The volume of money that is spent on cosmetics and medicines to help ease the process of aging and the changes that come with it is incredibly high1. With recent issues with health organisations, such as NHS, about budgets one of the main aims is to obtain cheaper treatments. An area where there could be more research into cheaper drugs could be certain diseases that can occur more commonly with aging, such as Alzheimer’s or type 2 diabetes. Alzheimer’s is caused by the degradation of nerve cells and type 2 diabetes is due to the same issue with pancreatic β cells, both resulting in a progressive age-associated decline in their function. A new aim for treatment in this area is targeting metabolism and manipulating certain biosynthetic pathways. A specific pathway, known as a salvage pathway, involves the biosynthesis of NAD (nicotinamide adenine dinucleotide) which stimulates the activity of sirtuins, in particular the SIRT1 (silent information regulator 1) family of NAD-dependent deacetylases2. They help to control essential biological processes when responding to many nutritional and environmental stimuli, so increasing the number of sirtuins could help to keep cells healthier for longer3. The link between sirtuins and the dependence for NAD infers a link between aging and metabolism4. One way to increase the activity of the sirtuins is to raise the levels of NAD, which can be done by increasing certain intermediates involved in the pathway which in turn will increase the levels of both NAD and sirtuins. This approach to stop the disease before it has formed will hopefully save money in the long term as there will be a reduced number of patients needing treatment and care for the illnesses.
The major precursor for NAD biosynthesis in mammals is nicotinamide rather than nicotinic acid, both are forms of vitamin B3. In the beginning of the NAD biosynthetic pathway with nicotinamide mammals use the unique enzyme nicotinamide phosphoribosyltransferase (NAMPT), which is the rate-limiting enzyme in this pathway. The enzyme catalyses the conversion of nicotinamide and 5’-phosphoribosyl-1-pyrophosphate (5’-PRPP) to nicotinamide mononucleotide (NMN). The second enzyme in this pathway, nicotinamide mononucleotide adenyltransferase (NMNAT), then converts NMN to NAD through adenylation reactions. As well as sirtuins then being produced nicotinamide is also2. The sirtuins the mediate the deacetylation reaction that couples lysinedeacetylation to NAD hydrolysis, which yields O-acetyl-ADP-ribose. The deacetylation means that ????????? This hydrolysis yields O-acetyl-ADP-ribose, which is the deacetylated substrate and nicotinamide.
In order to increase sirtuin activity by raising the NAD levels it would be sensible to first increase key intermediates in the pathway, which would in turn raise the NAD levels. Raising NAD directly is not a practical idea because observations in other research have shown this to cause serious hyperglycaemia in mice, probably due to glycogenolysis in the liver5. Using the rate-limiting enzyme NAMPT could work when manipulating the metabolic pathway. NAMPT has intra- and extracellular (iNAMPT and eNAMPT, respectively) forms in mammals. There are high levels of iNAMPT found in a wide range of tissues but an almost undetectable level in the pancreas and brain. However, eNAMPT is released through a separate secretory pathway and has better NAD biosynthetic activity when compared to iNAMPT. This is promising because neurons and pancreatic β cells both have very low levels of iNAMPT and rely on eNAMPT to be involved in NAD biosynthesis2. So increasing the NAMPT levels in the pathway could be done by inserting more eNAMPT into the cell as they are used to the NAMPT coming from an extracellular source anyway. This way of manipulating and taking advantage of the activity of sirtuins is expected to result in the cells staying healthier for longer.
If this alteration to the pathway is successful and a higher number of sirtuins are present in certain cells such as neurons and pancreatic β cells it could create huge benefits to the aging population. The benefit of reducing the number of people suffering with particular illnesses like Alzheimer’s and type 2 diabetes is hard to be argued with. The fact that the older generation can have a better quality of life without being held back by diseases makes the aging process less invasive onto their life. Those unlucky enough to be living with these illnesses, like type 2 diabetes, will be on long-term treatments which will be costing the NHS huge sums of money, and if these patients had been able to halt these diseases the money they would have used for medicine can be put into other areas of the healthcare system6,7. This is also the case with the money used for full-time or part-time care that is often required, especially for those suffering with Alzheimers, so by reducing the patients with Alzheimers would reduce the care time allocated and required by them8. It would be a worthwhile area to invest in as similar research has already shown positive results in different organisms so it should be possible in humans as the process is similar.
Although increasing the number of people staying healthier for longer and living to an older age is an optimistic idea, it would sadly cause problems in other areas that are not present at the moment. The demand for housing and shelter homes would increase with a higher percentage of the population being in the older age bracket, so the availability for accommodation would quickly decrease especially as it’s already a concern9, 10. There has been a lot of discussion recently about the fact that the post-World War 2 “baby boom” is now catching up with us as the majority of those babies are now the older generation that requires a lot more care which sadly drains money1. A different health risk may also come with altering the metabolism because certain cells such as neurons may stay functional for longer, when the rest of the body continues to age at a different speed. Putting the body out of sync in this way between different tissues and organs could cause problems that were not present before and would not be known how to be handled. Another problem that could occur with treatments like this is the idea that aging is a natural progression for the body and should not be tampered with. Medicines are available when patients become ill try to ease the suffering as much as possible, whereas altering the body before they have even get an illness could be seen as interfering with the body’s natural processes. It is a natural process that happens to all organisms, so it may be said that money could be spent on diseases that affect more of the younger population as they should have more time ahead of them and could give more back. There may be better targets for money in the health sector then as aging is a natural progression. Some medicines are there to ease the elderly if they are unwell, but should we try to actually halt or slow down the aging process so drastically. Is aging a good target for money and research or is it just a natural progression? A question might be good!?? Or in conclusion?
When looking into the idea of manipulating a part of metabolism and reading into similar successful research makes the process seem simpler and more achievable. The specific salvage biosynthetic pathway is incredibly useful as it links with the aging process, so harnessing its properties in this way is logical. However, it may be altering the natural aging process of the body and could cause different problems having a higher percentage of older generations, which might create disagreement when funding this research. ??? Yet, older people that would otherwise be suffering with debilitating diseases could enjoy life more, and money spent to treat the illnesses could be channelled into research for other diseases. Alzheimer’s is so difficult to treat and can be so difficult for the patients and those around them, so a potential treatment to stop it before it can progress in the body will surely be encouraged by the majority of the population.