Fight Aging!

Neurogenesis is the creation of new neurons from neural stem cell populations and their integration into existing neural networks in the brain, a process thought to be essential to memory, learning, and the limited recovery of the brain from injury. It is presently the consensus position in the research community that neurogenesis does takes place in the adult brain, not just during development, but this hasn't always been the case, and it remains a topic for some debate over the fine details. This is particularly the case because so much of the work relies on data obtained in mice and rats. Obtaining equivalent data from living human brains is challenging, and such data makes up very little of the supporting evidence for the present consensus.

Today's open access paper is interesting on two counts. Firstly, it is one of the few to put numbers to the age-related decline of neurogenesis in any part of the brain. Secondly, the researchers express some of their dissatisfaction with the present state of research into the question of adult neurogenesis, a position that is not uncommon in the scientific community. From their perspective, the small amount of neurogenesis in later life seems insufficient for it to be essential to cognitive functions such as memory. The numbers thus seem to indicate that a greater emphasis should be placed on changes in other processes that alter existing neural networks when it comes to understanding age-related cognitive decline.

Modelling adult neurogenesis in the aging rodent hippocampus: a midlife crisis

Adult hippocampal neurogenesis (AHN) has been a prolific topic of research and discussion for the last 30 years. The possibility of neuron renewal and the underlying promise of regeneration in the context of aging and neurological disease has been an important catalyst for the field that have attracted the attention of researchers, funding agencies, scientific journals, and the public. Due to the obvious limitations to perform studies on the human brain, functional inferences about adult neurogenesis have been collected almost exclusively in rodents, mostly in mice.

The functional relevance of new neurons relies on their distinct physiological properties during their maturation before they become indistinguishable from mature granule cells. Most functional studies have used very young animals with robust neurogenesis. However, this trait declines dramatically with age, questioning its functional relevance in aging animals, a caveat that has been mentioned repeatedly, but rarely analyzed quantitatively. In this meta-analysis, we use data from published studies to determine the critical functional window of new neurons and to model their numbers across age in both mice and rats. Our model shows that new neurons with distinct functional profile represent about 3% of the total granule cells in young adult 3-month-old rodents, and their number decline following a power function to reach less than 1% in middle aged animals and less than 0.5% in old mice and rats.

This acute decline of neurogenesis challenges the notion of a prominent functional role even in young adult animals, but particularly in middle aged and old animals, in which neurogenesis reach very low levels, well below 1% and the ratio of activated distinct functional neurons (here meaning new neurons 4-8-week-old exhibiting the differential physiology conferring them enhanced plasticity and excitability) drops to 3-5%. This functional controversy might be in part explained by experimental bias, as most functional studies have been performed in very young, sometimes adolescent rats and mice when they exhibit peak neurogenesis, disregarding the much lower levels of new neurons present in middle aged and old animals. For the same reason, extrapolation of those data to humans might not be very useful, as there might not be much interest in improving cognition of people in their 10s and 20s when they are in their cognitive prime, while it could be relevant to help people say beyond their 60s and 70s, when hippocampal function might take a hit due to aging or neurological disease.

We think our data provides a realistic framework to describe quantitatively adult neurogenesis in murine rodents, and based on these results, we find very difficult to reconcile - from a computational and from a commonsense perspective - that the low number of distinctly functional new neurons might have an essential role in the variety of functions in which they have been involved, a caveat that needs to be addressed in functional models of adult neurogenesis.