A deeper understanding of the molecular processes involved in psychological wellbeing in older adults is essential for advancing knowledge of underlying biological mechanisms. Leveraging proteomics data from 3,262 older adults (mean age=63.5 years, 55% female) of the English Longitudinal Study of Ageing (ELSA), we investigated the cross-sectional and longitudinal associations (before and after protein measurement) between 276 proteins and eudaimonic wellbeing, hedonic wellbeing, life satisfaction, and depressive symptoms, over 20-year span. For positive wellbeing, two proteins (DEFB4A and ECE1) were longitudinally associated with subsequent eudaimonic wellbeing trajectory. We further identified higher concentrations of 7, 8, and 2 proteins were linked to subsequent lower eudaimonic wellbeing, hedonic wellbeing, and life satisfaction, respectively. Sex differences in XCL1 and SLAMF7 were observed, associated with lower eudaimonic and hedonic wellbeing in males. These findings link human psychological wellbeing to regulation of several biological pathways, particularly involving cytokine regulation, neurotrophic signaling, inflammatory and immune systems.

The authors have declared no competing interest.

We would like to thank the participants in ELSA for their contribution to the research. The English Longitudinal Study of Ageing is funded by the National Institute on Aging (grant number R01AG17644) and the National Institute for Health and Care Research (198/1074-02). The National Institute of Aging (NIA) (grant Number [R01AG17644]) funded the proteomics data curation in ELSA. J.G. is supported by the NIA (grant Number [R01AG17644]). The funders had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical consent has been obtained for all waves and components of ELSA, according to the ethical approval system in operation at the time and in accordance with the Declaration of Helsinki.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The ELSA data is available on the UK Data Service.