Parkinson's Disease in the SENS View of Damage Repair

The Strategies for Engineered Negligible Senescence (SENS) is a view of aging as accumulated damage. Drawing from the extensive scientific literature on aging, the originators of SENS created an outline of the forms of cell and tissue damage that are fundamental causes of aging, in that they occur as a natural side-effect of the normal operation of our cellular biochemistry. So we might consider the loss of vital cells due to declining stem cell function, mutations to nuclear DNA and mitochondrial DNA, cross-linking of vital molecules in the extracellular matrix, accumulated metabolic waste in long-lived cells, generation of amyloids from misfolded proteins, and the accumulation of senescent cells, for example.

These forms of damage accumulate to cause other, downstream forms of damage and dysfunction that, collectively, give rise to degenerative aging and age-related mortality. Aging is a very complex in its details, but only because cellular biochemistry is very complex. Complex systems malfunction in response to damage in complex ways, but the root causes of aging, the forms of damage noted above, are much less complex and thus much easier to visualize, describe, and intervene in.

Because SENS specifies the forms of damage in some detail, it also describes what needs to be done in order to reverse the progression of aging: repair the damage. Removing damage that is disruptive to cell and tissue function allows cell and tissues to improve their function and restore a more youthful environment. That said, there are all too few examples in which an author picks a specific age-related disease and breaks down its pathology into SENS terms. Today's article does that for Parkinson's disease, and notes that multiple different forms of damage are significant in driving its progress, is the case for near all age-related conditions. Any one narrowly focused rejuvenation therapy that addresses only one form of damage will improve matters only somewhat. It won't solve the whole problem. The SENS view of medical development inevitably leads to the development and use of many different therapies in combination.

Repairing the Damage to Shake Off Parkinson's

While most aging people don't suffer clinically-diagnosable Parkinson's, it's unsettlingly common to be afflicted by what are called "mild parkinsonian signs" or "Parkinsonism:" about one in six people ages 65 to 74, nearly one-third of those 75 to 84, and over half of those 85 and older. In addition to having to live with less severe versions of many common symptoms of Parkinson's itself (see below), people with Parkinsonism are at roughly double the risk of death in any given year as people the same age without it. Scientists have made exciting progress against Alzheimer's disease recently, with two new AmyloSENS therapies having proven themselves in clinical trials and more benefits and insights continuing to roll in. So it's a good time to take stock of where we are with cellular and molecular aging damage-repair therapies that would prevent and reverse the second most common neurodegenerative aging disorder.

The most visible symptoms of Parkinson's, and the ones on whose basis people are diagnosed with the "disease," are what are called the "motor symptoms." These symptoms result from the progressive loss of - and damage to - a specific population of neurons located in an area of the brain called the substantia nigra pars compacta (SNc). There is enough built-in redundancy in the SNc that we continue losing these "dopaminergic" neurons for decades without any obvious problems. But once our supply of these neurons dwindles to beneath the "threshold of pathology," we can no longer make these fine adjustments to the movement-control signals, and the motor symptoms of Parkinson's subvert the movement of our faces, hands, and bodies. The rejuvenation biotechnology solution to this problem is to repair the damage by replacing the lost neurons. The good news is that scientists have been working on dopaminergic neuron transplantation for longer than any other kind of true cell replacement (RepleniSENS) therapy. BlueRock Therapeutics uses proprietary bioprocessing to create stable master cell banks of what they call "universal iPSCs," which they have found to be compatible with the immune system of any patient. BlueRock scientists then differentiate these cells into dopaminergic neurons for transplant into the brains of people with Parkinson's. They recently reported positive safety results from a Phase I trial.

Our brains accumulate aggregates comprised of the protein alpha-synuclein (AS) as we age, both inside and between our neurons. People suffering from diagnosed Parkinson's and closely-related neurological aging disorders bear especially high burdens of these aggregates. Fortunately, researchers are currently running clinical trials to test numerous AmyloSENS therapies to clear AS aggregates located outside of cells. Most of these trials are in Phase II. Unfortunately, no one has yet developed LysoSENS therapies to target AS aggregates inside the cell, and it's these intracellular AS aggregates that likely inflict the greatest harm. The main reason for this seemingly backward prioritization is that it's not obvious how you would target AS aggregates inside cells. Fortunately, there is a potential path forward. Several years ago, researchers reported on a novel way to smuggle antibodies into cells intact. If researchers could instead send in catalytic antibodies (catabodies) that would chop pathological aggregates into tiny pieces inside the cell. SENS Research Foundation scientists are working to develop this intracellular aggregate-targeting catabody approach right now.

As we age, a small percentage of long-lived cells that don't divide (such as neurons and muscle cells) get completely taken over by mitochondria that have suffered the loss of huge chunks of their DNA. And of all the cells in the body, the cell type that is most susceptible to this hostile takeover is the critical population of dopaminergic neurons whose loss is central to Parkinson's. It's not clear what the connection is between these DNA deletion-bearing mitochondria and the loss of dopaminergic neurons with age, but it seems safe to assume that even if they don't kill their host neurons, deletion-bearing mitochondria sweeping across the cell leads to an energetic brownout that makes any surviving neurons less effective. The MitoSENS lab at SENS Research Foundation is working to develop three different platform technologies (including the original MitoSENS strategy of allotopic expression) to prevent, replace, or bypass mitochondrial DNA mutations.

Astrocytes are a kind of cellular butler for brain neurons, serving them energy sources and keeping their environment orderly so they can do their job. But like many cell types, astrocytes can turn senescent with age in response to many kinds of stress and injury. Researchers have reported that the brains of people with Parkinson's have a higher burden of senescent astrocytes than do people the same age who are free of the disease. To see if senescent astrocytes were really driving Parkinson's-like degeneration in living mammals, the researchers conducted an experiment using mice in whom they could destroy senescent cells at will. Scientists had engineered these mice with ApoptoSENS "suicide genes" that would detonate in senescent cells anytime the scientists "pulled the trigger" by treating them with a drug that activates the genetic system. They treated one group of these Parkinson's-like mice with the drug that would activate the ApoptoSENS "suicide genes" in any senescent cells they might harbor, while leaving another group of Parkinson's mice untreated for comparison. The control Parkinson's mice suffered a massive loss of dopaminergic neurons, developed movement problems that stand in for the symptoms of Parkinson's, and lost much of their ability to generate new neurons elsewhere in the brain. But much of this damage and dysfunction was prevented when researchers gave Parkinson's mice an ApoptoSENS treatment.

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