B6d2f1

+26%

+31%

aData is presented as percent increase (+) or decrease (—) in lifespan of caloric restricted mice as compared to ad libitum fed mice. From Forster et al., 2003.

aData is presented as percent increase (+) or decrease (—) in lifespan of caloric restricted mice as compared to ad libitum fed mice. From Forster et al., 2003.

and insulin levels as seen in standard CR protocols (Anson et al., 2003).

The CR effect is not universal, however, and different strains show different levels of response to CR. Table 33.5 shows the survival response to CR by male C57BL/6 mice, DBA/2 mice, and the F1 hybrid between them (Forster et al., 2003). Note that while C57BL/6 showed a robust response to CR, with a 24% increase in both median and maximum lifespan, DBA/2 mice showed the opposite response, with a decrease in both median and maximum lifespan. The F1 hybrid, which lived longer than either parental strain under ad libitum (AL) feeding, showed a response to CR similar to the C57BL/6 parental strain. Willott et al. (1995) also reported that CR decreased lifespan in DBA/2 mice while increasing it in C57BL/6 mice, and Turturro et al. (1999) reported a similar result with male DBA/2 mice showing a 5% increase in lifespan. In the latter study, female DBA/2 showed a 30% increase in lifespan, illustrating a potent gender difference in this strain. In Turturro et al.'s study, both male and female C57BL/6 mice showed a similar increase in lifespan of about 40%. While these three studies gave similar results, the differences in lifespan changes due to CR (for example, 24% increase versus 40% increase for C57BL/6) illustrate that other factors, such as substrain, health status, diet formulation and environment, can affect experimental outcomes even when using inbred mice.

Most CR protocols are maintained from young adulthood through the rest of life, and there are conflicting reports on the benefits of CR when it is initiated later in life. Weindruch and Walford (1982) reported that CR initiated in mice in midlife produced beneficial results, while Forster et al. (2003) found that when CR was initiated at old age (22-25 months of age), mortality in the first 3 months was actually increased over that seen in the AL controls in 3 strains of mice studied (C57BL/6, DBA/2, B6D2F1). A study in F344BNF1 rats found no significant effect on lifespan and tumor burden when CR was initiated at midlife (17 months) or old age (24 months) (Lipman et al., 1998). However, a study in B6C3F1 hybrid mice, in which CR was initiated at 19 months, produced a 4-month increase in median lifespan over the AL controls (Dhahbi et al., 2004). While CR and AL groups had the same incidence of neoplasms, there was a delay in the onset in the CR group. These findings suggest that CR, or therapeutic targeting of the pathways altered by CR, may have potential for improving health in old age, even when the intervention is begun at midlife.

The effect of long-term CR on health varies by strain and also by pathology. While the general trend is that CR reduces the incidence of, or delays the onset of, most age-related pathologies, there are exceptions to the rule. For example, pancreatic atrophy is common in aged F344 and Brown Norway (BN) rats under AL feeding. Under CR, the incidence of pancreatic atrophy decreases in F344 rats but increases in BN rats (Lipman et al., 1999). CR delays the onset of cataracts in BN rats, but by old age, the incidence of cataracts was the same in CR and AL controls (Wolf et al., 2000). In F344 rats, the age of onset was the same in CR and AL but as the rats aged, the incidence of cataracts increased more in the AL rats than in the CR rats, so that the CR F344 rats showed a reduction in the incidence of cataracts at old age. And CR does not appear to moderate age-related hearing loss in most strains of mice (Willott et al., 1995). These findings serve to illustrate the complexity of biological aging and also the importance of genetic background on the rate of aging and the modulation of the rate of aging through interventions such as caloric restriction.

Husbandry and Environment

One of the advantages of the rodent model is that the health, housing and environment of the colony can be strictly controlled. This is an important consideration because diseases in the experimental population could confound interpretation of results or give misleading results. Specific pathogen-free (SPF) barriers are the norm for commercial rodent breeders for research purposes, but investigators should be aware of the health status of their institution's vivariums, as exposure to new pathogens could affect the immune status and physiological responses. Susceptibility to infectious diseases varies greatly. Mites pose only a minor problem in some strains, but in C57BL/6 mice, mites exacerbate the ulcerative dermatitis common in this strain (Andrews et al., 1994). Helicobacter species, first identified in the early 1990s and still endemic in some commercial colonies, cause little or no response in most strains of mice, but can cause inflammatory bowel disease, hepatitis, and hepatocellular cancer in some strains (Brayton et al., 2001). Ward et al. (1994) examined 20 strains of mice for Helicobacter hepaticus-induced pathology and found only six strains that showed susceptibility to liver disease, with BALB/c mice highly susceptible and C57BL/6 resistant. Hepatic lesions increased with age in both incidence and severity in susceptible strains, and the chronic hepatitis is very persistent. While rats are believed to be resistant to most

Helicobacter species, there may be effects that surface with more rigorous study.

The aged rodent has special health concerns unrelated to infectious disease, and extra vigilance is required even when they are raised under barrier conditions. Many strains of rodents are prone to developing tumors as they age. Tumors on the feet, jaw and joint areas may cause pain, loss of ambulatory function or difficulty eating even when they are relatively small (Nadon, 2004). Malocclusion, overgrown teeth, resulting from the lack of hard substrates on which to chew, is another problem in aged rodents (Nadon, 2004). Aged rodents should be checked weekly for evidence of tumors or other problems such as malocclusion.

Another consideration is the housing configuration. Rodents are social animals, and most do better in group housing because of the social enrichment. However, group housing can cause stress in rodents due to territorial behavior and aggression. Long-term group housing may lead to some losses due to fight wounds, so this should be taken into consideration when determining sample sizes. Aggression is quite variable between strains, and males are usually more aggressive than females. In the NIA aged rodent colonies, significant aggression is only found in the male BALB/cBy and DBA/2 mice. DBA/2 mice responded with a significant reduction in aggression when provided with Shepherd Shacks®, pressed paper huts that provide a nest environment. Male BALB/cBy mice did not respond favorably to the introduction of Shepherd Shacks®—they shredded them and went back to fighting. This experience illustrates the differences between strains, in that even a basic behavior like aggression has different causes and different solutions. Rats tend to be less aggressive than mice in general, and male F344 rats can even be group housed after being retired from a breeding program.

There are many forms of environmental enrichment available for rodents, including huts, tunnels, chew sticks, and nesting materials. The inclusion of some sort of enrichment appears beneficial under any circumstances, and there is abundant literature that shows that rodents prefer an enriched environment (reviewed by Olsson and Dahelborn, 2002). However, it is important to house experimental and control groups under the same conditions to avoid confounding the interpretation of experimental results. For example, environmental enrichment has positive effects on the brain, including increased plasticity and neuroprotective effects, so in studies of brain aging and cognitive changes it is essential that all groups are housed in identical environments to ensure that changes observed are due to the experimental protocol and not to differences in the environment.

One last concern must be noted when using rodents in biogerontology studies. There are important decisions to be made regarding the appropriate ages to be used, the number of time points required to accurately define age-related changes, and sample sizes that will provide

TABLE 33.6 Resources for studies with aged rodents

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