In this series of posts, I want to speculate on the future of human longevity. I will start with the current state of anti-aging research and move on to what is possible from there.
I am trying to assess the current state of life extension research. Obviously that is only my interpretation, as a layman person with only a high level understanding of the science involved. If you the reader spots a fault in my reasoning, please correct me in the comments. What I will expose here does not represent the consensus in the longevity community, if such can really be defined.
After the discovery of the yamanaka factors in 2006, which can induce pluripotency in any cells, it has been shown in several studies that transient expression of all or some of these factors can rejuvenate a cell, or an organism, without loss of cell identity (by “resetting” the epigenome). By rejuvenate, I mean that most hallmarks of aging are reversed. “most” does not mean the others are not reversed, it means they have not been properly studied in this context. There is a case to be made that all hallmarks are actually reversed if most of the cells of an organism is rejuvenated by way of epigenome reset.
Furthermore, numerous studies about parabiosis shows that exposed to an young environment, an old organ becomes young again. Infused in young blood, an old mice become young again.
We can infer two things from these facts:
- Whether from an old or young organism, a cell has the ability to clear all damages of aging and become phenotypically young again. Which means we don’t need to engineer the clearing of those damages, we “just” need to induce the cells to do the job.
- If a cell becomes old, it means they “chose” to do so. Which means they are programmed to do so, and must follow some sort of program. Parabiosis experiments hints strongly to the fact that the “age appropriate phenotype” instructions come from the blood.
This is very good news for an anti-aging cure. Even now, we know how to rejuvenate a mammal. It is at the moment very hard and risky, as it involves manipulating our genes to reset the epigenome. But it is not unreasonable to think we would sort out the issues if we choose this road, this is simply a matter of engineering.
But, and this is where it gets better, as we saw earlier we know that the aging regulation is at least in part made into the plasma. So another plan would be to find out those “aging instructions” and find a way to synthetize them cheaply rather than relying on young plasma, the production of which can not scale, and which has strong ethical concerns attached. There is actually a team of scientists who claims to have found the solution and have a therapy only a few years away. How this will pan out remains to be seen.
Whether by trying to directly reset the epigenome or trying to emulate a rejuvenating plasma, the plan is pretty straightforward, the science quite mapped out, as we will see below.
According to this review, there are four ways to reset the epigenome:
- Strategy 1: Somatic cell nuclear transfer (SCNT) experiments. SCNT involves transplantation of a cell nucleus into an enucleated egg/oocyte in order to generate a “cloned” animal with an equivalent genetic composition as the donor individual.
- Strategy 2: Extract cellular components (“reprogramming factors”) from pluripotent cells. Presumably the cytoplasmic “reprogramming factors” from the pluripotent cells can be isolated and concentrated to achieve a higher reprogramming efficacy.
- Strategy 3: A third strategy involves ectopic expression of defined transcription factors in somatic differentiated cells to generate induced pluripotent stem (iPS) cells. Delivery of the ectopic transcription factors can be achieved by viral approaches, such as the use of retrovirus, lentivirus, adeno-associated virus or Sendai virus, or by using episomal vesicles, or by direct mRNA or protein transfection.
- Strategy 4: iPS cells can also be generated by using combinations of microRNAs (miRNAs) or small chemical molecules without the needs of ectopic expression of reprogramming factors. We could argue that using plasma from a young organism falls into this category: the environment (the plasma) is acting as a signal to rejuvenate to the cells. Although the fourth item, it might be the safest and most powerful approach.
There are already several enterprises that are working on direct epigenome reset:
- Turn.Bio. They use the Strategy 4 (miRNAs). They are using several delivery POC to target various tissues, with the first therapies expected to target skin and lung. Delivery methods to some tissues is still to be defined.
- David Sinclair’s lab used gene therapy (Strategy 3). They showed a proof of concept, regenerating a damaged mouse’s eye. A stealth company, Iduna Therapeutics, has been spun out of it to translate the concept to the clinic.
- Juan Carlos Belmonte from the Salk Institute is investigating strategy 3
- Strategy 4 is also explored by Harold Katcher and his company Nugenics. They have shown impressive age reversal on rats in a (not yet peer reviewed) study.
- The publicly traded AgeX Inc. seems to be working on a drug that can reset the epigenome (Strategy 4)
- Alkahest is capitalizing on parabiosis studies (Strategy 4) to bring multiple therapies to the market. Instead of trying to find a common plasma fraction that would act on aging as a whole, they seek to find separate factors (that are either too low or too high in old plasma), so as to be able to bring differents therapies each targeting a specific disease of the old, in order to maximize revenue. I’ll come back to that in the second part.
- I also need to mention that various anti-aging interventions already exists which might or might not actually rejuvenate us. For example, stem cells and exosomes systemic delivery. These therapies are already available to paying customers in some countries around the world, and are associated with exceptional claims and anecdotal reports. Unfortunately, as far as I am aware, their anti-aging effect has never been investigated properly: no one has yet studied the effect on epigenetic age, which is the best marker we have of biological age. So we can only ignore those until they are properly vetted.
As you can see, if we actually take into account the recent progress made in understanding aging, we have a straightforward path toward actual rejuvenation. There is every indication that a therapy that can induce epigenome reset will be able to keep us biologically young indefinitely. We don’t even need the concept of longevity escape velocity, because we only need to develop the right type of anti-aging therapy once. Or at the very least the damages not cleared by this type of therapy would not be a problem for a long time.
We are past fundamental science, far into clinical translation. How much funding until the clinic? Ten millions? Fifty? One hundred? Maybe. But all of it can be provided by investors, and it’s really a drop in the bucket to bring the end to the suffering of hundreds of millions. How many years? Ten could be a reasonable estimate. That is, if the development of these companies goes full steam ahead.
That’s the state of longevity research. Technologically wise, we are very close to a cure. But of course, technology and science are the easy part. There are a lot of obstacles standing in the way of a post-aging society. We will explore them in the second part.