Proteomics in aging research: A roadmap to clinical, translational research

Abstract

The identification of plasma proteins that systematically change with age and, independent of chronological age, predict accelerated decline of health is an expanding area of research. Circulating proteins are ideal translational “omics” since they are final effectors of physiological pathways and because physicians are accustomed to use information of plasma proteins as biomarkers for diagnosis, prognosis, and tracking the effectiveness of treatments. Recent technological advancements, including mass spectrometry (MS)‐based proteomics, multiplexed proteomic assay using modified aptamers (SOMAscan), and Proximity Extension Assay (PEA, O‐Link), have allowed for the assessment of thousands of proteins in plasma or other biological matrices, which are potentially translatable into new clinical biomarkers and provide new clues about the mechanisms by which aging is associated with health deterioration and functional decline. We carried out a detailed literature search for proteomic studies performed in different matrices (plasma, serum, urine, saliva, tissues) and species using multiple platforms. Herein, we identified 232 proteins that were age‐associated across studies. Enrichment analysis of the 232 age‐associated proteins revealed metabolic pathways previously connected with biological aging both in animal models and in humans, most remarkably insulin‐like growth factor (IGF) signaling, mitogen‐activated protein kinases (MAPK), hypoxia‐inducible factor 1 (HIF1), cytokine signaling, Forkhead Box O (FOXO) metabolic pathways, folate metabolism, advance glycation end products (AGE), and receptor AGE (RAGE) metabolic pathway. Information on these age‐relevant proteins, likely expanded and validated in longitudinal studies and examined in mechanistic studies, will be essential for patient stratification and the development of new treatments aimed at improving health expectancy.

Proteomics and Epidemiological Models of Human Aging

“…Most recently, scientists realized that information on individual protein levels is insufficient to understand the complex mechanisms of aging and chronic diseases and the focus shifted to protein "signatures" or a multi-protein model (Tanaka et al, 2018;Lehallier et al, 2019;Moaddel et al, 2021). In our recent study, a weighted average of 76 proteins were found that correlated with chronological age, and independent of chronological age predict health outcomes (Tanaka et al, 2018).…”

“…High circulating levels of proinflammatory cytokines, such as IL-6 have been associated both cross-sectionally and prospectively with major age-related chronic diseases as well as with disability and frailty (Maggio et al, 2013). The mechanisms of these associations are unclear and have been connected with down-regulation of the biological activity of Insulin-like Growth Factor-1 (IGF-1), which contributes to the decline of muscle strength with aging (Maggio et al, 2013;Johnson et al, 2020;Moaddel et al, 2021). A number of other inflammatory biomarkers have been associated with aging and age-associated health and functional deterioration, including C-Reactive Protein, Cystatin-C, TNFalpha receptors I and II, Interleuking-1 receptor antagonists and many others (Dinarello, 2006;Jylha et al, 2007;Odden et al, 2010;Bauernfeind et al, 2016).…”

“…Two recent systematic reviews have identified age-associated proteins assessed with different methods and with different matrixes (Johnson et al, 2020;Moaddel et al, 2021). When enrichment analysis was performed on the list of proteins identified in these reviews, the biological pathways that emerged are widely recognized as playing a role in aging (Johnson et al, 2020;Moaddel et al, 2021).…”

“…Two recent systematic reviews have identified age-associated proteins assessed with different methods and with different matrixes (Johnson et al, 2020;Moaddel et al, 2021). When enrichment analysis was performed on the list of proteins identified in these reviews, the biological pathways that emerged are widely recognized as playing a role in aging (Johnson et al, 2020;Moaddel et al, 2021). These pathways include the human complement system, the IGF1 signaling pathway, the PI3K-Akt-mTOR-signaling pathway, the mitogen-activated protein kinases (MAPK) signaling pathway, the Hypoxia-inducible factor 1 (HIF-1) signaling pathway, cytokine signaling pathways, FOXO signaling pathway, Advance glycation end products (AGE)/receptor AGE (RAGE) pathway, folate metabolism and mRNA splicing-major pathway.…”

The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy

“…The immediate consequence of the decline in proteolytic capacity is the accumulation of long-lived proteins in aged organisms, many of which accumulate glycation-derived damage in their aminoacid sequences. The accumulation of AGEs occurs in an age-related and -dependent manner ( [4,9]) and a recent proteomic analysis in aging research has revealed that AGE biology contains an enriched metabolic pathway associated with age-associated proteomes [57].…”