Increased NADPH Levels Extend Life in Female Mice Only

Researchers here report on one of many attempts to slow aging via manipulation of antioxidant levels in cells, finding that the results are gender-specific. Over the past decade there have been mixed results from animal studies that use gene therapy and other methods to increase antioxidant levels in various parts of the cell. The idea is to reduce oxidative damage associated with aging, but it is not at all obvious that this is the mechanism by which aging is slowed in those approaches that do modestly extend life. The reactive oxidant molecules that cause damage are also signals, so changing the levels of these signals can have all sorts of effects on cellular metabolism, both positive and negative, and not all of which are fully understood at the present time. For example the general introduction of antioxidants throughout cells removes the benefits of exercise, as it blocks the mild increases in oxidative damage that the body reacts to in order to create those benefits. Targeting antioxidants to mitochondria only has produced modestly extended life spans with greater reliability, however.

The gradual accumulation of cell damage plays a very important role in the origin of ageing. There are many sources of cellular damage, however, which ones are really responsible for ageing and which ones are inconsequential for ageing is a question that still lacks an answer. The Oxidative Hypothesis of Ageing - also known as the Free Radicals Hypothesis - was put forward in 1956. Since then, the large majority of attempts to prove that oxidative damage is relevant for ageing have failed, including multiple clinical trials in humans with antioxidant compounds. For this reason, although the accumulation of oxidative damage with ageing is undisputed, most scientists believe that it is a minor, almost irrelevant, cause of ageing.

A group of scientists have tried to increase the global antioxidant capacity of the cells, rather than just one or a few antioxidant enzymes. To achieve this global improvement in the total antioxidant capacity, researches have focused on increasing the levels of NADPH, a relatively simple molecule that is of key importance in antioxidant reactions and that, however, had not been studied to date in relation to ageing. The researchers used a genetic approach to increase NADPH levels. In particular, they generated transgenic mice with an increased expression throughout their bodies of one of the most important enzymes for the production of NADPH, namely, glucose-6-phosphate dehydrogenase (or G6PD). "As anticipated, the cells in these transgenic animals are more resistant to highly toxic artificial oxidative treatments, thus proving that an increase in G6PD really improves antioxidant defences."

Furthermore, when researchers analysed long-lived transgenic animals, they noted that their levels of oxidative damage were lower than in non-transgenic animals of the same age. They also studied the propensity of these animals to develop cancer and found no difference, suggesting that enhancing G6PD activity does not have an important effect on the development of cancer. The greatest surprise for the team was when they measured the ageing process in the transgenic mice: the animals with a high G6PD expression and, therefore, high levels of NADPH, delayed their ageing, metabolised sugar better and presented better movement coordination as they aged. In addition, transgenic females lived 14% longer than non-transgenic mice, while no significant effect on the longevity of males was observed.



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