Rewriting the Senescent Cells chapter

I rewrote the Senescent Cells chapter of my book (How to Live Forever), reducing the focus on FOXO4-DRI, and including details about alternatives such as UBX0101, Navitoclax and Quercetin.

The latter two have already passed human safety trials, but are designed primarily as cancer treatments. They do have senolytic properties, but those are not as strong as the actions that the FOXO4-DRI peptide and UBX0101 have.

The rewritten chapter is about twice as long as the original, but I think it’s written better. The original chapter is more terse and factual, while the new version is more conversational. It includes the same information (and more), but is much easier to read.

At the end of the chapter, I explained that even though the drugs themselves might be very expensive, the most important of them (in my opinion), can probably be synthesised at home, if you put some time and effort into it.

FOXO4-DRI is a patented drug, meaning that the creators wanted to protect who could sell it. In order to do this, they needed to describe it in full, which they did in the patent application. This included the protein sequence.

Patenting something is done to exclude others from selling or importing the patented device. Patents can also exclude people from making or using the device, but if there is no profit made, and the self-use of the device does no harm to the inventor’s business, it is extremely unlikely that any action would be taken. And even if action would be taken, it would be a mere “stop doing that” from the courts.

Personally, I’m firmly on the side of people creating and using what they create – especially if it involves saving your own life – so I’m building a workshop/lab in order to create drugs such as FOXO4-DRI for my own use.

So far, I have the frame of the lab built, and I’ve bought and calibrated a 3D printer for designing and building the lab equipment itself. I’ll probably write a second book explaining all that when I’m at a sufficiently advanced stage. I’ve just paid for the mechanical and chemical parts for a dehumidifier, which I’ll need to design because there are no 3D-printed desiccant-wheel dehumidifiers already in existence that I know of.

Anyway – next week, I’ll rewrite another chapter. The chapter on fixing DNA replication with NAD+ looks like it might be the next highest in popularity, so it gets a rewrite.

Rewriting the Senescent Cells chapter

Last week, I rewrote the How to Live Forever book’s introduction chapter so I had two different copies. This lets me display one or the other randomly to each visitor to the website, letting me figure out through visitor interactions which chapter catches the attention more and is easier to read.

This week, after resetting the Introduction’s stats, I checked and the next-most popular page was “killing senescent cells with the FOXO4 DRI peptide”, so I’ll rewrite that this week.

The first thing I did was to rename it “Senescent Cells”, since the focus should really be on the problem, senescence, instead of the solution, senolytics. When I first wrote the chapter, the only senolytic that people were talking about was FOXO4-DRI, but since then, others such as UBX0101 and Navitoclax have been mentioned as well. There are about 25 or so senolytics in trial in various clinics. So, I renamed the chapter to be more about what senolytics are for, and not to be about a specific one.

When I rewrote the Introduction chapter, I basically just read the original, then paraphrased it. This was okay to do because the introduction is just a general overview – it doesn’t have a lot of details in it.

When rewriting every other chapter, though, more care needs to be taken. Every sentence has something to say, so I need to make sure that the rewrite includes everything that the original had.

The first rewrite will be a rough draft paraphrase, just like last week’s rewrite. But then I’ll go through carefully and make sure that I included everything written in the original, and finally will try to find new information to talk about, since the focus is no longer on the DRI peptide, but is now on senescent cells themselves.

This should be easy enough, because there are new human trials and new drugs that have come to light since I wrote the original.

I had another idea as well, which is to illustrate the concepts in cartoon form. This will let me explain visually some of the ideas that are hard to explain with words. Of course, I can’t draw, so this may take some redraws to get it right.

Because senolytics such as the FOXO4-DRI peptides are not currently available even to clinics, I will also include some information such as where to buy senolytics.

When will we be able to live forever

Based on the rate at which medicine is evolving, the answer to this question is a resounding “Now!”

Almost every disease has a cure or a cure-in-testing, and aging is just one of those diseases.

In the book How To Live Forever, I wrote four sections on ways that we already know to slow or even reverse aging, including telomere extension, senolytics such as FOXO4-DRI or UBX0101, calorie restriction, and increasing NAD+.

Of the four, three of them are in human trial at the moment, and the fourth has already been shown to reduce the incidence of tumours in humans.

Telomere extension has already been shown by Elizabeth Parrish to increase telomere length by 9%. This equates to about 10-15 years of life extension. This year, it was shown that telomere extension treatment in progeria sufferers results in decreased inflammation and decreased β-galactosidase almost immediately after treatment. Because humans live so long, it is hard to know for sure if live extension works. Progeria is basically a disease that increases the speed of aging in humans – if you can slow or cure progeria, there’s a good chance you’ve also made huge steps towards curing aging itself.

Senolytics are drugs that kill senescent cells – cells that have stopped replicating and producing new young cells, but which also refuse to die. Instead, they stick around spewing out inflammation proteins and causing other nearby cells to also go senescent, resulting in more and more of your cell population becoming old and useless. Senolytics such as FOXO4-DRI or UBX0101 work by covering the part of the FOXO4 gene which is stopping the cell from dying, thus forcing the cell into apoptosis (cell death), making room for new young cells.

Calorie restriction is shown in lab animals to reduce the incidence of tumours (cancers), and leading to longer (up to 50% longer!) lives as a consequence.

And finally, NAD+ is a catalyst which helps the mitochondria of your cells to work with oxygen to produce energy. In older people, the amount of NAD+ in your cells reduces, making it harder for the cell to produce energy, and sometimes resulting in DNA-replication errors. To increase NAD+ in your cells, you can either inject NAD+ directly, or ingest NMN (a precursor molecule that turns into NAD+ in the body).

There are a lot of other methods of living forever, but these are the big four at the moment.

longevity escape velocity

The main part of this website is the book, “how to live forever“, and even as it was written, I kept changing my mind about what the “thrust” of the thing was – is it simply a list of diseases? Is there a central premise? Does a step-by-step instruction set even exist?

I believe that I have the premise now (and will need to rewrite parts of the book now…), which is based around “longevity escape velocity” (note to self: good chapter name)

In the past hundred years, life expectancy at birth has increased in parts of the world from about 64.75 years in 1928, to 89.5 years today. The “life expectancy at birth” is the age at which actuarial calculations predict that humans will die, based on current conditions and past performance.

64.75 to 89.5 is an increase of about 25 years in one century. 25 extra years that a person might live.

While that sounds like a lot (25 years is almost half again of 60 years), it’s not enough to guarantee immortality.

Even if we repeat the trick this century, and tack on an extra 25.25 years to the expected 89.5 years (that a person in Monaco might expect to live), we still have an expected age at death of only 114.75.

As I pointed out in that previous post, though, life expectancy predictions are usually pessimistic, because they rely on the technology of the time, and cannot predict accurately what the future will bring.

The biggest change that we have made in the last few years is one that has not yet filtered down to the world’s clinics – instead of treating old age as a simple winding down and inevitable end to the body, we are now beginning to treat it as a disease that can be treated and cured.

The full “cure” for old age is not likely to appear for a very long time, but that does not matter, as we can concentrate on the more accessible “longevity escape velocity” as a near-term goal.

So what does “longevity escape velocity” mean?

Let’s say that every year, we discover how to let the average person live an extra half year, the current average age of death is 80, and you are 40. How long do you think it will be before you die (on average)? When you are 80 the average age of death will be 100. When you’re 100, the average age of death will be 110. When 110, 115. When 115, 117.5. On average, people will still die by 120, despite the progress.

This is because half a year is /less than/ one year.

But let’s say we discovered how to add on 1.5 years to the average lifespan every year, the current average age of death is 80, and you are 40.

When you are 80, the average expected age of death will be 120. When you are 120, it will be 210. Instead of being almost guaranteed dead at 120, you are now middle-aged!

Even if we have not discovered a total and final cure for old age, if you are 120 and have an extra 90 years to live /at that moment/, you are almost certain to find yet another way to push back that final curtain further, even if it’s not forever.

We are already discovering how to do these things.

The current accepted biological limit to human life is 126 years, because of something called the “Hayflick” limit, which is caused by telomeres shortening on DNA every time it replicates itself. But we have already found ways to lengthen this. Elizabeth Parrish, CEO of BioViva, became the first person to extend telomeres, extending her own by 9%, which equates to between 14 and 20 years extra, bringing her potential lifespan up to 140+ years.

It might even be possible to repeat the same treatment, so she has potentially worked around the Hayflick limit permanently.

This gives us all an extra few years of life to work on whatever the next issue is.

Aging is caused by a lot of different things happening to the cells of the body. Telomere shortening is just one.

Another is that your mitochondria lose the ability to absorb oxygen and convert it to energy as the years go on. By fixing this, we gain another few years. David Sinclair’s research with NAD+ addresses this issue.

Then there are senescent cells – cells which have reached their “end of life”, and yet stick around, taking up space that would be better used by younger cells, and giving out inflammation proteins. We can now selectively kill these cells with FOXO4-DRI and UBX0101 drugs.

All of these are treatments that add on multiple years to your life. And these have all been announced only in the last five years.

It might not be possible to predict the future accurately, but I’m fairly sure it will be a long one!

selective destruction of SnCs in cartilage

Senescent cells (SnCs) have a role to play in the healing of wounds, but they tend to stick around afterwards, causing eventually more harm than they relieve.

A team of scientists led by Chaekyu Kim of the John Hopkins University School of Medicine used a senolytic drug, UBX0101, to clear out SnCs accumulating in the cartilage of mice that were recovering from cuts to the anterior cruciate ligaments (ACL – ligaments that cross over each other in an X shape behind the knees).

They chose this area to study because it has been noted that ACL injuries have a tendency to accumulate SnCs after injury, causing post-trauma osteoarthritis.

After the cuts, UBX0101 was injected into some mice.

The mice that received the injections did not suffer from osteoarthritis after healing from the cuts, and were able to regenerate cartilage lost during the injury.

Unity Biotechnology, who created UBX0101, received $116,000,000 in a round of investment last year, from investors such as Jeff Bezos, May Clinic Ventures, Venrock, and ARCH Venture Partners.

While this particular study was focused on osteoarthritis, SnCs can accumulate in all tissues in the body, so senolytic drugs (which trigger apoptosis in those cells to clear them) out can have a large range of uses.