- Email: [email protected]
Aging in the mind
Editorial
TRENDS in Neurosciences Vol.27 No.10 October 2004
Aging in the mind Alex Verkhratsky1, Mark P. Mattson2 and Emil C. Toescu3 1
School of Biological Sciences, University of Manchester, G.38 Stopford Building, Oxford Road, Manchester M13 9PT, UK Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA 3 Department of Physiology, Division of Medical Sciences, The University of Birmingham, Edgbaston B15 2TT, UK 2
.ubi iam validis quassatum est viribus aevi Corpus, et obtusis ceciderunt viribus artusclaudicat ingenium, deliriat linguaque mensque – Lucretius (De Rerum Natura 3. 451) (‘When the body is shattered by the worthy power of age and when the limbs with blunted powers have fallen the mind limps and both speech and mind decline’) Immortality has long been a dream of many, whereas others would be happy to live a healthy life and die suddenly so as not to suffer the relentless deterioration of body, mind and spirit that will be the fate of most of us. With advancing age, the spectrum of mental decline loomed always larger. When Captain Lemuel Gulliver visited the immortal men of Luggnagg, he met with misery and desperation. These immortals, known as ‘Struldbruggs’, commonly acted like mortals until they were w30 years old, at which time they became melancholic and dejected. By 40 years of age, ‘they had not only all the Follies and Infirmities of other old Men, but many more which arose from the dreadful Prospect of never dying’. They had no memories of anything, except of what they learned and observed before the age of 40, and even that was still imperfect. By 90, they have lost ‘their Teeth and Hair, they have.no Distinction of Taste, but eat and drink whatever they can get, without Relish or Appetite’. In their conversations ‘they forgot the common Appellation of Things, and the Names of Persons, even of those who are their nearest Friends and Relations. For the same Reason they never can amuse themselves with reading, because their Memory will not serve to carry them from the beginning of a Sentence to the end; and by this Defect they are deprived of the only entertainment whereof they might otherwise be capable.’ [1]. Is an inexorable decline of mental performance inseparable from the process of aging? Starting from the ancient times this question was answered positively. As early as the 7th century BC, Pythagoras divided human life into five stages and called the last two (from 63 years old onwards) the ‘senium’, convinced that at advanced age ‘the system returns to the imbecility of the first epoch of infancy’ [2]. Hippocrates (460–377 BC) and Aristotle (384–322 BC), Galen (150–200 AD) and Celsus (1st century AD) were all convinced that mental decline is inseparable from aging and hence that life inevitably ends in dementia, although ‘very fortunately, few of the human species arrive’ Corresponding author: Alex Verkhratsky ([email protected]). Available online 5 August 2004
(Pythagoras, cited from Ref. [2]) to such an advanced age. Of the ancient thinkers, only Cicero (106–42 BC) was unconvinced by such a pessimistic perspective, and was the first to suggest that ‘senile imbecility.does not occur in all old men, but only in those of feeble mind’ [3], thus clearly drawing a boundary between physiological aging and neurodegenerative processes now known to be responsible for dementia. Even more surprising, Cicero knew how to resist the age-dependent cognitive decline, for he wrote ‘Age has to be fought against; its faults need vigilant resistance. We must combat them as we should fight a disease – following a fixed regime, taking exercise in moderation, and enough food and drink to strengthen yet not enough to overburden. However, the mind and spirit need even more attention than the body, for old age easily extinguishes them, like lamps when they are not given oil.Age will only be respected if it fights for itself, maintains its own rights, avoids dependence, and asserts control over its own sphere as long as life lasts’ [3]. As the 21st century begins, an understanding of the chemical basis for brain aging and associated diseases is emerging. Alzheimer’s disease (AD) and other forms of dementia are now clinically and pathologically defined, but the question of the relationship between aging and dementia, and the possibility of the latter evolving naturally from the former, is still open. One arena for this battle of ideas is that of brain morphology. Until the 1980s, the dogma of continuity between brain aging and AD was supported by data showing an age-dependent neuronal loss even in normal brain; however, this view has changed dramatically in the light of recent studies that found, using precise volumetric stereological techniques, very little or no neuronal loss in the brains of very old neurologically normal humans [4]. Instead, synapse dysfunction and/or loss could explain age-related decreases in brain functions [5]. Although it has been proposed that progressive synapse loss would eventually lead to dementia in individuals who live long enough [6], it is also possible that the circuit-specific alterations in synaptic connectivity with aging [7] are different from those that occur in neurodegenerative dementias. In AD, disease is defined by the presence of neurofibrillary tangles and b-amyloid plaques. Although tangles might occur in all individuals over 50, it has been suggested that the pathological effects are mediated by AD-specific deposition of b-amyloid [8]; also, some instances of AD do not display the presence of tangles [9].
www.sciencedirect.com 0166-2236/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2004.07.008
578
Editorial
TRENDS in Neurosciences Vol.27 No.10 October 2004
Advent of the age of molecular genetics and advances in cell biology have fostered a rapid increase in knowledge of the molecular and cellular mechanisms that underlie synaptic dysfunction and neuronal degeneration in aging and neurodegenerative disorders. The development of mouse models of AD, Parkinson’s disease and Huntington’s disease has led to rapid progress in identifying pivotal molecular alterations and their adverse consequences for neurons. It has become clear that there are pathogenic mechanisms common to each neurodegenerative disorder that are also observed, to a lesser extent, during normal aging. Prominent among these mechanisms are increased oxidative stress, impaired energy metabolism and cellular stress responses, perturbed cellular Ca2C homeostasis, and inflammatory processes. Genetic and environmental factors that can modify the adverse effects of aging on neurons are being identified. For example, individuals with a particular apolipoprotein E4 allele are at increased risk of AD, whereas physical exercise, cognitive stimulation and dietary restriction might decrease disease risk, progression of synaptic dysfunction and neuronal degeneration. This issue of Trends in Neurosciences describes recent progress made towards understanding mechanisms of adaptive and pathological brain aging, and their role in determining the healthspan of the brain. Signal transduction pathways that modify the aging processes in the brain are being identified and manipulations of these pathways are proving effective in protecting neuronal circuits in animal models of neurodegenerative disorders. Interestingly, some of the neurotransmitter and neurotrophic
factor signaling pathways in the brain can influence vulnerability to age-related maladies such as diabetes and cardiovascular disease. Studies of the oldest old are providing information on genes and environmental factors that promote longevity. Although much still remains to be understood, we are beginning to realize that mental decline is not inevitable with normal aging and that brain-based strategies for extending healthspan are possible. Acknowledgements We wish to thank Mary Harlow (Birmingham University) for help with the literary translation of the citation from Lucretius.
References 1 Swift, J. (1995) Gulliver’s Travels, Folio Society 2 Berchtold, N.C. and Cotman, C.W. (1998) Evolution in the conceptualization of dementia and Alzheimer’s disease: Greco-Roman period to the 1960s. Neurobiol Aging 19, 173–189 3 Cicero (2003) On Old Age. In On the Good Life, pp. 160–194, Folio Society 4 Peters, A. (2002) Structural changes in the normally aging cerebral cortex of primates. Prog. Brain. Res. 136, 455–465 5 Masliah, E. et al. (1993) Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43, 192–197 6 Terry, R.D. and Katzman, R. (2001) Life span and synapses: will there be a primary senile dementia? Neurobiol. Aging 22, 347–348 7 Smith, T.D. et al. (2000) Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J. Neurosci. 20, 6587–6593 8 Price, J.L. and Morris, J.C. (1999) Tangles and plaques in nondemented aging and ‘preclinical’ Alzheimer’s disease. Ann Neurol 45, 358–368 9 Terry, R.D. et al. (1987) Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 46, 262–268
ScienceDirect collection reaches six million full-text articles Elsevier recently announced that six million articles are now available on its premier electronic platform, ScienceDirect. This milestone in electronic scientific, technical and medical publishing means that researchers around the globe will be able to access an unsurpassed volume of information from the convenience of their desktop. ScienceDirect’s extensive and unique full-text collection covers over 1900 journals, including titles such as The Lancet, Cell, Tetrahedron and the full suite of Trends and Current Opinion journals. With ScienceDirect, the research process is enhanced with unsurpassed searching and linking functionality, all on a single, intuitive interface. The rapid growth of the ScienceDirect collection is due to the integration of several prestigious publications as well as ongoing addition to the Backfiles – heritage collections in a number of disciplines. The latest step in this ambitious project to digitize all of Elsevier’s journals back to volume one, issue one, is the addition of the highly cited Cell Press journal collection on ScienceDirect. Also available online for the first time are six Cell titles’ long-awaited Backfiles, containing more than 12,000 articles highlighting important historic developments in the field of life sciences. The six-millionth article loaded onto ScienceDirect entitled ‘‘Gene Switching and the Stability of Odorant Receptor Gene Choice’’ was authored by Benjamin M. Shykind and colleagues from the Dept. of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, College of Physicians and Surgeons at Columbia University. The article appears in the 11 June issue of Elsevier’s leading journal Cell, Volume 117, Issue 6, pages 801–815.
www.sciencedirect.com www.sciencedirect.com
TRENDS in Neurosciences Vol.27 No.10 October 2004
Aging in the mind Alex Verkhratsky1, Mark P. Mattson2 and Emil C. Toescu3 1
School of Biological Sciences, University of Manchester, G.38 Stopford Building, Oxford Road, Manchester M13 9PT, UK Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA 3 Department of Physiology, Division of Medical Sciences, The University of Birmingham, Edgbaston B15 2TT, UK 2
.ubi iam validis quassatum est viribus aevi Corpus, et obtusis ceciderunt viribus artusclaudicat ingenium, deliriat linguaque mensque – Lucretius (De Rerum Natura 3. 451) (‘When the body is shattered by the worthy power of age and when the limbs with blunted powers have fallen the mind limps and both speech and mind decline’) Immortality has long been a dream of many, whereas others would be happy to live a healthy life and die suddenly so as not to suffer the relentless deterioration of body, mind and spirit that will be the fate of most of us. With advancing age, the spectrum of mental decline loomed always larger. When Captain Lemuel Gulliver visited the immortal men of Luggnagg, he met with misery and desperation. These immortals, known as ‘Struldbruggs’, commonly acted like mortals until they were w30 years old, at which time they became melancholic and dejected. By 40 years of age, ‘they had not only all the Follies and Infirmities of other old Men, but many more which arose from the dreadful Prospect of never dying’. They had no memories of anything, except of what they learned and observed before the age of 40, and even that was still imperfect. By 90, they have lost ‘their Teeth and Hair, they have.no Distinction of Taste, but eat and drink whatever they can get, without Relish or Appetite’. In their conversations ‘they forgot the common Appellation of Things, and the Names of Persons, even of those who are their nearest Friends and Relations. For the same Reason they never can amuse themselves with reading, because their Memory will not serve to carry them from the beginning of a Sentence to the end; and by this Defect they are deprived of the only entertainment whereof they might otherwise be capable.’ [1]. Is an inexorable decline of mental performance inseparable from the process of aging? Starting from the ancient times this question was answered positively. As early as the 7th century BC, Pythagoras divided human life into five stages and called the last two (from 63 years old onwards) the ‘senium’, convinced that at advanced age ‘the system returns to the imbecility of the first epoch of infancy’ [2]. Hippocrates (460–377 BC) and Aristotle (384–322 BC), Galen (150–200 AD) and Celsus (1st century AD) were all convinced that mental decline is inseparable from aging and hence that life inevitably ends in dementia, although ‘very fortunately, few of the human species arrive’ Corresponding author: Alex Verkhratsky ([email protected]). Available online 5 August 2004
(Pythagoras, cited from Ref. [2]) to such an advanced age. Of the ancient thinkers, only Cicero (106–42 BC) was unconvinced by such a pessimistic perspective, and was the first to suggest that ‘senile imbecility.does not occur in all old men, but only in those of feeble mind’ [3], thus clearly drawing a boundary between physiological aging and neurodegenerative processes now known to be responsible for dementia. Even more surprising, Cicero knew how to resist the age-dependent cognitive decline, for he wrote ‘Age has to be fought against; its faults need vigilant resistance. We must combat them as we should fight a disease – following a fixed regime, taking exercise in moderation, and enough food and drink to strengthen yet not enough to overburden. However, the mind and spirit need even more attention than the body, for old age easily extinguishes them, like lamps when they are not given oil.Age will only be respected if it fights for itself, maintains its own rights, avoids dependence, and asserts control over its own sphere as long as life lasts’ [3]. As the 21st century begins, an understanding of the chemical basis for brain aging and associated diseases is emerging. Alzheimer’s disease (AD) and other forms of dementia are now clinically and pathologically defined, but the question of the relationship between aging and dementia, and the possibility of the latter evolving naturally from the former, is still open. One arena for this battle of ideas is that of brain morphology. Until the 1980s, the dogma of continuity between brain aging and AD was supported by data showing an age-dependent neuronal loss even in normal brain; however, this view has changed dramatically in the light of recent studies that found, using precise volumetric stereological techniques, very little or no neuronal loss in the brains of very old neurologically normal humans [4]. Instead, synapse dysfunction and/or loss could explain age-related decreases in brain functions [5]. Although it has been proposed that progressive synapse loss would eventually lead to dementia in individuals who live long enough [6], it is also possible that the circuit-specific alterations in synaptic connectivity with aging [7] are different from those that occur in neurodegenerative dementias. In AD, disease is defined by the presence of neurofibrillary tangles and b-amyloid plaques. Although tangles might occur in all individuals over 50, it has been suggested that the pathological effects are mediated by AD-specific deposition of b-amyloid [8]; also, some instances of AD do not display the presence of tangles [9].
www.sciencedirect.com 0166-2236/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2004.07.008
578
Editorial
TRENDS in Neurosciences Vol.27 No.10 October 2004
Advent of the age of molecular genetics and advances in cell biology have fostered a rapid increase in knowledge of the molecular and cellular mechanisms that underlie synaptic dysfunction and neuronal degeneration in aging and neurodegenerative disorders. The development of mouse models of AD, Parkinson’s disease and Huntington’s disease has led to rapid progress in identifying pivotal molecular alterations and their adverse consequences for neurons. It has become clear that there are pathogenic mechanisms common to each neurodegenerative disorder that are also observed, to a lesser extent, during normal aging. Prominent among these mechanisms are increased oxidative stress, impaired energy metabolism and cellular stress responses, perturbed cellular Ca2C homeostasis, and inflammatory processes. Genetic and environmental factors that can modify the adverse effects of aging on neurons are being identified. For example, individuals with a particular apolipoprotein E4 allele are at increased risk of AD, whereas physical exercise, cognitive stimulation and dietary restriction might decrease disease risk, progression of synaptic dysfunction and neuronal degeneration. This issue of Trends in Neurosciences describes recent progress made towards understanding mechanisms of adaptive and pathological brain aging, and their role in determining the healthspan of the brain. Signal transduction pathways that modify the aging processes in the brain are being identified and manipulations of these pathways are proving effective in protecting neuronal circuits in animal models of neurodegenerative disorders. Interestingly, some of the neurotransmitter and neurotrophic
factor signaling pathways in the brain can influence vulnerability to age-related maladies such as diabetes and cardiovascular disease. Studies of the oldest old are providing information on genes and environmental factors that promote longevity. Although much still remains to be understood, we are beginning to realize that mental decline is not inevitable with normal aging and that brain-based strategies for extending healthspan are possible. Acknowledgements We wish to thank Mary Harlow (Birmingham University) for help with the literary translation of the citation from Lucretius.
References 1 Swift, J. (1995) Gulliver’s Travels, Folio Society 2 Berchtold, N.C. and Cotman, C.W. (1998) Evolution in the conceptualization of dementia and Alzheimer’s disease: Greco-Roman period to the 1960s. Neurobiol Aging 19, 173–189 3 Cicero (2003) On Old Age. In On the Good Life, pp. 160–194, Folio Society 4 Peters, A. (2002) Structural changes in the normally aging cerebral cortex of primates. Prog. Brain. Res. 136, 455–465 5 Masliah, E. et al. (1993) Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43, 192–197 6 Terry, R.D. and Katzman, R. (2001) Life span and synapses: will there be a primary senile dementia? Neurobiol. Aging 22, 347–348 7 Smith, T.D. et al. (2000) Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J. Neurosci. 20, 6587–6593 8 Price, J.L. and Morris, J.C. (1999) Tangles and plaques in nondemented aging and ‘preclinical’ Alzheimer’s disease. Ann Neurol 45, 358–368 9 Terry, R.D. et al. (1987) Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 46, 262–268
ScienceDirect collection reaches six million full-text articles Elsevier recently announced that six million articles are now available on its premier electronic platform, ScienceDirect. This milestone in electronic scientific, technical and medical publishing means that researchers around the globe will be able to access an unsurpassed volume of information from the convenience of their desktop. ScienceDirect’s extensive and unique full-text collection covers over 1900 journals, including titles such as The Lancet, Cell, Tetrahedron and the full suite of Trends and Current Opinion journals. With ScienceDirect, the research process is enhanced with unsurpassed searching and linking functionality, all on a single, intuitive interface. The rapid growth of the ScienceDirect collection is due to the integration of several prestigious publications as well as ongoing addition to the Backfiles – heritage collections in a number of disciplines. The latest step in this ambitious project to digitize all of Elsevier’s journals back to volume one, issue one, is the addition of the highly cited Cell Press journal collection on ScienceDirect. Also available online for the first time are six Cell titles’ long-awaited Backfiles, containing more than 12,000 articles highlighting important historic developments in the field of life sciences. The six-millionth article loaded onto ScienceDirect entitled ‘‘Gene Switching and the Stability of Odorant Receptor Gene Choice’’ was authored by Benjamin M. Shykind and colleagues from the Dept. of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, College of Physicians and Surgeons at Columbia University. The article appears in the 11 June issue of Elsevier’s leading journal Cell, Volume 117, Issue 6, pages 801–815.
www.sciencedirect.com www.sciencedirect.com