Cell Reprogramming: Emerging Strategy to Extend Lifespan

The longevity research community has been blowing up lately.

On one side, Matt Kaeberlein’s study using rapamycin in companion pets is being carried out. His group’s new UW rapamycin study is also underway, while Nir Barzilai is recruiting for the TAME trial—Targeting Aging with Metformin.

But perhaps the most high-profile story in the longevity field today is the promise of cell reprogramming by ventures such as Altos Labs, a new biotech company backed by Jeff Bezos and Yuri Milner, featuring a who’s who of scientists as its team and advisors, including two Nobel Prize winners: Shinya Yamanaka and Jennifer Doudna.

Shinya Yamanaka shared the Nobel Prize in 2012 for the discovery of the very process that Altos Labs is hoping to leverage: reprogramming of somatic cells to induced pluripotent stem cells (iPSCs).

Soon after, Jennifer Doudna shared a Nobel Prize (in 2020) for her co-discovery of CRISPR genome editing.

With a scientific team equivalent to Hollywood A-listers, everyone is (justifiably) amped about the new direction science is moving in when it comes to longevity research.

And, as a testament to how “hot” the field is right now, the Salk Institute published a new paper in the prestigious journal Nature Aging on 7 Mar 2022, showing that partial long-term reprogramming restored a more youthful epigenetic signature to aging cells and resulted in lifespan extension in a premature aging mouse model.

So in order to understand what cellular reprogramming is, it’s important to learn the history of the Yamanaka discovery, as well as how exactly it was that people started realizing this discovery might mean the potential for cell rejuvenation.

In 2006, a lab located in Kyoto, Japan, headed by Shinya Yamanaka pioneered the iPSC technology, which used four particular genes (Oct3/4, Sox2, Klf4, and Myc) that encode for transcription factors, resulting in the conversion of somatic cells into pluripotent stem cells.

This discovery earned him the 2012 Nobel Prize, which he shared with Sir John Gurdon “for the discovery that mature cells can be reprogrammed to become pluripotent.”

Transcription factors are proteins that control the rate of DNA transcription to RNA. Due to the COVID-19 vaccines, more people are now familiar with messenger RNA (mRNA) and understand that from DNA, you get RNA, you get protein.

In order to make mRNA, DNA must be transcribed, a process that involves transcription factors (TFs).

The Yamanaka TFs are unique, in that once expressed, they turn somatic cells (i.e., any cells of the body which are not reproductive cells) into pluripotent stem cells—cells that have the ability to differentiate into most, if not all, types of cells in the body.

Because these pluripotent stem cells are not actual stem cells at their origin, they were named induced pluripotent stem cells (iPSC) to indicate they were artificially given potency.

So why is there such a hype around induced pluripotent stem cells?

For one, we know that adult stem cells are found in every organ of the body and are used to replenish dying cells and regenerate damaged tissues throughout life. However, the regenerative power of these stem cells appears to decline with age. This is supported by the observation that injuries heal much more slowly in older people than in young ones.

Because the functionality of our stem cells declines with age, therapies that can either rejuvenate somatic stem cells or—alternatively—artificially create fresh stem cells out of somatic cells in the body, are very exciting for longevity researchers.

In essence, what this research suggests is that we could, theoretically, have an unending pool of stem cells to replace damaged or dying cells when needed, thereby consistently reverting us to a more youthful version of ourselves.

If this sounds too good to be true, Altos Labs has raised $3B in funding to test whether cellular reprogramming can, indeed, revert cells to a younger age and therefore have a significant impact on the whole body.

So is there any other evidence to suggest Altos Labs is on to something?

The goals of cellular reprogramming in vivo are complex and potentially difficult to achieve: inducing pluripotency in an entire organism could potentially kill it within days—or turn cells cancerous.

It was therefore a massive surprise when David Sinclair’s lab (Lu et al.) published a paper in the prestigious journal Nature on how reversing age in the eyes of mice by cellular reprogramming restored vision.

The paper made a splash in the scientific community, as more people became aware of the potential benefits of cell reprogramming for longevity.

The ingenious aspect of this paper is that the authors used only three of the four Yamanaka factors, given that one of the transcription factors (Myc) is a proto-oncogene and can therefore promote cancer development.

A Nature editorial written by Stanford neuroscientist Prof. Andrew Huberman broke down the findings of a paper in a very easy-to-follow way.

Even more recently, research conducted by the Salk Institute and published in Nature Aging showed that in vivo long-term partial reprogramming with OSKM altered age-associated molecular changes and rejuvenated various tissues, such as the kidney and skin, as well as the organismal level in mice.

The rejuvenating effects were measured using epigenetic clocks, as well as metabolic and transcriptomic markers, including the expression of genes involved in senescence, inflammation, and stress response pathways.

These ground-breaking results are paving the way for companies such as Altos Labs and Life Biosciences to take it to the next level.

New research suggests it may not be necessary to express OSKM transcription factors in order to induce pluripotency.

A number of labs around the world are experimenting with the use of small molecules (SMs) for cell reprogramming.

A study published in the Aging-US journal used data mining and curation of available data to identify 92 SMs that may lead to induced pluripotency.

The authors categorized the identified molecules into epigenetic modifiers, signaling modifiers, metabolic modifiers, and others.

Some of the most well-known of these molecules include rapamycin, resveratrol, spermidine, caffeic acid, curcumin, epigallocatechin gallate (EGCG), fisetin, quercetin, vitamin A, vitamin C, but also valproic acid (VPA), dexamethasone, and dasatinib, among others.

The goal of future research will be to test whether these molecules, alone or in cocktails, can induce stem cell pluripotency.

It is safe to say that there has never been another period in our history when more people were interested in the study of longevity. With so many eyes on them, researchers are now emboldened and better supported by the research system to study novel aging therapies.

Altos Labs, Calico, Life Biosciences, and many other labs around the world are in a race to “solve aging.”

And while aging may not be something “solvable” after all, the quest for longevity will forever inspire human minds to strive for better, and healthier, lives.

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