Fight Aging!

Shift Bioscience is working on a way to improve mitochondrial function in old tissues. Mitochondria, as you might recall, are the power plants of the cell, responsible for producing chemical energy store molecules used to power cellular processes. Every cell has a herd of hundreds of mitochondria that replicate like bacteria and are culled when damaged by the quality control process of mitophagy. Mitochondrial function nonetheless declines with age, and this affects all cell activities. It is particularly relevant to age-related disease in energy hungry tissues such as the brain and muscles, but the detrimental effects are global throughout the body.

Aging degrades mitochondrial function via several mechanisms, and an important one is the loss of quality control, allowing broken mitochondria to overtake cells. Systematically removing those broken mitochondria on a consistent, ongoing basis should be beneficial, but the question has always been how to manage this feat. The present Shift Bioscience candidate small molecule drug enables functional, undamaged mitochondria to better outcompete their damaged peers for the limited supply of proteins needed to function. This can in principle tip the balance back towards healthy rather than dysfunctional mitochondria in a tissue.

You are proposing to search for small molecules that could potentially slow down progression of the epigenetic clock. Can you tell us a little bit more about your drug screening process?

It is very difficult to implement high-throughput drug screening for biological aging, since contemporary assays of biological age are cell based and can take months to complete. This would require millions of cell lines to be maintained in parallel for months, and this is simply too cost prohibitive. To overcome this challenge, we plan to utilize an approach called 'protein interference', where a library of protein fragments is delivered by virus to a population of cells containing a biological age-reporter. Each cell receives a unique protein fragment that may bind to any protein at any position, and through this binding, we could discover peptides that slow down, stop, or reverse biological aging. These protein fragments could be used as therapeutics or guide the design of small molecules.

Many of the hallmarks of aging influence the epigenetic aging clocks; what makes you consider the mitochondria the optimal target for therapeutic interventions?

The discovery of epigenetic aging clocks had particular significance to our company, as they provided the opportunity to audit our key hypothesis (e.g. mitochondrial dysfunction is an important part of aging). To do this, we measured the clock in human cells without a functional citric acid cycle, which severely reduces energy production by mitochondria. This caused a 16-year acceleration of the clock compared to control cells, which, to our knowledge, is the largest acceleration reported.

So far you claim to have identified one family of small molecules that appear to slow the epigenetic clock by at least 50% by restoring mitochondrial function in aged cells. Does this mean that the mitochondria are being repaired or replaced?

In mice, we have preliminary data indicating a deceleration of biological aging by 40% in the brain and 60% in the heart due to the small molecules (as defined by the epigenetic clock). Current evidence suggests that under such conditions, functional mitochondria are able to 'outbreed' dysfunctional mitochondria and become the dominant population. This is an example of overcoming damage by dilution, in contrast to conventional repair.

Cells have the unfortunate habit of favoring mutated mitochondria over healthy ones, and these damaged mitochondria can take over a cell in a relatively short time. How might we prevent the cells from making this poor choice so that they retain their healthy mitochondria?

Though our small molecule approach is closest to clinical development, there are other exciting approaches to combating mutated mitochondria in development. Aubrey de Grey has proposed transferring the mitochondrial DNA to the safety of the nucleus, an approach called 'allotopic expression'. This is not as far-fetched as it might seem, since evolution has already encouraged the vast majority of mitochondrial DNA to transfer to the relative safety of the nucleus. Why not finish off the job that evolution started? The second approach is to deliver endonucleases to mitochondria that specifically target and digest mutated mitochondrial DNA. Researchers have recently validated this approach in mouse models of mitochondrial disease.

So where are you now in terms of development of a therapy and potential human trials?

We are currently creating an enhanced molecule that overcomes some of the limitations of this small molecule family (e.g. they are quickly cleared out of the bloodstream). Once validated in cellular and animal models, we plan to target rare inherited mitochondrial diseases with this enhanced molecule because they provide the fastest route to the clinic.

Link: https://www.leafscience.org/an-interview-with-dr-daniel-ives-of-shift-bioscience/