The Yamanaka factors (four proteins, abbreviated OSKM) are a treatment that can completely reset any ordinary, functional cell into a pluripotent stem cell, able to regenerate tissues of any type. In the process, the cell loses epigenetic markers of age and reverts to an embryonic state. But differentiated cells are differentiated so they can be functional. Taking them all the way back to stem cells destroys their function. Remarkably, differentiated cells can be taken part-way back, becoming younger but not losing its functional identity. This has been done with pulsed doses of OSKD or with just three of the four factors, OSK. Last year, the Harvard laboratory of David Sinclair reported success rejuvenating the aged retinas of mice with this process.
Rejuvenating a whole body in this way is impractical. Precisely controlling the dosage and the timing of OSK to each cell cannot be achieved outside a Petri dish. To make matters worse, some of the treated cells have a tendency to grow into tumors.
Sinclair has been searching for other chemicals (besides the Yamanaka factors) that might have a rejuvenating effect at the cellular level without risking cancer and without problematic sensitivity to dosage and timing. With modern, computerized laboratories, it is practical to test thousands of chemicals shotgun-style in separate cell cultures, automating both the delivery of chemicals and the measurement of outcomes.
Recently, Sinclair reported the results of this process: Of the many combinations assayed in his shotgun experiments, six were identified that successfully rejuvenated cells in culture without the cells losing their identities and without causing cancer. “Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.”
This sounds like breakthrough science. Let’s look more closely.
What is the evidence that the cells are rejuvenated?
The new Sinclair article cites two lines of evidence
- Nucleocytoplasmic compartmentalization (NCC)
- An aging clock based on which genes are being transcribed
NCC was a new idea for me. There are certain proteins that belong in the nucleus, and they tend to leak into the surrounding cytoplasm as one sign of aging in the cel.
Aging clocks based on transcription are a promising idea but not as well developed as methylation clocks.
Maybe I’m too suspicious, but I’m inclined to ask: Why didn’t Sinclair choose one of the well-established, validated aging clocks as a target, for example the robust Horvath multi-tissue or multi-species clocks? If he was going to use a transcriptomic clock, why did he have to invent a new one, rather than use Lehalier’s clock? If he was going to introduce a new clock, why wouldn’t he validate it by reference to established aging clocks?
I wonder if there is an untold history of this research, in which the Sinclair lab tried and failed to rejuvenate cells as measured by the more conventional aging clocks.
Aging is not cell-autonomous
In different laboratories, aging research has been pursued via two pathways: top-down and bottom-up. Top-down researchers are looking for central coordination of the age state of the body, broadcast probably via signal molecules in the blood. (Michael Levin thinks that it may also occur through persistent patterns of electrical voltage.) Bottom-up researchers are looking for ways that individual cells lose focus and function with age.
The deep problem with Sinclair’s approach is that it derives from an overly reductionist perspective. Aging of the body is reduced to aging of individual cells. Aging of cells is understood as a blurring in the precision chemistry that the cell relies on for optimum health.
Other researchers (including the Conboys, Harold Katcher, and Izpisua Belmonte) are pursuing the top-down approach to rejuvenation, based on a paradigm in which aging is coordinated systemically, and not controlled at the cellular level. Interventions are in the bloodstream, through which biochemical signals transmit information about the age state of the body.
Sinclair repeats without qualification his prejudice that “aging is a loss of epigenetic information.” He cites his previous experiments as support for “the idea that a loss of epigenetic information, resulting in changes in gene expression, leads to the loss of cellular identity.” But we have learned that methylation changes and other epigenetic changes with age are a redirection as much as a loss of information. Some of the changes are predictable and programmed, and, indeed, the idea of a methylation clock depends on the regularity of methylation changes.
For the future
I like Sinclair’s idea for high-throughput screening of rejuvenation molecules. I would add that combinations should be tried after the first step of identifying promising single candidates. The example of OSKM demonstrates that combinations are able to achieve what no single chemical can do alone. In the discussion section, Sinclair indicates that his lab is already doing this, and that the work is guided by an investigation of the mechanisms of action of the chemicals that his screening procedure discovered.
The present work was done with human fibroblasts (cells from connective tissue) and the discussion section mentions that ongoing work to repeat the test with cells from other tissues. The screening procedure requires the extensive laboratory resources that Sinclair is able to command.
A consistent theme in my work is that aging is evolved, programmed, and centrally coordinated. I’ve cited diverse evidence for this, based on observation, not theory. As a paradigm to guide anti-aging research, there is an additional reason to research central control rather than cell-autonomous interventions. That is that engineering the rejuvenation of every cell in the body is a daunting task. In contrast, if aging is centrally controlled and communicated via biochemical signaling, we can expect that modification of the signaling environment ought to be far more accessible goal.