Modified protein promotes hair growth and fights ageing in mice

Friday March 24 2017

"Scientists create a chemical that can restore hair and give youthful energy," the Daily Mail reports; but these effects have only been achieved in mice. A modified protein called FOXO4-DRI has been successfully used to remove "broken ageing" cells.

The new study was looking at what are known as senescent cells. These are cells that have "aged" in that they have stopped dividing. Senescent cells are thought to contribute to both the ageing process in general, as well as age-related diseases, such as arthritis.

Researchers investigated whether a modified version of a protein called FOXO4-DRI was able to "seek and destroy" senescent cells from mice, in the hope this may counteract signs of ageing.

Researchers used naturally ageing mice as well as mice genetically modified to age more rapidly. They exposed both sets of mice to toxic chemotherapy drugs to place additional stress on their cellular functions.

They found FOXO4-DRI was able to neutralise toxicity caused by chemotherapy in the rapidly ageing and naturally ageing mice. It was also able to counteract loss of liver and kidney function, frailty and loss of fur density in the mice.

This is very early stage animal research and further studies are needed before FOXO4-DRI can be tested in humans.

It is likely that further research on FOXO4-DRI will be carried out, as a drug that could treat both hair loss and reverse some of the effects of ageing would have considerable commercial potential.

Where did the story come from?

The study was carried out by researchers from several institutions in the Netherlands, Austria and the US, including, Erasmus University Medical Center Rotterdam and the Buck Institute for Research on Aging, California. It was funded by grants from the NIH and NIA, the Austrian Science Fund, and the Royal Netherlands Academy of Arts and Sciences.

The study was published in the peer-reviewed scientific journal Cell. It is available on an open-access basis and is free to read online.

Generally, the media coverage on this study was well balanced – especially by BBC Online. The Mail was perhaps a little over-optimistic with its headline claiming the compound would "restore hair and give youthful energy." Though it did eventually go on to mention that this was a mouse study.

Coincidentally, this anti-ageing research in mice study was published the same time as another anti-ageing research in mice study (published in the journal Science).  

What kind of research was this?

This was an animal study which investigated whether targeting senescent cells – cells that have stopped dividing – could counteract damage to tissue in the body caused by medical treatments such as chemotherapy, as well as by ageing.

Senescent cells have been observed to impair tissue function, and are able to avoid apoptosis – the process of cell death – and as a result, continue to live on in the body for long periods of time. While cell death may sound like a bad thing, apoptosis actually results in the removal of unhealthy, aged cells.

The researchers wanted to explore whether there are ways in which senescent cells can be flushed from the body to reduce the impact of ageing.

In particular, they wanted to see if the use of cell-penetrating peptides (CPPs) would contribute to this. CPPs are able to block interactions between proteins. The researchers hoped that these could be used to target senescent cells.

Mice studies like this one are useful early stage research which can allow scientists to better understand the complex chemical interactions that take place in cells. However, further research is needed to see if these same effects will be observed in humans. The researchers based in The Netherlands plan to run human trials to explore their findings.

The first stage is likely to be a phase I trial, which are small trials used to assess whether a new drug is safe to use.

What did the research involve?

The research involved cells from naturally ageing mice and those genetically engineered to age rapidly. Cells were induced to senesce by ionising radiation or by the chemotherapy drug doxorubicin. They investigated whether apoptosis (cell death) pathways are different within these senescing cells, and tested whether different cell-penetrating peptides (CPPs) could alter these pathways and counteract the process of senescence.

While testing the effects of one CPP in particular, FOXO4, the researchers found that by modifying the peptide they could give it new properties. They tested the effects of the modified peptide, (called FOXO4-DRI), on senescing cells.

The mice were given FOXO4-DRI three times a week for 10 months, and their activity on a running wheel was tested over four days. Changes in fur density were also measured.

What were the basic results?

The researchers found that the CPP, FOXO4 when modified to FOXO4-DRI, has the capability to modulate the apoptosis-pathway in senescent cells. It worked by disrupting the interaction between FOXO4 and the tumour protein p53. This interruption causes apoptosis to take place within senescent cells, therefore causing cell death.

When it was well tolerated, FOXO4-DRI was able to neutralise toxicity caused by chemotherapy in both the rapidly ageing and naturally ageing mice. It was also able to counteract loss of liver and kidney function, frailty (as indicated by increased running activity) and loss of fur density in the mice.

How did the researchers interpret the results?

The researchers concluded: "Therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored."

"In any case, the here reported beneficial effects of FOXO4-DRI provide a wide range of possibilities for studying the potential of therapeutic removal of senescence against diseases for which few options are available."

Conclusion

This mouse study aimed to investigate whether there are ways to target and destroy senescent cells that have stopped dividing yet somehow avoid the normal cell-death pathways. Removing these cells could counteract damage to tissue in the body caused by medical treatments such as chemotherapy, and accelerated or natural ageing.

It essentially found that a modified peptide (FOXO4-DRI) was able to cause death of the senescent cells. In turn, this was able to counteract the liver and kidney cell toxicity induced by a chemotherapy drug, in addition to reducing frailty and loss of fur density in the mice.

Animal studies such as this are very early stage research, useful for better understanding the complex mechanisms that take place at a cellular level. However, further research is needed before this can be tested in humans.

Humans are not identical to mice therefore we don't know whether the biological effects would be the same.

Mice studies are able to give very little indication of the potential adverse side effects that such treatments might cause, or look into the long term implications. As one of the lead researchers succinctly put it about the limitations of using mice – "mice don't talk".

It is certainly far too early to suggest this as a potential anti-ageing treatment for humans, or a treatment to counteract the side effects of chemotherapy or radiotherapy.

Dr. Dusko Ilic (who was not involved in the study) from King's College London told the BBC: "The finding is impossible to dismiss. [But] until more high-quality research is done, it is better to be reserved about these findings."

Analysis by Bazian
Edited by NHS Choices