Enhanced FGF Signaling Reverses the Diminished Neurogenesis Observed in Old Mice

Neurogenesis, the creation of new neurons in the brain, slows with age. This is most likely an important contributing factor in the age-related loss of neural plasticity, the ability of the central nervous system to change, adapt, and to a limited degree repair itself. Here researchers show that they can increase the pace of neurogenesis in old mice by raising the level of fibroblast growth factor (FGF) signaling:

The mechanisms regulating hippocampal neurogenesis remain poorly understood. Particularly unclear is the extent to which age-related declines in hippocampal neurogenesis are due to an innate decrease in precursor cell performance or to changes in the environment of these cells. Several extracellular signaling factors that regulate hippocampal neurogenesis have been identified. However, the role of one important family, FGFs, remains uncertain. Although a body of literature suggests that FGFs can promote the proliferation of cultured adult hippocampal precursor cells, their requirement for adult hippocampal neurogenesis in vivo and the cell types within the neurogenic lineage that might depend on FGFs remain unclear.

Here, specifically targeting adult neural precursor cells, we conditionally express an activated form of an FGF receptor or delete the FGF receptors that are expressed in these cells. We find that FGF receptors are required for neural stem-cell maintenance and that an activated receptor expressed in all precursors can increase the number of neurons produced. Moreover, in older mice, an activated FGF receptor can rescue the age-related decline in neurogenesis to a level found in young adults. These results suggest that the decrease in neurogenesis with age is not simply due to fewer stem cells, but also to declining signals in their niche. Thus, enhancing FGF signaling in precursors can be used to reverse age-related declines in hippocampal neurogenesis.

Link: http://dx.doi.org/10.1523/JNEUROSCI.1469-15.2015


Speaking of the aging brain…

The recent large investments into curbing aging have mainly focused on developing pharmaceuticals that will increase the health and lifespan of individuals (e.g. Calico and Abbvie). Pharmaceuticals are an approach that could lead to therapies that increase health and average lifespans, but it might be overly optimistic to expect that a magic bullet (or bullets) can be developed in the next few decades that will have significant impacts on extending the human maximal lifespan – an asymptotic plateau that sits somewhere around 95-110 years. This is because the molecular damage that accumulates with age is not only remarkably complex, but it is also intertwined with the normal life-promoting biological processes of our bodies. A more straightforward approach to curbing aging that could, with the correct investments, come to fruition in the next decade or two is to exploit the tremendous strides taking place in regenerative medicine using organ, tissue, and cell transplants. In this case, rather than trying to slow down or repair the many forms of molecular damage, one simply replaces defective cells, tissues, or organs which can be derived from stem cells or in some cases prosthetics or artificial organs can be used.

Although just about any whole organ or body part can be replaced when damaged, we cannot replace our brains (for what I hope are obvious reasons). Nevertheless, replacement therapies for the brain at the cellular level are making more and more sense. Despite the myriad of specialized cell types and structures in the brain, each of which undergoes molecular and cellular decay with age, our deepening understanding of how the brain is normally formed early in life and how all the parts work together once mature is providing us with the conceptual framework necessary to attempt to rejuvenate it when it deteriorates with age. Importantly, the brain is a very plastic organ capable of accommodating a certain loss or addition of its principle cells, the neurons, while maintaining ongoing function. So recent advances in our ability to introduce new neurons that functionally integrate into existing networks to bolster function along with methods of rejuvenating the environment of neurons, including for example providing new blood vessels, will allow for brain rejuvenation. The question remains, when? Certainly, a concerted effort by neuroscientists, engineers, and physicians with the right financial backing would accelerate achieving this goal.

Posted by: Jean Hébert at March 8th, 2016 3:00 PM

Hi Jean Hébert !

Great analysis from a great professional researcher (I'm not one btw :). Not to be a downer.
Perhaps, that is the road block, how can we rejuvenate a brain, if we can't replace it (for brain self-identity reason) and it accumulates undegradable aggregates both intracellularly, and extracellularly, such as in cytosol that we can't degrade so far (such as carbonyls, lipofuscin, amyloids, crosslinks, drusen, ceroid, etc, although SENS is trying to degrade these with nanotech bacterial-degrading enzymes delivery even if this technology is non-existent ?) ? If these stumbling road blocks can't be overcome it's hard to imagine rejuvenation being capable of rejuvenating a human for extreme lifespan beyond current maximum lifespan. I believe that when we are capable of rejuvenating a mouse body, in entirety through organ replacement/cell/stem cell replacement, and it keeps on living multiple times beyond its regular maximal age; then, I think we will be very close to the holy grail of real rejuvenation allowing immortality, 'semi'-immortality or at the very worst, a triple lifespan or so. Monthly fresh earliest mesenchymal and adipose stem cell injection in mice have yielded therapeutic effects, but do nothing substantial on increasing its maximum lifespan. It leaves new organ replacement or cell replacement. We can't replace every organ (brain), but cell replacement could obviate that a lot by combining together with stem cell replacement; it stills does not solve lysosomal, proteasomal, intracellular (cells can be replaced to obviate that, I wonder if new cells free of junk would be capable of somehow cleaning their extra-cellular surroundings), extracellular, cytosolic and extracellular matrix undegradable DNA junk accumulation in tissues problems. Also, same thing for telomerase being devoid in certain post-mitotic somatic cells (although it was found that telomerase can be derepressed, in certain somatic telomerase-devoid cells, when they reach a very low telomere size (something due to the TRF2/TRF1/POT/Shelterin telomere proteins that keep telomeres stable and capped at low telomere size; it seems that at that point, telomerase is needed to maintain a continous short capped telomere that does not shorten further (to cell replicative senescence crisis), exactly like cancers do)) still this is contested and telomerase is barely visible in somatic cells (so basically, there is no telomerase all the way to the(se) (somatic) cell(s) death). Hayflick limit/replication end by telomere loss problem is another problem when telomerase is absent (to reduce cancer formation susceptility). Cell replacement obviates most of all these problems altogether (although Entire body cell replacement is still wishfull thinking now), except outside cell junk deposition problem. If cell replacement, in entirety is possible, I would guess that extra-cellular junk would abate dramatically to the point of almost being nill, same goes for oxidative stress (new cells keep things young and fresh like a young body with no or very little oxidative stress), allowing extreme centuries-long lifespan.

1. http://jem.rupress.org/content/212/11/1803

Posted by: CANanonymity at March 8th, 2016 9:15 PM

PS: my apologies, cytosol is only intracellular compartment, I meant the extracellular fluid. But it still leaves the extracellular fluid surrounding the cell/in which it bathes in; and the ECM (extra cellular matrix, like collagen crosslinks in it) large.

Posted by: CANanonymity at March 8th, 2016 9:31 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.