Fight Aging!

Ultimately, we live and die as the brain lives and dies. The rest of the body is a support system, a complex one to be sure, but probably not as complex as the brain. Repairing the cell and tissue damage of aging in the body seems a more tractable challenge, in that replacement is always an option. Replace cells, replace the gut microbiome, add new tissues grown in a lab to organs like the liver and thymus, or grow a new body and transplant the brain. A path of ever increasing control over cells, cell signaling, and regeneration implies a future in which all damaged tissue can be replaced in one way or another ... except for the brain, because the fine structure of brain tissue encodes the data of the mind. Here, a different solution is needed.

Today, of course, researchers understand all too little of the details. Medical biotechnologies are simple, barely at the stage of manipulating one gene or protein interaction at a time, unable to deliver therapeutics to only and exactly the cells that we want to affect, a search for points of intervention in which a change cascades in ways that are more rather than less favorable, discarding the many points of intervention that the present state of the art cannot influence. This will change, the future is golden, but it is worth looking at continued efforts to understand the fine details of aging in the brain with this in mind. The goal at the end of the day is a way to repair all of the biochemistry of the brain in situ, without loss of the data of the mind. How exactly that will be accomplished remains to be determined.

The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration

Currently, various treatment strategies are being investigated to slow or reverse ageing-associated diseases; unfortunately, no preventive or effective treatments have yet been identified. The major challenge associated with this process, thus far, remains the lack of highly efficient disease models of neurodegeneration. In this review, various ageing hallmarks were discussed, most of which have been associated with neurodegenerative diseases.

We propose that future studies of neurodegenerative diseases should focus on these hallmarks of ageing and that ageing models should be developed that show neurodegenerative disease phenotypes. Although this paper primarily focused on DNA damage, cellular senescence, and mitochondrial dysfunction, studies examining the relationships between the nucleus and mitochondria would reveal the mechanistic links between ageing and neurodegeneration. Other hallmarks, such as proteostasis, epigenetic deregulation, and telomerase inactivation, are also important. The loss of proteostasis results in proteasomal and autophagy defects in both Alzheimer's disease and Parkinson's disease, resulting in inflammation and senescence. Metabolic dysfunction has been shown to be associated with mitochondrial dysfunction, oxidative stress, and NAD+ levels.

Although cross-talk between inflammatory pathways and neurodegeneration has been recognized for the past two decades, very few therapeutic strategies have emerged from this line of research due to the lack of a high-throughput screening platform. To harness the therapeutic potential of inflammatory pathways, a better understanding of the neuroprotective role played by TNF-α and NF-κB remains necessary, and new models must be developed that are able to recapitulate microglia-induced neurodegenerative phenomena in vivo. However, neurodegenerative diseases are complex to decipher, and their central mechanisms are further complicated by the interactions that occur between genetic and environmental factors, which drive disease progression. A single-pathway-oriented therapeutic intervention might not be sufficient for the treatment of these complex disease, although combination therapies may be successful.

Identifying functional links between neurodegenerative diseases and ageing hallmarks could reveal new therapeutic avenues. A multi-target, evidence-based approach associated with non-pharmacological approaches, such as lifestyle modifications, may slow neurological disease progression in older individuals.