The blood proteome predicts the impact of circulating factors on age-related mitochondrial health

Circulating non-cellular factors, such as plasma proteins, contribute to various features of aging. To determine the impacts of endogenous circulating factors on human age-related bioenergetic decline, we treated primary human fibroblasts with serum samples representing the adult life-course. Our results demonstrate that the maximal mitochondrial bioenergetic capacity of fibroblasts treated with serum is negatively correlated with the chronological and epigenetic age of the serum donor. Using targeted proteomics, we identified plasma proteins associated with the bioenergetic effects of serum. We then utilized elastic net, a linear regression modeling technique, to derive a novel proteomic signature of age-related mitochondrial differences. MitoAge is a 25-protein signature of age-related mitochondrial health that predicts the systemic bioenergetic effects of circulating factors and is related to differences in physical function across human aging. Signatures that report on cellular hallmarks of aging, such as mitochondrial function, represent a new generation of mechanistically-informed biomarkers of biological aging. GRAPHICAL ABSTRACT: In this study, we describe the development of a novel proteomic signature, MitoAge. This signature was developed by utilizing human primary fibroblasts treated with serum samples representing the adult human life-course and analyzing how resulting respirometry correlated with chronological age, epigenetic age, and abundance of serum proteins. Utilizing machine learning techniques, we derived a 25-protein signature which can predict bioenergetics and physical features related to aging. Application and utility of this signature may be used to identify novel drivers of health and longevity.