Genetics
Note: This original manuscript is slightly different from the
final published version because of editorial changes.
Genetics is the branch of biology that deals with heredity (family likeness). Heredity is the passing of characteristics (traits) from parents to offspring. The genetics of aging is the science of heredity for traits related to aging such as: lifespan, age at menopause, age at onset of specific diseases in late life (Alzheimer's disease, prostate cancer, etc.), rate of aging (estimated through tests for biological age), rate-of-change traits, and biomarkers of aging (Arking, 1998). In practice, most studies are focused on lifespan, because other reliable markers of aging are lacking or less convenient to use. Therefore, the genetics of aging is closely related to the biology of lifespan (Gavrilov & Gavrilova, 1991).
Genetics is also the study of the fundamental chemical units of heredity called genes. Gene is a segment of deoxyribonucleic acid, DNA, carrying coded hereditary information. Genes are made up of four types of nitrogenous compounds (called 'bases') known by their first initials: A (adenine), C (cytosine), G (guanine), and T (thymine). The sequence, or code, is the order in which these four bases, 'letters of genetic code,' link up with the sugar deoxyribose and phosphate to form the DNA molecule. To determine the entire sequence of the 3 billion bases that make up human DNA (genome), the U.S. Human Genome Project was initiated in 1990. On June 26, 2000 Celera Genomics announced that it had identified in general the sequence of the human genome (with partial use of the Human Genome Project data). The final and complete sequence is expected by year 2003. Many researchers believe that the completion of the Human Genome Project will create a revolution in the identification of the genes involved in the aging process (Carnes et al., 1999).
The total number of genes in the human genome is still unknown with estimates ranging from 28,000 to 150,000 genes. By comparison, the fruit fly Drosophila melanogaster has 13,600 genes, while the bacteria Escherichia coli has only 4,300 genes. The number of gerontogenes (genes involved in the aging process) remains to be established, but there are no doubts of their existence. For example, in humans one of the forms of a gene coding apolipoprotein E (ApoE e2) is associated with exceptional longevity (more prevalent among centenarians) and decreased susceptibility to Alzheimer's disease (Martin et al., 1996; Finch and Tanzi, 1997).
Each gene occupies a specific position (locus) on a thread-like structure called a chromosome. Chromosome is the linear end-to-end arrangement of genes and other DNA, usually with associated protein and ribonucleic acid, or RNA. Chromosomes can be seen in cells with an ordinary light microscope. Every human cell (except egg and sperm cells) contains two sets of 23 chromosomes (one set from the mother and another set from the father for a total of 46 chromosomes). However, the proportion of aberrant cells with 'wrong' numbers of chromosomes increases with age, and this process may cause cancer and other diseases in later life (Arking, 1998).
Genetics also involves the study of the mechanism of gene action - the way in which genes produce their effect on an organism by influencing biochemical processes during development and aging. The first steps of gene action are well understood in molecular genetics and could be summarized by a simple schema: DNA --> RNA --> protein. In other words, the DNA genetic code ultimately determines the structure (amino acid sequence) of proteins. However, the final steps of gene action in shaping the complex structural, functional, and behavioral traits of the organism, as well as species lifespan and aging patterns, remain to be understood.
Although genes determine the features an organism may develop, the features that actually develop depend upon the complex interaction between genes and their environment, called gene-environment interaction. Gene-environment interactions are important because genes produce their effects in an indirect way (through proteins) and, therefore, the ultimate outcome of gene action may be different in different circumstances (Carnes et al., 1999). It is recognized from the effects of diet restriction on mice and other species that gene-environment interactions can greatly modify lifespan and the rate of aging. Understanding interactions between genes and restricted diet is important because caloric restriction is known to be the most effective way for lifespan extension and delaying age-related diseases in mammals (Finch and Tanzi, 1997).
Many of the genes within a given cell are inactive much or even all the time (repressed). Different genes can be switched on or off depending on cell specialization (differentiation) - a phenomenon called differential gene expression. Gene expression may change over time within a given cell during development and aging. Changes in differential gene expression are vitally important for cell differentiation during early child development, but they may persist further in later life and become the driving force of the aging process. Some researchers believe that pharmacological control over differential gene expression in later life may be a feasible approach in the future to slow down the aging process and to increase the healthy lifespan.
Occasionally changes may occur in a gene, or a chromosome set of a cell, making it different from original (wild) type. The process that produces such changes is called mutation. This term is also used to label the gene or chromosome set that results from mutation process. In many cases, mutations are caused by DNA damage, including oxidative damage (Martin et al., 1996), or radiation damage by ultraviolet light, ionizing radiation, and heat. Every time cells divide the risk of mutation increases. This is because mistakes (copy-errors) are likely to occur during copying (replication) of a huge DNA molecule in dividing cell (Vogel and Motulsky, 1997). Accumulation of deleterious mutations with age is one of the possible mechanisms of aging.
Genetics also involves the study of how aging and lifespan of progeny depend on parental characteristics, such as parental lifespan and parental age at child conception (Carnes et al., 1999). Familial resemblance in lifespan between parents and children is very small when parents live shorter lives (30-70 years) and very strong in the case of longer-lived parents, suggesting an unusual non-linear pattern of lifespan inheritance (Gavrilova et al., 1998). Also, children conceived by fathers at older age have more inborn mutations (Vogel and Motulsky, 1997) and may be at higher risk of Alzheimer's disease and prostate cancer in later life. Daughters conceived by fathers age 45 and older live shorter lives (on average), while sons seems to be unaffected, suggesting the possible role of mutations on paternal X chromosome (inherited by daughters only) in the aging process (Gavrilov and Gavrilova, 2000).
Bibliography
Arking, Robert. Biology of Aging: Observations and Principles, 2nd ed. Sunderland, Mass.: Sinauer Associates, 1998
Carnes, Bruce A., Olshansky, Stuart J., Gavrilov, Leonid A., Gavrilova, Natalia S., and Grahn, Douglas. "Human longevity: Nature vs. Nurture - fact or fiction." Perspectives in Biology and Medicine 42 (1999): 422-441
Finch, Caleb E., and Tanzi, Rudolph E. "Genetics of aging." Science 278, October 17 issue (1997): 407-411
Gavrilov, Leonid A., and Gavrilova, Natalia S. The Biology of Life Span: A Quantitative Approach, New York: Harwood Academic Publisher, 1991
Gavrilov, Leonid A., and Gavrilova, Natalia S. "Human longevity and parental age at conception." Pages 7-31 in J.-M.Robine et al. eds., Sex and Longevity: Sexuality, Gender, Reproduction, Parenthood. Berlin, Heidelberg: Springer-Verlag, 2000
Gavrilova, Natalia S., et al. "Evolution, mutations and human longevity: European royal and noble families." Human Biology 70 (1998): 799-804
Martin, George M., Austad, Steven N., and Johnson, Thomas E. "Genetic analysis of ageing: role of oxidative damage and environmental stresses." Nature Genetics 13 (1996): 25-34
Vogel,
Friedrich, and Motulsky, Arno G. Human Genetics. Problems
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