Rat Models

The Brown Norway (BN) rat is a highly robust model for the study of male reproductive aging [72-75]. This strain of rat has a long life span (up to 40 months), does not exhibit many of the age-related pathologies found in other rat strains, such as pituitary and Leydig cell tumors, and does not become obese. There are striking changes in the testes and epididymides of these animals, even though no systemic disease is apparent. Aging of the testis is marked by a gradual decrease in the percentage of normal seminiferous tubules and total sperm count [72] as well as the ability of Leydig cells to produce testosterone [76]; the expression of several genes and the activities of enzymes associated with testosterone production are also affected as a function of aging [77, 78]. At the cellular level, regressed testes display anomalies in the structure of the endoplasmic reticulum and nuclei of Sertoli cells (the niche-forming "nurse" cells that surround the germ cells and ensure their normal development), between which large intracellular spaces are observed rather than the normally embedded germ cells [79] . Importantly, the decreases seen in testis function in the BN rat with age have been reported also in aging men [80, 81]. There are also dramatic changes in the epididymal epithelial architecture [82] and epididymal gene expression [83] in aging BN rats.

Mating of male BN rats of increasing age (3-24 months) to young females resulted in an increase in preimplantation loss, a decrease in the average fetal weight, and a greater than threefold increase in neonatal deaths [84]. Together, these results clearly indicate that the quality of spermatozoa decreases as males age in this model. The actual basis for these observations remains unclear; however, it has been noted that there was a large increase with age in the number of sperm with an abnormal flagellar midpiece, suggesting that the formation of spermatozoa in the testes of older males was defective [85]. The percentage of motile spermatozoa was significantly decreased in the cauda epididymidis of old rats and the proportion of spermatozoa that retained their cytoplasmic droplet (a sign of lack of sperm maturation) was markedly elevated. Some of these effects are likely to be due to changes taking place in spermatozoa during the process of spermatogenesis (e.g., formation of the flagellum), while others could occur during sperm maturation in the epididymis (e.g., acquisition of motility).

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