7.4. EFFECT OF AGE ON DNA REPAIR

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

Species	Cells	Ages studied	Change with age
Mouse	Hepatocytes	1-18 months	50% decrease
	Neurons	4-24 months	53% decrease
	Lymphocytes	3-30 months	50% decrease
	Fibroblasts	2-30 months	30% decrease
	Lymphocytes	4-24 months	no change
Rat	Fibroblasts	3-31 months	50% decrease
	Kidney cells	5-30 months	50% decrease
	Hepatocytes	5-30 months	50% decrease
	Hepatocytes	3-20 months	50% decrease
	Hepatocytes	6-32 months	50% decrease
	Fibroblasts	6-40 months	20% decrease
	Hepatocytes	6-24 months	no change
Hamster	Brain cells	1-18 months	30% decrease
	Lung and kidney cells	1-18 months	no change
Rabbit	Chondrocytes	3-18 months	50% decrease
	Chondrocytes	18-52 months	no change
	Chondrocytes	3-24 months	no change
Human	Keratinocytes	17-77 years	30% decrease
	Leukocytes	13-94 years	40% decrease
	Keratinocytes	17-67 years	no change
	Lymphocytes	17-74 years	no change
	Chondrocytes	23-63 years	no change
	Fibroblasts	1-95 years	no change
	Keratinocytes	1-70 years	no 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.