Today's materials are a helpful overview of the brace of biotech companies working to slow or reverse aspects of mitochondrial aging. Mitochondria play a central role in core cellular processes and are important in degenerative aging. Every cell contains a herd of hundreds of mitochondria, the descendants of an ancient symbiosis between the first cells and bacteria that could help them survive. Each mitochondrion contains one or more copies of mitochondrial DNA, a small remnant of the original bacterial genome, just a few genes that evolution has yet to move to the cell nucleus. The mitochondrial population of a cell is dynamic: constant fission, fusion, swapping of protein machinery, and destruction by the quality control process of mitophagy when worn and damaged.
While mitochondria have many roles, their primary task is the packaging of the chemical energy store molecule ATP. This powers cellular operations, but its production is an energetic process by that produces a flux of oxidizing molecules as a byproduct. These molecules damage protein machinery in the cell via oxidative reactions, a form of damage that is constantly repaired, and which cells maintain antioxidant defenses to minimize. At low levels this is a beneficial signal for the cell to engage in greater repair efforts. At high levels it harms a cell.
There are several classes of mitochondrial problem that emerge with age. Firstly ATP production is reduced. Mitochondrial dynamics change: mitochondria become resistant to mitophagy, and falter in their tasks. Secondly, these changes also result in a greater production of oxidative molecules. Thirdly, mitochondrial DNA is less well protected and repaired than nuclear DNA, and some forms of mutational damage can produce malfunctioning mitochondria that outcompete their functional peers, taking over cells. This converts healthy cells into pathological exporters of oxidative molecules, damaging surrounding tissues through a range of related mechanisms. These include raised levels of oxidized cholesterol molecules in the bloodstream, contributing to the development of atherosclerosis by encouraging dysfunction in the macrophage cells responsible for keeping blood vessel walls clear of atherosclerotic lesions.
Something should be done about mitochondrial dysfunction in aging and age-related disease. It is very clearly implicated in the onset and progression of numerous age-related conditions. Numerous approaches are under consideration, with varying degrees of expected utility and progress towards availability. NAD+ upregulation, for example, attempts to correct one of the many observed changes in mitochondrial biochemistry. As presently practiced, using vitamin B3 derivative compounds, it is most likely less effective than structured exercise programs at achieving its goal. At the other end of the spectrum lie advanced biotechnologies in the early stages of development, such as copying mitochondrial genes into the cell nucleus via gene therapy in order to make mitochondrial DNA mutation irrelevant to aging. A great many other approaches lie between the two.
In this newsletter, we're going to take a look at all the longevity biotech companies that are developing therapies that target mitochondrial dysfunction - one of the "Hallmarks of Aging". Mitochondria companies make up one of the biggest subcategories in longevity biotech. This makes sense as mitochondria are an extremely critical component of our cells. There are ~20+ longevity mitochondria companies currently, ranging from early stage-startups to Nasdaq-listed public companies. From small molecule drugs to gene therapies and mitochondrial transfusions. Seven of the companies are in clinical trials today.
Aging is not an accepted clinical indication (yet). So the current playbook for longevity biotech companies is to target a disease that shares the same underlying cause as one of the hallmarks/targets of aging for their first clinical trials and expand from there. Usually, this means an age-related disease or a rare genetic disease. Mitochondrial dysfunction is implicated in many diseases of aging. Longevity companies targeting mitochondrial dysfunction generally choose clinical indications such as: mitochondrial diseases caused by mitochondrial DNA mutation or nuclear DNA mutations (LHON, Pearson syndrome, etc), muscle dystrophy diseases or muscle loss (Duchenne muscular dystrophy, Becker muscular dystrophy, sarcopenia), metabolic disorders (NASH, Obesity, NAFLD, Type 2 Diabetes), neurodegenerative disease (Alzheimer's, Parkinson's, etc), or conditions linked to oxidative damage (ischemia-reperfusion injury).
Mitochondria are complex. It's still an open question on how they drive aging. Hallmarks of Mitochondrial Aging? Mitochondria have their own DNA, membranes, ribosome, move around (sometimes outside of the cell!), undergo fission and fusion, and provide one of the most critical cellular functions. Since they are almost like their own organism they probably deserve their own "Hallmarks of (Mitochondria) Aging" paper. But just like the original Hallmarks paper, it will be filled with many correlations and questions while causation is not always clear.
Mitochondrial transfer is very promising. I'll admit I am biased towards replacement therapies for anti-aging when it makes sense. It's a clean philosophical approach that lends itself to engineering more than traditional drug development. And unlike stem cell therapies or cellular transplants mitochondria can be replaced easily without the need for extracellular scaffolding or any kind of extra in situ differentiation. There will likely be a number of challenges to work out, though (sourcing allogeneic mitochondria, systemic distribution, determining long-term side effects, etc). One caveat: It is possible that transplanting healthy mitochondria into an old and dysfunctional cellular environment will quickly impair the transplanted organelles. Also, we need to consider the microtubules mitochondria use to move around the cell.
Protect mitochondrial DNA or remove mutations? GenSight Biologics is definitely one of the most interesting biotech companies I have ever stumbled upon. And while their therapies aren't considered anti-aging at the moment (save for GS020 for dry AMD), the technology is a step towards possibly solving the problem of mitochondrial mutations. But even here it is not clear whether it is more important to protect mitochondrial DNA from new mutations or stop already mutated mitochondrial DNA from accumulating via clonal expansion (like Shift Bioscience). Some researchers have also proposed using various DNA editing techniques (TALENS, Zinc Finger Nuclease, CRISPR) to destroy mutant mitochondrial DNA.