Transient cellular reprogramming – a panacea for ageing-related disease?

This article is part of our Biotech Review of the Year - Issue 11 publication

The ethos of Bryan Johnson, a billionaire whose campaign to stop his biological clock has been quite public, can be conveniently summarised by the name of his recent book: “Don’t Die”.

Immortality might seem extreme to most, but what can biotechnology actually do to improve our longevity? Transient cellular reprogramming is one of many tools that researchers are now using to slow down, stop, or even reverse the ageing process in a bid to extend healthspans, and potentially lifespans.

What is ageing?

At a high level, ageing is the progressive decline in cell and tissue function, and cellular ability to deal with stress. This can lead to reduced physiological integrity and increased vulnerability to disease. There are twelve “hallmarks” that drive ageing, which are comprised of interlinking molecular, cellular and systemic factors: mitochondrial dysfunction, cellular senescence and chronic inflammation are a few core examples. Research into ageing explores options to combat the twelve hallmarks, and slow the overall decline in function of an organism during adulthood. 

Why do we age?

The prevailing hypothesis is called antagonistic pleiotropy. This theory suggests that deaths by external factors such as infection or accidents reduce older population pools such that natural selection has a reduced ability to counter traits that have damaging effects in later life. Therefore genes which improve survival in early life but may have negative effects in later life might be proliferated more than expected.

What effect does ageing have on disease?

Ageing is a risk factor for most diseases: in the UK, for instance, aggregate incidence across all cancers is nearly 4,000% higher at age 65-69 than age 20-24.¹ Healthy lifestyle choices like regular exercise and healthy eating habits may help prevent disease, and of course other lifestyle choices can encourage disease, but the effect of ageing stands orders of magnitude greater in terms of promoting degenerative and hyperplastic pathologies. 

Is ageing a disease?

The descriptions above raise some interesting questions: to what extent should we actually pathologise ageing; is ageing just a natural phenomenon of life; or is ageing something that humans should actively interfere with? Some argue that concentrating on the mechanisms of ageing themselves might give researchers new opportunities. Conversely, others argue that ageing isn’t a perfect indicator of disease, and that pathologising ageing will only serve to normalise age-related discrimination. Given that more research papers on ageing have been published in the last 10 years than in the preceding 100, humans do seem determined to understand ageing better. Research into ageing generally explores options to combat the twelve hallmarks, and slow – or even reverse – the overall decline in function of an organism during adulthood. 

Rejuvenation

Rejuvenation is the branch of science aiming to influence the ageing process. Flavonoids such as hesperetin and (poly)phenolic compounds like resveratrol are some of numerous small molecules in the rejuvenation pipeline targeting the hallmarks of ageing. Hesperetin can potentially be used as an activator of CISD2 (a gene which is involved in mammalian lifespan control); and resveratrol can potentially be used to prevent mitochondrial decay (one of the core hallmarks of ageing from above). Small molecules like these two examples are certainly exciting in their own right, but these are only delaying the effects of ageing to increase longevity.

How do we measure cell age?

Increasing longevity by turning back the biological clock rather than pausing or slowing it is arguably the more exciting prospect. When we discuss a biological “clock”, practically we are referring to the measurement of certain changes to the epigenome using something called an epigenetic clock. While somatic cells are ageing, their epigenome is subject to consistent methylation reactions (among other things). On this basis, researchers are able to deploy an epigenetic clock test which uses algorithms to derive an estimate for the age of the cell based on the varying levels of methylations in its DNA.

Can we turn back the clock?

Cellular reprogramming (CR) gives researchers the tools to do just this. CR uses four specific genes in somatic cells to reverse the signs of ageing measured by the epigenetic clock test. These four genes, known as Yamanaka factors, can be expressed in somatic cells to reprogram them, and reverse their developmental status all the way back to an embryonic stem cell-like state. After the CR process, these unspecialised cells are pluripotent, which means they can make any type of cell in the body, apart from placental cells and extra-embryonic tissue (only a totipotent cell, like a zygote, has the additional potential to form these). Unfortunately, these cells have lost all of their original cell identity and function. These pluripotent cells do have other uses, but losing cell identity reduces the utility of CR for the purposes of rejuvenation. It’s worth noting that, using the process of differentiation, stem cells can be encouraged to specialise, but we don’t yet have the functionality to produce all types of cell through this process.

Transient cellular reprogramming (TCR), which builds upon the CR process, is arguably one of the most appealing strategies for rejuvenation available today, although it is still fairly early in its development. The CR process is made up of three key steps: the initiation phase, where the genes required for starting the somatic cell are turned off; the maturation phase, where a tranche of stem cell genes are turned on; and the stabilisation phase, where the remaining tranche of stem cell genes are turned on. TCR provides a clever solution to the issue of the somatic cells losing their identity and function. During TCR, the expression of the Yamanaka factors is closely monitored and they are expressed for a briefer period of time: transiently, if you will. 

With careful monitoring, researchers, like those in Wolf Reik’s group at the Babraham Institute in Cambridge, are able to stop the reprogramming at the start of the maturation phase. The cells were left deformed, but once the factors were removed, the shapes were restored and the cells returned to normal.² This allowed the researchers to secure the rejuvenation benefits in the somatic cells without the full loss of identity and function.

A notable test of this technology took place last year on human skin cells. The Reik Group took cells from a donor and applied the TCR process. To the surprise of many, according to epigenetic clock measurements, certain features of ageing were reversed and the estimated cell age was reduced by 30 years. This was not a purely cosmetic change either, the cells exhibited different – more youthful - characteristics after the TCR treatment: the skin cells secreted more collagen after TCR treatment, as one would expect from a much younger skin cell; and the TCR treated skin cells performed better than their untreated kin in an in vitro assay measuring wound healing. The first change, in the context of the human body, could afford treated skin cells the ability to better maintain the integrity of the skin’s structure, potentially restoring it. The second change indicates that TCR-treated cells could speed up the healing process in the skin of older patients; this could be used in the treatment of abrasions, burns or cuts.

How is the industry responding?

From start-ups to big pharma, longevity has attracted a lot of attention in the industry. Altos Labs, with Jeff Bezos being one of their most high-profile investors, is a US-based start-up and likely the most notable in the anti-ageing field: Altos have secured $3 billion in capital. Currently there are two key areas of research for Altos, and they both relate to different aspects of epigenetic clocks: first, is enhancing our understanding of what epigenetic clocks actually capture, and how the epigenetic changes are related to subsequent changes in cellular state and tissue functioning; second, on the other end of the spectrum, is learning what factors actually drive the changes to these epigenetic clocks. 

Retro Biosciences is another exciting company which recently secured $180 million in funding from Sam Altman, OpenAI’s new (and old) CEO. They are focusing on cellular reprogramming techniques, autophagy and plasma-inspired therapeutics to combat ageing with a goal of extending human healthspan. In their words, they want to “add 10 years to healthy human lifespan”. 

Outside of the start-up realm, rapamycin, an antibiotic named after Rapa Nui (or Easter Island), where it was first found, has caught a lot of media attention. Historically, it has been used as an immunosuppressant to prevent transplant rejection. More recently, however, it has received widespread attention as a potential anti-ageing medicine which inhibits a kinase associated with ageing and senescence-associated diseases, called mTOR. At the time of writing, the third and largest trial of rapamycin in the ageing context (called the Test of Rapamycin in Aging Dogs, or TRIAD), is currently underway, with 580 dogs being given a low dose of the medicine (or a placebo) for a year, with two years of monitoring thereafter.

Ageing and disease have a complex relationship: the hallmarks of ageing contribute in different amounts to the broad array of diseases promoted by ageing. Each of these diseases will require careful consideration and extensive research, so the immortality that Bryan Johnson is seeking might not be an imminent reality; however, tools such as TCR better equip us in understanding and hopefully combating ageing-related diseases. There has been a healthy amount of investment into this field recently, and we expect this will continue to fuel innovation over the coming years.

With a globally ageing population, this field will no doubt become increasingly popular and important. We look forward to seeing what innovations lie ahead – they might even give us all the chance to live as long as a billionaire!

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^{1 These figures are from the 2020 Cancer Diagnoses (incidence) data tables hosted
by NHS Digital, and exclude non-malignant melanoma, here}

^{2 Details of the Reik Group’s work can be found here}