The science behind lifespan extension: Metabolic dysfunction
When you hear the term “metabolic health,” what do you think of? Maybe exercise, a healthy diet, or weight loss? Perhaps obesity? It’s not a term often heard in daily conversation, but it’s crucial in the field of aging, because metabolic health often declines as we and our dogs age.
At Loyal, we define metabolic health as the regulation of blood sugar and insulin levels, fat distribution and function, and the balance of key hormones. These factors significantly influence how aging impacts health and disease.
Our drug for senior dogs, LOY-002, aims to give dogs more healthy years by preserving metabolic health, and it’s currently in development under the FDA approval* process.
What is metabolic dysfunction?
Metabolic dysfunction isn’t just a single “disease.” Instead, it’s a set of interconnected processes that contribute to poor metabolic health. Our approach at Loyal is preventive — we aim to address the underlying causes of disease before they even start to appear. When targeting metabolic dysfunction, we want to interrupt the process. Once the vicious cycle of metabolic dysfunction starts, it’s very hard to break free of it.
That’s what LOY-002 does— it interrupts the cycle of metabolic dysfunction in dogs. We aim to give dogs longer, healthier years by preserving metabolic health for as long as possible.
This blog post is a high-level introduction to metabolic dysfunction, and it includes what we consider the most relevant components of this complex process.
Examples of diseases caused by metabolic dysfunction
As we and our dogs age, our metabolic health declines and increases our risk of developing age-related diseases. In dogs and humans, diseases like cognitive decline, cancer, sarcopenia (muscle wasting disease), and osteoarthritis (joint disease) appear with age. In humans, we can develop MASH (fatty liver disease), diabetes, and coronary artery disease.
Preserved metabolic health has been linked to 1.8 year increase in dog lifespan
We know from scientific literature that metabolic dysfunction causes shorter lifespan, and Loyal is running some of our own studies to support this as well (stay tuned!).
One area of research that has shown promise for improving metabolic health is calorie restriction. In studies from 2002 and 2008, Purina scientists showed the positive effects of caloric restriction on dogs’ lifespan. Calorie restricted dogs, who were given 25% less food than their littermates, showed significant health improvements,1,2 including:
A 1.8 year increase in lifespan compared to dogs eating a regular diet
A decrease in age-associated diseases like cancer and arthritis
1.5 year delay in development of arthritis
2 year delay in death among dogs who developed cancer
Not only did this study show an extension in lifespan, it demonstrated connections between metabolic health and lifespan.
Dogs who were not calorie restricted had higher levels of insulin in the blood and less healthy insulin function in their tissues2
Increasing insulin resistance independently predicted shorter lifespans and more chronic disease2
This study showed that healthspan and lifespan can be extended in dogs! Unfortunately, caloric restriction isn’t a long-term practical solution — without appropriate diet formulation and close monitoring, feeding incorrectly has the potential to cause malnutrition, which can be harmful to your dog’s health. Activating the same biological mechanism with a drug is an easier, and probably safer way to achieve the same results.You can read more about the above study in Dr. Brennen McKenzie’s piece on caloric restriction in dogs.
Why does my dog’s metabolic health decline over time? The impact of insulin resistance
Now that we know targeting metabolic dysfunction is beneficial for your dog’s lifespan and overall health, we can dive deeper into what causes metabolic dysfunction.
Your body utilizes glucose (sugar) found in food, which is a convenient fuel source for your cells. This glucose is transported in the blood to every tissue in the body, where it’s taken into cells to fuel all the work they do. Insulin acts like a key, opening the door of the cell to glucose so it can enter and be used as fuel.
With aging and metabolic dysfunction, these “doors” don’t open as readily, and glucose has a harder time getting into the cells. This is insulin resistance. The body compensates for this resistance by producing more and more insulin, leading to higher insulin levels in the blood.
In people, glucose and insulin build up in the blood, and often the result is diabetes. In both humans and mice, this increases the risk of diseases like obesity, cancer, cardiovascular disease, hypertension, cognitive decline, and frailty, and possibly in dogs as well.3,4 Dogs are a lot less likely to get diabetes than people, but long-term increases in insulin levels still have negative effects on their health.
Improving metabolic health by reducing insulin resistance and chronically high levels of insulin in the blood has been shown to improve health and reduce the risk of age-related diseases in humans and other species studied. We have reason to believe metabolic function can be improved in the same way in dogs, and we’re working on publishing our research to show this.
Subscribe to receive updates when we publish →
Adipose tissue dysfunction leads to metabolic dysfunction
Insulin isn’t the whole story. Adipose tissue, commonly known as body fat, also plays an important role. Adipose tissue is a special type of connective tissue found in the human body and its primary function is to store energy in the form of fat.
Adipose tissue stores fat (or more specifically, triglycerides — a type of lipid also found in your blood) when the body takes in more energy that you need to use right away. Adipose tissue not only stores fat (triglycerides), but it also releases fatty acids as a source of energy. (To be more precise, triglycerides are broken down into fatty acids and glycerol. The fatty acids are then able to be used as a source of energy.)
When this process becomes less efficient with age, adipose tissue stops listening to hormonal signals from insulin and fails to shut down the release of fatty acids (a source of energy). This results in excess fatty acids in circulation, contributing to insulin resistance and intensifying it elsewhere in the body. This phenomenon is known as adipose tissue dysfunction.
Read more about adipose dysfunction in dogs in our AJVR paper “Comparative geroscience” →
The role of fat redistribution in metabolic aging
These excess fatty acids from adipose tissue dysfunction also end up stored in different tissues around the body, affecting metabolic health and contributing to the cycle of metabolic dysfunction. In humans, fat stored in the muscle and around internal organs like the liver can make insulin resistance and inflammation worse and even increase the risk of developing sarcopenia, chronic inflammation, and diseases of the pancreas and liver.5,6
As dogs age, they may not always gain weight, but they often lose muscle and gain fat. For example, you may notice your dog’s hip bones protruding as they age. Exceptionally long-lived dogs resist muscle loss and fat gain7.
But it’s not only about the amount of fat, but also where it’s stored. When fat is stored in areas such as the glutes or legs (gluteofemoral fat), it’s healthier subcutaneous fat. In contrast, fat stored around internal organs is more unhealthy — this is known as visceral fat. This is how fat is redistributed in the body with age.
This redistribution towards unhealthy visceral fat exacerbates insulin resistance and further promotes adipose tissue dysfunction, which worsens the negative effects of aging on metabolic health.
These components all contribute to the vicious cycle of metabolic dysfunction
The above three processes (insulin resistance, adipose tissue dysfunction, and fat redistribution) are interlinked and are only a small part of a very complex process that leads to a decline in metabolic health associated with aging. The bottom line is that these metabolic changes interact in a vicious cycle that progressively increases metabolic dysfunction and health problems with aging.
The cycle of metabolic dysfunction in an aging dog.
So, what’s Loyal doing about all this?
Metabolic dysfunction is reduced when we decrease insulin resistance and minimize adipose tissue dysfunction. Right now, you can help delay the negative health consequences of metabolic dysfunction in your dog through diet and exercise, but in the future, we hope to slow the development of metabolic dysfunction and mitigate its negative health consequences through our drug for senior dogs, LOY-002.
LOY-002 reduces the development of metabolic dysfunction. By improving metabolic health, LOY-002 aims to extend healthy lifespan.
At Loyal, we’re continuing our research into all the components that make up metabolic dysfunction in dogs, which has historically been under-researched. We’re committed to sharing our findings along the way and publishing them via our website and in peer-reviewed journals.
Subscribe to our newsletter list →
Sources
Kealy RD, Lawler DF, Ballam JM, Mantz SL, Biery DN, Greeley EH, Lust G, Segre M, Smith GK, Stowe HD. Effects of diet restriction on life span and age-related changes in dogs. J Am Vet Med Assoc. 2002 May 1;220(9):1315-20. doi: 10.2460/javma.2002.220.1315. PMID: 11991408.
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
Kolb H, Kempf K, Röhling M, Martin S. Insulin: too much of a good thing is bad. BMC Med. 18(1):224 (2020) in I-013479-P-0019-XE
Dankner R, Shanik MH, Keinan-Boker L, Cohen C, Chetrit A. Effect of elevated basal insulin on cancer incidence and mortality in cancer incident patients: the Israel GOH 29-year follow-up study. Diabetes Care. 35(7):1538-43 (2012) in I-013479-P-0022-XE
Suganami T, Tanaka M, Ogawa Y. Adipose tissue inflammation and ectopic lipid accumulation. Endocr J. 2012;59(10):849-57. doi: 10.1507/endocrj.ej12-0271. Epub 2012 Aug 9. PMID: 22878669.
Aldahhan RA, Motawei KH, Al-Hariri MT. Lipotoxicity-related sarcopenia: a review. J Med Life. 2022 Nov;15(11):1334-1339. doi: 10.25122/jml-2022-0157. PMID: 36567835; PMCID: PMC9762358.
Penell JC, Morgan DM, Watson P, Carmichael S, Adams VJ. Body weight at 10 years of age and change in body composition between 8 and 10 years of age were related to survival in a longitudinal study of 39 Labrador retriever dogs. Acta Vet Scand. 2019 Sep 9;61(1):42. doi: 10.1186/s13028-019-0477-x. PMID: 31500653; PMCID: PMC6734441.
*FDA approval not guaranteed