The human brain may be the crown of
creation, but it tarnishes with time. Some cognitive capacities diminish even in
healthy aging, and risk of the most common neurodegenerative disorders,
Alzheimer's disease and Parkinson's disease, increases with advancing years.
For the most part, attempts to
understand brain aging and the diseases it brings have focused on neurons,
whose connections and communications underlie thought, feeling, and behavior. But
they are not the whole story.
"Neurons are the workhorses of
the brain, but they have to be very delicately maintained in an optimal
environment to do their job properly," says Donna Wilcock of the Sanders-Brown Center on Aging at the University of Kentucky. When
neurons misfire or die, "it's like the canary in the mine," Wilcock
suggests. "The real problem isn't that the canary's dead, but that it
didn't have the right air to breathe. The glia are responsible for that."
Glia, the “other” brain cells, maintain and support neurons. There are
three main types—microglia, astrocytes and oligodendrocytes—whose complex and
complementary functions include immune surveillance, tissue repair, electrolyte
regulation, and synapse formation and maintenance.
"I think in the Alzheimer's
field and in other neurodegenerative disorders as well, our appreciation for
non-neuronal cells and the role they may be playing has certainly increased in
the last 5-10 years," Wilcock says.
What changes with age
A 2017 paper in in Cell Reports extends
that appreciation to healthy aging. When researchers at UCL (University College
London) and the Francis Crick Institute explored diverse cell types in brains
at different ages, "we found that glia changed more than
neurons," says Jernej Ule, professor of molecular
neuroscience at the university and senior author of the paper.
The team examined post-mortem tissue of people who had died,
apparently free of neurodegenerative disease, between the ages of 16 and 101. Looking
at gene expression in multiple regions of the brain, they found that, as
previous research had suggested, overall activity increased in microglia, which
regulate the inflammatory response, and declined in oligodendrocytes, which
produce and maintain the myelin sheath that insulates axons.
"But what was most interesting to us was that regional
patterns of glial expression are diminished in aging, while neuronal patterns
are preserved," Ule says. In younger brains, the expression profiles of
genes specific for astrocytes and oligodendrocytes vary from region to region,
indicating that these cells function somewhat differently in each area. With
age, such regional differences become less marked.
The consequences of this loss of distinctive regional identity are
"an open question raised by our study that remains to be explored,"
Ule says. “Neurons and glia are tightly linked. The diminution of regional
expression is telling us that somehow this communication may become less
specific during the process of brain aging.”
One thing that the findings strongly suggest, he says, is that
"each brain region ages in a different way; the process isn't generic, but
very dependent on the types of interactions of neurons and glia within the
The biggest shift in region-specific glial expression, he points
out, were in the hippocampus and substantia nigra—areas implicated in
Alzheimer's and Parkinson's disease, respectively.
Taken together, changes in glial gene expression predicted age
more accurately than changes in neurons. The association was strongest in nine
genes that changed in all the brain regions that were examined.
Although the details of an age-disease connection remain unclear,
“there’s more and more evidence that the changes of aging can inform us about
the preclinical mechanisms of neurodegeneration,” he says. “Our assumption is
that if you can delay the aging process, slow it down, neurodegeneration may
never get to the [clinical] threshold.”
His team’s findings suggest the possibility of new targets for
intervention, Ule says. “While neurons for the most part can’t be replaced,
glial cells are able to proliferate. If there’s a defect in glia, there should
be a way to tease them back to a healthy system that can regenerate, and that
might prevent neurons from degenerating.”
"This is a great paper,"
says Donna Wilcock. "I think regional differences could be very important
in understanding different disease processes. We know that certain brain
regions are more susceptible to some of these pathologies than others, but
until now, never realized why that is. I think this may actually point to some
of those mechanisms."
The findings in this paper
"will lead to many novel hypotheses of disease," she says.
"We're all going to change a little bit of what we're thinking about; I
have some new ideas based on this.
"The fact that astrocytes and
oligodendrocytes shift their profile so dramatically in the substantia nigra—does
that mean we have to pay more attention to glia in Parkinson's disease? That's
the kind of queries that this paper opens up."
Clinical applications that emerge
indirectly, from testing such hypotheses, "may be significant in the long
run," she says.
The dancers and the dance
Other recent studies have focused on
the role of specific glial cells in aging and disease, with microglia the object
of special scrutiny, Wilcock says. The recognition that inflammation plays a significant
role in Alzheimer's and other neurodegenerative disease has brought these, the brain’s
principal immune cells, to the forefront. Microglia are also involved in the
formation of synapses, "making sure neurons are connecting properly, and
maintaining that connection," she says.
A 2016 review paper suggested that changes in microglia
underlie an age-related loss of resilience that makes the brain more vulnerable
to injury or disease.
"After a blow to the head, for
example, the young brain is able to recover and repair itself—amazingly
so," says Paula Bickford, professor of neuroscience at the
Center of Excellence for Aging and Brain Repair at the University of South
Florida, and lead author of the paper. "As we get older, some functions
that help brain repair don't work the same way. In fact, they make things
The dual nature of microglia makes
them a likely suspect. Sensitively attuned to their environment, these glial
cells are designed to respond immediately to chemical signals and to deal with whatever
is not supposed to be there—dying cells, viruses, the wrong kind of protein.
"They're the first responders to injury," says Bickford.
The microglial response takes two
forms. Through "classical" activation they express cytokines that
initiate inflammation, and highly reactive oxygen molecules that destroy
invading organisms. "Alternative" activation generates anti-inflammatory
cytokines and trophic factors, promoting healing processes that clean up
damaged tissue and facilitate the growth of new blood vessels and neurons.
Microglia can be in both activation states
concurrently. These are normally kept in balance, but with aging the
pro-inflammatory classical response gets the upper hand.
"Some studies show that a
consequence is the decreased ability to get rid of tau protein and beta
amyloid, making the brain more susceptible to neurodegenerative disease,"
says Bickford. "Improving resilience won't eliminate the pathology--it
won't keep you from getting Alzheimer's disease. But it could help modify
progression, to lengthen the time you're healthy.”
To be sure, microglia don't age
Other studies have shown that
astrocytes, which also have a hand in neuron defense and regeneration, become less functional and less responsive with age. When time reduces the generation
of oligodendrocytes from progenitor cells, myelin production falls, compromising communication among
The elements combine in an immensely
complicated, interlocking system. "There's a lot of signaling that we
don't understand," says Wilcock. "Microglia communicate with
oligodendrocytes. Astrocytes and microglia have intimate communication with
each other through cytokines; there’s a tight relationship between these cells.”
Astrocytes and neurons are closely linked through bidirectional signaling.
Through insight into “the complete consort
dancing together,” (as the poet T.S. Eliot wrote in a meditation on
time), findings like the
regional changes identified in the Cell
Reports paper may help us understand how the brain ages, how age-linked
diseases develop, and how we might intervene to forestall or restore the damage.