Senescence, when cells can no longer divide and replicate, is central to aging. Accumulation of these senescent cells can be induced by excessive stress or replication of cells and reduces the ability of tissues to function and regenerate in aged organisms. Involved in this process is an enzyme called nicotinamide phosphoribosyltransferase (Nampt) that is critical for the synthesis of an essential compound called nicotinamide adenine dinucleotide (NAD+), which plays a role in cellular metabolism, health, and aging. It was recently reported that cells taken from genetically modified mice with artificially activated Nampt were protected from senescence caused by excessive replication, but whether these cells are tolerant of stress-induced senescence remains unknown.
A research team led by investigators from the Nara Institute of Science and Technology in Japan published an article in the journal Genes to Cells showing that cells from genetically modified mice that have an artificially activated form of Nampt possess resistance against stress-induced premature senescence in a laboratory dish. “Our results demonstrate that NAMPT/NAD+ functions to protect cells not only from replicative senescence but also from stress-induced premature senescence,” said the investigators in their publication. They proposed that activation of NAMPT activity or increases in NAD+ levels would protect tissues from the accumulation of premature non-replicating cells, thereby maintaining healthy aging.
The accumulation of these cells that no longer divide and replicate in aged organisms is mainly stress-induced. There are several kinds of stress that can affect cells to induce premature senescence. One is called oxidative stress, an imbalance between damaging molecules called free radicals and protective antioxidants in your body. Another kind of stress emanates from a cell structure called the endoplasmic reticulum (ER), where abnormal proteins accumulate, causing harm to cells. The accumulation of abnormal proteins triggers the unfolded protein response (UPR), a cellular repair mechanism that clears the abnormal proteins and restores cellular health and function.
Studies have shown that non-replicating human and mouse cells have diminished NAMPT followed by NAD+. Artificial activation of NAMPT promotes increased NAD+ levels in cells, delaying the onset of cellular senescence. But these effects were observed in cells undergoing senescence induced by excessive cellular replication and not stress. For these reasons, the researchers from the Nara Institute of Science and Technology examined the role of NAMPT in cells undergoing senescence induced by stress.
To do so, the researchers used oxidative and ER stressors to induce premature senescence in genetically modified mouse cells carrying an artificially inserted activated form of Nampt. When treated with an oxidative stressor, the investigators saw that cells with artificially activated Nampt were able to divide and multiply more than unaltered cells. They also found that cells with artificially activated Nampt treated with an oxidative stressor were less senescent compared to unaltered cells. These findings show that artificial activation of NAMPT protects mouse cells from premature senescence induced by oxidative stress.
The investigators saw similar results for cells with artificially activated Nampt when treated with an ER stressor. That is, they saw that cells with artificially activated Nampt replicated more and were less senescent than unaltered cells when treated with an ER stressor. Moreover, the cells containing the artificially activated Nampt induced the UPR gene program more than the unaltered cells, which likely helps to avoid cellular senescence.
“Together with our previous and current reports, we were able to show that activation of the NAMPT/NAD+ axis acts as protection against both replicative senescence and stress-induced premature senescence,” said the investigators. They suggest that this study could accelerate research regarding not only administration of NAD+ precursors but also the development of NAMPT active compounds to protect tissues from the accumulation of premature senescent cells to maintain healthy aging.