Fight Aging!

The Methuselah Foundation has a record of seed funding early stage biotech and medical companies that are undertaking novel work that is (a) relevant to aging or tissue repair and (b) not already in progress to any meaningful degree elsewhere. Funding startups is one way to push forward the state of the art, providing support for research that is almost at or just past the point of initial technology demonstrations in the laboratory. The list of companies funded by the Methuselah Foundation includes the bioprinting company Organovo, an investment that has paid off handsomely in all senses of the phrase, and more recently Oisin Biotechnology, a new initiative focused on senescence cell clearance. The latest investment, announced a few days ago, is focused on getting to an answer on a novel approach to therapies for Alzheimer's disease:

Could a New Approach to Alzheimer's Move Us Closer to a Cure?

Leucadia Therapeutics LLC, a biotechnology company focused on treating and preventing Alzheimer's disease, using patent-pending technology to correct the cause of the disease rather than its effects, and Methuselah Foundation, a public charity incentivizing innovation in regenerative medicine, today announced a joint partnership to develop a novel therapeutic strategy to treat Alzheimer's disease. The company will use this investment to accelerate development of novel therapy with the goal of beginning clinical trials in 2018.

Leucadia Therapeutics Chief Scientific Officer, Douglas Ethell, Ph.D., said, "This is an exciting event for LT as it frees us from fundraising and allows us to focus our efforts on getting into the clinic as soon as possible." Under this agreement, the Methuselah Foundation has made an equity investment in Leucadia Therapeutics LLC. Over the next 3-5 years, Leucadia will develop and test a novel therapeutic device to treat the underlying cause of Alzheimer's disease.

As you can see the release provides no scientific details, but that's fine - information is available elsewhere. The scientist leading this effort, Douglas Ethell, has a background in dementia and stem cell research, and gave a talk on the underpinnings of his new approach at Rejuvenation Biotechnology 2015 entitled "CSF Hydrodynamics at the Cribform Plate: Has the Cause of Alzheimer's Disease Been Under or Over Our Noses All Along?" Unfortunately the video and abstract for this presentation are not yet published online, but we can instead look at a 2014 paper in which Ethell outlines the evidence for his hypothesis that Alzheimer's is caused by an age-dependent decline in drainage of cerebrospinal fluid through narrow passages in the head, a process that may normally assist in removal of unwanted metabolic waste - such as the amyloid associated with Alzheimer's disease.

Disruption of Cerebrospinal Fluid Flow through the Olfactory System May Contribute to Alzheimer's Disease Pathogenesis

Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-β (Aβ) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal submucosa.

Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Aβ removal from those areas - among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis - all of which have been linked to AD risk.

I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Aβ oligomers and other metabolites from the MTL.

Ethell is not the only researcher providing evidence for this sort of idea, that the failure of drainage channels for cerebrospinal fluid is important in the development of dementia, and that these failures are essentially mechanical and structural issues in the same way as, say, stiffening of blood vessels is a mechanical and structural issue. Underlying cellular problems that involve the accumulation of forms of biochemical damage are what give rise to these mechanical and structural failures, but then the proximate issue that causes disease is that the system of tissues no longer pumps or flexes or drains fluid correctly. There are similar hypotheses for the declining integrity of the choroid plexus, a filtration system for cerebrospinal fluid, to be a proximate cause of Alzheimer's disease. It is certainly the case that amyloid levels in the brain appear to be dynamic on a short timescale; there is a lot of support for the view of Alzheimer's disease as the result of a slow failure of a constant, ongoing clearance of metabolic wastes rather than a slow accumulation of metabolic wastes with little clearance.

One of the good points about the failing drainage hypothesis is that it is comparatively cheap to test, and that test is what the Methuselah Foundation is buying here. Any way to restore the declining mechanisms involved, even if forcing the situation without repairing the underlying causes, will suffice for that test. If it the resulting treatment leads to reduced levels of metabolic waste in the brain, which should happen fairly rapidly if those waste levels are dynamic on a short time scale, then the hypothesis is correct. If it doesn't, then it is probably incorrect. This is medical science at its best and most practical.