Ataxia-telangiectasia (A-T) is a debilitating, multifactorial genetic illness marked by nervous system degeneration, most frequently during infancy or early childhood. Premature aging disorders such as A-T are commonly associated with the breakdown and leakage of the power packs that create energy for our cells (mitochondria), as well as senescence — a halt in cell growth and replication required to prevent our organs from deteriorating. These events also occur during normal aging, although not at such a young age and fast rate.
In a paper published in Aging Cell that the accumulation of damaged mitochondria and senescent cells occurs in cells from A-T patients, cultured human cells, and animals that model the illness. The team discovered that increasing NAD+ levels clears damaged mitochondria and prevents senescence in A-T mice.
A-T is a rare genetic disorder characterized by neurodegeneration, sterility, and immune deficiency. Inflammatory symptoms in A-T patients are thought to be caused by immature immune cells. The ATM kinase enzyme controls DNA repair activities. Loss of mitochondrial function is another age-related factor. Multiple studies link A-T characteristics to mitochondrial dysfunction. Dysfunctional mitochondria can age cells and animals, can induce senescence.
DNA Loss from Mitochondria Is Associated with Premature Aging
This work investigated whether mitochondrial dysfunction and senescence were present in cells from A-T patients, ATM-deficient brain cells, and mice. They discovered that cells from A-T patients and those without ATM exhibit defective mitophagy, which promotes the release of mitochondrial DNA into the cytoplasm. This accumulation of cytoplasmic DNA activates an antiviral immune response termed STING in the brain, triggering a powerful pro-inflammatory response.
Increased NAD+ Maintains Mitochondrial Populations in Balance
It next demonstrated that increasing the cell’s NAD+ level decreased the buildup of fragmented DNA floating around in the cytoplasm. They believe that the NAD+ boosting is accomplished through the activation of mitophagy because the NAD+ precursor nicotinamide riboside (NR) failed to prevent senescence after being inhibited in the presence of mitophagy.
Additionally, the team discovered that increasing NAD+ levels affected not just ATM-deficient cells but also behavior. In addition, it protected against neuroinflammation and senescence in ATM-deficient cells and mice by improving mitochondrial function, decreasing cytoplasmic DNA, and inhibiting STING activation. When NAD+ levels were restored in ATM-deficient mice, they also regained motor function. NAD+ supplementation is important and effective in conditions like A-T or normal aging where NAD+ levels are low.