Aging of the cerebral cortex differs between humans and chimpanzees Chet C. Sherwooda,1, Adam D. Gordonb, John S. Allenc, Kimberley A. Phillipsd, Joseph M. Erwina,e, Patrick R. Hoff,g, and William D. Hopkinsh,i aDepartment of Anthropology, The George Washington University, Washington, DC 20052; bDepartment of Anthropology, University at Albany–Sate University of New York, Albany, NY 12222; cDornsife Cognitive Neuroscience Imaging Center and Brain and Creativity Institute, University of Southern California, Los Angeles, CA 90089; dDepartment of Psychology, Trinity University, San Antonio, TX 78212; eDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060; fFishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029; gNew York Consortium in Evolutionary Primatology, New York, NY; hDepartment of Psychology, The Agnes Scott College, Decatur, GA 30030; and iDivision of Psychobiology, Yerkes National Primate Research Center, Atlanta, GA 30322 Edited by C. Owen Lovejoy, Kent State University, Kent, OH, and approved June 29, 2011 (received for review November 8, 2010) Several biological changes characterize normal brain aging in An improved understanding of the neurobiology of aging in humans. Although some of these age-associated neural alterations great apes (i.e., chimpanzees, bonobos, gorillas, and orangutans) are also found in other species, overt volumetric decline of par- would help resolve this issue. Unfortunately, there is a paucity of ticular brain structures, such as the hippocampus and frontal lobe, information from these species, despite the fact that they com- has only been observed in humans. However, comparable data on prise our closest living relatives and have the longest lifespan of the effects of aging on regional brain volumes have not previously any nonhuman primate, potentially extending into their 60s under been available from our closest living relatives, the chimpanzees. medical care in captivity (22). Current evidence indicates that In this study, we used MRI to measure the volume of the whole brain aging in great apes displays both similarities and differences from humans. For example, deposits of amyloid-β protein in the brain, total neocortical gray matter, total neocortical white matter, form of diffuse plaques and vascular lesions have been noted in frontal lobe gray matter, frontal lobe white matter, and the hip- the hippocampus and neocortex of aged chimpanzees, gorillas, pocampus in a cross-sectional sample of 99 chimpanzee brains and orangutans (23, 24), and there is evidence of humanlike encompassing the adult lifespan from 10 to 51 y of age. We compared neurofibrillary tangles from a 41-y-old female chimpanzee (25). these data to brain structure volumes measured in 87 adult humans Furthermore, one study of postmortem brain weight in chim- from 22 to 88 y of age. In contrast to humans, who showed a panzees found a minimal rate of decline over adulthood (26). decrease in the volume of all brain structures over the lifespan, Despite these similarities, however, the majority of gene expres- chimpanzees did not display significant age-related changes. Using sion changes in the neocortex during aging have been found to an iterative age-range reduction procedure, we found that the differ among humans, chimpanzees, rhesus macaques, and mice significant aging effects in humans were because of the leverage (27, 28), and humans are more vulnerable than great apes to age- of individuals that were older than the maximum longevity of related neurodegenerative diseases, such as Alzheimer’s disease, chimpanzees. Thus, we conclude that the increased magnitude of Parkinson disease, and other forms of dementia (3). brain structure shrinkage in human aging is evolutionarily novel In this study, we test the hypothesis that human brain aging and the result of an extended lifespan. patterns are a result of evolving a longer lifespan compared with the great apes. To do this, we examined whether chimpanzees display human-like age-related decline in the volume of regions raits that distinguish humans from other primates include of the cerebral cortex. We measured the total neocortical gray enlargement of the brain and increased longevity (1, 2). T matter, total neocortical white matter, frontal lobe gray matter, Consequently, humans are unique among animals in being sus- frontal lobe white matter, and hippocampus in humans and ceptible to certain neuropathologies, such as Alzheimer’s disease, chimpanzees from MRI using manual segmentation protocols in the later stages of life (3–5). Even in the absence of disease, that were similar in both species. The age ranges under in- however, healthy aging in humans is marked by variable degrees vestigation encompassed the adult lifespan for both species un- of neural deterioration and cognitive impairment (6). Diffuse der natural conditions, extending into old age (29, 30). amyloid-β deposits, dendritic attrition, reduced synapse numbers, loss of NMDA receptors, and degeneration of myelinated axons Results have all been observed to preferentially affect regions of the human cerebral cortex that are involved in learning, memory, and The volumes of regions of interest (ROI) were examined using executive function (7, 8). These same changes also accompany multiple regressions in each species separately. Each model in- normal senescence in other primate species and correlate with the cluded a term for sex and either linear, quadratic, or cubic disruption of cognition (3, 9, 10). polynomial regression terms for age. The models for each ROI were compared to determine the best fit to the volumetric data In addition to these microstructural and molecular changes, fi in vivo MRI studies of humans have shown that aging also by evaluating the statistical signi cance of the age terms. involves whole-brain volumetric decline, as well as selective re- – Humans. As has been shown in other studies, the humans in our gional shrinkage (11 13). Within the cerebral cortex, the frontal fi lobe and hippocampus are especially vulnerable to age-associated sample exhibited a signi cant aging effect for all brain structure atrophy (14–16). In contrast to humans, however, such dramatic volumes that were measured (Table 1). Linear models were the age-related reduction in the size of these structures has not been observed in macaque monkeys based on manual volume tracing studies (17–19). More subtle volume loss of prefrontal cortex Author contributions: C.C.S., J.S.A., K.A.P., J.M.E., P.R.H., and W.D.H. designed research; subregions (i.e., dorsolateral prefrontal cortex and anterior cin- C.C.S., J.S.A., and W.D.H. performed research; C.C.S. and A.D.G. analyzed data; and C.C.S., gulate cortex) in macaques, however, has been reported (20, 21). A.D.G., J.S.A., K.A.P., J.M.E., P.R.H., and W.D.H. wrote the paper. Because macaque monkeys and humans are separated by ∼30 The authors declare no conflict of interest. million y of independent evolution, these species differences raise This article is a PNAS Direct Submission. the question of whether the more pronounced effects of neuro- 1To whom correspondence should be addressed. E-mail: [email protected]. degenerative changes in human aging are unique and potentially This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ANTHROPOLOGY related to an extended lifespan. 1073/pnas.1016709108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1016709108 PNAS | August 9, 2011 | vol. 108 | no. 32 | 13029–13034 best fit for the reduction of neocortical gray matter volume (sig- matter, and hippocampus also showed decreases that were asso- nificance of age effect: P < 0.001) and frontal lobe gray matter ciated with aging (Table 2 and Fig. S1). volume (significance of age effect: P < 0.001) with age (Fig. 1). The decline in total neocortical white-matter volume was best fit Chimpanzees. In vivo MRI of 69 chimpanzees revealed that total fi P < brain volume does not vary significantly with age from 10 to 45 y, by a cubic age function (signi cance of age effect: 0.001), as P was the decline in frontal lobe white matter (significance of age and there is no interaction effect between sex and age ( = 0.369) (Table 1 and Fig. S2). In contrast to humans, the total effect: P < 0.001) (Fig. 2). Hippocampus volume loss was best fi P neocortical gray matter, frontal lobe gray matter, and hippo- characterized by a cubic model (signi cance of age effect: = campus did not exhibit age-related changes in volume (Fig. 1 and 0.003) (Fig. 1). Additionally, there was a main effect of sex for all Fig. S3). In addition, neither the volume of the neocortical white ROIs: males had larger brain structure volumes than females. To matter nor frontal lobe white matter displayed significant asso- determine whether the frontal lobe and hippocampus ROIs ciations with age (Fig. 2, Table 1, and Fig. S4). All ROIs showed a differential rate of age-related change in volume com- exhibited a significant main effect of sex in chimpanzees: males pared with the rest of the brain, we examined frontal lobe gray had larger volumes for all brain structures than females. Because matter as a fraction of total neocortical gray matter, frontal lobe the relative measures of frontal lobe gray matter, frontal lobe white matter as a fraction of total neocortical white matter, and the white matter, and hippocampus represent the proportional size ratio of hippocampus volume over total neocortical gray matter. All of each structure within an individual, chimpanzee brains that fi ratios were logged before inclusion in regression models. These were scanned postmortem and subject to xation could also be relative measures of frontal lobe gray matter, frontal lobe white included in these analyses.