Nuclear DNA Damage, Aging, and Stem Cells

Nuclear DNA damage accumulates with age, but is it a cause of aging? This open access paper illustrates why there is a question - as for many studies, the results do not point unambiguously in one direction or another. "Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of aging. Here we tested this hypothesis in healthy individuals of different ages by examining unrepaired DNA double-strand breaks (DSBs) in hematopoietic stem/progenitor cells matured in their physiological microenvironment. ... The highest inter-individual variations for non-telomeric DNA damage were observed in middle-aged donors, [where] the individual DSB repair capacity appears to determine the extent of DNA damage accrual. However, analyzing different stem/progenitor subpopulations obtained from healthy elderly (>70 years), we observed an only modest increase in DNA damage accrual, [but] sustained DNA repair efficiencies, suggesting that healthy lifestyle may slow down the natural aging process. ... Based on these findings we conclude that age-related non-telomeric DNA damage accrual accompanies physiological stem cell aging in humans. Moreover, aging may alter the functional capacity of human stem cells to repair DSBs, thereby deteriorating an important genome protection mechanism leading to exceeding DNA damage accumulation. However, the great inter-individual variations in middle-aged individuals suggest that additional cell-intrinsic mechanisms and/or extrinsic factors contribute to the age-associated DNA damage accumulation." Meaning that nuclear DNA damage may or may not be a primary cause of aging, and may or may not be important in comparison to other factors.


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