Germ Stem Cells and Aging

Inevitably, if aging germ stem cells (GSCs) are unable to efficiently prevent, intercept, and repair oxidative damage caused by oxidative stress, they will accumulate cellular damage over the years. The prevention of ROS-mediated damage is mainly dealt with by antioxidants; these are reduced in aging spermatozoa [86]. The combined effects of increased ROS production, reduced antioxidant activity, and reduced efficiency of the aging cell's repair mechanisms will result in aging germ cells with

'DECREASED ANTIOXIDANT DEFENSE SYSTEM j

Fig. 7.1 Schematic representation of the impact of aging on male germ cells and of potential consequences for progeny outcome

a reduced capacity to manage oxidative stress. The interactions and consequences of increased ROS production and decreased antioxidant defenses with advancing age are depicted in Fig. 7.1.

Although there have been many studies looking at the role of stem cells in aging, only a handful have examined the role of stem cells specifically in terms of testis aging. The regenerative potential of any organ within the body, including the testis, is dependent on its stem cells. However, stem cells in some tissues appear to have a finite number of divisions for repopulation and regeneration, i.e., the Hayflick limit (around fifty cell divisions) discussed above [87] . This hypothesis was put forth based on lung fibroblast divisions in vitro; since then, it has been demonstrated that cells in a number of other tissues can undergo many more divisions in a lifetime without changing morphology and function; for example, intestinal stem cells undergo around 1,000 divisions in the lifetime of a mouse and probably many more in the lifetime of a human [88]. The testis also does not appear to conform to the Hayflick limit as the production of sperm requires many more divisions of SSCs to continually produce mature spermatozoa. If SSCs were to conform to the Hayflick limit, it would only be possible to produce sperm for a maximum of approximately 10 years. Since men produce sperm into old age, clearly the Hayflick hypothesis does not hold for the testis. Indeed, SSCs are estimated to have undergone 380

'DECREASED ANTIOXIDANT DEFENSE SYSTEM j mitotic divisions by the time a man reaches the age of 30 years (840 mitotic divisions by 50 years) [4]; however, with each additional replication, the possibility of causing errors in the germ line increases, making paternal age a major potential source of new mutations [89] .

As one of the main morphological features of the aging testis is regression due to germ cell loss, the question as to what is responsible for causing this loss is central. There are a small number of theories suggesting that it is either an accumulation of DNA damage in the SSCs or that there is an age-associated decrease in the support of the Sertoli cells and thus the nurturing niche of the SSCs is no longer able to support the maintenance and division of these cells. While some studies suggest that it is the failure of the SSC niche that causes diminished fertility in older males, and not the ability of SSCs to self-renew [90, 91], others demonstrate, using SSC transplantation in mice, that not only the ability of the niche to sustain spermatogenesis decreases with age, but also that the number and the activity of SSCs decline with advancing age [92]. Using transplantation of SSCs to determine age-related alterations, another group concluded that there was no change with age; however, this group did not study advanced age, as had the other investigators, since they used only animals that were no older than 1 year of age [93].

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