The expanding universe of canine aging science

By Brennen McKenzie, MA, MSc, VMD

Aging is the single most important risk factor for disability, disease, and, ultimately, death in adult dogs.¹ It has long been viewed as inevitable and immutable, but decades of scientific research have demonstrated aging is more appropriately understood as a modifiable risk factor for these negative health outcomes.

Aging is simply biology—a set of cellular and molecular processes that progressively reduce the physiologic and functional capacity of dogs to maintain a state of health and well-being.^2,3 The better we understand that biology, the greater our ability to mitigate the impact of aging with medical interventions and to extend lifespan and healthspan.

The last few years have seen an explosion of interest in canine geroscience and potential methods for extending healthy lifespan in dogs. Companies are developing pharmaceuticals to target the deleterious mechanisms of aging. The Dog Aging Project (DAP), a community science endeavor, collects survey data from thousands of dog owners to better understand how dogs age.⁴ This group also evaluates rapamycin as a potential pharmaceutical that can reduce the negative impact of aging on health.^5,6

Academic researchers are studying the biology of canine aging and developing clinical metrology instruments to quantify how aging affects health, function, and well-being. Margaret Gruen, DVM, PhD, and Natasha Olby, VetMB, PhD, DACVIM (Neurology), with their team at the North Carolina State University, have done extensive research on tools to measure frailty,⁷ and they are currently investigating the potential for rehabilitation to reduce frailty and extend healthspan.⁸

Frailty in dogs has also been the focus of veterinary researchers in Europe, and several research projects have examined the potential for using biomarkers to assess biological age.^9,10

This enthusiasm suggests we are at a tipping point where the accumulated knowledge about aging biology, developed primarily in rodents but also in invertebrates, humans, and even in dogs, can potentially support the development of clinical interventions. Research is flourishing to characterize the aging process in dogs, and develop and validate instruments for quantifying biological age, as well as test interventions to preserve and restore health and functional capacity in aging dogs.

Many potential targets for such interventions have been identified through geroscience research. As with other risk factors impacting canine health, such as obesity, genetics, neutering, and specific diseases, it is unlikely a single, perfect "silver bullet" will be found that eliminates the risks associated with aging. Extending healthy lifespan will ultimately involve a combination of approaches that include lifestyle interventions, such as diet and exercise practices, and medical interventions, such as drugs, gene therapies, and others not yet identified.

Approaches to extending healthy lifespan in dogs

Researchers at Loyal, a biotech company based in San Francisco, Calif., are developing drugs targeting specific elements of canine aging biology. The two main programs the team has developed are focused on mitigating the artificially shortened lifespan of large and giant dogs³² and on extending healthy lifespan in dogs of almost any size by improving metabolic health.³³

Longer life for larger dogs

It is well established large body size is associated with shorter lifespan in dogs (Figure 1).^11–13 This is contrary to the general pattern in mammals, where large species tend to have longer lifespans than smaller species. In dogs, the shorter life expectancy of larger dogs appears to be a consequence of genetic and metabolic changes created by intensive artificial selection for greater body size.^13–15

One major component of this is the persistent elevation throughout the life of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). This overexpression of GH and IGF-1 has been associated with impaired metabolic health (such as decreased insulin sensitivity),^16,17 frailty,¹⁸ and decreased lifespan and healthspan in several species.¹⁹ Reductions in GH and IGF-1 levels through genetic and pharmacologic interventions have been shown to improve and extend lifespan in laboratory animal models.¹⁹

Benefits of caloric restriction

The most successful intervention studied so far to extend healthy lifespan is caloric restriction (CR).^20–22 This involves a significant reduction in mean daily calorie intake (typically 20-40 percent below the level that ordinarily maintains a normal body condition) without inducing malnutrition. Studies in invertebrates, rodents, primates, and dogs have shown caloric restriction delays age-associated disease and frailty, and extends lifespan.^22,23

One caloric restriction study conducted by a pet food company involved assigning Labrador retriever puppies to either CR or free-feeding (after several years, this was changed to quantity-limited feeding to maintain a normal body condition score and prevent obesity).²² Littermates were randomized to these two groups, and all other aspects of their lives, including diet, husbandry, and veterinary care, were identical. These dogs were intensively monitored for the remainder of their lives. The dogs in the CR group lived nearly two years longer on average and experienced delayed onset of some age-associated diseases (Figure 2).²²

The ancestors of most extant animals lived under conditions of variable and unpredictable resource availability. Energy, micronutrients, and all the materials necessary for growth, function, and reproduction were sometimes abundant and sometimes scarce. This is selected for systems to monitor the intake of these materials and adjust physiologic function as appropriate (aka nutrient sensing, one of the major hallmarks of aging biology).²⁴

During times of abundance, systems supporting activity, growth, and reproduction are active to take advantage of the available resources. During times of scarcity, these systems are inhibited, and processes supporting repair and recycling are activated. It would be maladaptive for an individual to store energy and build tissue or to reproduce in times of scarcity that would not support the survival of the individual or its offspring. Instead, evolution has produced mechanisms for preserving resources, repairing tissues, and optimizing cellular functions during such times to keep individuals alive and prepared for the next period of abundance. Such mechanisms also happen to support extended lifespan and healthspan.

As an example, both natural aging and chronic overabundance of resources (as is experienced by most companion dogs that are regularly overfed) lead to metabolic dysfunction. Insulin resistance and hyperinsulinemia, accumulation and dysfunction of adipose tissue, especially in the visceral compartment, and dyslipidemia are all seen with aging, as well as with overfeeding and obesity.²⁵ Such a state of poor metabolic health is associated with an increased risk of frailty and aging-associated diseases.^26–28

One important way in which caloric restriction impacts health and longevity is through preserving and improving metabolic health. In the caloric restriction study, for example, higher insulin sensitivity was independent predictors of longer lifespan.²² In preclinical work of biotech startup Loyal, researchers found insulin, as well as other components of metabolic health, such as dyslipidemia and biomarkers of adipose function, to be associated with both frailty and quality of life in aging dogs.²⁶ Other researchers have demonstrated negative impacts of adipose accumulation, again particularly visceral adipose, on metabolic health and lifespan.^29–31

Caloric restriction, therefore, likely extends lifespan, at least in part, by preserving and restoring metabolic health. However, CR is not a viable strategy for extending healthspan and lifespan in companion dogs. Severely curtailing feeding would interfere with the human-animal bond, and it is easy to do harm through malnutrition if diet and health are not very closely monitored in dogs undergoing CR. The hypothesis of researchers at Loyal is a safer, more practical way to achieve the benefits of CR is through pharmacologic activation of relevant physiologic pathways.

One of the company's products intended to mimic CR and support metabolic health in dogs is currently being tested in a large, multicenter clinical trial. The STAY study is a randomized, placebo-controlled, double-blinded trial with a protocol accepted by the FDA as appropriate for use as part of the new animal drug approval process. Researchers are planning to enroll more than 1,000 dogs at roughly 70 small-animal practices throughout the country. Further, researchers are assessing not only lifespan but also multiple measures of health, frailty, and quality of life. Apart from assessing the safety and efficacy of LOY-002, the data from this study will be invaluable in furthering our understanding of aging in dogs.

Science shows the way

Not surprisingly, excitement about the burgeoning field of canine geroscience and the potential to extend healthspan and lifespan and improve patient welfare has led to a proliferation of approaches not always based on solid science. Proponents of various diets and supplements often claim these can extend lifespan, but there is not yet reliable data to support such claims. Some veterinarians are already prescribing off-label drugs approved for other uses in humans, such as rapamycin and metformin, with claims about longevity benefits.

These claims have also not yet been proven in people or dogs. Waiting for new treatments to be available is tough, especially when our patients and our own pets are visibly aging. However, the best way to effectively extend healthy lifespan in dogs and to ensure our interventions do more good than harm is to follow a rigorously scientific and evidence-based approach. This means building on the abundant existing geroscience research done in other species but also committing to doing the necessary studies in dogs to validate our understandings and test new hypotheses and interventions.

The future is bright for a more proactive and preventive approach to the problem of aging so long as we follow the path illuminated by sound science.

Brennen McKenzie, MA, MSc, VMD, graduated from the University of Pennsylvania School of Veterinary Medicine and has worked as a small-animal general practitioner since 2001. He is also past-president of the Evidence-based Veterinary Medicine Association and the author of the SkeptVet Blog, a resource for pet owners and veterinary professionals promoting science-based pet care. In 2023, he received the VIN Veritas award for science communication. Beginning in 2021, Dr. McKenzie began splitting his time between his clinical duties and serving as director of Veterinary Medicine for Loyal, a San Francisco-based biotechnology company developing drugs to extend healthy lifespan in dogs. Columnists' opinions do not necessarily reflect those of Veterinary Practice News.

References

1. McKenzie B, Chen FL, Gruen M, Olby N. Canine Geriatric Syndrome: A Framework for Advancing Research in Veterinary Geroscience. Front Vet Sci. 2022;9. doi:10.3389/fvets.2022.853743
2. McKenzie BA. Comparative veterinary geroscience: mechanism of molecular, cellular, and tissue aging in humans, laboratory animal models, and companion dogs and cats. Am J Vet Res. 2022;83(6):ajvr.22.02.0027. doi:10.2460/ajvr.22.02.0027
3. McKenzie BA, Chen F, LaCroix-Fralish ML. The phenotype of aging in the dog: how aging impacts the health and well-being of dogs and their caregivers. J Am Vet Med Assoc. 2022;260(9):963-970. doi:10.2460/javma.22.02.0088
4. Kaeberlein M, Creevy KE, Promislow DEL. The Dog Aging Project: Translational Geroscience in Companion Animals. Mamm Genome Off J Int Mamm Genome Soc. 2016;27(7-8):279-288. doi:10.1007/s00335-016-9638-7
5. Urfer SR, Kaeberlein TL, Mailheau S, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. GeroScience. 2017;39(2):117-127. doi:10.1007/s11357-017-9972-z
6. Holland S, Ferguson A, Creevy K, Anderson R, Reed M. CANINE COGNITION ASSESSMENTS IN THE TEST OF RAPAMYCIN IN AGING DOGS (TRIAD). Innov Aging. 2024;8(Supplement_1):1134-1135. doi:10.1093/geroni/igae098.3639
7. Russell KJ, Mondino A, Fefer G, et al. Establishing a clinically applicable frailty phenotype screening tool for aging dogs. Front Vet Sci. 2024;11. doi:10.3389/fvets.2024.1335463
8. Research Study for Senior Dogs: Targeting Frailty To Improve Healthspan and Well-Being. College of Veterinary Medicine. January 6, 2025. Accessed January 7, 2025. https://cvm.ncsu.edu/research-study-for-senior-dogs-targeting-frailty-to-improve-healthspan-and-well-being/
9. Herzig S, Zollinger A, Texari L, et al. A biological age based on common clinical markers predicts health trajectory and mortality risk in dogs. GeroScience. Published online October 1, 2024. doi:10.1007/s11357-024-01352-4
10. Thompson MJ, vonHoldt B, Horvath S, Pellegrini M. An epigenetic aging clock for dogs and wolves. Aging. 2017;9(3):1055-1068. doi:10.18632/aging.101211
11. Fan R, Olbricht G, Baker X, Hou C. Birth mass is the key to understanding the negative correlation between lifespan and body size in dogs. Aging. 2016;8(12):3209-3222. doi:10.18632/aging.101081
12. Urfer SR, Wang M, Yang M, Lund EM, Lefebvre SL. Risk Factors Associated with Lifespan in Pet Dogs Evaluated in Primary Care Veterinary Hospitals. J Am Anim Hosp Assoc. 2019;55(3):130-137. doi:10.5326/JAAHA-MS-6763
13. Kraus C, Pavard S, Promislow DEL. The size-life span trade-off decomposed: why large dogs die young. Am Nat. 2013;181(4):492-505. doi:10.1086/669665
14. Greer KA, Hughes LM, Masternak MM. Connecting serum IGF-1, body size, and age in the domestic dog. AGE. 2011;33(3):475-483. doi:10.1007/s11357-010-9182-4
15. Rimbault M, Beale HC, Schoenebeck JJ, et al. Derived variants at six genes explain nearly half of size reduction in dog breeds. Genome Res. 2013;23(12):1985-1995. doi:10.1101/gr.157339.113
16. Friedrich N, Thuesen B, Jørgensen T, et al. The Association Between IGF-I and Insulin Resistance. Diabetes Care. 2012;35(4):768-773. doi:10.2337/dc11-1833
17. Vila G, Jørgensen JOL, Luger A, Stalla GK. Insulin Resistance in Patients With Acromegaly. Front Endocrinol. 2019;10:509. doi:10.3389/fendo.2019.00509
18. Lemaréchal R, Hoummady S, Barthélémy I, et al. Canine Model of Human Frailty: Adaptation of a Frailty Phenotype in Older Dogs. J Gerontol A Biol Sci Med Sci. 2023;78(8):1355-1363. doi:10.1093/gerona/glad006
19. Vitale G, Pellegrino G, Vollery M, Hofland LJ. ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians' Perspective. Front Endocrinol. 2019;10. doi:10.3389/fendo.2019.00027
20. Giacomello E, Toniolo L. The Potential of Calorie Restriction and Calorie Restriction Mimetics in Delaying Aging: Focus on Experimental Models. Nutrients. 2021;13(7):2346. doi:10.3390/nu13072346
21. Di Francesco A, Deighan AG, Litichevskiy L, et al. Dietary restriction impacts health and lifespan of genetically diverse mice. Nature. 2024;634(8034):684-692. doi:10.1038/s41586-024-08026-3
22. Lawler DF, Larson BT, Ballam JM, et al. Diet restriction and ageing in the dog: major observations over two decades. Br J Nutr. 2008;99(4):793-805. doi:10.1017/S0007114507871686
23. Fontana L, Partridge L, Longo VD. Dietary Restriction, Growth Factors and Aging: from yeast to humans. Science. 2010;328(5976):321-326. doi:10.1126/science.1172539
24. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-278. doi:10.1016/j.cell.2022.11.001
25. McKenzie B, Peloquin M, Tovar A, et al. Feeding dogs a high-fat diet induces metabolic changes similar to natural aging, including dyslipidemia, hyperinsulinemia, and peripheral insulin resistance. Am J Vet Res. 2024;85(6):ajvr.23.11.0253. doi:10.2460/ajvr.23.11.0253
26. McKenzie BA, Peloquin M, Graves JL, et al. Changes in Insulin, Adiponectin and Lipid Concentrations Are Associated with Frailty and Reduced Quality of Life in Dogs. Loyal; 2025.
27. Smith GK, Paster ER, Powers MY, et al. Lifelong diet restriction and radiographic evidence of osteoarthritis of the hip joint in dogs. J Am Vet Med Assoc. 2006;229(5):690-693. doi:10.2460/javma.229.5.690
28. Yam PS, Butowski CF, Chitty JL, et al. Impact of canine overweight and obesity on health-related quality of life. Prev Vet Med. 2016;127:64-69. doi:10.1016/j.prevetmed.2016.03.013
29. Salt C, Morris PJ, Wilson D, Lund EM, German AJ. Association between life span and body condition in neutered client-owned dogs. J Vet Intern Med. 2019;33(1):89-99. doi:10.1111/jvim.15367
30. Müller L, Kollár E, Balogh L, et al. Body fat distribution and metabolic consequences - Examination opportunities in dogs. Acta Vet Hung. 2014;62(2):169-179. doi:10.1556/AVet.2013.057
31. Lottati M, Kolka CM, Stefanovski D, Kirkman EL, Bergman RN. Greater omentectomy improves insulin sensitivity in nonobese dogs. Obes Silver Spring Md. 2009;17(4):674-680. doi:10.1038/oby.2008.642
32. https://www.nytimes.com/2023/11/28/science/longevity-drugs-dogs.html
33. https://www.cbsnews.com/colorado/news/colorado-pet-owners-veterinarians-drug-trial-extend-life-loyal-stay-study/