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Genetics

Genetics is the branch of biology that deals with heredity—the passing of characteristics (traits) from parents to offspring. The genetics of aging deals with the studies of heredity for traits related to aging, such as life span, 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. In practice, most studies are focused on life span, 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 life span.

Genetics is also the study of the fundamental chemical units of heredity, called genes. A gene is a segment of deoxyribonucleic acid (DNA), which carries 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 link up with the sugar deoxyribose and phosphate to form the DNA molecule. To determine the entire sequence of the three billion bases that make up human DNA (the human genome), the U.S. Human Genome Project was initiated in 1990. On 26 June 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 complete sequence is expected to be known by 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.

The total number of genes in the human genome is still unknown, with estimates around forty-two thousand 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 for apolipoprotein E (ApoE ε 2) is associated with exceptional longevity and decreased susceptibility to Alzheimer's disease.

Each gene occupies a specific position (locus) on a thread-like structure called a chromosome. A chromosome is the linear end-to-end arrangement of genes and other DNA, usually with associated protein and ribonucleic acid (RNA). Chromosomes can be seen in cells with an ordinary microscope. Every human cell (except egg and sperm cells) contains two sets of twenty-three chromosomes—one set from the mother and another set from the father, for a total of forty-six chromosomes. However, the proportion of aberrant cells with "wrong" numbers of chromosomes increases with age, and this may cause cancer and other diseases in later life.

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 can be summarized by a simple schema: DNA → RNA → protein. According to this schema, genetic information is first transmitted from DNA to RNA (first arrow corresponding to transcription process), and then from RNA to protein (second arrow corresponding to translation process). 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 an organism, as well as species life span 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 the ultimate outcome of gene action may be different in different circumstances. It is recognized from the effects of diet restriction on mice and other species that gene-environment interactions can greatly modify life span and the rate of aging. Understanding interactions between genes and a restricted diet is important because caloric restriction is known to be the most effective way to extend life span and delay age-related diseases in mammals.

Many of the genes within a given cell are inactive (repressed) much, or even all, of the time. 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 life span.

Occasionally, changes may occur in a gene or in a chromosome set of a cell, making it different from the 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 or radiation damage (by ultraviolet light, ionizing radiation, or 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 a dividing cell. Accumulation of deleterious mutations with age is one of the possible mechanisms of aging.

Genetics also involves the study of how the aging and life span of progeny depend on parental characteristics, such as parental life span and parental age at conception. Familial resemblance in life span 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 nonlinear pattern of life span inheritance. Also, children conceived by fathers at an older age have more inborn mutations and may be at higher risk of Alzheimer's disease and prostate cancer in later life. Daughters conceived by fathers age forty-five and older live shorter lives, on average, while sons seems to be unaffected in this regard, suggesting the possible role of mutations on the paternal X chromosome (inherited by daughters only) in the aging process.

LEONID A. GAVRILOV NATALIA S. GAVRILOVA

BIBLIOGRAPHY

ARKING, R. Biology of Aging: Observations and Principles, 2d ed. Sunderland, Mass.: Sinauer Associates, 1998.

CARNES, B. A.; OLSHANSKY, S. J.; GAVRILOV, L. A.; GAVRILOVA, N. S.; and GRAHN, D. "Human Longevity: Nature vs. Nurture—Fact or Fiction." Perspectives in Biology and Medicine 42 (1999): 422–441.

FINCH, C. E., and TANZI, R. E. "Genetics of Aging." Science 278 (1997): 407–411.

GAVRILOV, L. A., and GAVRILOVA, N. S. The Biology of Life Span: A Quantitative Approach. New York: Harwood Academic Publisher, 1991.

GAVRILOV, L. A., and GAVRILOVA, N. S. "Human Longevity and Parental Age at Conception." In Sex and Longevity: Sexuality, Gender, Reproduction, Parenthood. Edited by J.-M. Robine, et al. Berlin: Springer-Verlag, 2000. Pages 7–31.

GAVRILOVA, N. S., et al. "Evolution, Mutations and Human Longevity: European Royal and Noble Families." Human Biology 70 (1998): 799–804.

MARTIN, G. M.; AUSTAD, S. N.; and JOHNSON, T. E. "Genetic Analysis of Ageing: Role of Oxidative Damage and Environmental Stresses." Nature Genetics 13 (1996): 25–34.

VOGEL, F., and MOTULSKY, A. G. Human Genetics. Problems and Approaches, 3d ed. Berlin: Springer-Verlag, 1997.

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Medicine EncyclopediaAging Healthy - Part 2