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Genetics: Parental Influence

GENETICS: PARENTAL INFLUENCE

Studies examining the factors that affect both longevity and the diseases associated with aging have traditionally focused on the interaction of inheritance (genetics) and lifestyle (environment) on adults. Specific genetic backgrounds have been demonstrated to be risk factors for diseases that occur later in adult life, such as some types of cancers and neurodegenerative diseases. Similarly, certain environmental factors, such as a poor diet, have also been demonstrated to have detrimental physiological effects, leading to an increased incidence of strokes, diabetes, heart disease, or other maladies. Conversely, certain interventions, such as caloric restriction in adult animals, can dramatically extend longevity. However, while the impact of genetics and environment on the occurrence of age-related processes has been extensively studied in adults, the impact of these factors during early developmental events is not so well known. For example, is it possible that parental age at conception can have an influence on the course of aging in the succeeding generation? Can an environmental effect, such as malnutrition, have permanent consequences on offspring if it occurs during or immediately after gestation? What, in fact, are the ramifications of parental age and maternal nutrition on disease and longevity in offspring, and what potential mechanisms underlie these effects?

Parental age

Retrospective studies have reported that older parentage can adversely affect aging in offspring, with some studies reporting stronger contributions from either maternal or paternal sources. For example, in a report by Leonid Gavrilov and colleagues in 1997, analysis of records of European aristocracy revealed that female offspring of older fathers had a significantly reduced life span. Because the effect was related to a paternal source and only influenced female offspring, mutations inherited via the paternal X-chromosome were suspected. As reviewed by Juan Tarin and colleagues in 1998, there are also several diseases associated with older paternal age, including Wilms' tumor, Apert's syndrome, and Marfan's syndrome, among others. Gwen McIntosh, in a 1995 study that controlled for maternal age and known chromosomal abnormalities, found an increased incidence of birth defects as a function of increasing paternal age. Older paternal age has also recently been associated with an increased incidence of prostate cancer and brain cancer. It has been conjectured in the copy error hypothesis of L. S. Penrose that spermatozoa are more prone to mutations than oocytes, due to the larger number of divisions they have undergone with age. A review by Crow reports that DNA duplication during gametogenesis is the period when mutations most readily occur.

Aging of female oocyte stocks can also have an effect on the appearance of disease in adult offspring. One of the more familiar circumstances is an aberration in chromosome number, known as aneuploidy, which can cause severe developmental problems and compromise life span. Many cases are manifested as trisomy, where three copies of a chromosome (instead of the normal two) occur with increased frequency with advancing maternal age. For example, Down syndrome (trisomy 21), which results in short stature, mental deficiencies, physiological problems, and a shortened life span, is caused by maternal problems in chromosome separation (nondisjunction), resulting in the appearance of an extra chromosome 21. Trisomy of other chromosomes also occurs in lesser frequencies in newborns, such as chromosome 18 (Edwards' syndrome) and chromosome 13 (Patau's syndrome). In the majority of cases, nondisjunction of maternal origin appears to be responsible for the trisomic condition, although a small percentage of cases involve the paternal source.

Maternal nutrition

The study of long-term effects of maternal nutrition on offspring has a rich and extensive history. The hypothesis, referred to as fetal origins, fetal programming, or metabolic imprinting, addresses the permanent effect that maternal undernutrition may have on physiological systems in the offspring, reportedly affecting glucose regulation, lipid metabolism, cardiovascular disease, blood pressure, and obesity. Human studies on the imprinting effect have been conducted retrospectively, utilizing records to establish vital statistics on newborns. Aspects of health, physiological fitness, and mortality in newborns were followed up many years later, during adulthood. Studies on men born in Herefordshire, England, demonstrated that those with the lowest birth weights were more likely to have higher mortality rates from coronary heart disease. Similarly, low-birth-weight males were more likely to develop noninsulin-dependent diabetes and impaired glucose tolerance, inferring that low-birth-weight babies were deprived nutritionally during development. Data from the Dutch famine of World War II, which resulted in maternal malnutrition, more directly tested gestational malnutrition and demonstrated that glucose tolerance was indeed decreased years later in surviving adults.

Epidemiological studies are limited by their retrospective nature, especially over issues of controls, sampling bias, and concerns over adjustment for confounding factors. In attempts to address some of these concerns, animal studies have been conducted, and in some cases they have supported the fetal origins hypothesis on issues of body composition, cardiovascular disease, and glucose tolerance. However, animal studies must be interpreted with caution, due to questions of species differences in the expression of pathology. Given the large collection of human and animal data on the subject, the fetal origins hypothesis remains topical, though it requires additional research to test its accuracy.

While many of these hypotheses will require elucidation through future study, new technology will greatly assist in the process. Previous studies have also suggested areas of research to help test fetal programming, such as permanent modification of gene expression and alterations in cell number. Epigenetic mechanisms, where heritable changes in gene function occur without changes in DNA sequence, provide another interesting mechanism by which fetal programming can occur. Finally, the techniques of in vitro fertilization with gametes from older parents, as well as cloning of differentiated adult cells, may provide new information on the effect of early development on aging in successive generations and help discern the role of genetics and environment on these complex issues.

Steven Kohama

See also Genetics; Longevity: Reproduction; Mutation.

BIBLIOGRAPHY

Crow, J. F. "Spontaneous Mutation in Man." Mutation Research 437 (1999): 59.

Gavrilov, L. A.; Gavrilova, N. S.; Kroutko, V. N.; Evdokushkina, G. A.; Semyonova, V. G.; Gavrilova, A. L.; Lapshin, E. V.; Evdokushkina, N. N.; and Kushnareva Y. E. "Mutation Load and Human Longevity." Mutation Research 377 (1997): 6162.

Hemminki, K., and Kyyronen, P. "Parental Age and Risk of Sporadic and Familial Cancer in Offspring: Implications for Germ Cell Mutagenesis." Epidemiology 10 (1999): 747751.

Joseph, K. S., and Kramer, M. S. "Review of the Evidence of Fetal and Early Childhood Antecedents of Adult Chronic Disease." Epidemiologic Reviews 18 (1996): 158174.

McIntosh, G. C.; Olshan, A. F.; and Baird, P. A. "Paternal Age and the Risk of Birth Defects in Offspring." Epidemiology 6 (1995): 282288.

Nicolaidis, P., and Petersen, M. B. "Origin and Mechanisms of Non-disjunction in Human Autosomal Trisomies." Human Reproduction 13 (1998): 313319.

Tarin, J. J.; Brines, J.; and Cano, A. "Long-Term Effects of Delayed Parenthood." Human Reproduction 13 (1998): 23712376.

Waterland, R. A., and Garza, C. "Potential Mechanisms of Metabolic Imprinting That Lead to Chronic Disease." American Journal of Clinical Nutrition 69 (1999): 179197.

Zhang, Y.; Kreger B. E.; Dorgan, J. F.; Cupples, L. A.; Myers, R. H.; Splansky, G. L.; Schatzkin, A.; and Ellison, R. C. "Parental Age at Child's Birth and Son's Risk for Prostate Cancer: The Framingham Study." American Journal of Epidemiology 150 (1999): 12081212.

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