Models of Germ Cell Aging 741 Mouse Models

To examine the mechanisms of aging, several inbred strains of mice, such as the senescence-accelerated mouse (SAM) [66], and transgenic mouse models, such as Klotho [67], or mice having null mutations or overexpresssing several enzymes associated with oxidative stress [48] have been developed. There are at least fourteen strains of senescence-prone inbred strains (SAMP) and four senescence-resistance strains (SAMR); the SAMP life span is 40% shorter than SAMR. Interestingly, SAMP1 mice have an early maturation and rapid decline in their spermatozoa production with advancing age [68]. Studies comparing testicular histology between SAMP1 and SAMR1 mice reveal that regressive changes in the testes of SAMP1 occur by 6-7 months, with degradation of seminiferous tubules and spermatogenic epithelium defects appearing much earlier than expected [66]. All SAMP mice have a shorter reproductive period, terminating by the age of approximately 6-months; by 9-10 months of age, SAMP1 mice have a depopulation of the seminiferous tubules, morphologically abnormal germ cells, and atrophy in SAMP1 testes [66], However, surprisingly, by the age of 14-16 months the spermatogenic epithelium is restored, indicating that SAMP mice possibly have mechanisms/factors that can reverse the abnormalities associated with aging. These findings have been explained in additional studies that show four genes (ankyrin repeat and SOCS box-containing 8 (Asb-8), germ cell-specific gene 1, T-complex polypeptide 1b, and activator of cAMP responsive element modulator in testis) implicated in the regulation of late-stage spermatogenesis that are downregulated in aged SAMP1 mice [68] . This study highlights the difficulties in discriminating whether accelerated aging in animal models is due to the normal aging processes or is a possible manifestation of pathologies.

The klotho mutant mouse model has been proposed as one that resembles human aging [69], Disruption of a single gene, klotho, that encodes a secreted protein results in a mutant mouse that manifests phenotypes resembling premature aging [67]. Homozygous klotho mice have shortened life spans to 60.7 days, decreased activity, and displayed infertility and atrophy of the genital organs. The klotho mouse model has been used to investigate the molecular mechanisms of normal human aging as well as human diseases in which there is premature aging or accelerated aging, such as progeria and Werner syndrome, but has not yet been used to investigate mechanisms of male germ cell aging.

Studies using mouse models that lack any known or induced mutations have demonstrated reduced quality in aged spermatozoa; histological observations reveal changes in testicular architecture, such as an increased number of vacuoles in germ cells, thinning of the seminiferous epithelia, and reduction in the number of spermatocytes [70]. Additionally, an increase in the frequency of germ cell mutations was identified [71], Mouse models have also been used to assess both stem cell aging and the stem cell niche; these studies are described below.

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