A deep dive into metabolic dysfunction in aging dogs for vets
In the last newsletter, we touched briefly on some of the mechanisms driving aging in dogs, and one of these was metabolic dysfunction. Since this is the key target of LOY-002, we wanted to explore this process in a bit more detail.
It turns out that deleterious changes in energy and lipid metabolism are a common feature of aging in many species, from worms and flies to humans and dogs. What we learn from one species can be surprisingly useful in understanding aging in another, and in developing treatments to mitigate its harmful effects. As always, of course, there are also small but sometimes meaningful differences (humans are not just big dogs any more than cats are small dogs!).
Three of the core elements of aging-associated metabolic dysfunction are-
Insulin resistance and hyperinsulinemia
Adipose tissue dysfunction and redistribution
Dyslipidemia
Figure 1 illustrates some of the relationships between these elements of metabolic dysfunction.
Figure 1. Relationships between key components of metabolic dysfunction in aging dogs.
Insulin resistance and hyperinsulinemia
As vets, we often tend to think of insulin only as deficient and associated with hyperglycemia (in the Type I diabetes mellitus dogs sometimes get) or excessive and associated with hypoglycemia (in patients with insulinomas). However, during normal aging without either of these diseases, dogs will often experience both increases in circulating insulin levels and decreases in the responsiveness of peripheral tissues to the actions of insulin (known as insulin resistance).
This occurs in other species as well. Both humans and cats often experience a vicious cycle or increasing insulin resistance >> hyperglycemia >> greater insulin secretion until the pancreatic beta cells finally fail and the patient develops Type II diabetes mellitus. However, dogs appear able to tolerate this feedback loop almost indefinitely, and they are not known to develop hyperglycemia or Type II diabetes because of it.
Unfortunately, ever-increasing insulin resistance and hyperinsulinemia has other negative consequences. Insulin has anabolic effects on muscle, so increasing insulin resistance can contribute to muscle wasting and weakness (sarcopenia). As an anabolic hormone, insulin at persistently high levels can also contribute to the development of neoplasia, and it may exacerbate chronic inflammation. Finally, hyperinsulinemia interacts with adipose tissue dysfunction to exacerbate dyslipidemia and abnormal accumulation of lipids in multiple tissues (lipotoxicity), which have deleterious effects on the health and function of these tissues.
Adipose tissue dysfunction and redistribution
A consistent feature of aging in several species studied is the redistribution of adipose tissue from the subcutaneous to the visceral compartment. While subcutaneous fat is a generally benign energy storage organ, visceral fat is more metabolically active, often in deleterious ways.
Increased visceral fat has been associated with increased circulating lipids, insulin resistance, chronic inflammation, tissue lipotoxicity, sarcopenia, and multiple age-associated diseases. The evidence in dogs is still quite limited, but it is generally consistent with the patterns seen in other species: dogs do appear to experience relative increases in visceral fat during aging, with similar negative metabolic and clinical effects.
Dyslipidemia
Changes in circulating lipids occur in aging dogs which are very similar to those seen in humans. While dogs do not develop the atherosclerotic vascular disease typically associated with dyslipidemia in people, these changes appear to be associated with other negative metabolic and clinical outcomes, including exacerbated insulin resistance and effects on both lifespan and healthspan. Hyperlipidemia in dogs has also been associated with pancreatic, hepatic, and ocular disease.
It is common for clinicians to dismiss mild or moderate elevations in cholesterol, triglycerides, or other circulating lipids as normal, benign aging changes. Some species of lipids that are clinically important in people are not routinely measured in dogs. However, there is growing evidence that these changes may be indicators, or even causal factors, for aging-associated decline in metabolic and clinical health. Further research is needed to clarify the role of dyslipidemia in assessing the impact of aging on healthy dogs.
Effects of metabolic dysfunction on healthspan and lifespan
The negative effects of metabolic dysfunction are well established in humans and in laboratory model species, such as rodents. Insulin resistance, hyperinsulinemia, adipose dysfunction and redistribution, and dyslipidemia are all associated with poorer health and quality of life, with specific diseases of aging, and with increased mortality risk.
As always, there is less evidence available in dogs. However, we do know that these elements of metabolic dysfunction do occur in dogs, and preliminary evidence suggests they have similar harmful effects. For example, the Purina caloric restriction study showed that severe reduction in calorie intake, without micronutrient deficiencies or malnutrition, can extend lifespan and delay age-associated diseases significantly in dogs. This study also identified better insulin sensitivity as a predictor of improved survival.
Other research indicates that increased visceral adipose is associated with increased insulin resistance and greater risk of cardiovascular disease in dogs.1-5 We also have data from preclinical studies (which we are working on publishing soon) showing that changes in metabolic health are associated with some clinical indicators of health and function in dogs.
The STAY study will be a rich source of valuable information to help us understand the role metabolic dysfunction plays in healthspan and lifespan in dogs. Apart from the importance of evaluating the potential safety and efficacy of LOY-002, this study will make significant contributions to our understanding of canine aging.
LOY-002 and metabolic dysfunction
The strongest evidence that LOY-002 can extend lifespan and reduce or delay mortality due to aging-associated disease will, of course, come from the STAY study. However, there is already evidence from pre-clinical research in dogs that the drug combats metabolic dysfunction. More information about the drug and how it works will be available soon, and you will be the first to know!
LOY-002 has been shown to combat both deleterious adipose tissue dysfunction and redistribution as well as peripheral insulin resistance. Because these mechanisms are key elements to the pathogenesis of aging-associated disease, we believe that it will help maintain metabolic health and retard the development of some of the negative health outcomes associated with aging.
The ultimate goal, of course, is to extend healthy lifespan for dogs. Hopefully, this additional information about metabolic dysfunction and how it contributes to morbidity and mortality in aging dogs will illustrate why we believe LOY-002 is likely to be beneficial, and also how important your work in STAY is not only to understanding the effects of this drug but also extending our knowledge about the biology of canine aging.
Want to dive deeper?
If you want even more details about metabolic dysfunction and aging, here are some publications, from Loyal and other researchers, to get you started!
McKenzie, BA. Comparative Veterinary Geroscience: Mechanism of molecular, cellular, and tissue aging in humans, laboratory animal models, and companion dogs and cats. Amer J Vet Res. 2022;83(6):ajvr.22.02.0027 https://doi.org/10.2460/ajvr.22.02.0027.
McKenzie BA. Peloquin M. Tovar A. Graves JL. Ratcliff E. Tucker K. Vo K. Greenwood K. Halioua-Haubold CL. Juarez-Salinas D. 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;15:1-11.
Peloquin M, Tovar A, Graves JL, Stefanovski D, Tucker K, Marietti E, Greenwood K, Halioua-Haubold CL, Juarez-Salinas D. Saturated fatty acid concentrations are predictive of insulin sensitivity and beta cell compensation in dogs. Sci Rep. 2024 Jun 2;14(1):12639
Adolphe JL, Silver TI, Childs H, Drew MD, Weber LP. Short-term obesity results in detrimental metabolic and cardiovascular changes that may not be reversed with weight loss in an obese dog model. Br J Nutr. 112(4):647-56 (2014)
Kim SP, Ellmerer M, Van Citters GW, Bergman RN. Primacy of hepatic insulin resistance in the development of the metabolic syndrome induced by an isocaloric moderate-fat diet in the dog. Diabetes. 52(10):2453-60 (2003) in I-013531-H-0002-OT
Lottati M, Kolka CM, Stefanovski D, Kirkman EL, Bergman RN. Greater omentectomy improves insulin sensitivity in nonobese dogs. Obesity (Silver Spring). 17(4):674-80 (2009) in I-013479-H-002-OT
Müller L, Kollár E, Balogh L, Pöstényi Z, Márián T, Garai I, Balkay L, Trencsényi G, Thuróczy J. Body fat distribution and metabolic consequences – Examination opportunities in dogs. Acta Vet Hung. 2014 Jun;62(2):169-79.
Thengchaisri N, Theerapun W, Kaewmokul S, Sastravaha A. Abdominal obesity is associated with heart disease in dogs. BMC Vet Res. 10:131 (2014)
Sources
Adolphe JL, Silver TI, Childs H, Drew MD, Weber LP. Short-term obesity results in detrimental metabolic and cardiovascular changes that may not be reversed with weight loss in an obese dog model. Br J Nutr. 112(4):647-56 (2014)
Kim SP, Ellmerer M, Van Citters GW, Bergman RN. Primacy of hepatic insulin resistance in the development of the metabolic syndrome induced by an isocaloric moderate-fat diet in the dog. Diabetes. 52(10):2453-60 (2003) in I-013531-H-0002-OT
Lottati M, Kolka CM, Stefanovski D, Kirkman EL, Bergman RN. Greater omentectomy improves insulin sensitivity in nonobese dogs. Obesity (Silver Spring). 17(4):674-80 (2009) in I-013479-H-002-OT
Müller L, Kollár E, Balogh L, Pöstényi Z, Márián T, Garai I, Balkay L, Trencsényi G, Thuróczy J. Body fat distribution and metabolic consequences – Examination opportunities in dogs. Acta Vet Hung. 2014 Jun;62(2):169-79.
Thengchaisri N, Theerapun W, Kaewmokul S, Sastravaha A. Abdominal obesity is associated with heart disease in dogs. BMC Vet Res. 10:131 (2014)