A Little Research on the Metabolism of the Aging Brain

The brain is enormously complex, and as is true of almost every aspect of metabolism there is far more left to map than is already known. The entirely of the knowledge of human biochemistry is really just a sketch of the starting points for further exploration. The final finished catalog of everything there is to know about how a baseline human functions and ages will be truly vast in comparison to today's databases. Building this catalog will be the work of decades yet, even given the rapid and accelerating pace of progress in biotechnology. This is why many researchers believe that little meaningful progress is possible in the near term towards treating aging and extending healthy life spans. To their eyes the process of development is to first achieve a much greater understanding of how exactly every relevant cellular mechanism changes during aging, and then build ways to alter the operation of aged metabolism based on that new knowledge. This is not a short term vision, and making any meaningful progress will be a slow and expensive undertaking.

This state of affairs is exactly why we need more proactive shortcuts based on an engineering approach to medicine and aging. A great deal is in fact known, proven, and hypothesized with reasonable evidence when it comes to the cellular and molecular damage that causes aging. There is a solid list of the types of damage involved, a list finalized more than twenty years ago with no new additions since then even in this period of great progress in biotechnology. Thus it is reasonable to think it is fairly complete. If researchers develop means to repair that damage, then knowing how exactly the damage interacts and progresses - with great complexity - to cause aging becomes much less important. This is how the engineering approach works: you build using present knowledge where it is cost-effective to bypass the need to gain further knowledge. You won't win all the time, but it is a strategy that should produce far better results in the near term. There is every reason to hurry development of treatments for degenerative aging, given that the cost of delaying a day in the effective treatment of aging is more than 100,000 lives lost.

Here are two examples of the sort of research presently underway into the unmapped areas of brain biochemistry relevant to aging. These are very thin slices of a vast field of science:

Neuropeptides and Aging: Breaking the Signaling Barriers Within the Body

The complexities of the brain are still largely unrevealed. Associations between neuronal decline with age and the onset of disease have been identified, but the specific mechanisms that regulate this decline are still unknown. Between neuron morphological changes, alterations of neuronal signals, and accumulation of protein masses in various brain regions, the realms of research are far and wide. As brain functions are responsible for approximately 20% of the body's energy usage, further understanding of neurological function is essential for ensuring a longer and healthier life.

Neuropeptides are responsible for communicative signals between neurons and other regions of the body. Neuropeptide signaling changes with age, and frequently these changes induce detrimental effects in neurons. They are packaged in large dense core vesicles and cleaved by enzymes at each end to reach their mature forms, which then interact with G protein-coupled receptors to induce signaling. These receptors can be local, but may also be found in other regions of the body, which means that malfunction in a given neuropeptide's production or transport can result in dysfunction in multiple systems.

Interestingly, levels of the neuropeptide oxytocin are decreased in old mice plasma. Furthermore, knocking out oxytocin can diminish the formation of new muscle fibers upon injury induction, providing evidence to the possibility that age-related decreases in oxytocin can cause an age-related inability to regenerate muscle. Another neuropeptide that decreases with age is gonadotropin-releasing hormone (GnRH1), which is linked to inflammation and the stress response. Injection of GnRH1 into the brains of older mice restored neurogenesis in the hippocampus (the memory-forming center of the brain), which is a process known to decrease with age. The effects of altered neuropeptide levels can be profound, as is seen in the example of montane and prairie voles. Differing levels of vasopressin and oxytocin result in drastically differing social patterns, despite similar genetics between the two species. Such subtle differences in the regulation of neuropeptides are just an example of why it's important to understand how alteration in neuropeptide signaling with age can contribute to a potential decline in health.

The Aging Brain: Synaptic Regulation and Aging

Our brain is constantly changing, adjusting to the environment based on input. At the same time, there seems to be mechanisms in place to resist change. At the junctions between neurons and their targets, known as "synapses", there are mechanisms to ensure that the amount of signal sent from neurons and the sensitivity of the target cells are in constant balance. There is increased interest in how this homeostatic mechanism changes with age, as disruption in synaptic homeostasis may be causal to disease. Hence it may be possible to increase lifespan via interventions that restore optimal activity of synapses.

Involvement of TOR in increasing synaptic function is particularly interesting in light of the association of TOR inhibition and longevity. Disruption of the TOR pathway in yeast, nematodes, fruit flies, and mice increases lifespan significantly. Could the benefits of reducing TOR activity in part be explained by TOR's role in increasing synaptic function? There seems to be an overarching theme of disrupted synaptic function in neurodegenerative diseases, but whether this synaptic dysfunction is causal or consequential is still unknown.


I think that an insight into the aging human brain can help develop therapies that can not only improve the mental health of senior citizens but also reduce the economic burden of geriatric healthcare.

Posted by: Jacky at April 29th, 2015 6:56 AM
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