The Goal of Using Stem Cells to Repair the Aging Brain

Some aspects of aging cannot be repaired through the use of therapies that manipulate or deliver stem cells. Accumulations of metabolic waste that the body cannot break down occur both inside and in between cells, for example. Growing levels of DNA damage, both nuclear and more importantly mitochondrial, also cannot be addressed with stem cell treatments that look much like today's transplant therapies. This still leaves many secondary consequences of aging that can be partially repaired by inducing temporarily enhanced regeneration in an old individual, however. Joint and heart tissue damage are perhaps the most obvious, but there is a much longer list of benefits to be realized even using comparatively crude stem cell transplants.

Eventually the successors to today's treatments will provide more comprehensive fixes to the issues of aging stem cells. At present they are temporary patches that do little to address the root causes of dysfunction - and so the mechanisms of aging will proceed to eat away what has been shored up at an ever faster rate. But treatments in the foreseeable future will provide wholesale replacement of worn cell populations, such as the age-damaged cells of the immune system, or renewal of specific populations of stem cells to restore tissue maintenance to something closer to youthful levels, organ by organ. There will also be a move beyond cell transplants towards efforts to reprogram or signal existing cells in order to alter their behavior. These treatments will provide a more lasting bulwark against aging, though without other forms of repair therapy to achieve such goals as clearing metabolic waste and repairing DNA damage, this too will be broken down all too quickly.

The stem cell research field is admirably focused on repair of age-related conditions. Much of the future revenue of this field depends on producing effective regeneration in the old, as the aged suffer almost all of the conditions that are most obviously treated with stem cell technologies. Thus the research community must find ways to make these treatments work and work well in aged individuals. The dynamics of the situation forces researchers to get to grips with the nature of aging insofar as it impacts stem cell function.

Here a researcher considers the work that must yet be accomplished in order to produce means of reliably manipulating the stem cells present within an individual's brain. The goals here include spurring greater feats of repair and regeneration, or the creation of a larger stream of new brain cells to make up losses due to age and injury.

Endogenous stem cells for enhancing cognition in the diseased brain

Adult neural progenitor cells or neural stem cells (NSCs) persist in the adult human brain [and] some brain regions display an unexpected capacity for newborn neuron migration and survival. Several milestones need to be achieved prior to considering functional repair [in the brain through use of NSCs]. These include, but may not be limited to:

(1) Understanding the mechanisms leading to NSC quiescence and loss with aging. Several mechanisms are involved in the different regulatory steps of NSC self-renewal and loss. We will emphasize some of the mechanisms leading to NSC loss with aging. Once these mechanisms are identified, we should be able to amplify the pool of NSCs and direct their differentiation.

(2) Identifying the molecules responsible for fate determination of NSCs and their daughter cells to generate glia or neurons of different types, including interneurons and long projection neurons.

(3) Determining the inhibitory molecules that make the adult brain resistant to repair. Some repair has been reported in the cortex of rodents, but it is abortive possibly due to an unfriendly environment.

(4) Finally, although we can genetically manipulate NSCs in rodents, it is a different issue in humans. Delivery systems need to be improved. Each of this point is further discussed below.

Despite the hurdles outlined above and the length of time that will be required for achieving brain repair and cognitive enhancement, we cannot fail to pursue our investigations of the four fields outlined above. Overall, the present energetic study of stem cell biology and brain delivery systems will provide a better understanding of brain development, endogenous responses to injuries, and additional therapeutic approaches for brain repair, and hold great promise for broadening the therapeutic options available for maintaining and restoring cognition following brain injury and during neurodegenerative diseases.


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