The DNA Damage Response Falters in Old Stem Cells

Efficient DNA repair is necessary to prevent cells from becoming dysfunctional or senescent in response to stochastic nuclear DNA damage. This is particularly important in stem cell populations, as there is no outside source to replace their losses, or repair persistent dysfunction. Researchers here note that the DNA damage response fails to trigger sufficiently in old intestinal stem cell populations, and this may be an underlying contributing cause of higher levels of cellular senescence in these cells.

Aging is related to disruption of tissue homeostasis, which increases the risks of developing inflammatory bowel diseases (IBDs), and colon cancer. However, the molecular mechanisms underlying this process are largely unknown. Various age-related dysfunctions of adult tissue-resident stem/progenitor cells (TSCs, also known as somatic stem cells) are associated with perturbation of tissue homeostasis. Restoration of stem cell functions has attracted much attention as a promising therapeutic strategy for geriatric diseases.

The intestinal epithelium is one of the most rapidly renewing tissues in the body. Lgr5-expressing intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. Therefore, dysfunction of ISCs may be important for the disruption of intestinal homeostasis and subsequent induction of functional disorders. However, the influence of aging on the functions of ISCs and induction of diseases is largely unknown.

Recent studies demonstrated that accumulation of senescent cells promotes organismal aging. Cells become senescent in response to various aging stresses, such as oxidative stress, telomere shortening, inflammation, irradiation, exposure to chemicals, and the mitotic stress, all of which induce DNA damage. Numerous types of DNA damage occur naturally and are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. The mutation rate is highest in the small and large intestines. However, the influence of aging on the DDR in ISCs has not been studied.

Here, we compared induction of the DDR, inflammation, and mitochondrial biogenesis upon irradiation between young and old mouse ISCs in vivo. Induction of the DDR and expression of associated proteins were decreased in old ISCs. The DDR was sustained in old differentiated cells, suggesting that only the responsiveness to DNA damage was perturbed and DDR capacity was potentially sustained in old ISCs. Our results suggest that the competence of the DDR in ISCs declines with age in vivo.

Link: https://doi.org/10.1186/s41232-019-0096-y

Comments

@Norse: Read about the "Kalergi Plan" and you'll understand why this decline in birth rates in the West was engineered. Automation taking away many routine and rote jobs, as well as speeding creative ones ( https://selectbiosciences.com/conferences/index.aspx?conf=LOACWC2019 ), should be seen as an opportunity to more effectively deploy labor, not scale back humanity.

Posted by: Tom Schaefer at May 16th, 2019 10:35 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.