Replenishing NAD+ Reduces Defects in Patient Cells with Frayed Chromosome Ends

NR supplementation alleviates defects in cells from dyskeratosis congenita patients.

Stretches of repetitive DNA called telomeres stop the ends of chromosomes from fraying or sticking to each other, much like the plastic tips on the ends of shoelaces. These protective ends also make sure DNA gets copied properly when cells replicate. Telomere length is closely tied to aging, and when telomere length gets whittled down, cells age faster. What’s more, there’s a complex set of conditions called telomere biology disorders defined by dysfunctional telomere maintenance. One such disorder is a rare inherited disease called dyskeratosis congenita, a bone marrow failure syndrome, for which there are no effective treatments.

A research team led by investigators from the National Institute on Aging reported in The EMBO Journal that cells from patients with dyskeratosis congenita and mice with short telomeres display lower levels of a vital molecule called nicotinamide adenine dinucleotide (NAD+). They go on to show that NAD+ levels can be replenished with the supplement nicotinamide riboside (NR), which ameliorates the defects seen in cells from patients with dyskeratosis congenita and mice with short telomeres. “These findings reveal a direct, underlying role of NAD+ dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere‐driven diseases,” said the investigators in the article.

Telomere erosion as well as dysfunction of the cell’s powerhouse, the mitochondria, are hallmarks of biological aging and contribute to telomere biology disorders. The impairment of mitochondria and defective DNA damage responses accelerates telomere dysfunction and severely reduces the replicative lifespan of dyskeratosis congenita cells through a phenomenon called cellular senescence. Also, declining levels of NAD+ has recently emerged as a feature of aging in humans and animal models. This happens in part due to the increase in levels of an enzyme that uses NAD+ called CD38, which has been shown to distort the activities of other enzymes that depend on NAD+ in aged mice.

In this study, Liu and colleagues found that cells from dyskeratosis congenita patients and mice with critically short telomeres have lower NAD+ levels, causing defects in enzyme‐related signaling networks vital to mitochondrial health. Along these lines, they showed that when CD38 consumes NAD+, it reduces the availability of NAD+ to enzymes called PARPs and SIRTs that function in telomere and mitochondrial maintenance. 

To understand how elevated CD38 levels contribute to the NAD+ decline observed during aging, Liu and colleagues looked at CD38 levels in dyskeratosis congenita cells compared to cells without the disorder. They saw that CD38 levels were higher in dyskeratosis congenita cells, and this elevation was reduced when the DNA damage response to shortened telomeres was blocked. These findings support the notion that the DNA damage response induced by telomere dysfunction results in the hyperactivity of CD38, which drives the imbalance of NAD+ levels and thereby limits the NAD+ availability for PARP and SIRT enzymatic activities.

When they added an NAD+ precursor called NR or an inhibitor of CD38 activity in dyskeratosis congenita cells, NAD+ levels were restored and the cellular consequences of telomere dysfunction in cells from dyskeratosis congenita patients improved. Also, NR supplementation and CD38 inhibition restored PARP and SIRT activities, which impeded telomere DNA damage, mitochondrial impairment, and the onset of senescence in dyskeratosis congenita cells.

The results from this study by Liu and colleagues support the idea that telomere abrasion affects NAD+ levels and related biological pathways, thereby contributing to telomere and mitochondrial abnormalities as well as cellular senescence. “Our findings indicate that critically short telomeres and telomere dysfunction leads to loss of NAD+ homeostasis and establish a new linkage between dysfunctional telomeres and mitochondria that contributes to the deleterious consequences of telomere dysfunction,” said the investigators in the article.

The findings also establish how telomere dysfunction contributes to other hallmarks of aging and telomere biology diseases and pave the way for therapeutic intervention in telomere biology disorders. “The NAD+ mechanism‐based intervention strategies developed in this study may serve as a stepping stone for the future treatment of human telomere biology disorders such as DC,” concluded the investigators in the article.

 

 

 

 

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