Previously, we introduced some congenital genetic disorders in rats (click here to review), and we believe you now have a deeper understanding of rat genetic diseases!

In this issue, we will be discussing another factor that is often overlooked but can significantly impact rat health  age. Get ready to learn more about the impacts of rodent age on health!

1. Overview

Lab rats, like most mammals, are susceptible to a variety of age-related neoplastic (tumor-causing) and non-neoplastic diseases. The types, incidence rates, and severity of these conditions can vary significantly depending on the rat population or strain, microbial status, experimental procedures, and breeding methods (including dietary restrictions, fasting, etc.).

2. Chronic Progressive Nephropathy (CPN) in Rats

Chronic Progressive Nephropathy (CPN) is a significant age-related renal disease in rats and is one of the most common causes of death in rats used in lifelong studies. CPN is also referred to as old rat nephropathy. CPN is progressive in nature and is more common in male rats than in female rats.

Presentation of CPN in Lab rats:

  • CPN lesions can be observed by the naked eye in rats older than 6 months, characterized by depressions on the renal cortex surface. Due to cortical interstitial fibrosis, removal of the renal capsule may tear the cortical parenchyma. In rats older than one year, as the condition worsens, the cortical surface becomes increasingly irregular, and white lesions may appear.
  • Under the microscope, characteristic changes in the renal glomeruli include thickening of the basement membrane, thickening of the capillary tufts, adhesion of Bowman's membrane layers, and segmental glomerular sclerosis.
  • As the condition progresses, many tubules in the cortex and medulla become dilated and filled with eosinophilic proteinaceous material. Secondary hyperparathyroidism can occur in the late stages of renal dysfunction, leading to widespread dystrophic calcification.

The exact
 pathogenic mechanism of CPN is not clear and is likely multifactorial:

(1) Strain: The incidence of CPN varies among strains, suggesting a genetic predisposition. Sprague-Dawley and F-344 strains have higher incidence rates, while Wistar and Long-Evans strains have lower rates.

(2) Gender: Gender is a determining factor in CPN development. Male rats develop CPN earlier, have a higher incidence rate, and experience more severe lesions than female rats at any specific age.

(3) Diet: Diet is a significant factor in CPN development, and it is also the most suitable way to control it through dietary management. It is now established that moderate dietary restriction significantly reduces the incidence and severity of CPN in rats of different age groups compared to ad libitum (free) feeding.

3. Renal Calcium Deposition Syndrome

Renal calcium deposition syndrome refers to the deposition of calcium phosphate in renal tissues, also known as nephrocalcinosis. Additional factors contributing to the development of renal calcium deposition syndrome are as follows:

  • Renal calcium deposition syndrome is more common in female rats.
  • Apart from gender, the incidence varies with age and strain. It can occur as early as 7 weeks of age in F-344 rats, with an incidence rate of up to 50%, while Sprague-Dawley and Wistar rats have lower incidence rates, ranging from 0-7%.
  • In BDIX rats, the incidence is particularly high and influenced by various nutritional components in the diet. High calcium, high phosphate, a low calcium-phosphate ratio, or low magnesium can increase the incidence and severity of the condition. However, due to strain-specific differences, it is still unclear whether these dietary mineral contents are the determining factors for renal calcium deposition syndrome.

4. Urolithiasis

Urolithiasis is the presence of mineral deposits in the urine (uroliths), occasionally found in the renal pelvis and/or bladder, with the bladder being more commonly affected. The primary components of uroliths are calcium phosphate and ammonium magnesium phosphate (struvite).

Uroliths can be occasionally observed in aged rats, but if they occur in rats younger than 6 months, it typically indicates a bacterial infection, such as bladder stones often associated with ascending infection by Escherichia coli. Rats prone to urinary tract infections, such as diabetic and obese Zucker rats, are more likely to develop uroliths and may often have concurrent renal hydronephrosis.

5. Chronic Myocardial Disease

Chronic myocardial disease is a major cause of death in aging male rats of various strains, including Sprague-Dawley, when maintained under free feeding conditions. Similar to CPN, the incidence of this disease can be significantly reduced through moderate dietary restriction, such as reducing calorie intake by 25-30% compared to ad libitum feeding.

Chronic myocardial disease is commonly referred to as cardiomyopathy or chronic progressive cardiomyopathy and can first be observed as early as 3 months of age. The disease may exhibit the following pathology in lab rats:

  • Enlargement of the heart can be visible to the naked eye, occasionally accompanied by pale streaks.
  • The increase in heart weight is closely associated with the extent of damage observed in histological examinations, with microscopic findings of myocardial fiber necrosis and mononuclear interstitial infiltration.
  • In the later stages of the disease, fibrosis may become more pronounced. The most commonly affected myocardial areas are the papillary muscles and the interventricular septum.

6. Skin and Hair Abnormalities

There are a variety of hair and skin abnormalities across various lab rats, often attributed to strain backgrounds, gender, and age.

Presentation of Skin and Hair Abnormalities in Lab rats:

  • The most common skin and hair abnormalities in aged experimental rats is a loss of fur or sparse coat, especially on the back. This phenomenon is observed in nearly all populations or strains, with Brown Norway rats being particularly prone to it.
  • Aging albino rats often exhibit a yellowish appearance due to the accumulation of sebum on the skin.
  • The number of scale rings covering the tail increases with age, reaching up to 190 rings at 1 year of age and becoming more prominent, with a yellowish color. The yellow substance near the tail and ear can also turn black, likely due to oxidation and/or bacterial action.
  • Male rats may accumulate brown scales on the skin, which can cover the 'normal' color of the skin and can be peeled off. These scales are commonly found on the back, tail, and perineal area. They do not occur in castrated male rats. The nature of the pigment is unclear, but it may be oxidized lipids or amino acids.

7. Pulmonary alveolar histiocytosis

Pulmonary alveolar histiocytosis is very common in the lungs of aged rats from many populations and strains. Pulmonary alveolar histiocytosis is unrelated to viral pneumonia, as affected animals are seronegative, and lymphocytic infiltration is minimal, limited to areas of macrophage aggregation. The etiology of pulmonary alveolar histiocytosis is not clear but can be ruled out as infectious.

Presentation of Pulmonary Alveolar Histiocytosis in Lab rats:

  • Pulmonary alveolar histiocytosis appears as white to pale brown lesions on the pleural surface, typically with a diameter of about 1 mm.
  • In unexpanded lungs, the lesions may be slightly elevated above the pleural surface.
  • Microscopically, the alveolar clusters are often located beneath the pleura or adjacent to terminal bronchioles, containing numerous large, pale, foamy macrophages.
  • Occasionally, cholesterol crystals can be seen in denser aggregates of macrophages, and mild lymphocytic infiltration may be observed around nearby blood vessels, possibly in response to proinflammatory mediators released by the macrophages.

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[1]Fox J G, Anderson L C, Otto G, et al. Laboratory Animal Medicine:Third Edition[M]. 2015.