NAD+ and Cellular Senescence in Intestinal Tissue Organoids

Organoids are a useful intermediary step between cell cultures and animal studies, allowing for investigations to be carried out in a structured tissue that is much closer to the real thing than cells in a petri dish. Researchers here use intestinal tissue organoids derived from old mice to show that raised levels of NAD+ suppress markers of cellular senescence - which most likely indicates suppression of activity rather than outright destruction of senescent cells to any great degree, given what we know of how calorie restriction affects NAD+ and senescent cells.

NAD+ levels are connected to mitochondrial function, and fall with age. A growing industry is now selling various means to raise NAD+ in order to improve mitochondrial function and thus tissue function. Some of these appear to be beneficial in early trials, while others seem ineffective. Past research has connected NAD+ with cellular senescence, or mitochondrial function with cellular senescence, but rigorous data on the size of the effect has yet to be produced. This narrow slice of the benefits of increased mitochondrial function is unlikely to compare favorably with the effects of senolytics, the outright destruction of senescent cells in large numbers.

Here we have demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3K27, inducing suppression of Wnt signaling and a decrease of cell proliferation in intestinal epithelial organoids derived from aged mice. In these organoids, we also observed accumulation of SA-β-gal, a decrease in the expression of DNA methyltransferases and an increase in the expression of p21, indications of cellular senescence.

Epigenetic silencing of Lgr5 and induction of senescence occurs in aged intestinal organoids. The stem cell marker Lgr5 was substantially expressed in young intestinal epithelial organoids, whereas it was faintly expressed in aged intestinal organoids. Examination of DNA methylation levels around the Lgr5 promoter region revealed no significant difference in DNA methylation between young and aged intestinal organoids. Since Lgr5 is an activator of the Wnt signaling pathway, epigenetic silencing of Lgr5 results in suppression of Wnt signaling, which may lead to decreased cell proliferation and activation of senescence-associated genes such as p21 due to suppression of DNA methylation.

Recently, calorie restriction experiments have highlighted Sirt1 as a possible longevity gene. Sirt1 has histone acetyl transferase activity and its expression is regulated by the concentration of NAD+. Aging leads to a reduction of NAD+ in the body, and it has been reported that supplementation of NAD+ induces longevity and stem cell activation. Here, intestinal epithelial organoids derived from aged mice grew larger, forming crypt-like structures after treatment with NMN, a key NAD+ intermediate. The aged intestinal epithelial organoids treated with NMN showed an increase of proliferative activity, activation of Lgr5 and Sirt1, and suppression of p21 and p16, suggesting that treatment with NMN was able to ameliorate senescence-related changes in intestinal epithelia and could have potential application as an anti-aging intervention.


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