Fighting aging and disease

December 12, 2017

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Although few things in life are certain, the fact that you die at some point is. Not a particularly happy prospect, but it remains a fact. But will it remain a certainty for much longer? Inspired by anti-aging experiments performed on mice, this article discusses the findings of these researches and what kind of impact these results could have on the world.
For a long time now, scientists and doctors have worked on extending life expectancy and dreamed of finding the elixir of life. But what has not been mentioned that often is the fact that there is a significant difference between lifespan and so-called healthspan. The way things currently are, is that, yes, we are getting older than ever before. However, the way in which we grow old, as our bodies begin deteriorating at an older age and we start showing signs of diseases and decline in important body functions, is not optimal. We now live longer, but we also spend more time in pain, being sick or being in hospital. The health sector of our economy has to make huge expenses in order to account for this. As the percentage of elderly relative to people under 65 is increasing, it will soon be a huge strain on the working population to support the retired. If the retirement age would remains, it will come down to a shortage in workforce and will cause the government to spend more while it generates less revenue from taxes, as retired people tend to pay less taxes.

Figure: The aging of the population is already affecting western economies greatly, with the UK as an example.
Scientists are trying to shift the attention of the medical community from optimizing lifespans to optimizing healthspans. Growing older while also remaining healthy would solve most of the problems stated above. As people can work longer, with less risk of becoming sick, they generate more money (because they can pay more taxes) and cost less at the same time. Several notable findings have been done during the past years, that make a longer, healthy life seem within reach.

The aging process

First of all, it is helpful to know why we age. Our bodies are made up of an extremely large amount of cells. For your body to function and to keep functioning, old cells are constantly replaced with new ones, at a rate of millions per second. This happens by means of cell division, a process by which a ‘parent cell’ divides into two ‘daughter cells’. Inside the parent cell, a replica of the DNA is made, after which the cell splits up. For all cells, except for reproductive cells, these two daughter cells are genetically identical to each other. However, this does not go on for ever. There is a certain limit, known as the Hayflick limit, that says that for some animals, cell division eventually halts. For humans, this occurs on average after 52 divisions. After each division, the DNA is shortened a little bit, and this accumulates to DNA damage, causing a cell to cease to divide. After this, two things can happen. Normally, a cell just dies. But some cells block the protein that tells them when it’s time to die. These cells become, what is called, senescent cells after their last division. These cells do not contribute to the functioning of the body, but remain metabolically active.
As we get older, a few things change that influence this process. The most important change that is a supposed reason for getting older is that our bodies cannot replace cells at the same rate as it did before. Senescent cells accumulate in the body’s tissue, which could be both due to the fact that the immune system cannot fight these cells anymore or the fact that the production of these cells is elevated. The percentage of senescent cells present in the body grows over time. Because they remain metabolically active, they compromise our body in its important functions such as tumour repression and wound healing. This accounts for the increased risk of diseases that the elderly often deal with.
Another thing that happens, is an accelerated cell death. This occurs due to the shortening of the DNA that happens after each division, resulting in cells that have too many mistakes in their DNA to remain working. These cells die instead of becoming senescent cells. In itself, this is a good thing, as the cells do not carry on to hinder the body. On the other hand, as cell division has slowed down, the amount of cells in the body also decreases. So the older we get, the amount of cells in our body decreases, but the part of the cells that is senescent is increasing and this makes that the normal functioning of our body demands more energy and that we are prone to disease.

FOXO4 and NAD+

This aging process eventually leads to death, either from a disease or a lethal body function dropping out. The largest contribution to this comes from the senescent cells; the cells that do not die, but continue to interfere with your body repairing itself. The assumption made by scientists from the Erasmus University Medical Centre in Rotterdam was that attacking these senescent cells would contribute to an extended healthspan. The protein mentioned before that makes sure that old cells die, is called p53. Senescent cells also contain a protein, called FOXO4, that tells this p53 not to cause self-destruction. The scientists figured out a way to interfere with this FOXO4-p53 communication, and causes the senescent cells to commit ‘cell suicide’. They designed a FOXO4 peptide that was expected to distort the communication between the proteins, and at the same time only affect senescent cells.
As for the experiment itself, mice were treated for 10 years, receiving an infusion of this peptide three times a week. The results that appeared, all occurred at different stages in the experiment. Already after 10 days, mice that were missing patches of hair started growing new fur and the fur grew thicker in general. Also in the early stages of the experiment, it showed that the mice who did receive the infusions began enjoying other physical benefits, such as increased fitness and an increase in healthy kidney function. Because mice are genetically quite similar to humans, this senescent cell cure will soon be tested on people, making it one of the first steps towards ‘curing’ aging.
However, this discovery of the FOXO4 peptide is not the only progress made in this field of science. Another candidate for the life extension elixir is NAD+. This is a coenzyme that basically tells our cells to look after themselves (in terms of when they are damaged or at the end of their life). As we age, we start underproducing this enzyme. Another experiment performed on mice, executed by scientists at the Harvard University Medical School, showed that as they were treated with a substances that triggered them to increase NAD+ production, production of skin, brain and stem cells was boosted. The treated mice were able to repair the DNA that got damaged during cell division and therefore, lifespan as well as healthspan was prolonged.
Apart from all this research possibly coming down to the first anti-aging remedy, it is also very promising in our fight against cancer. Just as senescent cells, tumour cells do not die. In fact, tumour cells never stop replicating themselves. Tumour cells are formed when a cell division goes wrong, and a mistake in the cell’s DNA is created during DNA replication. This makes the cell aggressive and it starts taking up the space of healthy cells. As tumour cells do not know the Hayflick limit, the cancer keeps growing and growing. The protein p53 that is present in cells, is not only a protein that keeps a cell informed about its time to die, but it is also a protein that fights the formation of tumour cells. So when scientist started treating cancer cells with the same FOXO4 peptide (again, tested on mice), not only did the amount of senescent cells decrease,  tumour cells were also attacked. More research is being done right now to determine whether this peptide could become an actual antidote for cancer, but it seems a very promising finding so far.

Testing on humans

As you may have noticed by now, all of these experiments have been performed on mice. The reason for this, is that mice show genetical similarities to humans, especially when it comes to the structure of DNA replication. This also means that the way cancer arises in human cells, is similar to the way that it occurs in the cells of mice. None of the substances discussed above have been tested on humans so far, but scientists are working hard to realize this in the near future. It remains to be seen whether humans will have the same response to these therapies, but it could be life changing for a lot of people. If, for example, the injection of the FOXO4 peptide turns out to have the same effect on human cancer cells, development of a new cell therapy could be started, that could be a possible replacement for chemotherapy in the future, or even prove to be more useful in fighting cancer. Other than that, both the FOXO4 peptide and NAD+ could be of use in extending the amount of years in which people are active and energetic, such that also the amount of years spent working could be prolonged.
On the other hand, these treatments would be rather expensive and rare, definitely in the first years. Questions that might arise, could be in terms of whether costs for these treatments would be compensated by insurance. And if not, who will get the priority; the seriously ill or the people who can actually afford it? It would be too early to worry about these things though, as no progress in testing on humans has been made so far and it remains to be seen whether the current findings  will actually bring scientists a step closer in their quest for the fountain of youth.

This article is written by Sabina Kamerling.

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