[Show abstract][Hide abstract] ABSTRACT: Researching the effects of aging in the male reproductive system is not trivial. Not only are multiple changes at molecular, cellular and endocrine levels involved, but any findings must be discussed with variable individual characteristics, as well as with lifestyle and environmental factors. Age-related changes in the reproductive system include any aspect of reproductive function, from deregulation of the hypothalamic-pituitary-gonadal axis and of local auto/paracrine interactions, to effects on testicular stem cells, defects in testicular architecture and spermatogenesis, or sperm with decreased functionality. Several theories place mitochondria at the hub of cellular events related to aging, namely regarding the accumulation of oxidative damage to cells and tissues, a process in which these organelles play a prominent role, although alternative theories have also emerged. However, oxidative stress is not the only process involved in mitochondrial-related aging; mitochondrial energy metabolism, changes in mitochondrial DNA or in mitochondrial-dependent testosterone production are also important. Crucially, all these issues are likely interdependent. We will review evidence that suggests that mitochondria constitute a common link between aging and fertility loss.
Frontiers in bioscience (Scholar edition) 01/2013; S5:181-197.
[Show abstract][Hide abstract] ABSTRACT: There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation through dysregulation of the RAS protein pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare disorders related to paternal age (e.g., Apert syndrome, achondroplasia), this process is known as "selfish spermatogonial selection." This mechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews the mutational profile of sperm as men age, and enriches de novo mutations in the offspring of older fathers that preferentially affect specific cellular signaling pathways. This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. The authors outline hypotheses to test this model. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications.
American Journal of Psychiatry 05/2013; · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nonallelic homologous recombination (NAHR) between highly similar duplicated sequences generates chromosomal deletions, duplications and inversions, which can cause diverse genetic disorders. Little is known about interindividual variation in NAHR rates and the factors that influence this. We estimated the rate of deletion at the CMT1A-REP NAHR hotspot in sperm DNA from 34 male donors, including 16 monozygotic (MZ) co-twins (8 twin pairs) aged 24 to 67 years old. The average NAHR rate was 3.5×10-5 with a seven-fold variation across individuals. Despite good statistical power to detect even a subtle correlation, we observed no relationship between age of unrelated individuals and the rate of NAHR in their sperm, likely reflecting the meiotic-specific origin of these events. We then estimated the heritability of deletion rate by calculating the intraclass correlation (ICC) within MZ co-twins, revealing a significant correlation between MZ co-twins (ICC = 0.784, p = 0.0039), with MZ co-twins being significantly more correlated than unrelated pairs. We showed that this heritability cannot be explained by variation in PRDM9, a known regulator of NAHR, or variation within the NAHR hotspot itself. We also did not detect any correlation between Body Mass Index (BMI), smoking status or alcohol intake and rate of NAHR. Our results suggest that other, as yet unidentified, genetic or environmental factors play a significant role in the regulation of NAHR and are responsible for the extensive variation in the population for the probability of fathering a child with a genomic disorder resulting from a pathogenic deletion.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.