Undulating changes in human plasma proteome profiles across the lifespan

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Abstract

Aging is a predominant risk factor for numerous chronic diseases that limit healthspan ₁. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues _{2–
10}, which supports a hypothesis that age-related molecular changes in blood could provide novel insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18–95 years old) and developed a novel bioinformatics approach, which uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh, and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways, which might offer potential targets for age-related diseases.

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Most cited references 33

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Gene Ontology: tool for the unification of biology

Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)

Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.

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Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

Saul Villeda, Kristopher E Plambeck, Jinte Middeldorp … (2014)

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

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Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med.

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 5 November 2019

Publication date (Electronic): 05 December 2019

Publication date (Print): December 2019

Publication date PMC-release: 05 June 2020

Volume: 25

Issue: 12

Pages: 1843-1850

Affiliations

[1 ]Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA

[2 ]Wu Tsai Neurosciences Institute, Stanford University, Stanford, California, USA

[3 ]Paul F. Glenn Center for the Biology of Aging, Stanford University, Stanford, California, USA

[4 ]Department of Veterans Affairs, VA Palo Alto Health Care System, Palo Alto, California, USA

[5 ]Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA

[6 ]Institute of Cognitive Neuroscience and Psychology, Hungarian Academy of Sciences Research Centre for Natural Sciences, Budapest, Hungary

[7 ]Clinical Bioinformatics, Saarland University, Saarbrücken, Germany

[8 ]Institute for Aging Research, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

[9 ]Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA

[10 ]University of Bologna, Bologna, Italy

[11 ]National Research Lobachevsky State University of Nizhny Novgorod, Russia

[12 ]Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA

Author notes

Author Contributions

B.L. and T.W.-C. planned the study, D.B., C.F., S.M., J.V., S.S. and N.B. provided human plasma samples, N. S., S.E.L and H.Y performed the mouse experiments, B.L analyzed the data with contributions from T.N. and A.K., P.M.L. developed the shiny app, B.L., D.G. and T.W.-C. wrote the manuscript, A.K, C.F, S.M, J.V., S.S., N.B. and T.W.-C. supervised the study, all authors edited and reviewed the manuscript.

[* ]Correspondence: twc@ 123456stanford.edu (T.W.-C.) and lehallib@ 123456stanford.edu (B.L.)

Article

Manuscript ID: NIHMS1541641

DOI: 10.1038/s41591-019-0673-2

PMC ID: 7062043

PubMed ID: 31806903

SO-VID: 7677cdcf-50a4-4242-84a3-e5f3b3e2e4e1

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Undulating changes in human plasma proteome profiles across the lifespan

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Most cited references 33

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Gene Ontology: tool for the unification of biology

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

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