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. 2025 Sep;24(9):e70144.
doi: 10.1111/acel.70144. Epub 2025 Aug 4.

A Frailty-Based Plasma Proteomic Signature Capturing Overall Health and Well-Being in Older Adults

Sanish Sathyan  1   2 , Fangyu Liu  3 , Toshiko Tanaka  4 , Luigi Ferrucci  4 , Emmeline Ayers  1   2 , B Gwen Windham  5 , Tina Gao  6 , Erica F Weiss  1 , Julián Candia  4 , Josef Coresh  7 , Nir Barzilai  6   8 , Sofiya Milman  6   8 , Keenan A Walker  3 , Joe Verghese  1   2
Affiliations

A Frailty-Based Plasma Proteomic Signature Capturing Overall Health and Well-Being in Older Adults

Sanish Sathyan et al. Aging Cell. 2025 Sep.

Abstract

Frailty is an age-related syndrome characterized by an increased vulnerability to adverse health outcomes in the face of stressors. By deriving a blood-based proteomic signature for frailty, the current study aimed to enhance the understanding of frailty biology and created a person-specific predictor for the risk of frailty and other adverse age-related health outcomes. A 25-protein signature (proteomic frailty index [pFI]) predictive of the cumulative frailty index (FI) in the LonGenity cohort was derived using a penalized regression method. The pFI was significantly correlated with the FI at baseline (Pearson r = 0.58) and showed significant associations with age-related chronic conditions, incident mortality, and clinical measures. In an independent cohort of 5195 participants in the Atherosclerosis Risk in Communities study, pFI was successfully validated with measured FI (r = 0.61, p < 0.001) and was associated with physical frailty at baseline (p < 0.001). The pFI was significantly associated with physical, clinical, and cognitive measures, as well as incident mortality (HR [95% CI] = 1.13 [1.12-1.14]) and dementia (HR [95% CI] = 1.07 [1.05-1.09]) after accounting for demographic factors. The pFI was further validated against FI (r = 0.45, p < 0.001) in a second independent study in 654 participants from the Baltimore Longitudinal Study of Aging. In conclusion, we identified and validated a 25-protein signature as an index of frailty that also captures overall well-being, health, and risk for key age-related diseases.

Keywords: SomaScan assay; frailty; proteomic frailty index; proteomics.

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Conflict of interest statement

Dr. Coresh has served on the SomaLogic scientific advisory committee during 2022–2023. The remaining authors declare no competing interests.

Figures

FIGURE 1
FIGURE 1
Proteomic Frailty Index. (a) Key proteins graphically depicted based on the contribution towards pFI. (b) Correlation of observed cumulative frailty index and predicted frailty index using proteomic data. Correlation of predicted frailty using proteomic markers and cumulative frailty index was 0.58. (c) Sex specific correlation showing similar level of Pearson correlation. (d) Correlation of pFI with chronological age.
FIGURE 2
FIGURE 2
Proteomic Frailty Index and mortality. (a) Kaplan–Meier survival curves for time to death for LonGenity participants based on proteomic frailty index tertile (b) ROC curves for model containing pFI and FI with mortality. AUC of the pFI and FI model was 0.82 accounting for age and sex. (c, d) Kaplan–Meier survival curves for time to death for ARIC and BLSA participants respectively based on proteomic frailty index tertile. Model adjusted for age, sex, race‐center composite variable (ARIC) or race (BLSA).
FIGURE 3
FIGURE 3
Association of pFI with prevalent physical frailty in ARIC (a) and BLSA (b) at baseline for the analysis.
FIGURE 4
FIGURE 4
Proteomic Frailty Index and Dementia Kaplan–Meier survival curves for time to incident dementia for ARIC visit 5 participants based on proteomic frailty index tertile.
See this image and copyright information in PMC

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