With this emerging motif of science and technology it is revealed that aging related dysfunctions is associated with mitochondrial programming. Mitochondrial disruption or their damage may results couple of abnormal chattels within the cell and this result in the onset of aging and cell death. It is reported that mitochondrial aging leads to the reduced ATP production, induction of reactive oxygen species and less total mitochondrial DNA replication. NAD+ acts as an efficient player in this mitochondrial programming because it acts as a cofactor in the mitochondrial metabolic pathways, either catabolic or anabolic to produce energy currency. Currently scientists trying to reverse aging by the appliance of stem cells to rebuild and renovate NAD+ levels within the cell.
Role of Sirutins proteins in the regulation of aging:
Sirutins are class of specialized proteins that are involved in mitochondrial growth by the activation of proliferator-activated receptor c coactivator (PCG-1a) including chromatin structure by deacetylating histones and involved in metabolic pathways integrity. For their complete action NAD+ levels are required.
Scientists reported interestingly that levels of sirutins not decreased with age only the level of NAD+ decreases which affects the activity of sirutins and resultantly decreased mitochondrial mass.
With this new era of biotechnology, stem cell therapy gained popularity in treating different medical conditions. Researchers have demonstrated that two types of stem cells can be used i.e. multipotent adult stem cells and pluripotent stem cells which are found in embryonic tissues.
In mitochondria, two enzymes are responsible for the production of NAD+. Nucleotide transdehydrogenase and mononucleotide adenylyl transferase3 but it is revealed that due to cellular senescence levels of these two enzymes reduced leading to mitochondrial activity disruption. NNT enzymes localized in the inner membrane of mitochondria and responsible for the electron transfer from NAD to NADPH and by this way it maintains redox potential within the mitochondria to reduce oxidative stress and prevent aging. Similarly, NMNAT3 is also a mitochondrial enzyme responsible for the synthesis of NAD.
Stem cell therapy to reverse aging:
Stem cell therapy becoming popular day by day for therapeutic use to treat human medical conditions. Scientists reported that stem cells also lose the capability of self-renewal with aging like somatic cells but it is possible to reprogram stem cells to their self-renewal phase. With the process of aging p16 is a cell cycle inhibitor which increases with the age and this protein acts as a biomarker for aging and cellular senescence. This cellular senescence inhibits the production of stem cells and cause hurdle in their activity but reprogramming experiments by scientists and researchers demonstrated that it is possible to reprogram stem cells to produce enough NAD levels to restore aging. but Currently scientists overexpressed the levels of these two enzymes into the mesenchymal stem cells. Investigators reported that process of cellular senescence is delayed in the mesenchymal stem cells and this results in the prolonged production of NAD+ levels within the mitochondria and increased activity of SIRT3 activity for maintenance of cellular integrity. Scientists reported that low levels of NAD+ levels are the main hurdle in reprogramming experiments and demonstrated that reduced levels of replicative senescence in Mesenchymal stem cells after the overexpression of NNT and NMNAT3.
Cellular proliferation and metabolic processes are tightly linked with each other. Recently reported hypothesis named as “Geroncogenesis” which depicts that with aging chances of tumorigenesis increases due to decreased metabolic reprogramming because of low levels of NAD+. This process can be reversed by reprogramming experiments in stem cells and prevent tumorigenesis.
Agents that contribute to increased level of NAD+ in human body:
Scientists now successfully developed nutraceutical of NADH which is the reduced form of NAD and it is commercially available. Vitamin B3 has potential to raise the levels of NAD in the body, researchers claimed that by taking vitamin B3 can increase level of NAD at least in younger people.
Another important factor that scientists revealed that could help to increase level of NAD is Caloric Restriction (CR) and exercise can efficiently have helped human body to restore levels of NAD within the body and can slower down the process of aging.
In conclusion, NNT and NMNAT3 are two important drivers of cell that can reduce the process of aging by their overexpression in mesenchymal stem cells by reprogramming experiments. This stem cell based reprogramming can helpful to restore cellular age and to reverse aging.
Recent breakthrough in stem cell advancement has made ideal source for future medical treatments and therapies. Currently scientists are working on MSCs by developing a novel protocols and methods so that their activity should be enhanced to combat with different disorders.
- Son, M. J., Kwon, Y., Son, T., & Cho, Y. S. (2016). Restoration of mitochondrial NAD+ levels delays stem cell senescence and facilitates reprogramming of aged somatic cells. Stem Cells, 34(12), 2840-2851.
- Mendelsohn, A. R., & Larrick, J. W. (2014). Partial reversal of skeletal muscle aging by restoration of normal NAD+ levels. Rejuvenation research, 17(1), 62-69.
- Ullah, I., Subbarao, R. B., & Rho, G. J. (2015). Human mesenchymal stem cells-current trends and future prospective. Bioscience reports, 35(2), e00191.