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Undulating changes in human plasma proteome profiles across the lifespan.

ABSTRACT: Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2-10, which supports a hypothesis that age-related molecular changes in blood could provide new 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 new bioinformatics approach that 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 that might offer potential targets for age-related diseases.

SUBMITTER: Lehallier B

PROVIDER: S-EPMC7062043 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Undulating changes in human plasma proteome profiles across the lifespan.

Lehallier Benoit B Gate David D Schaum Nicholas N Nanasi Tibor T Lee Song Eun SE Yousef Hanadie H Moran Losada Patricia P Berdnik Daniela D Keller Andreas A Verghese Joe J Sathyan Sanish S Franceschi Claudio C Milman Sofiya S Barzilai Nir N Wyss-Coray Tony T

Nature medicine 20191205 12

Aging is a predominant risk factor for several chronic diseases that limit healthspan<sup>1</sup>. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues<sup>2-10</sup>, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 ...[more]

PMID: 31806903

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Project description:Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their in vivo half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn's immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases.

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Undulating changes in human plasma proteome profiles across the lifespan.

Publications

Undulating changes in human plasma proteome profiles across the lifespan.

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