You know the story, and it happens to us all eventually: the older we get, the harder our brains find it to learn and remember new things. There are likely to be a myriad of reasons why the brain gets increasingly worse as we age, but these reasons are still poorly understood. Like the old saying goes, you cannot teach an old dog new tricks – but what if science could?
Boosting old brains with stem cells
A common point that is raised whenever the rejuvenation of older people is discussed is the plausibility of reversing biological age in the brain. The concern that while it may be possible to rejuvenate tissues and organs elsewhere in the body, it may not be quite so easy or indeed even possible in the aging brain.
Stem cell exhaustion, one of the hallmarks of aging, describes the steady loss of the stem cells that supply our organs and tissues with fresh healthy cells. This gradual loss of the stem cell populations in various tissues and organs is very likely a reason why our brains become increasingly poor as we age. One proposed solution to help rejuvenate aging brains is to replace the lost stem cells there by transplanting them or or spurring them to divide.
For a team of researchers at the Center for Regenerative Therapies of TU Dresden, the question isn’t why the aging brain declines like this – it’s how they could do something to restore cognitive function in the aged brain by increasing the number of stem cells there.
In the new study, the researchers stimulated the small population of neural stem cells that reside in the brain, encouraging them to multiply. By boosting the population of these cells, the number of neurons that they created also increased. The researchers observed that these new neurons survived and formed new contacts with nearby existing neurons in the brains of old mice.
Old brains, new tricks
For the next step, the team focused on the ability of the mice to navigate effectively. Navigation is typically one of the cognitive abilities that fails as we get older, and it happens in mice just like it does in people when they get old. When we are young, we learn to navigate in new places by building mental maps of those places, but when we get old, we lose the ability to build these maps. To compensate for this loss, our brains instead learn the movements needed to reach a destination, noting the various turns and steps it takes to reach somewhere. While similar, only mental map building allows an individual to navigate well when in a new place or needing to reach a new destination.
So, could that decline be reversed by increasing the neurons in the brain?
Thankfully, the answer appears to be yes. In the study, the old mice with boosted stem cell and neuron populations actually recovered the ability to build mind maps like younger mice. Perhaps even more intriguingly, these mice experienced delayed cognitive decline, including memory preservation during their natural lifespans.
The researchers suggest this is due to a region of the brain known as the hippocampus, which, in young mice and humans, plays a key role in memory, particularly remembering locations and events and building mental maps for navigation. As we age, we stop using this part of the brain and switch to other regions more closely associated with the development of habits.
The researchers were able to reverse this brain region change, reverting the old mice back to using the hippocampus again. The mice could then navigate using the mental map strategy used by young mice and became better at finding their way around.
Functional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain’s endogenous reserve of neural stem cells.
This new study suggests that it is plausible that the aging brain could be rejuvenated using a repair-based approach to replacing lost stem cells. There have been various attempts in the past to transplant fresh stem cells that were harvested from the patient and multiplied outside the body, but it seems increasingly clear that the same end might be achieved by stimulating in situ populations of existing stem cells.
Perhaps most importantly of all, this study demonstrates that age-related cognitive impairment is not a one-way street and that the brain can be rescued from it. Just as other organs and tissues have been shown to rejuvenate given the right stimuli, the brain also appears to be no exception to this rule. Thanks to this study, it seems that it really is now possible to teach an old dog new tricks!