Rejuvenation science

I’d like to take things in another direction after all of the tension on the website recently. I’d like to talk about the science that is dearest to my heart.

A lot of you may know from my backstory already but I had a very insular upbringing and that in combination with my autism that meant I did not have a normal childhood. Plus I like many autistic people have something of a Peter Pan syndrome. As a child adults would sometimes say of me ‘he will make a better adult than a child.’ As an adult I am now often accused of being childish and frankly I feel more at home around the culture and activities of younger people.

So it is no accident that my career has taken me in the direction of anti-ageing science. And I would like to share with you A recent history of anti-aging science and some of current cutting edge developments.

Rapamycin

On Easter island also known as the island of rapanui they found a rare bacteria in the soil. From this bacteria they isolated a drug known as rapamycin. Rapamycin was and sometimes is used as an immunosuppressant to prevent organ rejection.

However they discovered when they gave it in large quantities to animals In lab conditions it extended their lifespan. It also improved health in old age. A common refrain that we will often see that anti-aging therapy does not merely extend life it also improves health in old-age.

For a long time it was known that precisely controlled starving of animals could extend their lifespan.  I say controlled because while the number of calories in the diet is reduced the minerals and nutrients are not. Rapamycin appears to operate through the same mechanism.

It was discovered a protein mTOR which literally stands for mammalian target of rapamycin had its activity suppressed by the drug. MTOR complex one is a key control switch for the creation and destruction of protein in cells. When it is in a high state cells create many proteins in preparation for the growth and division of the cell. But when it is in a low state the cell starts collecting damaged protein and eating it. It is believed that this eating of damaged protein makes the cells healthier and younger in their behaviour.

Of course rapamycin is an immunosuppressant you can’t easily give the same high levels you give to animals to humans without serious risk of infection. After all you can’t lock humans in germfree labs.

Telomerase

At the end of every DNA chromosome is a structure called a telomere. Somewhat like the little protective plastic sheaths on the ends of shoelaces. And under normal circumstances each time our cells DNA is copied as cells divide telomeres gets slightly shorter. This prevents cells dividing an indefinite number of times, the so-called heyflicks limit. It’s useful in preventing cancer. There are number of ways of restoring telomeres to their normal length and one is telomerase. Telomerase can lengthened telomeres. Almost every cancer expresses high levels of telomerase. However as human beings age the telomeres of their cells and especially their stem cells become too short. This reduces the number of stem cells that are able to divide to keep the body repaired drastically. They did an experiment in mice where they genetically engineered them to have higher levels of telomerase. When they applied the therapy to old mice it increased their lifespan by 13% and quite surprisingly didn’t seem to cause any increase in the rate of cancer. Of course mice are not human beings.

NF kappa B

NFKB is a protein associated with inflammation and damage inside of the cell. levels of NFkB within the body have been shown to elevate as we age. When various different signals are triggered inside a cell NFKB transitions from its dormant to its active state. In its active state it triggers the activation of a wide range of different genes. These genes are typically associated with inflammation and cell survival.

When a cell becomes sufficiently badly damaged it generally has 2 fates. It can undergo programmed death where the cell neatly destroys itself without causing damage to the surrounding area. this is called apoptosis. The second option is a kind of a limp mode where the cell will not divide and has limited activity but continues to survive. This is a form of senescence.

NFKB seems to promote senescence in most cell types. Blocking the activity of NFkb has been shown to rejuvenate mouse skin. Reducing the activity of NFKB in a region of the brain that governs hormone activity has been shown to increase the amount of Gondatropin releasing hormone GnRH that is produced. This not only helps counteract the age related reduction in hormone production in the body as a whole it also seems to protect the brain from neurodegenerative diseases like Alzheimer’s.

However NFKB is essential to the normal function of the immune system. In particular the B cells that produce antibodies cannot mature properly without it.

Senolytics

As previously mentioned many cells enter a mode known as senescence as they become old and damaged. Senescent cells will not die they also generally will not divide and unfortunately they usually produce something called SASP The senescence associated secretary phenotype. It turns out that old cells, senescent cells, actually produce chemicals that cause the cells around them to age faster or to at least function more poorly. So there was some interest in what would happen if you were able to kill these cells selectively.

So a clever scientist found a way to genetically engineered a mouse that had a death gene but could be linked to a very specific trigger. In this particular case the trigger was a combination of the mouse being fed a certain chemical and the individual cell having a gene activated called P16ink. P16ink is a gene associated with the stable long-term senescence of cells. Ironically providing the chemical signal that activated this gene did not shorten the animals lifespan in fact it increased it and improved their health. Ironically killing the cells with the aged phenotype in the body increased lifespan.

At some point people started to discover chemicals that killed senescent cells in preference to ordinary cells. These chemicals are known as senolytics. Most of them have too many severe side-effects to be used in the levels but show good effects in animals and cell culture. However scientists are looking at ways to combine these chemicals with other chemicals to allow them to be used at lower levels.

One particular area where this may be tested in humans before long is in children cancer survivors. It’s long been known that radiation therapy creates a lot of senescent cells. It’s also known that children who undergo radiation therapy do tend to have shorter lives and more health problems later in life. Studies in animals suggest applying senolytics to animals that have experienced radiation therapy can help reduce the impact of radiation therapy on their health in later life and clinicians are interested in trialling this in children receiving radiation therapy for cancer.

PEPCK-C

Not every discovery in aging actually began as an attempt to understand or alleviate aging. A group of scientists wanted to understand the function of the gene called PEPCK-C that is normally active in the liver. So they genetically engineered a mouse in which this gene would also be active in the muscle.

In the process they extended the mouses lifespan considerably and created mice that were much healthier in Old age. These mice have exceptionally developed musculature and incredible strength and stamina. They are also hypersexual and remain sexually active and fertile longer than normal mice. they also have exceptional appetites eating roughly twice what a normal Mouse would.

It turns out that PEPCK-C is a key protein controlling the process of the conversion of fat and protein into sugar in the liver. The fact increasing its activity in the liver can cause Type II diabetes by flooding the bloodstream with more sugar than cells are ready to absorb. However when PEPCK-C operates inside energy hungry muscle cells they do not need to absorb that sugar they can make it inside of themselves this means that the muscles are able to directly feed off the protein and fat in the bloodstream without relying upon the liver.

This again demonstrates a profound impact that metabolism has on aging. Well it’s possible the muscles may be secreting positive factors that improve the health of the animal it’s also quite likely that the lower levels of fat and protein in the bloodstream help create a situation similar to caloric restriction even though the animals are eating twice as much.

An amusing aside about the research paper describing this work. It ends with the observation that it would be completely unethical but also completely possible to replicate this experiment in human beings.

Cellular reprogramming

If you think about it logically you have come from cell divisions but I’ve been happening for countless generations not many of your life but of all of your ancestors lives. You came from a zygote but that zygote came from a sperm and an ovum cells which divided out of the cells of your parents who came from zygotes. We know not only the body ages but also the cells in it individually. But If our cells just kept ageing each generation would be progressively decrepit and more aged than the last.

at some point in human development cellular aging is reset. We now know this seems to happen shortly after conception. particularly The process is happening in embryonic stem cells.

For sometime now we’ve been able to create induced pluripotent stem cells which are affectively adult cells that have been reprogrammed to behave as embryonic stem cells. And we have discovered that in the process of creating these cells they are also reset in terms of aging.

The process involves forcing the cells to express certain genes known as Yamanaka factors. However we have now discovered that by not expressing these factors consistently but rather switching them on and off quickly we can cause ordinary adult cells to develop a rejuvenating effect without returning to embryonic stem cell like behaviour.

We’ve demonstrated we can do this in in cells both human and mice cells but we’ve also been able to do it to entire mice bodies.

Mice were genetically engineered that would express these Yamanaka factors in response to being fed a particular chemical. They were then fed this chemical for two days a week. Not only were the mice rejuvenated but mice that had been genetically engineered to also have a rapid aging disease similar to progeria had this disease halted by the therapy.

Considerable research is underway into trying to achieve this effect in a way that can be applied to human beings. The task of expressing a set of genes in the entirety of a human body only two days a week is going to require innovation in genetherapy. many laboratories are focused upon trying to activate these genes using drugs. But it remains unclear if that’s in fact possible.

The modern research effort

It used to be that if you talked about rejuvenation therapy you were looked upon as a nutcase certainly in the 80s and 90s many scientists felt that way. Now there are multiple organisations pouring large amounts of money into ageing research including googles company calico and Jeff Bezos‘s altos. They’re multiple anti-aging conferences where scientists gather from around the world to discuss the study of rejuvenation. Hell rejuvenation science even has its own rap song now.

https://youtu.be/WRRGsNyp7gU