Recently concluded research studies – and other studies taking place now – in Brazil and abroad have helped researchers become acquainted with the details of chemical and biological phenomena that are characteristic of aging, especially of the brain and other organs of the central nervous system that control the way we see the world and interact with it. Conducted on healthy animals and people, several of these studies are expected to contribute within the upcoming years to a more accurate definition of the frontier that separates typical changes resulting from natural aging from those that characterize the onset of annihilating neurodegenerative diseases such as Alzheimer’s, which afflicts approximately 5% of the people over the age of 60, and has become more common as the years move on. According to some specialists, this frontier resembles a broad band rather than a thin line.
“Establishing what is part of a healthy aging process and narrowing this frontier might result in earlier identification of people prone to developing these diseases and take the necessary measures to try and stop them from progressing”, says psychiatrist Geraldo Busatto, coordinator of the University of São Paulo/USP’s Laboratory of Psychiatric Neuro-imaging, who has been investigating the brain’s natural aging process.
This knowledge is becoming increasingly important as the human population ages at an unheard-of rate in different regions of the planet. The population of adults over the age of 60 is expected to grow continuously in the course of this century – this growth will be faster in the first half, according to projections published in Nature magazine at the beginning of 2008 – and will increase from 10% of the world’s population in 2000 to 22% in 2050 and 32% in 2100. At the beginning of the next century, Japan will become a nation of old people: half of the Japanese population will be over the age of 60. The situation will not be any different in Brazil. The number of people over the age of 60 is expected to triple until 2050, up from the current 9% to 29%, according to data announced by the Brazilian Institute of Geography and Statistics/IBGE. Concurrently with increased life expectancy, public and private expenditures are expected to grow, in view of the fact that the elderly use up more health care resources than the younger people do. Estimates published years ago by James Lubitz in two articles in the New England Journal of Medicine give an idea of how much a few additional years of life cost in the United States. A person who dies at the age of 65 spends approximately US$ 31.2 thousand in the last year of his or her life. A person who lives an additional 25 years, to the age of 90, disburses US$ 235.4 thousand, most of it on medical and nursing care.
EDUARDO CESARIn this graying world, which will demand a revision of the retirement and work systems, those who desire to see their grandchildren and great-grandchildren grow up certainly want to reach the end of their lives in both good physical and mental shape. Even though any kind of anti-aging pill is still light years away, science can help people reach the age of 80 in good health, with a sharp mind and many more years ahead of them, thus undoing, to a certain extent, the unattractiveness of old age described by Shakespeare, who wrote about old age in the comedy As you like it in the typically ironical manner of the British. Shakespeare wrote this play 400 years ago, when very few people lived beyond the age of 30. According to Jacques, one of the characters in the play, the seventh and last phase of life was similar to a second childhood, without the vitality and freshness of infancy and characterized by losses: teeth, eyesight, taste, memory – in short, everything.
Eight years ago, the teams headed by Busatto and two epidemiology specialists from USP – psychiatrist Paulo Rossi Menezes and psychologist Marcia Scazufca, began to conduct a survey at hospitals, public health care centers and private clinics in a region inhabited by approximately 1.3 million people, located in the western part of São Paulo City. They wanted to identify adults who had availed themselves of mental care services for the first time because of the onset of psychosis, a disorder that provokes distortions in the perception of reality. The researchers’ objective was to obtain images of these people’s brains and check whether there were any alterations in the brains. The researchers also invited neighbors without physical or mental health problems to be the parameter for comparison – normally, people living in the same neighborhood share a similar physical environment and have very similar social, economic, and cultural levels. The group from USP used Magnetic Resonance Imaging to get images of the brains of 89 healthy people ranging from the ages of 18 to 50. The group also got images of 102 healthy men and women ranging from the ages of 65 to 75, chosen from among 2.072 people who had participated in another study conducted in partnership with psychiatrist Homero Vallada.
“This survey has given us a better idea of the brain’s aging process in the Brazilian population, whose life history differs greatly from that of the European or North American population”, says Busatto, one of the coordinators of the research study. The initial analyses of this work are now beginning to surface in the form of scientific articles, one of which was published in March in the Neurobiology of Aging and the other one is scheduled to be published shortly in the American Journal of Neuroradiology. The findings were also presented at two international congresses held in Paris in early July. What did these findings reveal? Many things. One of them is that the brain undergoes a significant elimination of cells (neurons) as it ages naturally – some estimates state that this number corresponds to 50 thousand dead cells a day that are eliminated from the ages of 20 to 75, totaling a loss of 10% of the brain cells human beings are born with; this loss is higher in the region that matures later on – namely, the cortex, a very thin layer that covers the two cerebral hemispheres. In the manner of an orchestra conductor, the cerebral cortex coordinates the processing and storing of the information captured by the senses (sight, hearing, taste, touch and smell), and the movements. The cortex concentrates the cell bodies (the central region, the site of the nucleus or command center) of most of our 100 billion neurons. The cortex, which is a light shade of gray, and the brain’s smaller inner portions that also contain the cell bodies of the neurons, comprise what is popularly referred to as gray matter.
Based on the images of the brains of people ranging from the ages of 18 to 50 years, Débora Terribilli and Maristela Schaufelberger calculated the volume of the grey matter and that of the white matter, where the neurons’ axons are concentrated. They are responsible for the connection with different regions of the brain and other organs of the central nervous system. The researchers noticed that the brains of older people had significantly less gray matter, especially in two regions of the central nervous system: the right prefrontal cortex and the left hemisphere of the cerebellum – the volume in other brain regions varied very little. Located in the anterior part of the brain, right above the eyes, the prefrontal cortex is associated with action planning, complex movements and abstract thought. The cerebellum, located in the inferior posterior portion of the head, coordinates the movements (especially such fine movements as pulling a thread through the eye of a needle) and plays an important role in the acquisition of memory, attention, impulse control and perception of environmental information.
Busatto actually expected to find some reduction of the gray matter in some portions, in view of the fact that, after being totally formed at the end of infancy, the brain and other organs of the central nervous system begin to shrink slowly and progressively, not representing any important damage or disease. The most intriguing fact, however, was that this loss of gray matter did not occur continuously and did not homogeneously affect the prefrontal cortex and the cerebellum.
Two biological phenomena seem to explain this finding. One of them is the late maturing of the cortex, which provokes the elimination of the connections (synapses) among the unused neurons. This is referred to by specialists as synaptic pruning. Synaptic pruning interrupts the communication between these cells, just as telephony cables at a central station do when they are removed. However, synaptic pruning can occur together with the creation of new connections and even with the formation of new neurons (neurogenesis), which can result in a variation in the volume of the gray matter. The second transformation, which generally occurs up to the third or fourth decade of a person’s life, is the continuing growth of a protective layer of myelin that covers the axon. This speeds up the transmission of nerve impulses and influences the calculation of the relative volume of the gray matter. “Only part of the loss that we observed was due to the death of neurons”, Busatto explains.
From the end of adolescence to adulthood, the reduction of gray matter was speedier and more intense among men than among women. This result, detailed by the USP group in an article published in Neurobiology of Aging journal, coincides with the findings of a study conducted in Japan. This study is scheduled for publication in the same journal in the upcoming months. The team from the Development, Aging and Cancer Institute of Tohoku University, headed by Yasuyuki Taki, conducted a six-year follow-up of 381 inhabitants of Sendai, whose ages ranged from 28 to 87 years. Images taken at the beginning and at the end of the research study showed a swifter decline of gray matter in the male population. Although the volume of gray matter in the brains of men is approximately 10% higher than in women – an average of 673 milliliters in men in comparison to 606 milliliters in women – men undergo gray matter loss more speedily from the third to the eighth decade of life. At the end of the experiment, the average volume in men corresponded to 640 milliliters and of women to 589 milliliters. Once again, two reasons seem to justify this sharper decline in men. First of all, men are more prone to cardiovascular problems, which reduce the blood flow to the brain and increase the death of the neurons. Moreover, women are naturally protected up to the age of 50 or thereabouts. Thanks to mechanisms that are still not very clear, female hormones – estrogen being one of them – seem to reduce the death of brain cells.
As the years go by and physical strength diminishes, an important change occurs in the loss pattern of the brain’s gray matter. The reduction in the number of neurons – such reduction previously restricted to some parts of the cortex, a very young portion of the central nervous system from the evolutionary point of view, as it only began to develop 60 million years ago when the first primates appeared – also begins to swiftly affect an inner and more primitive portion of the brain – namely, the limbic system, which contains the hippocampus, a seahorse-shaped structure associated with learning, long term memory and recent memory.
From the age of 70 onwards, the men had a sharper loss of neurons in the hippocampus than in other parts of the brain, Pedro Curiati noticed when he analyzed the images of the central nervous system of 102 healthy elderly people. In women, he noticed a swift decline of gray matter in the entire brain from the age of 70 onwards. “When analyzed together, this data helps us understand some of the clinical changes found in healthy elderly people, such as more difficulty in learning new tasks or creating new memories”, states psychiatrist Tânia Ferraz Alves, one of the authors of the research study.
It makes sense that the speedier loss of neurons during the normal aging process begins in the frontal cortex and lasts for a longer period of time in this region. “The cortex is formed of billions and billions of cells, which provides it with a physiological reserve, because many of these cells have redundant functions, while the hippocampus has only hundreds of thousands of neurons”, says neurologist Fernando Cendes, from the State University of Campinas/ Unicamp, one of the coordinators of the Cooperação Interinstitucional de Apoio a Pesquisas sobre o Cérebro/CInAPCe brain research program funded by FAPESP.
By means of a word and image memory test, Cendes and neurologists Benito Damasceno and Marcio Balthazar analyzed the memory and integrity of the brain of 47 people over the age of 50 (16 people were healthy, 15 had mild cognitive impairment and 17 with early stage of Alzheimer’s). The individuals with mild cognitive impairment and those with Alzheimer’s had a reduction of gray matter in two portions of the limbic system – in the hippocampus and in the thalamic nuclei – in comparison to healthy people. According to Balthazar, the main difference lies in the quantity of neurons that had been lost – this quantity is higher in people with Alzheimer’s. Another outstanding difference: people with Alzheimer’s also had a loss of white matter, according to data published in the European Journal of Neurology in 2009.
As important as finding and measuring the loss of gray matter is knowing what causes this loss. Recently, two groups from São Paulo found some indications of biochemical changes that commonly occur during aging and unleash cell death – this might explain, at least partially, the loss of neurons that is observed in the elderly. Some years ago, Elisa Kawamoto and Cristoforo Scavone, from USP’s Molecular Neuropharmacology Laboratory, contacted Tania Marcourakis and Ricardo Nitrini, who were doing research on Alzheimer’s, to propose a partnership: they wanted to study people with Alzheimer’s and look for some special characteristic that could be used as a biological marker of the disease, which nowadays is still confirmed by means of autopsy. Papers published at that time suggested that Alzheimer’s, which leads to progressive memory loss and to the loss of the capacity to carry out functions essential for life, such as eating, seemed to affect the entire body and not only the central nervous system.
Upon analyzing the protein activity of two kinds of blood cells (red blood cells and platelets), Elisa and Scavone discovered a major alteration. People with Alzheimer’s had pronounced, above-normal nitrous oxide levels. Extremely versatile, nitrous oxide is an essential compound for life; it functions as a neurotransmitter of the central nervous system. In excess, however, it kills cells – nitrous oxide generates molecules called free radicals, which damage the cell proteins. The researchers still had to verify whether the exaggerated production of this compound was exclusive to Alzheimer’s or a characteristic of aging.
Back in the lab, Scavone and Elisa conducted tests on rats from the ages of 6 to 24 months, which, roughly speaking, is comparable to human beings from late adolescence to the age of 85. This time they found over-production of nitrous oxide in the blood cells and in the neurons of the prefrontal cortex of the elderly animals. This was a sign that the biochemical imbalance should show up during the aging process.
There was more. Researchers knew that the neurons of the cerebral cortex were more susceptible to damage that comes with Alzheimer’s than the neurons of the cerebellum. But they had no idea which factor conferred this resistance. Elisa discovered that the cells of the cerebellum produced higher levels of a protein – the Brain-Derived Neurotropic Factor/BDNF – that helps preserve and stimulates the proliferation of neurons. The levels of BDNF were also higher in the cortex of young rats than in the cortex of the elderly rats. “The decreased production of this neuroprotective compound and the increase of free radicals weakens the cell”, says Elisa, who is currently doing research work at the US’s National Institute of Aging. Elisa is researching the capacity of natural compounds such as curcuma to fight free radicals.
While researching the cause of death of elderly rats, pharmacologists Soraya Smaili and Guiomar Lopes, from the Federal University of São Paulo, noticed that the increased levels of free radicals inside the brain damage the membrane of the mitochondria, one of the cell’s most important organelles. The mitochondria transforms the sugar (glucose) available in the blood into energy. When the membrane is altered, the mitochondria release proteins that unleash cell death. “Aging seems to produce a number of alterations that, alone, do not cause cell dysfunctions, but, when they occur together, kill the cells”, says Soraya.
While people are waiting for a treatment to be found – if it ever will – to minimize the effects of aging, those who intend to reach the end of their lives in good shape have some means that are available to everyone. One of them is physical exercise. Tests on animals have shown that keeping the body moving constantly improves the blood flow and the oxygenating of the brain and stimulates the production of neurons. In tests conducted on elderly people, Arthur Kramer, from the University of Illinois, noticed that aerobic activities, such as walking, help improve the functioning of the cortex, the performance of cognitive tasks and the growth of the hippocampus. “People who have never exercised before can always begin”, says Andréa Deslandes, from the Federal University of Rio de Janeiro, who has written a paper on the mechanisms through which exercising can delay aging.
A person who never gets up from the sofa to reach out to the remote control of the TV set has another means: staying intellectually active. When investigating the brain of people who died over the age of 80 and were apparently healthy from the neurological point of view, USP’s Ricardo Nitrini discovered that one out of every four elderly people had the injuries that were associated with Alzheimer’s. “The explanation for the good shape these people were in was the fact that they were highly educated with a high intellectual level”, he states. Activities that demand a mental effort, such as planning the fastest way to get to the street market or doing crossword puzzles or reading help a lot. In the opinion of neuroscientist Iván Izquierdo, a specialist on memory, reading is the best way to maintain active synapses. “When a person is reading, he or she is using various kinds of memory”. Izqueirdo stated at an interview many years ago. “People who can’t or who don’t know how to read should ask someone to read to them so that they can use their hearing memory.”
TERRIBILLI, D. et al. Age-related gray matter volume changes in the brain during non-elderly adulthood. Neurobiology of Aging. Being printed.
TAKI, Y. et al. A longitudinal study of gray matter volume decline with age and modifying factors. Neurobiology of Aging. Being printed.(credits)