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Aging, The Molecular Concepts


The somatic mutation theory of aging first was proposed by Failla (23). He hypothesized that the accumulation of mutations in the genetic material of somatic cells with age results in a decrease in cellular function. Subsequently, Szilard (24) formulated what we now know as the somatic mutation theory of aging. According to this theory, the age-related accumulation of mutations randomly inactivates "vegetative" genes (genes important for the functioning of the somatic cells of the adult), which results in a decrease in organ function. He hypothesized that when the number of functionally surviving cells declines with age to a critical level, death will occur. In 1967, Alexander extended the somatic mutation theory of aging and suggested that DNA damage per se, apart from its role in inducing mutations, was important in aging (25). He proposed that the age-related accumulation of unrepaired DNA damage in cells results in a reduction in transcription. If expression of essential proteins is reduced or inhibited, a cell may lose function and/or viability, and this could be a primary cause of aging. These theories were supported by the observations that DNA damage and mutations in the genome increase with age (for review see 26). The accumulation of DNA damage and mutations is in part determined by the efficiency of DNA repair. Therefore, a simple prediction in relation to the somatic mutation theory of aging is that the ability of cells to repair DNA declines with increasing age. When DNA repair declines with age and eventually falls below a threshold level necessary to maintain the integrity of the genome, unrepaired damage and mutations accumulate in the genome of the cell (27). Over the past two decades, a large number of laboratories have attempted to study the effect of aging on DNA repair. In many of these studies, DNA repair was measured as unscheduled DNA synthesis (UDS) after the cells were exposed to ultraviolet (UV) radiation.

Table 7.I
Effect of age on UV-induced unscheduled DNA synthesis
SpeciesCellsAges studiedChange with age
MouseHepatocytes1-18 months50% decrease
Neurons4-24 months53% decrease
Lymphocytes3-30 months50% decrease
Fibroblasts2-30 months30% decrease
Lymphocytes4-24 monthsno change
RatFibroblasts3-31 months50% decrease
Kidney cells5-30 months50% decrease
Hepatocytes5-30 months50% decrease
Hepatocytes3-20 months50% decrease
Hepatocytes6-32 months50% decrease
Fibroblasts6-40 months20% decrease
Hepatocytes6-24 monthsno change
HamsterBrain cells1-18 months30% decrease
Lung and kidney cells1-18 monthsno change
RabbitChondrocytes3-18 months50% decrease
Chondrocytes18-52 monthsno change
Chondrocytes3-24 monthsno change
HumanKeratinocytes17-77 years30% decrease
Leukocytes13-94 years40% decrease
Keratinocytes17-67 yearsno change
Lymphocytes17-74 yearsno change
Chondrocytes23-63 yearsno change
Fibroblasts1-95 yearsno change
Keratinocytes1-70 yearsno change

UDS has been observed to decrease approximately 30-50% in cells from animals and humans with increasing age (Table 7.I). However, there are also studies that show no change in UDS with age.

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