A decline in cognitive function is a normal consequence of ageing. Most of us begin to experience mild memory loss as we get older. The speed at which the brain processes information also slows down, and reasoning ability becomes impaired. For reasons that are still unclear, the rate of this decline is accelerated in some, and these people go on to develop Alzheimer’s disease or some other form of dementia.

Imagine taking a pill that could slow down or reverse this age-related decline in cognitive function. That may one day be possible, if the results of a new study are to be believed. The new research, published in the current issue of the journal Nature, shows that the blood of young mice contains as yet unidentified proteins that can promote the generation of new brain cells in old mice.

We now know that the mammalian brain contains neural stem cells that continue to generate new cells throughout adulthood. The discovery of this process – adult neurogenesis – is perhaps the most significant finding of modern neuroscience, as it overturned the long-held view that the adult brain is incapable of regenerating itself and opened up the possibility of developing stem cell-based therapies for neurological conditions such as stroke and Parkinson’s disease.

New brain cells are generated by the division of stem cells found in two discrete regions of the brain. One of these regions, the subventricular zone, generates cells that migrate to the olfactory bulb; the other, called the subgranular zone, produces cells that migrate into the hippocampus, a brain structure known to be critical for learning and memory formation. Newborn cells contribute to these functions, and it is likely that age-related cognitive decline is related to a reduction in the rate at which new cells are produced.

Earlier work has shown that the neural stem cells are located close to blood vessels. This prompted Tony Wyss-Coray of Stanford University and his colleagues to investigate the possibility that neurogenesis may be regulated by chemical cues delivered to the brain in the blood. To do so, they performed surgery to create artificial Siamese twin mice, allowing for the exchange of blood between each pair of animals. They created three different types of twins: young adult mice joined to each other, old mice joined to each other and young mice joined to old mice.

The researchers killed the animals five weeks after the surgery and analysed their brains to determine the number of newly generated cells. This is done by injecting a synthetic chemical called 5-bromo-2’deoxyuridine (BrdU), which resembles one of the four main chemical components of DNA, and is incorporated into newly synthesised DNA. Antibodies that bind specifically to BrdU can then be used to detect where it is located in a tissue sample. In the adult brain, the only cells containing new DNA are those that have just been produced by the division of neural stem cells.

The pairs of young mice had about the same number of newborn neurons in the dentate gyrus as unpaired mice of the same age. This was also the case for pairs of old mice. Remarkably, though, the brains of old mice paired with young mice contained significantly more new cells than unpaired old mice, and those of young mice paired with old ones contained significantly less than unpaired young animals.

These results suggest that chemicals found in the blood of old mice inhibit the generation of new brain cells, whereas chemicals in the blood of young mice promote it. The researchers then injected blood from young or old mice into young adults. Again, they found that animals injected with old blood had far fewer newborn neurons in the hippocampus than those injected with young blood, confirming that old blood contains soluble factors that inhibit neurogenesis.

Next, they investigated the effects of old blood on cell function. They took slices of hippocampal tissue from the brains of young mice paired with young and old ones, and impaled cells with microelectrodes to examine their electrical properties. In the tissue slices from young mice, a decrease in long-term potentiation (LTP) was observed. LTP is a form of synaptic plasticity, in which connections between neurons are strengthened.

As LTP is widely believed to be critical for learning and memory, Wyss-Coray’s group speculated that age-related changes in the composition of blood may be linked to the decline in cognitive function that occurs with ageing. To find out, they trained young mice on two different tasks. In the fear conditioning task, the animals are given a small electric shock at the same time as a sound is played. When this is done repeatedly, they learn to associate the two stimuli, and then exhibit fear behaviour (freezing) when they hear the sound on its own. In the memory task, the animals are placed into a water maze, and quickly learn the location of a hidden platform.

All of the mice performed similarly on both tasks. After the training, some of them were injected with blood from old mice, and made to perform the same tasks again. The performance of these animals on both tasks worsened – they exhibited less freezing when played the sound in the fear conditioning task, and an impaired ability to remember the location of the submerged platform in the water maze.

Finally, the researchers used a technique called proteomics to compare the proteins found in blood from young and old mice before and after pairing them with animals of the same or a different age. They identified six signalling molecules whose levels were elevated in both young animals paired with old ones and unpaired old mice.

One of these, CCL11, decreased neurogenesis when injected into the bloodstream of young mice or directly into the hippocampus, but this effect was abolished when it was administered with a neutralizing antibody. CCL11 also impaired their performance on the fear conditioning and memory tasks, and inhibited the differentiation of neural stem cells maintained in a culture dish.

Together, these results show that age-related changes in the composition of blood are linked to the decline in adult neurogenesis that occurs with age. The researchers plan to use a similar approach to identify the proteins in young blood that stimulate neurogenesis. They also suggest that these rejuvenating factors have the potential to alleviate the decline in cognitive function that occurs with ageing.

Reference: Villeda, S et al (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, DOI: 10.1038/nature10357