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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1843-1850 |
| Number of pages | 8 |
| Journal | Nature Medicine |
| Volume | 25 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2019 |
Funding
All participants from the Interval cohort gave informed consent before joining the study and the National Research Ethics Service approved this study (11/EE/0538) The LonGenity study was approved by the Institutional Review Board (IRB) at the Albert Einstein College of Medicine. The IRB has determined that our research using VAseattle, GEHA, PRIN06 and PRIN09 cohorts does not meet the definition of human subject research per STANFORD's HRPP policy because 1) we are not obtaining or receiving private individually identifiable information 2) data or specimens were not collected specifically for this study 3) no direct intervention or interaction. For these reasons, this part of the study did not require approval from the IRB We thank the members of the Wyss-Coray laboratory for feedback and support. We thank the clinical staff for human blood and plasma collection/coordination. We thank A. Butterworth for his help in getting access to the INTERVAL proteomics data. The AddNeuroMed data are from a public–private partnership supported by EFPIA companies and the European Union Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection were I. Kłoszewska (Lodz), S. Lovestone (London), P. Mecocci (Perugia), H. Soininen (Kuopio), M. Tsolaki (Thessaloniki) and B. Vellas (Toulouse); imaging leads were A. Simmons (London), L.O. Wahlund (Stockholm) and C. Spenger (Zurich); and bioinformatics leads were R. Dobson (London) and S. Newhouse (London). This work was supported by National Institutes of Health National Institute on Aging (NIA) F32 1F32AG055255 01A1 (D.G.), Hungarian Brain Research Program Grant No. 2017-1.2.1-NKP-2017-00002 (T.N.), the Fulbright Foreign Student Program (T.N.), the Cure Alzheimer’s Fund (T.W.-C.), Nan Fung Life Sciences (T.W.-C.), the NOMIS Foundation (T.W.-C.), the Stanford Brain Rejuvenation Project (an initiative of the Stanford Wu Tsai Neurosciences Institute), the Paul F. Glenn Center for Aging Research (T.W.-C.), NIA R01 AG04503 and DP1 AG053015 (T.W.-C.) and the NIA-funded Stanford Alzheimer’s Disease Research Center P50AG047366, NIA K23AG051148 (S.M.), R01AG061155 (S.M.), the American Federation for Aging Research (S.M.), R01AG044829 (J.V. and N.B.), NIA R01AG057909 (N.B.), the Nathan Shock Center of Excellence for the Basic Biology of Aging P30AG038072 (N.B.) and the Glenn Center for the Biology of Human Aging (N.B.). Human cohort characteristics. INTERVAL cohort. Participants in the INTERVAL randomized controlled trial (ISRCTN24760606) were recruited with the active collaboration of the National Health Service (NHS) Blood and Transplant (http:// www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping were co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr. ac.uk/) and the NIHR Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. The INTERVAL study was funded by NHS Blood and Transplant (11-01-GEN). The academic coordinating center for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194) and the NIHR Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust. Proteomic assays were funded by the academic coordinating center for INTERVAL and Merck Research Laboratories (Merck & Co.). A complete list of the investigators and contributors to the INTERVAL trial was previously reported15. The academic coordinating center would like to thank blood donor center staff and blood donors for participating in the INTERVAL trial. For more information, see the Nature Research Reporting Summary. Proteomics measurements from 3,301 human plasma samples (1,685 males and 1,616 females) from two different subcohorts were used for this study. Age ranged from 18 to 76 years with a median age of 45 years (first quartile=31; third quartile=55). Sample selection, processing and preparation were detailed previously26.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology