Dopamine Receptor Level Influences Mouse Lifespan via Behavioral Changes

An interesting study here shows that lower levels of dopamine D2 receptor (D2R) achieved via genetic engineering in mice lead to a modestly reduced life span. This result appears to be mediated by behavioral changes, such as lesser physical activity, greater food intake, and consequently higher body mass, rather than by any other mechanism.

Dopamine (DA) is known to be implicated in a variety of functions including reward and physical mobility. The DA system has been known to be vulnerable to the effects of aging. Human imaging studies have shown that the rate of D2R loss during aging occurs at approximately 10% per decade. While it is apparent that D2R decreases in both human and rodent brains as a result of physiological deterioration following senescence, the functional consequences of this decline on behavior and lifespan are not fully understood. The D2R ability to modulate reward seeking behavior, motivation, and expectation of a reward, influences feeding behavior. Alterations in the DA reward system can lead to abnormal eating behavior; the down regulation of D2R receptor signaling is thought to reduce sensitivity to reward, providing an incentive to overeat.

An enriched environment (EE) is characterized by sensory, motor and social stimulation relative to standard housing conditions. The incorporation of exercise is an important component of an EE and its benefits have been shown to be a powerful mediator of brain function and behaviour. To determine whether the D2R gene is involved in the mechanism of environmental enrichment, different housing conditions were examined in mice. This study hypothesized that the D2 gene, in the presence of an EE, significantly influenced lifespan, body weight, and locomotor activity.

Results supported the hypothesis. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/-) and knockout (Drd2 -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/- EE mice lived 22% and 21% longer than Drd2 -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.

These data provide the first evidence of the role of D2R gene on lifespan in mammals. Mice with normal or reduced expression of the D2 gene and housed in an EE showed significant increases in lifespan. However, mice deficient in D2 failed to benefit from an EE. The D2 gene function appears to be a critical mediator linked to the behavior and lifespan effects associated with an EE. D2's mediating role, however is environment-dependent and was not observed in mice raised in DE conditions. The anti-aging and neuroprotective factors associated with exercise may be the key factor as to why Drd2 +/+ and Drd2 +/- EE mice showed increased lifespan in comparison to their DE cohorts.



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