Anthropometrics and Baseline, Untargeted Omics to Characterize Older Adults with Frailty Pursuing Physical Therapy: A Pilot Study

<em>Background</em>: Older adults are vulnerable to frailty which can lead to adverse outcomes. Physical therapy (PT) has proven to be a robust intervention to prevent and potentially reverse the frailty phenotype in this population. However, the underlying biological mechanisms of frailty are still heavily debated and unclear. Metabolomics and proteomics are ways to measure blood biomarkers and proteins, which can perhaps characterize frailty from a molecular perspective. Thus, we examined baseline metabolomic/proteomic biomarkers alongside baseline and follow-up physical function/anthropometric measures and subjective physical function questionnaires associated with different frailty states, with a goal of advancing precision medicine in a pilot study of older adults pursuing physical therapy. <em>Methods</em>: We conducted a prospective study of 18 adults (&ge;65 years) from primary care, referred to physical therapy. Frailty was classified using both a modified Cumulative Deficit Index (38 variables), and the Fried Frailty Index (5 variables). Baseline and follow-up gait speed, grip strength, Katz Activities of Daily Living (ADL; 0-50), Lawton Instrumental Activities of Daily Living (IADL; 0-100), Community Health Activities Model Program for Seniors (CHAMPS) (hrs/wk doing moderate activity), Brief Resilience Scale (BRS), Patient Activation Measure (PAM-13), and Pittsburgh Fatiguability Scale were assessed. Baseline plasma samples underwent untargeted metabolomics and proteomics. Proteomics used Mag-Net enrichment to detect low-abundance proteins, followed by LC-MS/MS analysis on a Thermo Neo-Orbitrap Astral. Metabolomics involved methanol extraction and CE-MS/MS analysis using a 908Devices ZipChip-Thermo Fusion Lumos. <em>Results</em>: The mean participant age was 77.1&plusmn;5.5 (33% female). Using the Cumulative Deficit Index, 12 participants were classified as pre-frail and 6 as frail; and according to the Fried Frailty Index, 6 participants were classified as robust, 7 as pre-frail, and 5 as frail. When stratifying by the Cumulative Deficit Index, baseline gait speed (p=0.01), IADL scores (p=0.005), and CHAMPS scores (p=0.02) significantly favored the pre-frail group. When stratifying by the Fried Index, baseline ANOVA tests showed significant differences in gait speed (p=0.03), IADL (p&lt;0.001), CHAMPS (p=0.04), PAM-13 (p=0.03), and Pittsburgh Fatiguability (p&lt;0.001). Proteomics analysis showed that among 4,300 quantified proteins, ~60 differed with regard to the Cumulative Deficit Index (p&lt; 0.05; log2-fold change &plusmn;0.5) with ~40 proteins elevated in frail individuals, including nucleosome-related proteins (H2B, H3C1, H2AC3, H3-4). Metabolomic analysis assessed ~275 metabolites, quantifying 115. Nicotinamide was significantly down-regulated in the frail group (p&lt; 0.05; log2-fold change &lt;0.8). <em>Conclusions</em>: This pilot study suggests that circulating nucleosomes&ndash;complexes of histones and DNA&ndash;may serve as biomarkers for aging and related conditions. And analyzing such histones in conjunction with nicotinamide&mdash;a precursor of NAD⁺ and key coenzyme in DNA repair and mitochondrial function&mdash;can potentially delineate one&rsquo;s oxidative stress profile and susceptibility to DNA damage, which in turn, can be related to age-related conditions and functional decline in older adults.<strong><br /></strong>