Abstract
Aging is accompanied by a host of social and biological changes that correlate with behavior, cognitive health and susceptibility to neurodegenerative disease. To understand trajectories of brain aging in a primate, we generated a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques. We demonstrate that age-related changes in the level and variance of gene expression occur in genes associated with neural functions and neurological diseases, including Alzheimer’s disease. Further, we show that higher social status in females is associated with younger relative transcriptional ages, providing a link between the social environment and aging in the brain. Our findings lend insight into biological mechanisms underlying brain aging in a nonhuman primate model of human behavior, cognition and health.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1714-1723 |
| Number of pages | 10 |
| Journal | Nature Neuroscience |
| Volume | 25 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2022 |
ASJC Scopus subject areas
- Neuroscience(all)
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Multiregion transcriptomic profiling of the primate brain reveals signatures of aging and the social environment. / Cayo Biobank Research Unit.
In: Nature Neuroscience, Vol. 25, No. 12, 12.2022, p. 1714-1723.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Multiregion transcriptomic profiling of the primate brain reveals signatures of aging and the social environment
AU - Cayo Biobank Research Unit
AU - Chiou, Kenneth L.
AU - DeCasien, Alex R.
AU - Rees, Katherina P.
AU - Testard, Camille
AU - Spurrell, Cailyn H.
AU - Gogate, Aishwarya A.
AU - Pliner, Hannah A.
AU - Tremblay, Sébastien
AU - Mercer, Arianne
AU - Whalen, Connor J.
AU - Negrón-Del Valle, Josué E.
AU - Janiak, Mareike C.
AU - Bauman Surratt, Samuel E.
AU - González, Olga
AU - Compo, Nicole R.
AU - Stock, Michala K.
AU - Ruiz-Lambides, Angelina V.
AU - Martínez, Melween I.
AU - Wilson, Melissa A.
AU - Melin, Amanda D.
AU - Antón, Susan C.
AU - Walker, Christopher S.
AU - Sallet, Jérôme
AU - Newbern, Jason M.
AU - Starita, Lea M.
AU - Shendure, Jay
AU - Higham, James P.
AU - Brent, Lauren J.N.
AU - Montague, Michael J.
AU - Platt, Michael L.
AU - Snyder-Mackler, Noah
N1 - Funding Information: We thank those who make our research possible, particularly the CPRC and the Cayo Santiago Field Station staff, without whom we would not be able to study this amazing system. We also thank the staff of the Sabana Seca Field Station for assistance with sample collection and J. Cao, A. Lea, N. Simons, R. Campbell, J. Tung, I. Schneider-Crease and the University of Washington Basic Biology of Aging training group for valuable feedback at various stages throughout the project. Funding for this research was provided by the National Institutes of Health (R01-MH118203 to M.L.P., U01-MH121260 to N.S.-M., M.L.P., and J. Shendure, R01-MH096875 to M.L.P., R01-AG060931 to N.S.-M., L.J.N.B., and J.P.H., R00-AG051764 to N.S.-M., R01-NS097537 to J.M.N., R35-GM124827 to M.A.W., K99-AG075241 to K.L.C. and P40-OD012217 to M.I.M.), the National Science Foundation (BCS-1800558 to J.P.H. and BCS-1752393 to A.R.D.) and a pilot grant to N.S.-M. from the Brotman Baty Institute. K.L.C. was supported by National Institutes of Health fellowship T32-AG000057 during this research. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (https://commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc., subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc., subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research. (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101825 and MH101820), the University of North Carolina Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810) and the University of Pennsylvania (MH101822). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v8.p2. The results published here are in whole or in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org/). MayoRNAseq data were provided by the following sources: The Mayo Clinic Alzheimer’s Disease Genetic Studies, led by N. Taner and S. G. Younkin, Mayo Clinic, Jacksonville, FL, using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer’s Disease Research Center and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216 and R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, AZ. The Brain and Body Donation Program is supported by the NINDS (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the NIA (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. MSBB data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt from Mount Sinai School of Medicine. ROSMAP data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation and ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNA-seq), R01AG48015 (monocyte RNA-seq) RF1AG57473 (single-nucleus RNA-seq), U01AG32984 (genomics and whole-exome sequencing), U01AG46152 (ROSMAP AMP-AD and targeted proteomics), U01AG46161 (TMT proteomics), U01AG61356 (whole-genome sequencing, targeted proteomics and ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP) and the Translational Genomics Research Institute (genomics). Additional phenotypic data can be requested at www.radc.rush.edu. Funding Information: J. Shendure is a scientific advisory board member, consultant and/or cofounder of Cajal Neuroscience, Guardant Health, Maze Therapeutics, Camp4 Therapeutics, Phase Genomics, Adaptive Biotechnologies, Scale Biosciences and Sixth Street Capital. M.L.P. is a scientific advisory board member, consultant and/or cofounder of Blue Horizons International, NeuroFlow, Amplio, Cogwear Technologies, Burgeon Labs and Ashurst Cognitive Health and receives research funding from AIIR Consulting, the SEB Group, Mars Inc., Slalom Inc., the Lefkort Family Research Foundation, Sisu Capital and Benjamin Franklin Technology Partners. All other authors declare no competing interests. Funding Information: We thank those who make our research possible, particularly the CPRC and the Cayo Santiago Field Station staff, without whom we would not be able to study this amazing system. We also thank the staff of the Sabana Seca Field Station for assistance with sample collection and J. Cao, A. Lea, N. Simons, R. Campbell, J. Tung, I. Schneider-Crease and the University of Washington Basic Biology of Aging training group for valuable feedback at various stages throughout the project. Funding for this research was provided by the National Institutes of Health (R01-MH118203 to M.L.P., U01-MH121260 to N.S.-M., M.L.P., and J. Shendure, R01-MH096875 to M.L.P., R01-AG060931 to N.S.-M., L.J.N.B., and J.P.H., R00-AG051764 to N.S.-M., R01-NS097537 to J.M.N., R35-GM124827 to M.A.W., K99-AG075241 to K.L.C. and P40-OD012217 to M.I.M.), the National Science Foundation (BCS-1800558 to J.P.H. and BCS-1752393 to A.R.D.) and a pilot grant to N.S.-M. from the Brotman Baty Institute. K.L.C. was supported by National Institutes of Health fellowship T32-AG000057 during this research. Funding Information: The results published here are in whole or in part based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.org/ ). MayoRNAseq data were provided by the following sources: The Mayo Clinic Alzheimer’s Disease Genetic Studies, led by N. Taner and S. G. Younkin, Mayo Clinic, Jacksonville, FL, using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer’s Disease Research Center and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216 and R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, AZ. The Brain and Body Donation Program is supported by the NINDS (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the NIA (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research. MSBB data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by E. Schadt from Mount Sinai School of Medicine. ROSMAP data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation and ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNA-seq), R01AG48015 (monocyte RNA-seq) RF1AG57473 (single-nucleus RNA-seq), U01AG32984 (genomics and whole-exome sequencing), U01AG46152 (ROSMAP AMP-AD and targeted proteomics), U01AG46161 (TMT proteomics), U01AG61356 (whole-genome sequencing, targeted proteomics and ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP) and the Translational Genomics Research Institute (genomics). Additional phenotypic data can be requested at www.radc.rush.edu . Funding Information: The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health ( https://commonfund.nih.gov/GTEx ). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc., subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc., subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research. (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101825 and MH101820), the University of North Carolina Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810) and the University of Pennsylvania (MH101822). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v8.p2. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/12
Y1 - 2022/12
N2 - Aging is accompanied by a host of social and biological changes that correlate with behavior, cognitive health and susceptibility to neurodegenerative disease. To understand trajectories of brain aging in a primate, we generated a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques. We demonstrate that age-related changes in the level and variance of gene expression occur in genes associated with neural functions and neurological diseases, including Alzheimer’s disease. Further, we show that higher social status in females is associated with younger relative transcriptional ages, providing a link between the social environment and aging in the brain. Our findings lend insight into biological mechanisms underlying brain aging in a nonhuman primate model of human behavior, cognition and health.
AB - Aging is accompanied by a host of social and biological changes that correlate with behavior, cognitive health and susceptibility to neurodegenerative disease. To understand trajectories of brain aging in a primate, we generated a multiregion bulk (N = 527 samples) and single-nucleus (N = 24 samples) brain transcriptional dataset encompassing 15 brain regions and both sexes in a unique population of free-ranging, behaviorally phenotyped rhesus macaques. We demonstrate that age-related changes in the level and variance of gene expression occur in genes associated with neural functions and neurological diseases, including Alzheimer’s disease. Further, we show that higher social status in females is associated with younger relative transcriptional ages, providing a link between the social environment and aging in the brain. Our findings lend insight into biological mechanisms underlying brain aging in a nonhuman primate model of human behavior, cognition and health.
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UR - http://www.scopus.com/inward/citedby.url?scp=85142610972&partnerID=8YFLogxK
U2 - 10.1038/s41593-022-01197-0
DO - 10.1038/s41593-022-01197-0
M3 - Article
C2 - 36424430
AN - SCOPUS:85142610972
VL - 25
SP - 1714
EP - 1723
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 12
ER -