| Mitochondrial theories of aging
|
| Mitochondrial theories of aging are a blend of biological and chemical theories, treating aging as the result of chemical damage to mitochondrial DNA (mtDNA). Mitochondria contain proteins specified by both nuclear and mitochondrial DNA, however only 13 mitochondrial proteins are encoded by mitochondrial DNA. While this may seem trivial, these include essential subunits of the three proton pumps and ATP synthase. MtDNA is especially sensitive to mutations: mitochondria are the major site of ROS production in the cell, mtDNA is not protected by a sheath of histones, and mitochondria have limited capacity for DNA repair.
|
Mitochondrial diseases commonly involve defects of energy metabolism, including the pyruvate dehydrogenase complex, pyruvate carboxylase, complexes I, II, III, and IV, cytochrome c, ATP synthase (complex V), and biosynthesis of ubiquinone. These defects can be caused by mutations in both nuclear and mitochondrial DNA, but mtDNA suffers many more mutations than nuclear DNA. Such defects often result in the accumulation of lactic acid because of impaired oxidative phosphorylation, and may cause cell death, especially in skeletal (myopathies) and cardiac muscles (cardiomyopathies) and nerve (encephalopathies) tissues, which are heavily dependent on oxidative metabolism (Chapters 8 and 13). The number of mitochondria and multiple copies of the mitochondrial genome in the cell may provide some protection against mitochondrial dysfunction as a result of mutation.
|
| TELOMERES - A CLOCK OF AGING |
| Telomeres are the repetitive sequences at the ends of chromosomal DNA, typically thousands of copies of short, highly redundant, repetitive DNA, TTAGGG in humans (Chapter 30). DNA polymerase requires a double-stranded template for DNA biosynthesis. During normal DNA replication, RNA primers at the 5' end of the template serve to initiate DNA synthesis. However, at the extreme ends of the chromosomes, DNA synthesis is restricted, because there are no sequences further upstream for DNA primase engagement. Therefore, each round of chromosome replication results in chromosome shortening. The enzyme telomerase is a reverse transcriptase containing an RNA with a sequence complementary to the telomere DNA. It functions to maintain the length of telomeres at the 3'-end of chromosomes. Telomerase is found in fetal tissues, adult germ cells and in tumor cells. but the somatic cells of multicellular organisms lack telomerase activity. This has led to the hypothesis that shortening of the telomere may contribute to the Hayflick limit and is involved in aging of multicellular organisms. Increased expression of telomerase in human cells results in elongated telomeres and an increase in the longevity of those cells by at least 20 cell doublings. Cells from individuals with premature aging diseases (progeria) also have short telomeres. In contrast, cancer cells, which are immortal, express an active telomerase activity. All of these observations suggest that the decrease in telomere length is associated with cellular senescence and aging. Knockout mice, in which the telomerase gene has been deleted, have chromosomes lacking detectable telomeres. These mice have high frequencies of aneuploidy and chromosomal abnormalities. The disease, autosomal dyskeratosis congenital, features a mutation in the telomerase locus, with inability of somatic cells to reconstitute their telomeres, and hence loss of epidermis and hematopoietic marrow. This disease has many of the characteristics of accelerated aging. |
|
