Does the Brain Really Age?
by John Medina, Ph.D.| Geriatric Times |  |
September/October 2000 | |
Vol. I | |
Issue 3 |
I admit to being totally embarrassed. As of this writing, I am the proud father of two boys, aged 3 years and 6 months. While that's not a source of embarrassment, it does mean I am suffering not only the memory effects of middle age (more on that in a moment) but also the memory impairment of getting three hours of sleep a night for days on end. That combination is what created the embarrassment, which occurred at a social function at my home.
A young job candidate was gazing at a picture of my boys: Young job candidate: So, Dr. Medina, I see you have children. What are their names? How old are they? Me: Yep, those are my kids. The oldest is Joshua, and his younger brother is Noah. Noah is 4 months old, and Josh is…well, Josh is…" Still me (silent, and thinking):…How old is Josh? Young job candidate (silence) Me (out loud): He's uh…(beginning to panic) his birthday...When's his birthday? My wife: Josh is 3 years old, dear. Me (relieved, embarrassed): Yah, that's right. Three years old. Josh is 3 years old, born in 1997. Young job candidate (silent, but probably rolling her eyes)
And that's not the first time such memory burps have occurred with me. Over the months, I have silently given a variety of names to this temporary memory loss, the vast majority of them unprintable in this publication. I only take heart when I realize that many of my friends and colleagues are also experiencing such lapses, even if they, like me, are only in their early 40s.
This commonality speaks to a general anxiety on the part of lots of people as they get older, even if they don't have kids. Called senior moments or half-heimer's by people who are willing to have a sense of humor about it all, many folks feel they are experiencing age-related forms of cognitive decline (only the most obvious appearing to be memory-related). It occurs even if they are getting a full night of sleep. As people age, the anxiety may increase, for there are a number of cognitive symptoms-definitely not indicative of the aging process-that presage abnormal dementia.
At least that's what some people think. From a research perspective, parsing out what is the normal aging process from specific disease states can be a very tricky thing to do, especially in the realm of thinking.
In this column, we are going to explore some of this ambiguity by discussing cognitive decline, aging and dementia. We will start with some evolutionary theory, move to neuronal counting and finish with some concluding thoughts on the difficulties of doing such research. Ultimately, we are going to discover that science, perhaps surprisingly, really doesn't have an easy way to filter the difference between a pathological neuronal state and the normal behavior of, say, a sleep-deprived father attempting to remember the age of his children.
A Missing Framework
One of the trickiest aspects of doing research on the aging process is attempting to provide a biological framework for a process that may not have a framework at all. That's why some theorists (and even bench types) have been unexpectedly frustrated in their attempts to explain the difference between a normal aging process and a disease state. Let me explain.
A number of anthropologists and sociobiologists believe that large percentages of populations living into their 70s and 80s is a happy artifact of modern technology. The number of years a cave dweller might have been expected to live was probably no more than 20 to 25. That would be just enough time to get through puberty, have kids and see them through puberty.
If that was the case, then selective pressure would no longer have existed (or would at least be so modified as to need reinterpretation) as prehistorical adults got older. The aging process as we know it might not be a process at all. It might simply reflect a genetic freefall of biological processes no longer in the active gunsights of selective pressure. That's why some researchers believe there is no biological framework for aging, just a collision of increasingly deregulated processes inside an organism with increasing terrestrial tenure.
That idea is not without controversy, of course. Some researchers believe selective pressure existed to get the "old" generation out of the way, competition for scarce energy resources being what it was (and is). Aging is a simple way of culling the herd. Others respond by saying nonsense to the whole thing, pointing out that fertility can continue for several decades after a 19th birthday.
The real answer to the question of whether there is an overarching biological framework that explains aging is that nobody knows. Grumpy molecular biologists, like myself, don't really put much intellectual stock in such theoretical speculations anyway. Don't get me wrong; I think the effort is worthwhile. An explainable framework might really inform the question as to what is disease and what is aging in a more rigorous way. But we don't have one, and we are going to talk about two theories concerning the aging of the brain that could really use such a framework in our attempt to understand the aging process. As we will discover, these theories are opposed to each other, and neither does a very good job of separating these issues from normal pathology.
A Tale of Two Theories
The underlying process that describes how human nerves age can be summed up in two words: nerves die.
In fact, it's a massacre. You lose between 30,000 and 50,000 a day. By the age of 65, almost 1/10 of the brain cells you had as a young adult have vanished. All the synaptic connections disappear as well, and unless there is redundancy, so will the behaviors they mediate. The tragic aspect of this loss is that there is very little real regeneration (although there is recent evidence suggesting new neural growth occurs in adults in selected areas). But for the vast majority of neurons, the following is true: no new ones will form once you pass what is called the perinatal stage of development (about four weeks after birth). Because these nerves don't regenerate, the loss will be permanent.
The incredible erosion of nerve cells has spawned two theories concerning the aging of human nerves, as mentioned above. One theory is the depressing Neuronal Fallout Model, the other is the more hopeful Neuronal Plasticity Model. We will briefly examine salient points in each theory.
Considering the number of nerves that exist versus the number of nerves that die, an essential question is: how many nerves have to die (and where must the destruction occur) before a particular behavior is extinguished? This question isn't easy to answer. The brain has this nasty habit of representing the same information in multiple sites. There is evidence that even the characteristics of a single object are parcelled out to various physical regions in the brain.
Even though such redundancy occurs, the Neuronal Fallout Model assumes that the attrition will eventually show up in behavioral loss. This model infers that, as we age, progressive neural loss will exhaust the brain's reserve capacities. This destruction results in the decline of sensory, motor and integrative functions. If a particular "master" nerve, which may control the functional status of many other subordinate nerves, dies, a cascade of degeneration will occur. All of the functions it mediated will be lost. Considering the enormous interactive neural webs within the brain, this loss might reverberate through distant regions, changing patterns of communication system-wide. This depressing model posits inexorable, unflinching and deleterious behavioral effects due to the absence of nerves in aging people. This destruction is selective, with different areas undergoing specific types of damage, a fact that can be empirically observed. A summary of a few affected areas of destruction is provided in the illustration.
The Second Model
Advocates of the Neuronal Plasticity Model have one word for those in the Fallout camp. That word is: nonsense.
The heart of this alternate hypothesis has to do with the fact that neural pathways within the brain are not nearly so set in stone as once believed. Neurons exist that grow new axons or longer dendrites when neighboring neurons are damaged. As mentioned above, there is evidence to suggest that neurons can grow clear into adulthood. Even non-regenerating neurons may have the ability to change their synaptic associations with other healthy nerves. The biology of learning may involve actual physical synaptic changes in the associations between existing neurons. These data do not point to some brain that slowly sets up like poured concrete, but to a living organ fully interactive with its environment.
These ideas can affect deeply how the aging human brain is viewed. In the Neuronal Plasticity Model, the effects of the neural destruction need not be permanent. Other neurons can take the place of fallen neighbors, establishing new synaptic connections, preserving in part the lost functions. Some researchers believe there is actually a net gain in the density of synapses as the years roll along. There is evidence that intellectual decline can be slowed or even reversed if certain cerebral training regimens are employed later in life. New pathways may be constructed simply by undergoing new experiences or new training. In this model, the brain is not treated like a deteriorating, progressively crippled old organ. Rather, it is considered to be an active, resilient thinking machine, fully capable of interacting with its environment.
Any Resolution in Sight?
As of this writing, there is still no proper resolution of these two ideas. There is still so much to learn about how neural connections affect outward behavior, most of what we think happens must fall into the realm of "comment." For example, many have pointed out that older citizens continue to make tremendous contributions well into their old age, an idea that fits in quite nicely with the plasticity model. Bertrand Russell wrote Human Society in Ethics and Politics at the age of 82. Leopold Stokowski conducted the debut of Charles Ive's "Symphony No.4" at the age of 83. Frank Lloyd Wright completed the architectural plans for the Guggenheim Museum at the age of 89. He died at age 91 before it was completed. The idea that human minds must inevitably shut down in their maturity should take a back seat when compared to these accomplishments.
Or at least we'd like to think so.
Others point out that we remember these achievements precisely because they are rare. They point to the legions of patients in adult care facilities with crippling dementias; the number that suffer from Alzheimer's disease (AD); older people with severe memory loss, with severe strokes and so on. They advocate the idea that because neural loss is inexorable, severe behavioral changes are inevitable too. This regardless of the plasticity of the human brain.
Some of these opposing comments can be distilled into a specific piece of data. Whether one believes in neuronal fallout or plasticity, the central biological fact of neural cell loss must be confronted. The question is whether the observed plasticity can completely overtake or compensate for the losses observed in aging human brains. And for that question, the jury is still out. In fact, the jury may be confused. Since we are not yet at a point where we can ask a nerve what its favorite color is, we don't know whether Bertrand Russell was the norm or the exception.
So What About Pathology?
When these theories are overlaid with the concept of disease processes, one finally observes why the issues are so confusing. Are people in nursing homes there because they have a disease, or because they are simply getting old? One might think that diseases such as AD would give us clues. One could easily point out that Alzheimer's is a disease complete with its plaques and tangles; it just happens to occur later in life. The confusing thing, of course, is that many people get plaques and tangles during their lives, yet have absolutely no manifestation of the symptoms of AD. Others show very few plaques and tangles and yet fully manifest in textbook fashion what appears to be AD. This ambiguity is seen most clearly in the gene work. To date, the genes that have been isolated explain less than 2% of the AD observed in the clinical setting.
The critical question, of course, is attempting to find the relationship of dementia to the aging process. Most dementias are not observed until after age 65. Are all of these diseases, too, or simply artifacts of aging? Most folks past their seventh decade show some kind of cognitive decline (especially hard hit is short-term memory). To attempt to categorize these phenomena-while not at all helping to answer the question-a new clinical category has been conjured up. The syndrome is called cognitive impairment, a memory deficit that falls somewhere between normal age-related functioning (whatever that is) and Alzheimer's disease.
Of course, normal age-related functioning itself can be explained (or confused) simply by saying that both the Neuronal Fallout and Plasticity Models are correct. It is possible, for example, that some people have genetic predispositions to constantly repair normal, age-related neural damage. In this view, the plasticity model works in concert with neuronal fallout to slow the pace of cognitive decline. Others may not have such efficient repair mechanisms, and thus they undergo comparatively more damage. How much damage is eventually experienced may depend upon how inefficient their repair mechanisms actually are.
There is no real way to summarize these data. I simply wish to point out that while it may seem naturally intuitive to observe the aging process related to cognitive function and to separate all this from disease states, scientific investigation proves that the questions aren't straightforward. If we could come up with an overarching theory of the aging process, we might very well be able to provide a framework that allowed us to separate normal processes from disease functions. Such a framework might inform clinical practice; it might even provide strong research directions for those looking to stem aging's inevitable advances in our brains. Most important, it might even provide explanations for middle-aged scientists, who absolutely adore their children and burned the very hours of their birth deep into memory, but can't for the life of them figure out how old they are.
Dr. Medina, a former faculty member at the University of Washington School of Medicine, is now founding director and CEO of the Talaris Research Institute, a brain research center devoted to the science of early learning.