Proteomics-based aging clocks in midlife and late-life and risk of dementia

Authors: SEDAGHAT, SANAZ - University Of Minnesota; PARK, SAEUN - University Of Minnesota; WALKER, ROB - University Of Minnesota; WANG, SHUO - University Of Minnesota; LIU, JIALING - University Of Minnesota; HUGHES, TIMOTHY - Wake Forest University School Of Medicine; SABAYAN, BEHNAM - University Of Minnesota; TANG, WEIHONG - University Of Minnesota; CORESH, JOSEF - New York University School Of Medicine; PANKOW, JAMES - University Of Minnesota; WALKER, KEENAN - National Institute On Aging (NIA, NIH); CASANOVA, RAMON - Wake Forest University School Of Medicine; DUBIN, RUTH - University Of Texas Southwestern Medical Center; DEO, RAJAT - University Of Pennsylvania; ROTTER, JEROME - Harbor-Ucla Medical Center; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); GANZ, PETER - University Of California San Francisco (UCSF); LUTSEY, PAMELA - University Of Minnesota; GUAN, WEIHUA - University Of Minnesota; PRIZMENT, ANNA - University Of Minnesota

Submitted to: Communications Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/4/2025
Publication Date: 8/14/2025
Citation: Sedaghat, S., Park, S., Walker, R.F., Wang, S., Liu, J., Hughes, T.M., Sabayan, B., Tang, W., Coresh, J., Pankow, J.S., Walker, K.A., Casanova, R., Dubin, R., Deo, R., Rotter, J.I., Wood, A.C., Ganz, P., Lutsey, P.L., Guan, W., Prizment, A. 2025. Proteomics-based aging clocks in midlife and late-life and risk of dementia. Communications Medicine. 5. Article 353. https://doi.org/10.1038/s43856-025-01096-y.
DOI: https://doi.org/10.1038/s43856-025-01096-y

Interpretive Summary: Obesity is known to contribute to faster biological aging, and this study explored whether people who are biologically "older" than their actual age—measured using proteins in the blood that increase as we age—are more likely to have memory and thinking problems or develop dementia. Data from several large national studies was used create "aging clocks" based on these proteins to estimate biological age in midlife and late-life. People whose biological age was higher than their real age performed worse on cognitive tests and were more likely to develop dementia, especially later in life. The study suggests that accelerated aging can be a warning sign for future brain health problems, and highlights the need to understand how excess weight may speed up aging and affect brain health to help guide prevention efforts that reduce the risk of dementia.

Technical Abstract: Biological age can be quantified by composite proteomic scores, called proteomics-based aging clocks (PACs). We investigated whether a discrepancy between chronological and biological age in midlife and late-life is associated with cognition and dementia risk. We used two longitudinal population-based studies: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA). PACs were created in ARIC at midlife (mean age: 58 years, 57% female, n=11,758) and late-life (mean age: 77 years, 56% female, n=4934) using elastic net regression models in two-thirds of dementia-free participants and validated in the remaining one-third of participants. Proteomics-based age acceleration (PAA) was calculated as residuals after regressing PACs on chronological age. We validated the midlife PAC in the MESA cohort (mean age: 62 years, 52% female, n=5829). We used multivariable linear and Cox proportional hazards regression to assess the association of PAA with cognitive function and dementia incidence, respectively. In ARIC, every five years, PAA is associated with lower global cognition: difference: -0.11, 95% confidence interval [CI]: -0.16, -0.06) using midlife PAA and difference: -0.17, CI: -0.23, -0.12 using late-life PAA. Midlife PAA is associated with higher dementia risk (hazard ratio [HR]: 1.20 [CI: 1.04, 1.36]) and more prominently when using late-life PAA (HR: 2.14 [CI:1.67, 2.73]). Similar findings are observed in MESA: PAA is associated with lower global cognitive function (difference: -0.08 [CI: -0.14, -0.03]) and higher dementia risk (HR:1.23 [CI: 1.04, 1.46]). Accelerated biological age is associated with lower cognition and a higher risk of dementia in midlife and more prominently in late life.