Researchers find clue to repair of aging DNA

When NAD+ (red) binds to the DBC1 protein (beige), it prevents DBC1 from attaching to and blocking the activity of a protein critical for DNA repair.David Sinclair

Our DNA gradually accumulates errors, or mutations, over time. Many factors, such as tobacco and radiation from sunlight, are known to actively damage DNA. Cells also naturally accumulate a certain number of mutations with each division. Although our cells have sophisticated mechanisms for repairing DNA, errors inevitably slip through.

As we age, the ability of cells to repair damaged DNA declines, enabling more mutations to collect. Most mutations are harmless, but some can cause serious problems. Cancer, for example, is caused by mutations that allow cells to grow and divide uncontrollably. Other mutations can cause subtle but still harmful changes.

DNA damage is considered an important component of the aging process. Scientists are just beginning to understand some of the key molecules involved. Enzymes called sirtuins, which control several biological pathways, are known to play a role in aging. A compound called nicotinamide adenine dinucleotide (NAD⁺), which regulates key signaling pathways in the cell, is known to interact with sirtuins and declines with age. Among its many roles, NAD⁺ also interacts with a key DNA-repair protein called PARP1. Yet another protein called DBC1 is known to inhibit sirtuins.

Researchers set out to investigate how these components might work together to affect the aging process. The team was led by Dr. Jun Li at Harvard Medical School and Dr. David Sinclair at Harvard Medical School and the University of New South Wales School of Medicine in Sydney, Australia. The study was funded in part by NIH’s National Institute on Aging (NIA). Results appeared in Science on March 24, 2017.

The scientists found that DBC1 forms a complex with PARP1 and inhibits PARP1 from repairing DNA. NAD⁺ interferes with this interaction. It binds to the same part of DBC1 that interacts with PARP1. Thus, as NAD⁺ levels decrease with age, more DBC1 protein is left to bind PARP1 and prevent it from repairing damaged DNA.

The researchers gave old mice with lower levels of PARP1 activity a NAD⁺ precursor compound to raise levels of NAD⁺. The compound restored PARP1 activity and reduced DNA damage. It also reduced DNA damage in mice exposed to radiation.

The reason that NAD⁺ declines with age is unknown, but this work suggests it might account for why DNA repair capacity declines with age. “Our results unveil a key mechanism in cellular degeneration and aging, but beyond that they point to a therapeutic avenue to halt and reverse age-related and radiation-induced DNA damage,” Sinclair says.

Boosting NAD⁺ levels could have several practical uses. These might include reducing the side effects of chemotherapy and radiation exposure, preventing cancer, and slowing some aspects of aging. Whether NAD⁺ has such potential in humans is a subject for future study.

—by Harrison Wein, Ph.D.