In this recent interview with Aubrey de Grey touches on a number of areas of progress made by the research and development community in recent years, projects that lead towards rejuvenation therapies based on the Strategies for Engineered Negligible Senescence (SENS). In the SENS view, supported by a very sizable literature accumulated over the past century, aging is caused by underlying processes of damage accumulation. What we think of as aging is a diverse collection of downstream consequences of that damage. Periodically repairing the underlying damage, allowing the normal maintenance of the body to continue as it would in youth, remains the most promising approach to aging. Senolytic drugs to clear senescent cells are one example of a rejuvenation therapy based on SENS, and in animal models senolytics produce very impressive results on near all age-related conditions assessed to date.

Ariel VA Feinerman: Can you name the most big breakthrough in each SENS programme since our interview in 2017?

Aubrey de Grey: Well, let’s see…

RepleniSENS: probably the initiation of a clinical trial in Japan using iPSC-derived dopaminergic precursors to cure Parkinson’s Disease. Other such trials are imminent in the USA.

OncoSENS: definitely the main thing is 6-thiodeoxyguanine, or just THIO for short, which is essential “WILT 2.0″. It turns telomerase into a suicide gene, killing cells quickly, rather than waiting for them to divide into telomere-less oblivion.

ApoptoSENS: I’d say it’s the successful extension of mouse lifespan with a senolytic. It’s a big surprise that just one SENS intervention can have a substantial lifespan effect when initiated late in life.

AmyloSENS: the definitive confirmation that immune therapies can eliminate amyloid in the Alzheimer’s brain. Even though there is basically no cognitive benefit, it’s a very important thing to know for the future, especially for other amyoloids that are more causal.

LysoSENS: definitely the success of our atherosclerosis team in developing a drug to extract oxidative cholesterol from plaques. That has now become a spinout company, Clarity Therapeutics.

GlycoSENS: the spinning-out of another company, Revel Pharmaceuticals. which is developing cross-link-breakers. That was the result of the pioneering work at Yale that we funded for several years.

MitoSENS: the main thing in our team is a new way to increase the amount of protein that our transferred genes make, but also it’s really important that our work over the past few years has gained a lot of respect from mainstream experts who used to think it was never going to work.

Ariel VA Feinerman: Previously you have said that there are two types of epigenetic changes, reversible shift, which is a reaction to the cellular environment, and irreversible noise, which is stochastic. Now researchers claim that epigenetic changes are because of double strand breaks. This type is not shift or noise because this is stochastic and reversible using the Yamanaka factors (OSKM). Can you comment on this?

Aubrey de Grey: The problem is that OKSM doesn’t only eliminate noise – it eliminates (very nearly) all epigenetic marks, whether noise or signal. The only reason it can be therapeutic is because doing just a little bit of that wiping of information seems to be OK – the cell can use the residual signal as a guide to rebuild the lost signal, whereas the proportion of the noise that was also removed is really gone. Sounds good! Except … that in the body (even the young adult) there are a lot of cells that are most of the way to becoming cancerous. These cells are in what we can think of as an epigenetically fragile state: it doesn’t take much to tip them over the edge, because their cell-cycle stabilisation defences are already damaged. So, all in all, I am currently quite pessimistic about the future of OKSM-based rejuvenation.

Ariel VA Feinerman: Is any progress with ALT cancer?

Aubrey de Grey: There has been plenty of progress in the past five years, yes, but not by us – indeed, the progress by others that has led to us deprioritising it. But there is still some way to go to find a generic approach to attacking it. I am optimistic, because ALT basically relies on the maintenance of an unstable equilibrium between DNA damage and repair, which should be vulnerable to other stressors.

Ariel VA Feinerman: How does THIO work? How can we protect stem cells from THIO?

Aubrey de Grey: THIO is a brilliant discovery. It works by turning telomerase into a suicide gene. Specifically, telomerase incorporates it into the telomere, but that disrupts the structure that lets the telomere do its job of preventing the cell’s DNA repair machinery from joining chromosomes together. So chromosomes do get joined together, and that leads rapidly to cell death. Stem cells, even the most rapidly-dividing ones, have such tiny amounts of telomerase as compared to cancer cells that they are not significantly harmed by the dose and duration needed to kill a telomerase-positive cancer.

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