Fight Aging!

The materials here report on efforts to screen for small molecule compounds that can reduce the age-related decline of mitochondrial function observed in neurons - and indeed throughout the body. Screening the contents of compound libraries is a process that might sound simple, and conceptually it is, but it is a complex task to build a cost-effective system and supporting logistics to screen for a novel outcome. In this case the outcome is a reversal of at least some degree of reduced mitochondrial function in neurons from old tissue, as well as improvement in important aspects of neural function.

Every cell contains a herd of a few hundred mitochondria, the distant descendants of ancient symbiotic bacteria, evolved to become fully integrated component parts of the cell. They still replicate like bacteria, can fuse and split and pass around pieces of their protein machinery, and contain a small remnant genome. Mitochondria have many roles, but are primarily responsible for producing adenosine triphosphate (ATP), chemical energy store molecules that are used to power cellular processes. This is a fairly energetic activity that has the side-effect of producing reactive oxidative molecules that damage cell structures; in a normal, youthful metabolism this is entirely compensated for by repair processes, and is in fact used as a signal. For example, it enables some of the benefits of exercise by linking increased energy production to increased cell maintenance and muscle tissue growth. Age-related disruption of ATP production is particularly important in energy-hungry tissues such as the brain and muscles. Less energy means loss of function, and in the case of the brain that contributes meaningfully to the progression of neurodegenerative conditions.

The evidence of recent years suggests that the proximate cause of the problem is changes in gene expression that impair the balance between mitochondrial fission and fusion, which in turn promotes the presence of large and damaged mitochondria that are challenging for the cellular maintenance process of mitophagy to recycle. Everything goes downhill from there. Approaches such as mitochondrially targeted antioxidants and NAD+ upregulation, both shown to modestly slow aging in laboratory species and improve tissue function in human trials, may produce their benefits in large part because they change mitochondrial behavior in ways that allow mitophagy to function more efficiently, clearing out damaged and dysfunctional mitochondria.

Compounds protect brain cells' energy organelle from damage linked to Alzheimer's, ALS, Parkinson's

A new screening platform has enabled scientists to discover a set of drug-like compounds that may powerfully protect brain cells from dangerous stresses found in Alzheimer's and other neurodegenerative diseases. The screening platform allows researchers for the first time to rapidly test libraries of thousands of molecules to find those that provide broad protection to mitochondria in neurons. Mitochondria are tiny oxygen reactors that supply cells with most of their energy. They are especially important for the health and survival of neurons. Mitochondrial damage is increasingly recognized as a major factor, and in some cases a cause, for diseases of neuronal degeneration such as Alzheimer's, Parkinson's, and ALS.

The scientists, in an initial demonstration of their platform, used it to rapidly screen a library of 2,400 compounds, from which they found more than a dozen that boost the health of neuronal mitochondria and provide broad protection from stresses found in neurodegenerative disorders. The researchers are now testing the most potent of these mitochondria-protectors in animal models of Alzheimer's, amyotrophic lateral sclerosis, and other diseases, with the ultimate goal of developing one or more into new drugs. "It hasn't yet been emphasized in the search for effective therapeutics, but mitochondrial failure is a feature of many neurodegenerative disorders and something that must be corrected if neurons are to survive. So I'm a big believer that finding mitochondria-protecting molecules is the way to go against these diseases."

Neuron-based high-content assay and screen for CNS active mitotherapeutics

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from amyloid-β toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria.

The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.