Systemic rejuvenating factors and human aging phenotypes.

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Recent animal studies have identified several polypeptides or proteins that can reverse or accelerate aging phenotypes. These candidate “rejuvenating factors” include growth/differentiation factor 11 (GDF11), growth/differentiation factor 8 (GDF8), and inhibitors of GDF11 and GDF8: GDF11 and GDF8 propeptides, follistatin, follistatin-related protein 3, WFIKKN1, and WFIKKN2. Two other important candidates are oxytocin and eotaxin. Although these circulating rejuvenating factors are associated with aging phenotypes in animal models, a major unanswered question is whether these circulating proteins or polypeptides are relevant to human aging phenotypes. These polypeptides or proteins have been difficult to study in the blood using conventional immunoassays, since some of the peptides or proteins exist in multiple isoforms, undergo post- translational modifications such as cleavage or terminal degradation, or have high sequence identity with each other. In addition, circulating antagonists can inhibit the biological activity of GDF8 and GDF11. In order to overcome these obstacles, we developed a novel multiplexed selected reaction monitoring assay using liquid chromatography-tandem mass spectrometry that measures thirteen plasma proteins or polypeptides representing eight important proteins in rejuvenation research. We will test the hypothesis that plasma concentrations of these candidate rejuvenating factors are independently associated with and predict specific aging phenotypes in older adults. Our aim is to conduct a comprehensive assessment of circulating rejuvenating factors and their relationships to specific aging phenotypes in humans. To address this aim, we will measure these circulating factors in participants of the Baltimore Longitudinal Study of Aging (BLSA) and the Lifestyle Interventions and Independence for Elders (LIFE) Study. Aging phenotypes will include prevalent and incident sarcopenia, lower extremity physical performance, mobility disability, cognition, memory, cardiac hypertrophy, osteoporosis, insulin resistance, and anemia. By the end of the project, we should be able to verify or refute the association of these candidate rejuvenating factors with phenotypes of human aging. Verification of a role for rejuvenating factors in human aging phenotypes should advance risk stratification and targeting of specific pathways in the prevention or treatment of adverse aging outcomes.