Biophysical and biomolecular determination of cellular age in humans

Abstract

Ageing research has focused either on assessing organ- and tissue-based changes, such as lung capacity and cardiac function, or on changes at the molecular scale such as gene expression, epigenetic modifications and metabolism. Here, by using a cohort of 32 samples of primary dermal fibroblasts collected from individuals between 2 and 96 years of age, we show that the degradation of functional cellular biophysical features—including cell mechanics, traction strength, morphology and migratory potential—and associated descriptors of cellular heterogeneity predict cellular age with higher accuracy than conventional biomolecular markers. We also demonstrate the use of high-throughput single-cell technologies, together with a deterministic model based on cellular features, to compute the cellular age of apparently healthy males and females, and to explore these relationships in cells from individuals with Werner syndrome and Hutchinson–Gilford progeria syndrome, two rare genetic conditions that result in phenotypes that show aspects of premature ageing. Our findings suggest that the quantification of cellular age may be used to stratify individuals on the basis of cellular phenotypes and serve as a biological proxy of healthspan.

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Figure 1: Changes in cell biophysics: a hallmark of ageing.
Figure 2: Comprehensive biomolecular assessment of age-dependent cellular phenotypes.
Figure 3: Cellular heterogeneity: a hallmark of ageing.
Figure 4: Univariate and bivariate age-associated parameters provide a reliable prediction of the functional age index of donors on the basis of cellular features.
Figure 5: Cellular biological age prediction on the basis of morphological features.

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Acknowledgements

We acknowledge the financial support for this work by the National Institutes of Health; grant numbers U54CA143868 (D.W.), R01CA174388 (D.W.) and P30AG021334 Johns Hopkins Older Americans Independence Center (J.W.). Special thanks to M. Maggioni, and Q-L. Xue for feedback and discussion with regards to the statistical methodologies employed in this study.

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J.M.P., D.W., J.W. and J.S.H.L. conceived and designed the study. J.M.P., W.W., S.M., J.D. and I.A. performed the experiments. J.M.P., P.-H.W. and D.W. analysed the results. P.-H.W. and J.M.P. developed the analysis software and algorithms. J.C. and R.F. generated and analysed the secretion microchip data. D.W., P.-H.W., D.M.G. and J.W. supervised the study. J.M.P., D.W. and J.W. wrote and edited the manuscript.

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Correspondence to Denis Wirtz.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary figures, tables and references. (PDF 1443 kb)

Supplementary dataset

Replicative history of the cells, and parameter list and correlations. (XLSX 2520 kb)

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Phillip, J., Wu, P., Gilkes, D. et al. Biophysical and biomolecular determination of cellular age in humans. Nat Biomed Eng 1, 0093 (2017). https://doi.org/10.1038/s41551-017-0093

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