Journal of Neurocytology 31, 581–593 (2002) The effects of normal aging on myelin and nerve fibers: A review∗ ALAN PETERS Department of Anatomy and Neurobiology, Boston University School of Medicine, 715, Albany Street, Boston, MA 02118, USA [email protected] Received 7 January 2003; revised 4 March 2003; accepted 5 March 2003 Abstract It was believed that the cause of the cognitive decline exhibited by human and non-human primates during normal aging was a loss of cortical neurons. It is now known that significant numbers of cortical neurons are not lost and other bases for the cognitive decline have been sought. One contributing factor may be changes in nerve fibers. With age some myelin sheaths exhibit degenerative changes, such as the formation of splits containing electron dense cytoplasm, and the formation on myelin balloons. It is suggested that such degenerative changes lead to cognitive decline because they cause changes in conduction velocity, resulting in a disruption of the normal timing in neuronal circuits. Yet as degeneration occurs, other changes, such as the formation of redundant myelin and increasing thickness suggest of sheaths, suggest some myelin formation is continuing during aging. Another indication of this is that oligodendrocytes increase in number with age. In addition to the myelin changes, stereological studies have shown a loss of nerve fibers from the white matter of the cerebral hemispheres of humans, while other studies have shown a loss of nerve fibers from the optic nerves and anterior commissure in monkeys. It is likely that such nerve fiber loss also contributes to cognitive decline, because of the consequent decrease in connections between neurons. Degeneration of myelin itself does not seem to result in microglial cells undertaking phagocytosis. These cells are probably only activated when large numbers of nerve fibers are lost, as can occur in the optic nerve. A reminiscence When I was asked to contribute an article to this is- Since my association with Sandy had its beginnings in sue of Journal of Neurocytology, dedicated to Sandy the structure of myelin, it seems appropriate for me to Palay, I considered a number of possible topics and in now return to that topic. Forty years ago, my interest the end decided to write about my recent studies of the was in the formation and structure of central myelin: effects of age on myelin sheaths. In a sense, this com- now it is the other end of spectrum, how myelin sheaths pletes a circle, because I first met Sandy in 1960 in Delft react to aging and how their structure alters. when we were both at the European Regional Confer- ence in Electron Microscopy: he talked about the neu- Introduction rosecretory cells in the preoptic nucleus of fishes and I gave a paper on the structure of myelin sheaths in the The majority of studies on the effects of aging on the central nervous system. We met again the following nervous system have focused on the changes that occur year in London at the 1961 meeting of the Anatomical as a consequence of Alzheimer’s disease. This is under- Society of Great Britain and Ireland, and I persuaded standable because the effects of this disease are devas- Sandy to come to Edinburgh in 1962 to give the Ramsey tating to both patients and their families, but because Henderson Trust Lectures. This was the beginning of of this focus, the effects of normal aging on the nervous a long friendship and a productive scientific associ- system received little attention and studies only began ation that culminated in the two of us collaborating to appear frequently some 25 years ago. And yet as hu- with Harry Webster to write “The Fine Structure of the man longevity increases and brings about an increase Nervous System’’, which was first published in 1970. in the number of citizens that are elderly, we need to This atlas with text ran into three editions, and is prob- understand what is happening to the brain during nor- ably one of the most quoted books in neuroanatomy. mal aging, and what underlies the cognitive declines ∗Grant sponsor: N.I.H. National Institute on Aging. Grant 1PO AG 00001. 0300–4864 C 2003 Kluwer Academic Publishers 582 PETERS often associated with normal aging. Many older peo- uated and considered to be normal. In Alzheimer’s dis- ple show a decline in short term memory; increase in ease there is a significant neuronal loss from cerebral forgetfulness; increase in the time it takes to learn new cortex. information; and a slowing of the speed of response In recent studies of the effects of normal human ag- to challenging situations. Unfortunately, these cogni- ing more attention has been paid to the selection of the tive changes can often affect the ability of older peo- material being studied and to the way in which neu- ple to lead independent lives, and it is only by un- rons are counted, and it is now generally agreed that derstanding what is happening in the aging nervous although there might be a slight loss of cortical neu- system that any possible alleviations can be proposed. rons during normal aging, it is nowhere as extensive as Another reason for needing to know what is happen- early reports would suggest (see Morrison & Hof, 1997; ing to the normally aging brain is that pathological Peters et al., 1998). changes, such as those occurring in Alzheimer’s dis- Because of the problems in obtaining adequately ease, can appear late in life, and are superimposed preserved human material some investigators have upon a background of the normal aging changes that turned to non-human primates, such as the rhesus have preceded them. Consequently it is important to monkey, to study normal aging. The advantages of know what types of changes are produced by normal using non-human primates are that they have a life aging and how they differ from the ones that are disease span of only 35 years (Tigges et al., 1988), as opposed related. to the human life span of 75 to 90 years; they show cognitive deficits similar to those of humans; and they do not develop Alzheimer’s disease. Furthermore, The effects of normal aging on numbers the cognitive status of the monkeys can be assessed of cortical neurons by psychological tests adapted from those used on Studying the effects of normal aging on the human humans (e.g., Bachevalier et al., 1991; Albert & Moss, brain and correlating any alterations with declines in 1996; Herndon et al., 1997) and brain tissue can be cognition presents problems. Delays in obtaining hu- optimally preserved for morphological studies, so that man tissue for examination after death result in deterio- useful correlations can be made between cognitive ration of cells and their components, making it difficult status and alterations in structure. to carry out useful morphological studies. In addition Interestingly, the first studies of the effects of age on it is rare that the cognitive status of an individual has the monkey brain also led to the conclusion that cor- been accurately recorded before death. These factors tical neurons are lost with age (Brizzee, 1973; Brizzee undoubtedly played a role in the development of the et al., 1975), but as with the human studies, more recent popular concept that the cognitive decline associated studies of the non-human primate cortex (summarized with normal aging is brought about by a significant in Peters et al., 1998) have concluded that there is no loss of cortical neurons. significant loss of cortical neurons with age from these In the first studies of the effects of age on the hu- non-human primates. This conclusion has led investi- man cortex Brody (1955, 1970) concluded that as many gators to seek alternative explanations for the cognitive as 50% of neurons are lost with age. Other investiga- decline and to examine other components of the central tors concurred with this conclusion (see Peters et al., nervous system. In our case, we have begun to focus on 1998), and it was not until the 1980s that Haug and the effects of age on the myelinated nerve fibers in the Terry and their colleagues produced contrary evidence. cerebral hemispheres. Thus, Haug and his colleagues (Haug, 1984, 1985; Haug et al., 1984) showed that many of the early re- The formation of myelin ports of loss of cortical neurons with age could be attributed to the fact that upon fixation the brains The myelin sheaths in the central nervous system are of younger individuals shrink more than those of produced by oligodendrocytes. During development, older ones, which have more myelin. Consequently, processes of oligodendrocytes enclose lengths of ax- when sections of cortical tissue are examined, the ons that are to be myelinated, and the outer faces of young brains show higher neuronal packing densities the trilaminar plasma membrane of the enclosing pro- than those of older individuals. After making correc- cess come together to form a mesaxon. Subsequently tions for this differential shrinkage, Haug and his col- the oligodendrocyte process elongates to form a spiral leagues concluded there is no significant loss of neu- wrapping around the enclosed axon. In this wrapping rons from the human cerebral cortex with age. Terry the outer faces of the trilaminar plasma membrane et al. (1987) reached a similar conclusion and sug- in successive turns of the spiraling oligodendrocyte gested that much of the neuronal loss recorded in ear- process come together to form what will be the intrape- lier studies could be attributed to brains of some in- riod or intermediate line of the mature sheath.