Most attempts to show that oxidative damage is relevant for aging have not been successful, including many trials with antioxidant compounds. Because of this, although the accumulation of oxidative damage with aging is uncontested, most scientists believe that it is merely a minor, almost inconsequential, cause of aging. A team of scientists from the Spanish National Cancer Research Centre (CNIO) headed by Manuel Serrano, in collaboration with a group from the University of Valencia, directed by José Viña, and researchers at IMDEA Food from Madrid, have attempted to increase the global antioxidant capacity of the cells, instead of just one or a few antioxidant enzymes. They concentrated on increasing the levels of NADPH, which is a simple molecule that is of prime importance in antioxidant reactions, yet has also had not been yet studied in relation to aging. They employed a genetic approach to increase NADPH levels, generating transgenic mice with an increased expression throughout their bodies of one of the most crucial enzymes for the production of NADPH, glucose-6-phosphate dehydrogenase (otherwise known as G6PD).
The results, were published in the journal Nature Communications, and show that an increase in G6PD and as a result, in NADPH, increased the natural antioxidant defenses, shielding it from oxidative damage, decreasing aging-related processes such as insulin resistance, and increasing longevity. Furthermore, when the scientists analyzed long-lived transgenic animals, they found that their levels of oxidative damage were lower than in non-transgenic subjects of the same age. They found no difference in the tendency of these animals to develop cancer. The biggest surprise was when the team measured the aging process in the transgenic mice. They discovered that the animals with high levels of NADPH delayed their aging, metabolized sugar better and presented better coordination as they aged. Also, transgenic females lived 14% longer than the non-transgenic mice, though no significant effect was seen in the longevity of the males. “This increased longevity, although modest, is striking taking into account that until now attempts to increase longevity by manipulating individual antioxidant enzymes had failed,” said Pablo Fernández-Marcos, co-first author of the study and researcher at IMDEA Food. The researchers in the study point to the use of pharmacological agents or nutritional supplements that increase NADPH levels as possible tools for delaying the aging process in humans and age-related diseases, such as diabetes, and others. Vitamin B3 and its derivatives are responsible for the synthesis of NADPH precursors and are potential candidates for future studies.
