the numerous problems with acupuncture in general, this study also failed to include blinding, placebo controls, or other methods necessary to produce reliable and clinically useful research evidence.

These studies illustrate that while there is some encouraging evidence for stem cell treatments in dogs with osteoarthritis, and even a few quite persuasive studies,8,9 the research is often at high risk of bias and error and lacking the sample sizes and methodological rigor needed for confidence in therapeutic claims. The research evidence for other applications of this technology is no better, and often it is quite a bit weaker. The research in other companion animals, such as cats, is negligible, though the evidence in horses is a bit stronger than in dogs.

Stem Cell Safety
Limited evidence for efficacy almost always means limited evidence for safety as well, since we can only know the risks of a given treatment through the same robust research studies needed to show it works. As mentioned earlier, there are reports of serious adverse effects in humans from unapproved stem cell therapies. There are few such reports in companion animal patients, but it is not clear that anyone is really looking for them.

The limited clinical studies we do have, and the somewhat larger collection of lab animal studies done in dogs, suggests that the risks of stem cell therapies are low, particularly for autologous treatments.1,2 This is reassuring, but we must bear in mind the lack of targeted and long-term safety studies and the biologic complexity of stem cell therapies. There is certainly much we have yet to understand about these treatments, and it may well be that greater knowledge identifies not only more potential benefits but also unanticipated risks.

Bottom Line
Stem cell therapies have always presented a dilemma for me. On the one hand, they are based on plausible hypotheses founded in extensive basic science research. If these hypotheses prove true, then stem cells have the potential to provide dramatic health benefits to veterinary patients, including treatments for diseases we cannot currently treat safely and effectively. Who wouldn’t be excited by that!

On the other hand, stem cell therapies are a model for the backwards process of developing therapies in veterinary medicine. Insufficiently tested treatments based on very limited evidence are marketed and given to thousands of patients over many years with remarkably little oversight or incentive for manufacturers to conduct the kind of rigorous investigation we ought to have to ensure the welfare of patients. This is a dangerous way to develop novel therapies, and it can easily do harm. 

I am cautiously optimistic that in the next decade we will reach the point of having several safe and effective stem cell products that have been adequately tested, and beyond that we may even be able to realize some of the more dramatic possibilities of these therapies, such as regeneration of lost nerve function or safer and more effective treatment for chronic degenerative and inflammatory diseases. 

It is easy to get impatient with the progress of science. If it turns out that speculations about the potential of stem cell therapies were correct, this will likely encourage some to see shortcutting the scientific process as justifiable. I will be happy to have the treatments for my patients that stem cell therapies may offer once they are adequately validated, but I remain convinced that we need to be more patient, and more dedicated to testing such therapies thoroughly before we put them into widespread use.

References

1.        Voga, M., Adamic, N., Vengust, M. & Majdic, G. Stem Cells in Veterinary Medicine—Current State and Treatment Options. Front. Vet. Sci. 7, 278 (2020).

2.        MB, G., A, A. & GT, S. Mesenchymal stem cell basic research and applications in dog medicine. J. Cell. Physiol.234, (2019).

3.        Lo, B. & Parham, L. Ethical issues in stem cell research. Endocr. Rev. 30, 204–13 (2009).

4.        Kimura, K. et al. Efficient Reprogramming of Canine Peripheral Blood Mononuclear Cells into Induced Pluripotent Stem Cells. Stem Cells Dev. 30, 79–90 (2021).

5.        Hoffman, A. M. & Dow, S. W. Concise Review: Stem Cell Trials Using Companion Animal Disease Models. doi:10.1002/stem.2377

6.        Bauer, G., Elsallab, M. & Abou?El?Enein, M. Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell?Based Interventions. Stem Cells Transl. Med. 7, 676 (2018).

7.        Kang, M. H. & Park, H. M. Evaluation of adverse reactions in dogs following intravenous mesenchymal stem cell transplantation. Acta Vet. Scand. 56, 16 (2014).

8.        Harman, R. et al. A Prospective, Randomized, Masked, and Placebo-Controlled Efficacy Study of Intraarticular Allogeneic Adipose Stem Cells for the Treatment of Osteoarthritis in Dogs. Front. Vet. Sci. 3, 81 (2016).

9.        Black, L. L., Gaynor, J., Dean Gahring, D. & Cheryl Adams, D. Effect of Adipose-Derived Mesenchymal Stem and Regenerative Cells on Lameness in Dogs with Chronic Osteoarthritis of the Coxofemoral Joints: A Randomized, Double-Blinded, Multicenter, Controlled Trial*. Vet. Ther. 8, (2007).

10.      Vilar, J. M. et al. Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs. BMC Vet. Res. 9, 131 (2013).

11.      Black, L. L., Gaynor, J., Adams, C., Dhupa, S. & Sams, A. E. Effect of Intraarticular Injection of Autologous Adipose-Derived Mesenchymal Stem and Regenerative Cells on Clinical Signs of Chronic Osteoarthritis of the Elbow Joint in Dogs*. Vet. Ther. 9, (2008).

12.      Shah, K. et al. Outcome of Allogeneic Adult Stem Cell Therapy in Dogs Suffering from Osteoarthritis and Other Joint Defects. Stem Cells Int. 2018, 7309201 (2018).

13.      Mohoric, L., Zorko, B., Ceh, K. & Majdic, G. Blinded placebo study of bilateral osteoarthritis treatment using adipose derived mesenchymal stem cells. Slov. Vet. Res. 53, 167–74 (2016).

14.      Kriston-Pál, É. et al. Characterization and therapeutic application of canine adipose mesenchymal stem cells to treat elbow osteoarthritis. Can. J. Vet. Res. 81, 73–78 (2017).

15.      Cuervo, B. et al. Hip osteoarthritis in dogs: a randomized study using mesenchymal stem cells from adipose tissue and plasma rich in growth factors. Int. J. Mol. Sci. 15, 13437–60 (2014).

16.      Marx, C. et al. Acupoint injection of autologous stromal vascular fraction and allogeneic adipose-derived stem cells to treat hip dysplasia in dogs. Stem Cells Int. 2014, 391274 (2014).

Posted in Science-Based Veterinary Medicine | 1 Comment

Can We Help Our Dogs to Live Longer & Healthier Lives?

One of the first logical questions for a good skeptic to ask when thinking about canine aging biology is whether it is plausible that we can extend lifespan (years lived) and healthspan (healthy years lived) in dogs. Is there reliable evidence that aging is not something immutable and inevitable but something we can actively alter? If so, how strong is that evidence, what does it suggest we should try, and what do we still need to learn?

The good news is that there are decades worth of research showing that lifespan can be extended and age-associated disease reduced in a variety of species. Much of this research has involved lab animals, such as roundworms, fruit flies, and mice. Such studies are useful for understanding basic principles in bilogy, and they suggest hypotheses to test in other species, but they aren’t sufficient to prove a given treatment or preventative intervention will work. There are even some laboratory studies in dogs that strengthen the basic understanding of aging and how we might influence it, but again this only gets us so far. 

Fortunately, we have more than this. While we can’t predict whether specific drugs or many other treatments will work until we’ve done the science to test them, we know that healthspan and lifespan can be extended in dogs because it’s been done! The one method that has been shown effective in many different animals, including dogs, is dietary restriction.

Dietary restriction is defined as a reduction in calorie and nutrient intake without malnutrition. The specific details vary among studies, but in general the key appears to be reducing total calorie intake significantly (perhaps 20-40%) without inducing micronutrient deficiencies. There are some other strategies that have proven effective or appear promising (e.g. changes in protein intake, intermittent fasting), but overall the best evidence is for total calorie reduction.

The good news is that there is strong evidence for the benefits of calorie restriction in dogs.  One long-term study in Labrador retrievers paired littermates by sex and weight and then randomly assigned one to unrestricted feeding and the other to a calorie intake 25% less than it’s paired littermate. In order to avoid obesity in the control dogs, at about 3 years of age the protocol was changed so these dogs were fed to maintain an optimal body condition rather than ad libitum, but the calorie-restricted dogs were still fed 25% less than their paired littermates ate. The study ran until the last dogs died.

The calorie restricted dogs had a medium lifespan of 13 years, 16% longer than the 11.2 years in the control group. Calorie restricted dogs also developed arthritis 1.5 years later on average than the control dogs. Some dogs developed cancer in both groups, but the average age of death from this cause was 2 years later in the restricted calorie group (11.6 years vs 9,7 years). 

There is, unfortunately, also bad news. Dramatic, lifelong caloric restriction is not a practical method of extending lifespan and healthspan in dogs, primarily because it is too difficult for dog owners to control their feeding practices appropriately. Obesity is a tremendous and growing problem in companion dogs. We seem unable to feed our dogs appropriately even to maintain a healthy weight, so the chances that we will succeed in restricting their calorie intake sufficiently to obtain significant lifespan and health benefits seem low. Food is part of how we express love for our animal companions, and rational feeding practices are surprisingly tough to implement.

Fortunately, there may be alternatives. Studies of dietary restriction have taught us a lot about the fundamental biology of aging, and there are many potential means to achieve some of the benefits of caloric restriction other than feeding dramatically less food to our dogs. The composition of diets, the timing of feeding, and medicines which mimic aspects of the physiologic response to dietary restriction are all promising avenues of research. 

While no clearly effective anti-aging therapy is yet available, we have already proven that aging can be influenced. There are many different ongoing research efforts aiming to translate the decades of knowledge concerning aging biology into more, healthier years for our dogs. Science will ultimately tell us which, if any, will work and what the relative risks and benefits will be, as is always the case, but having a plausible hypothesis and established potential mechanisms is a good first step. 

Posted in Aging Science | 4 Comments

When to Spay Your Dog: SkeptVet and Dr. Andy Roark on the Cone of Shame Podcast

During my latest visit to the Cone of Shame Podcast with Dr. Andy Roark, we discuss when to spay your dog.

Posted in Presentations, Lectures, Publications & Interviews | 6 Comments

Grain-free Diets and Heart Disease in Dogs: Two New Studies

I have to admit, I didn’t think I would again be addressing the topic of diet-associated dilated cardiomyopathy (DCM) so soon after my recent podcast and post summarizing the debate. But the science around this topic is racing ahead, and there are two new studies to talk about.

Adin, D. et al. (2021) Effect of type of diet on blood and plasma taurine concentrations, cardiac biomarkers, and echocardiograms in 4 dog breedsJournal of Veterinary Internal Medicine. John Wiley & Sons, Ltd, p. jvim.16075. doi: 10.1111/jvim.16075.

The first study compared heart ultrasound findings and blood tests associated with heart function in dogs from breeds with and without a known predisposition to DCM and eating a variety of types of diet. Here is the breakdown of these categories:

Breeds
At risk for genetic DCM- Doberman Pincers
Suspected risk for dietary DCM- Golden Retrievers
No known DCM risk- Whippets and Schnauzers

Diets
Grain-free (GF)
Grain-inclusive (GI)Diets the FDA has indicated may be a risk factor for DMC because they contain pulses, legumes or potatoes in the top 10 ingredients (FDA PLP)
Diets not containing these ingredients (FDA non-PLP)

Because the study specifically targeted healthy dogs, the goal was not to identify DCM or to show a relationship between this disease and diet. The goal was to see if any changes in the heart could be detected that might suggest some negative effects of diet below the level of clinical disease. 

Of the numerous factors evaluated, most showed no difference between the different groups. One significant difference was a higher level of the blood marker high-sensitivity cardiac troponin (hs-cTnl) in dogs on GF and FDA PLP diets than on the GI and FDA non-PLP diets. This biomarker is associated with damaged heart muscle, so the difference could suggest that there is some damage occurring in dogs on these diets that has not risen to the level of clinical disease yet. This would fit with findings of other studies that indicate the length of time a dog is on a grain-free diet is associated with the development and severity of changes to the heart, so the effect of diet may be a slowly progressive or cumulative one.

Another finding was that taurine levels were higher in dogs on GF diets than on GI diets. This is different from the finding of a previous study in Golden retrievers which found low taurine levels in dogs with DCM on GF diets. 

Overall, the research is showing rather consistently that taurine is probably only a factor in diet-associated heart disease in some breeds (especially Goldens), and it doesn’t seem to be related to any effect of GF diets in most other breeds.

In general, this study provide weak support for the hypothesis that GF and FDA PLP diets might have negative effects on the heart, but in these healthy dogs most measurements were normal in both groups, so no strong conclusions can be drawn.

Walker, A. L. et al. (2021) Association of diet with clinical outcomes in dogs with dilated cardiomyopathy and congestive heart failureJournal of Veterinary Cardiology. Elsevier. doi: 10.1016/J.JVC.2021.02.001.

The other study took a different approach. This was a retrospective study, meaning the investigators looked back at medical records to compare dogs with DCM and with congestive heart failure (CHF) for whom the diet fed at the time of diagnosis and treatment was known. They compared dogs who were eating a GF diet when diagnosed and were then switched to a GI diet with those who were already on a GI diet when they developed DCM. 

The hypothesis was that dogs on a GF diet who changed foods would have a better outcome than dogs on a GI diet when both were treated with the same standard medical therapies. This may not seem to make sense at first if GF diets are supposed to damage the heart. However, in dogs that develop DCM and heart failure at least partly due to something in their diet, there is a chance that changing the diet could actually help make the heart work better. These dogs could benefit from both the usual treatments and a diet change. However, in dogs who develop DCM without any contribution from the diet, there isn’t anything to add to standard medical treatment to help them, so they wouldn’t do as well as dogs who could benefit from changing foods. 

The results supported this hypothesis pretty well. While overall the difference in survival time was not statistically significant (344 days go dogs initially on GF diets compared to 253 days for dogs on GI diets), this difference became both larger and statistically significant when the dogs the sickest dogs who died within a week of diagnosis were excluded. In this group, the dogs changed from GF to a GI diet lived an average of 465 days compared with only 263 days for dogs already on a GI diet at diagnosis). This makes sense since the dogs who died right after being diagnosed were probably too sick already for the potential benefits of diet change to have time to be felt.

The study also found that dogs on GF diets developed DCM earlier (average of 6 years old) than dogs on GI diets (average of 9.3 years old). The longer a dog has been fed a GF diet before diagnosis, the less time they lived after developing DCM. Dogs changed from a GF diet to a GI diet also were more likely to be able to reduce or discontinue the use of the main medications used to treat their heart disease (furosemide and pimobendan), suggesting again that the GF diet was harmful and that diet change provided an added benefit to standard medical treatment.

The ultrasound findings for the two groups did not differ in most respects. However, a couple of values did improve more in the GF dogs than in the GI dogs.

Overall, this study provides moderate evidence to support the hypothesis that GF diets have negative effects on the heart which can be partially or fully reversed with diet change. While this kind of study can’t prove GF diets cause heart disease in dogs, it does add to a growing body of information that implicates these diets as at least a risk factor. If patients improve more with changing from a GF diet to a GI diet and medical therapy together than with medical therapy alone, that looks pretty suspicious for some negative effect of these diets on heart function. More definitive studies will need to be done, but since these are complex and time-consuming to conduct, it is worthwhile to consider this kind of evidence in the meantime when making choices about what to feed our dogs and what to recommend to clients.

Posted in Nutrition | Leave a comment

Cone of Shame Podcast Interview- The Bloody Battle Over Grain-free Diets

Here is the interview I did last month with Andy Roark over at the Cone of Shame podcast. this time we talk about the issue of grain-free diets and heart disease in dogs. Check it out!

Posted in Presentations, Lectures, Publications & Interviews | 1 Comment

Seresto Flea & Tick Collars: The New Satanic Panic?

Like many vets around the country, I’ve had a sudden wave of panicked calls and emails from clients about a dramatic article that appeared in USA Today yesterday. The article essentially claims that the Seresto flea and tick collar is injuring and killing huge numbers of dogs and some humans. Despite all the weaselly linguistic tricks to imply neutrality and plausible deniability if called out on making this accusation, no reasonable person could read this article and not get the message that this product is deadly and that the EPA is callously ignoring the danger, likely because they are in the pocket of Big Pesticide. 

This article is an example of the horrifyingly bad journalism that we see all too often concerning the safety of pet healthcare products. It is full of anecdote and innuendo and guilt-by-association, but devoid of the kind of actual data that might tell us whether the fear the author wants to incite is justified. As veterinarians, we have all been through this before. The web sites, Facebook pages, sloppy journalism, and even lawsuits claiming the pets are being harmed by Rimadyl and other NSAIDs, and TrifexisFebreezeSwiffer, and of course vaccines are a fact of life for anyone in pet health professions. 

It is easy to blame a particular product or treatment for something bad that happens to our pets. We naturally search for explanations when our companions are sick, and we tend to fixate on concrete things we can see and touch and potential causes we are primed to be suspicious of. Both reports of the real dangers of some pesticides, industrial chemicals, and medicines as well as the irrational demonization of all of these by opponents of mainstream medicine have implanted an automatic anxiety about the safety of such products in all of our minds. 

When a pet falls ill suddenly, we look around for a reason. The food or medicine or vaccines or pest control products we may be using come readily to mind. Invisible viruses and bacteria, internal causes inside the body that we can’t see, and other common but intangible causes are less noticeable, and so less likely to be blamed. This availability bias is a classic psychological quirk that impedes our ability to accurately assess risk and identify the causes of undesirable events. It’s why we are more afraid of airplanes and sharks than cars and mosquitoes, even though the former are a lot less likely to hurt us than the latter.

Finally, there is an unfortunate tendency in the media to shock and disturb rather than inform, which this article illustrates. Such media coverage can easily lead to excessive and inappropriate panic about risks that are smaller than made to appear in the media or even entirely unreal. The Satanic Abuse panic of the 1980s is a classic illustration of this. Hysterical and dramatic reporting of individual claims that people had been ritually abused by Satan worshippers went from fringe publications to mainstream media. Despite years of widespread coverage and the ruining of people’s lives by unfounded allegations, hard evidence never emerged to substantiate these claims. While some individuals undoubtedly did experience abuse of some kind, the media generated both a fictional cause to blame and a surge of unreliable anecdotes by presenting the initial reports in a melodramatic and irresponsible way. Sadly, finding and fixing the really dangers behind such claims was only hampered by this media coverage, and the same is often true of health scares such as those I mentioned earlier.

The Claims
Before we try to answer the question whether or not the Seresto collar is safe for our dogs, let’s look at the claims of this article and what they are based on. The writer begins, as usual in these kinds of scare pieces, with a heartbreaking anecdote of a pet dying. The owner believes this death was caused by the flea and tick collar she used, and the writer of the article jumps right from that to the claim that this product has been  “linked to hundreds of pet deaths, tens of thousands of injured animals and hundreds of harmed humans.” The emotional setup here is clear, and the message that the product is dangerous probably doesn’t require any actual evidence for most people at this point. But the author does provide a link to support this claim. So what is that about?

The link is to a collection of reports on the EPA web site of illnesses and deaths in dogs using the Seresto collar. Seems pretty damning, doesn’t it? Here’s the trouble: Those numbers are simply collections of spontaneous reports made to the agency. Zero investigation has been done to show the reports are accurate or that there really is a connection between the product and the events described. The purpose of such reporting sites is to create a place for people to raise concerns. Agencies in charge of various public health areas collect and monitoring these spontaneous reports for signals suspicious for a problem that merits investigation. If a pattern is seen that suggests there might be a safety issue, the agency can investigate to determine if there is a real concern or not.

This is what happened with the issue of grain-free diets and heart disease that I have written about several times. The FDA saw a change in the number of reports received and began an investigation. Two years later, the nature of any association between these diets and the disease is still being studied, and their role, if any, in causing heart disease is still unclear. The fact that people reported their observations about heart disease and what they were feeding their dogs isn’t proof of a causal role, just a collection of anecdotes that may or may not signal a real problem. Rigorous scientific investigation is how we find out if health products are causing harm, not simply accepting every scary anecdote as true. 

The same issue has come up innumerable times over many years with regard to vaccines and the Vaccine Adverse Event Reporting System (VAERS), managed y the CDC and the FDA. VAERS collects unsubstantiated anecdotal reports about possible harm from vaccines. Despite the overwhelming evidence for the safety of vaccination in general and most vaccines in common use, these reports are frequently cited by antivaccine activists to “prove” that vaccines are causing tremendous harm. One doctor actually submitted a report that a vaccine caused him to turn into the Incredible Hulk, and this report would still be in the VAERS database if he had not allowed the government to delete it.

Such databases are useful surveillance tools that can provide early signals of real problems, but they are also full of uncorroborated and inaccurate reports and speculation. They are not reliable evidence for a causal role of any product or medicine in harm done to people or animals. This, again, requires appropriate scientific investigation.

What else does this article rely on to support the clear claim that Seresto collars are killing dogs and injuring people? There are several strategies at play here. One is the use of unrelated cases of harm from pesticides to poison the well and imply that claims about the dangers of Seresto must be true since other pesticides have caused harm. The fact that claims have been made about harm from other pesticides (some true and some also unproven) aren’t relevant at all to the question of whether Seresto is safe or not, but they exacerbate the general anxiety or fear about pesticides to strengthen the reader’s willingness to accept negative claims about it. Clever rhetorical technique, I suppose, but not a legitimate form of argument that leads to the truth.

The citation of experts is also used to suggest Seresto is unsafe and the EPA is failing to protect the public. Quotes are provided from a “senior scientist… who has a doctorate in cell and developmental biology” at an environmental watchdog group and a “retired EPA employee… who worked as both a scientist and communications officer.” Noticeably absent from the expertise consulted is anyone with a specialty in veterinary toxicology or parasitology. Since assessing the safety and effectiveness of parasite control methods and the impact of toxins on veterinary patients is the central area of expertise for people in these fields, such individuals would have been far more likely to have relevant and informed opinions on the scientific question of whether or not Seresto is safe. Not including them is a pretty transparent technique for building a one-sided argument. I have heard from two veterinary toxicologists, a parasitologist, and a veterinarian with a national poison control center, and none of them found the allegations of widespread serious harm from the Seresto collar credible. Hopefully, people with appropriate expertise will weigh in on this issue publicly soon. 

The Science
So is there scientific evidence and, if so, what does it tell us? There are published studies and reviews of the safety of both active ingredients in Seresto, imidacloprid and flurmethrin, as well as studies of the combination in the product itself. As usual, these provide a much more nuanced picture of the risks and benefits. It would be implausible and unreasonable to claim that no dog had ever experienced adverse effects from this or any other parasite preventative. As I point out forcefully and often, no medical intervention that does anything at all is without risks, so the important issue is understanding what the risks and benefits actually are and how they compare.

Imidacloprid is a common pesticide that has been used and studied extensively for decades. This EPA document provides a relative recent overview of the available evidence. Research in dogs and cats has shown extremely low risk, and this product has been used extensively for many years without any consistent or reliable evidence of the kinds of extreme harm depicted in this article. As always, some adverse effects from excessive or inappropriate use or in unusually susceptible individuals can occur, but overall there is nothing in the evidence concerning imidacloprid to justify the level of anxiety directed at Seresto in this piece.

The other ingredient, flumethrin, is a synthetic pyrethroid pesticide, a class that has also been studied and used extensively for a long time in dogs. Cats are especially sensitive to this class of agents, and they are not typically recommended for this species, but dogs are much less likely to experience adverse effects when pyrethroids are used properly. Those cases of harm that do occur are typically associated with improper dosing. Studies of flumethrin in dogshave found limited evidence of toxicity at doses well above recommended use for parasite prevention.

More importantly,  there is published research evidence investigating the use of the combination of these ingredients in the Seresto collar. These have shown some adverse effects, but nothing even approaching the kind of common and devastating effects suggested by this article:

Stanneck 2012

In cats, a total of 28 events were suspected to be related to study medication… 23 in the [Seresto] (9.0%) and 5 in the control group (5.6%) [using a different parasite collar]. This difference was not statistically significant (p > 0.4; Fisher’s exact test). [These events were] were generally mild dermal reactions (alopecia, pruritus, mild contact dermatitis).

In dogs, in the [Seresto] group 3 events (alopecia, hair coloration, dermatitis) and in the [control] group 4 events (alopecia, flea infestation, pruritus, aggressive behaviour towards a collar wearing animal) were scored as being related to the study medication. The difference between the two groups was not statistically significant (P > 0.16; Fisher’s exact test)

Krudewagen 2015

Small Non-Controlled Clinical Safety Study
No clinically relevant adverse event related to der- mal or systemic safety occurred and no abnormalities concerning general health were noticed during the course of the study. 

Controlled safety studies – Seresto®/ Advocate®
All dogs tolerated the treatment well. Two out of 51 treated dogs showed transient skin alterations in the region of collar application, namely a crusty spot (approx. 1 cm diameter) on one day, respectively a moderate erythema of small (< 1 cm) to medium size (1 – 4cm) for about two days. Further findings in the treated group that were considered unlikely to be treatment related were conjunctivitis and a congested nasolacrimal duct in one dog, and a hot spot in the tail region of the same dog that showed erythema in the collar region. In the control group one dog also showed wounds and crusts in the neck region. No further clinical signs were present. 

Blood hematology and clinical chemistry 
No clinically relevant changes were detected for any parameter in the dog or cat study.

There are neither dermal nor systemic safety issues with the particular combination of the three actives imidacloprid, flumethrin and moxidectin in adult cats and dogs…

There is also research evidence showing that this product is effective in reducing flea and tick infestations, which can have the benefits of reducing allergy symptoms and protecting dogs against infectious diseases (and 23) spread by these parasites. These benefits have to be weighed against any potential harm. 

Finally, in terms of safety the available data has been evaluated by public agencies in many countries and found not to support claims of significant health risks. While the article accuses the EPA of a gross failure and dereliction of duty in not acting aggressively on the anecdotal reports it has received, as I pointed out earlier, such reports appear with many healthcare products, and these often turn out not to be accurate. It is possible that the risk here has been underestimated, but the burden of showing that with hard evidence remains on those making the claim.

One more issue that this article ignores is the subject of knockoff or lookalike products. Unfortunately, if a veterinary product is successful, it is common for other companies to make products that appear similar but have different ingredients in order to capture some of this market. It is also not unusual for fake replicas of a brand-name product to be produced in some countries and sold online as if they were the original product. These knockoffs have not passed the regulatory safety testing required of properly approved products. They may very well be less safe, and this can confound efforts to assess the accuracy of adverse event reports for these products. Such fake Seresto collars have made their way into the market, and it is possible some reports of harm may involve these rather than the original product.

Bottom Line
So what’s the bottom line? Is Seresto a perfectly safe and effective parasite preventative or a poison decimating the dog populations? The truth, of course, is between these extremes. There are undoubtedly some risks to this product, and it is possible that they are greater than has so far appeared in the scientific literature. The research done on this product has mostly come from companies and investigators with a financial interest in it, and that always raises some concern about the potential for bias in the data. On the other hand, such concern doesn’t somehow make collections of unsubstantiated anecdotes a reliable source of data. The fact that some people think Seresto has harmed them or their dogs is not, alone, evidence that it has. 

I don’t personally recommend Seresto for my patients because I find other parasite preventatives more convenient to use. I do have clients using it, and some doctors at my practice do prescribe it, and none of us have seen the kind of terrible effects depicted in this article. That is, of course, only more anecdote, but before we panic because of scary stories, it is worth remembering that there are many veterinarians and pet owners who have not had any negative experience with this product. 

I hope that additional research shows that the concerns raised in this article are unfounded, but if it turns out the risks are greater than we currently realize, that will be important information. Unfortunately, rigorous scientific investigation takes time; a lot more time and work that sensationalist medial reporting. My hope is that reasonable people will respond to this latest example of poor-quality reporting in a reasonable way. We likely should take a careful, objective look at the safety data for this product, and perhaps conduct further research if warranted. We should not panic and blame every bad thing that happens to us or our dogs on the latest media bogeyman. 

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Are NSAID Pain Relievers Dangerous for Your Dog?

One of the most common and useful class of medications available to veterinarians are the non-steroidal anti-inflammatories (NSAIDs). These treat pain and inflammation, and the evidence for their safety and effectiveness is robust (12). Like all medications that have any meaningful benefits, NSAIDs do have potential side effects. However, these are well-characterized, and in most cases with proper dosing and monitoring, NSAIDs can be used safely to treat pain in dogs and in cats.

Unfortunately, NSAIDs are also one of the most heavily demonized medications available, particularly by those who are critical of  science-based medical therapies or promote alternative medicine approaches. Despite the evidence for the safety of NSAIDs, and the successful use of these drugs to reduce suffering in tens of thousands of pets, some critics would have us believe they are pure poison and inevitably cause injury or death. The many alternatives recommended often have little or no evidence to show they are as safe or as effective as NSAIDs. The reality is that there are few other oral pain medications that have been demonstrated to work safely in dogs and cats, and the push for alternatives to NSAIDs has often led to widespread use of drugs that either don’t work (e.g. tramadol) or that we haven’t yet tested adequately to know if they work or not (e.g. CBD, gabapentin). 

I have reported on the safety and efficacy of NSAIDs several times in the past. It is clear from abundant studies that these drugs are very effective for pain, certainly the best oral analgesic we have for dogs and often a good choice for cats as well (34567). In terms of safety, one review found that the rate of adverse events was very low, with no significant difference in the rate of adverse events between the NSAID and placebo when placebos were used. Out of 1589 dogs in the studies reviewed, only 1 experience a severe reaction requiring hospitalization for treatment.

A more recent systematic review found that adverse effects were reported at rates from 0% to as high as 37.5% of dogs. However, the drugs, study characteristics, and patient populations different widely, so it was not possible to directly compare particular drugs or studies. 

Interestingly, when the highest quality studies were considered (randomized, placebo-controlled clinical trials), no difference in adverse effects was detected between dogs receiving NSAIDs and those on placebo. Though it is clear that such side effects do, of course, occur in some dogs on NSAIDs, and while real clinical patients are likely to respond differently than research subjects, this at least suggests that worries about common and severe harm from these medications are not justified.

Other evidence, including trials used to gain FDA approval, show that dogs on NSAIDs can experience minor problems, such as self-limiting vomiting and diarrhea, or potentially more severe problems such as stomach bleeding, worsening of pre-existing kidney disease, or liver failure. However, the rates of these problems are extremely low, and they must be balanced against the life-limiting pain caused by arthritis, the clear efficacy of NSAIDs in relieving this pain, and the great deal of uncertainty about the safety or benefit of alternative treatments.

There has recently been an increase in concerns about NSAID safety, instigated in part by Dr. Karen Becker, a prominent advocate for alternative therapies whom I have discussed here many times, and Rodney Habib, a social media influencer who misrepresents himself as a pet health expert. This centers on a new study that seems, at first glance, to support the notion that NSAIDs are dangerous and commonly cause patient harm. However, the reality is, as always, more complex and nuanced.

Mabry, K., Hill, T. and Tolbert, M. K. (2021) ‘Prevalence of gastrointestinal lesions in dogs chronically treated with nonsteroidal anti-inflammatory drugs.’, Journal of veterinary internal medicine. J Vet Intern Med. doi: 10.1111/jvim.16057.

This study involved comparing the findings of video capsule endoscopy (VCE) in dogs taking NSAIDs with dogs not on these medications and looking for signs of injury to the lining of the stomach or intestines. VCE is a procedure in which a dog swallows a very small automated camera that takes pictures of the gastrointestinal tract as it passes through and is eventually retrieved from the feces. It is a relatively new procedure, and while it is a useful way to visualize the GI tract, there is limited information available on what is normal or abnormal in different patient populations.

The study compared VCE images from 12 dogs who had been taking an NSAID for at least 30 days with the findings from 11 dogs evaluated for gastrointestinal disease who were not on this kind of medication. Two investigators assessed the pictures taken for signs of erosions, small defects in the lining of either the stomach or small intestines. NSAIDs can cause these erosions, as well as deeper and more serious lesions known as ulcers, so it would not be surprising to see some in a through look at the inside of the GI tract, and this is what the study found.

Of the 12 dogs on NSAIDs, 9 (75%) had erosions in the stomach and 6 (50%) in the small intestine, with 83% of the dogs having erosions identified in one or the other part of the system. This was compared to 3/11 (27%) of the control dogs not taking NSAIDs who had erosions on VCE examination. This finding might be disturbing if we could conclude that this means NSAIDs are harming 83% of the patients taking them. This is not however an appropriate conclusion, nor is it what the authors of the study are claiming.

The most important thing to bear in mind when looking at this study is that none of the dogs taking NSAIDs had any clinical symptoms associated with the medicine. No vomiting, no weight loss, no diarrhea, no loss of appetite, absolutely no sign that the erosions seen on VCE had any meaningful effects. This contrasts from the very real orthopedic pain these dogs had, which is why they were taking NSAIDs in the first place. 

Apart from the important fact that the erosions seen by VCE didn’t cause any apparent symptoms, there are some other reasons to be skeptical of the significance of these findings. The dogs taking NSAIDs were not evaluated prior to starting the medications, so it is unknown how many of them might have already had erosions not related to the drugs. Almost 30% of the dogs not taking NSAIDs also had erosions on VCE, so it is likely that some of the dogs in the NSAID group would have had them before starting the medication. This is also a very small study, and there were differences in the breeds and health status of the dogs in the two groups that limit our ability to generalize the results to other patient populations.

The authors of the study were clearly aware of the limitations of the findings and also the potential for misinterpretation and misuse of their results. They state very clearly in the paper:

The clinical relevance of our findings is unclear, and we do not recommend withholding NSAIDs if dogs require pain control, or that all NSAIDs be administered concurrently with gastroprotectants. Lesions were subclinical in all dogs, and none were known to later develop clinical signs of ulceration…Ultimately, the presence of lesions might not have clinical relevance if none of the affected dogs ever go on to develop clinical signs of ulceration.

While it is worth investigating the issue of asymptomatic GI tract erosions associated with NSAIDs and identifying when these might cause actual clinical symptoms, how we might prevent them, and other ways in which this technique could help us make NSAID use even safer, this study does not undermine the already robust evidence that NSAID use in dogs and cats has significant benefit and rarely causes serious harm. Discontinuing NSAID treatment to avoid lesions detectable only by VCE and which caused no symptoms would mean taking away effective pain treatment for no clinical benefit, and this is not in the best interests of these dogs. 

Replacing NSAIDs with other treatments that have far less evidence to show safety and effectiveness is also not a reasonable response to these findings. Dr. Becker and others frequently recommend unproven supplements and alternative therapies for pain that have not been shown to work. The assumption that these treatments are safer than NSAIDs or can partially or fully replace these medications is simply another unproven claim, a roll of the dice based on opinion, anecdote, and little or no reliable scientific evidence.

The goal of all medical treatment is to maximize patient well-being and minimize risk, though such risk can never be completely eliminated. At this time, the evidence is clear that NSAIDs are still the most effective oral pain reliever we have for dogs and cats, and their risks when properly used are small compared to their benefits. Other and better treatments are certainly need, and these will eventually be developed through the slow, rigorous process of scientific research. It is unfortunate that some vets and other proponents of alternative therapies will use these findings to frighten pet owners and encourage them to reduce their use of proven safe and effective pain relief in favor of untested or unrpoven alternatives.

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Why do Dogs get Old? Some Basic Theories of Aging.

Dogs’ lives are too short. Their only fault, really.

Agnes Sligh Turnbull

The question of why our dogs have to get old can be primarily a rhetorical one, expressing our dismay at the process. It can also be a philosophical question, which is how it has most often been treated historically. Aging and death have long been viewed as intrinsic and inevitable features of human and canine existence, to be accepted or raged against and to be explained mostly in metaphysical terms. Whether the changes of aging are seen as an unavoidable playing out of the mechanisms of an impersonal universe or as a necessary journey designed for us by a benevolent creature, metaphysical explanations serve to address our feelings about getting old and our longing for meaning, not the mechanisms of the process. 

Proximate and Ultimate Causes
When we view the question of why we and our animal companions age as a scientific one, the emphasis shifts to understanding the process itself more than the purpose or meaning of it. Science often frames explanations of biological phenomena in terms of ultimate and proximate causes. Ultimate causes answer the question of “why,” though not necessarily from a teleological perspective (that is, with a view to explaining the purpose of the phenomenon). The ultimate explanation for biological processes, like aging, tend to involve the conditions that lead to the existence of the process we are interested in, often emphasizing the evolutionary forces favoring its development. Proximate causes are more an answer to the question “how.” They focus on the detailed mechanisms involved rather than why these mechanisms have taken the particular form they have. 

A simple example of the difference between ultimate and proximate explanations might be the difference in body size between male and female mammals and how this varies between species. Male dogs, for example, are only slightly larger than females, while adult male elephant seals are nearly three times as large as females. The proximate explanations or mechanisms for these differences might have to do with the timing of growth and development, the influence of sex-specific hormones, and other physiologic mechanism. If, for example, males continue growing for a longer period of time, they might on average end up larger than females simply because of an overall longer growth period. If male elephant seals have a growth period and rate of growth that are relatively longer and faster than those of male dogs compared with the females of each species, this would explain why male elephant seals are so much larger than female seals while male dogs are only a little bigger than female dogs.

Ultimate explanations for these size differences, however, would be evolutionary explanations for why they came to exist. Sexual selection theory, for example, argues that the degree of difference in size between males and females has to do with the importance of physical competition between males for the chance to mate. Most male elephant seals never get to mate, but the biggest and strongest can monopolize large groups of females, so only the genes of the largest males make it to the next generation. This leads to evolutionary pressure for greater and greater size in males, without having much effect on the size of females. In dogs, however, one male doesn’t monopolize mating to nearly the same degree, and the advantages of being bigger than other males are less, while the disadvantages (such as needing more food) push against the evolution of greater size. There are other possible explanations for this particular difference, but this illustrates the general difference between proximate and ultimate explanations in biology.

We can apply this same approach to answering the question of why and how our dogs age. Let’s start with some potential theories about the ultimate explanations for aging. Why can’t dogs simply live forever without changing? Or why don’t they live 150-200 years like some tortoises do, or at least as long as we do? 

Ultimate Theories of Aging
Programmed Senescence
One early idea was that evolution favored aging and death of one generation as a way to “make room” for the next. If animals stayed young forever and never died, then their world would get crowded, food and other resources would become insufficient, and the species at a whole might be threatened with extinction. This certainly sounds like a realistic concern given the effect we humans are having on our world as we increase our numbers and our lifespan! However, the problem with this idea is that evolution doesn’t have a way of working towards the “good of the group.” Evolution happens because of differences in reproductive success between individuals within a population. If one big elephant seal fathers a lot of babies and none of the smaller males get to breed, then the next generation of males will have the genes for being big, not small. If this means there isn’t enough food and all the males starve, well, natural selection doesn’t have a way to take that into account.

Antagonistic Pleiotropy and the Disposable Soma
From an evolutionary perspective, a better explanations is that aging is the result of adaptations that have benefits for the young, leading to more reproductive success and the spread of those genes, but that also have costs later in life. Say, for example, small bull elephant seals need less food than larger males, and they are less likely to be caught and eaten by sharks than their more visible and slower comrades. Maybe the really big males even get cancers relatively early in life because the growth hormones that make them so big also stimulate abnormal tumor growth. As a result, small males might live longer than big males and be less likely to get cancer. We might think that evolution would favor this, since it’s obvious a “healthier” set of adaptations that leads to a longer, healthier life. 

However, the fact remains that the big males get to father a lot more baby seals than the little guys. This means that the genes that make them big have an advantage and dominate the next generation, even though they come along with greater risk of an early death from starvation, predation, and cancer. This is a hypothetical example of the concept of antagonistic pleiotropy. Genes that convey a reproductive advantage early in life are favored by evolution, and tend to persist, even though they lead to harm and maybe a shorter, sicker life in the long run than competing genes.  Such a mechanism might explain why organisms have evolved “imperfectly” to age and die. 

The is related to the concept of the disposable soma (“soma” being the Greek word for “body” and referring to all the cells other than the “germ cells” involved in making offspring). This theory suggests that animals have limited resources, such as energy and the raw materials for making and repairing body tissues. These resources can be used to grow and create the soma, or they can be used to reproduce. There is a tradeoff between these activities, and the optimal balance depends on the specific circumstances of a particular species. Some animals may live in unstable and unpredictable environments. The most effective evolutionary strategy in this situation might be to hurry up and have as many offspring as possible as fast as possible. Doing so takes energy away from growth and maintenance of the body, so you might age fast and die young, but you’d leave a lot of offspring (and genes!) behind. If you waited around and spent a lot of your energy of keeping yourself healthy, you’d have fewer offspring and if the unstable environment suddenly killed you off, you wouldn’t have maximized your reproduction very effectively.

Other species live in more stable and predictable circumstances, and this favors a slower approach to life. Individual humans don’t typically have hundreds or thousands of babies, but we spend a lot of time and energy looking after the few we do have to make sure they survive to grow up and reproduce in turn. This strategy works if the environment gives us a chance to stick around a while, but it requires spending more energy and resources on keeping ourselves alive and healthy so we can put in the necessary investment in our limited number of offspring. This theory helps explain differences in the lifespan of different species in terms of their evolutionary history and reproductive strategies. 

These are only simplified versions of some of the more prominent ultimate theories, but they give a flavor for the way aging biology attempts to explain the apparent “flaws” of aging and death in terms of the operation of evolution and natural selection. Such explanations do not, however, give us much opportunity to intervene and influence lifespan and healthspan. If our pattern of aging is fixed by our evolutionary history, then isn’t it fundamentally unalterable? 

This is where proximate explanations of aging come in. The detailed mechanisms of how age-associated changes in health occur is where we can look for opportunities to influence the processes and improve lifespan and healthspan.

Proximate Theories of Aging
This is an enormous subject that has developed over decades and is still the focus of copious and fast-paced research. The devil in medical science is always in the details, and the details are legion and complex in the field of aging biology. In future posts I hope to explore specific mechanisms and potential anti-aging interventions, but for now I will start with a simplified summary of some of the more prominent ideas about how we and our dogs age.

Wear and Tear 
Most of us think of aging as the accumulation of physical damage over time, the gradual effects of wear-and-tear on the body. There is an idea that turns up periodically each of us had a predetermined and limited number of heartbeats, and when we used them up, we would die. If true, this theory would suggest we should do everything we can to conserve our hearbetas and minimize our activity. (This is often associated with the astronaut Neil Armstrong, who was mistakenlyclaimed to have said “I believe that every human has a finite number of heartbeats.  I don’t intend to waste any of mine running around doing exercises.”) 

The reality, as usual, is more complicated. It turns out that slower hear rates are often associated with lifespan, both between and within species. Hamsters have much shorter lifespan than humans, and also a much faster heart rate (c.f. this page for comparisons of heart rate and life expectancy between species). There is also evidence that higher resting heart rates in humans predict a higher risk of death than lower heart rates. However, this is not because faster heart rates use up a fixed number of possible heartbeats. The relationship between body size, metabolic rate, and lifespan between species is complicated and not always consistent. And within humans, slower hear rates are a function of better physical condition (among other factors), which reduces risk of death. It turns out that temporarily speeding up your heart during exercise leads to a lower resting heart rate and better health, so there is no excuse to avoid working out in order to “save” your heartbeats!

Other examples of the physical wear-and-tear hypothesis have turned out to be equally unreliable. Arthritis in joints isn’t just caused by use, and again people who exercise often have better joint health for longer than people who use their joints less because they are more sedentary. We can’t explain aging as just physical parts wearing out with use.

Accumulated Damage
However, some aspects of the physical wear-and-tear idea do carry over into more nuanced and complex theories of aging. We do accumulate damage on a cellular and molecular level over time, and our body can only do so much to repair that damage. The balance between damage of critical components and their repair and replacement likely is part of the loss of function we and our dogs experience as we age. I hope to explore more detailed aspects of this theory in the future. Some of the proposed examples of the types of damage that accrue over time include: mutations in DNA, methylation of DNA and effects of this on gene expression, telomere shortening, oxidative damage to cells and mitochondria, cross-linking and glycosylation or aberrant folding of proteins, and the persistence of nonfunctional or dysfunctional senescent cells within specific tissues. These are all examples of accumulation of damage over time that overwhelms repair systems and leads to the loss of resilience and function associated with age. This can be thought of, in some sense, as a wear-and-tear phenomenon, though not in the strict physical sense of the original idea.

Neuroendocrine Hypotheses
Another theory for how aging works is that changes in various complex and interrelated hormonal systems that control many bodily functions are the core mechanisms behind the physical and functional decline seen in aging. Organs such as the hypothalamus and the pituitary in the brain, the testes and ovaries, the adrenal glands, and others are all connected with the nervous system in an intricate web of feedback relationships that regulate hormones and most physiologic activities. Over time, these systems may come out of balance or certain elements may falter or fail, and this leads to the generalized functional losses associated with aging. There is no question that the neuroendocrine axis is a critical component of the aging process, but there isn’t yet strong evidence for a single master switch or mechanism that cane explain all the features of aging. 

Other Theories
There is research evidence to support a role in aging for many other processes, including free radicals and oxidative damage, mitochondrial dysfunction and a decrease in total energy available to power bodily functions, epigenetic factors and changes in gene expression, and others. There is clearly also a connection, in humans at least, between behavior and aging. Lack of physical activity, poor nutrition, smoking and other toxin exposures, social isolation, and many other behavioral factors influence how our bodies and our abilities change with time. There is less evidence in dogs, of course, but so much of the basic biology of living and of aging are shared between human and dogs, it is likely that behavioral factors are important for healthy aging in our canine companions as well.

As I go forward on this journey into the field of aging biology, I hope to explore many of the specific theories of aging in more detail and look at the strength of evidence for particular testable hypotheses. Of course, the long view is focused on what do these theories allow us to do to influence aging, in our dogs and in ourselves? Having finally come to a mechanistic, scientific perspective on aging as a biological process like any other, we are making great progress in understanding how it works. This opens the door to therapies that can extend life and health. 

The concept of a magical fountain of youth is, of course, mythical and not practically useful. Proponents of alternative and pseudoscientific health practices have long claimed to have answers to the problem of aging. Simplistic interpretations, or misinterpretations, of scientific aging research and unjustifiable extrapolation from theories and weak preliminary evidence to clinical interventions and panaceas are the bread and butter of alternative medicine, and these are all part of unscientific approaches to aging. From exuberant claims for the benefits of antioxidant supplements and foods, to wild assertions about how to prevent or reverse mitochondrial damage, to many other unfounded claims, pseudoscience flourishes on the margins of the aging biology world as it does in so many areas of cutting edge science. My goal, as always, is to follow the evidence, complex, nuanced, and even sometimes unsatisfying or disappointing as it may be. The only reliable path to improvement in health for our pets, in aging as in all other areas of medicine, is through rigorous scientific research. 

I think there is reason for optimism about the potential to develop therapies that extend lifespan and healthspan in our dogs. Talk of “curing aging” isn’t reasonable or responsible, but the idea that aging is incomprehensible and immutable is also unjustified. We have already been tremendously successful at extending the length of our lives, and those of our pets, by reducing the risks of death associated with many causes, from infectious disease to trauma to cancer. We have also had success in extending the productive, functional portion of our life, though this has not kept pace with the increase in lifespan, and it is more common for pets and humans to experience prolonged periods of declining health and function at the end of life. My hope is that we will continue making progress extending life and will bring our ability to extend health up to speed to match this progress. As always, let me know what specific questions you have about aging science in dogs and cats, and I will do my best to answer them here.

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