Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21–107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2–30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.
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The SOMAscan proteomic data are available in Supplementary Table 16 of a previous study20. According to Danish legislation, transfer and sharing of individual-level data requires prior approval from the Danish Data Protection Agency, which requires that data sharing requests be dealt with on a case-by-case basis. For this reason, the data cannot be deposited in a public database, and data presentation at an individual level is avoided. However, we welcome any enquiries regarding collaboration and individual requests for data sharing.
All codes can be made available upon request from the corresponding author.
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We thank G. Eschweiler, B. Wegenast-Braun, O. Preische, T. Gasser (Tübingen, Germany), L. Walker (Atlanta, GA), O. Hahn (Stanford) and all other members of our laboratories for helpful comments. This work was made possible by a generous grant from Cure Alzheimer’s Fund (S.A.K. and M.J.), the National Institute on Aging (DP1-AG053015 to T.W.-C.) and the NOMIS Foundation (T.W.-C.). The Danish Aging Research Center is supported by a grant from the VELUX Foundation and funded the centenarian study. We also thank the participants of this study for their time and personal contribution.
The authors declare no competing interests.
Peer review information Nature Aging thanks Henne Holstege, Thomas Perls and P. Eline Slagboom for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a-c, Plasma NfL concentration of the human age cohort presented in Fig. 1b. Scatter plots for (a) log NfL concentration, (b) log NfL concentration for females versus males, and (c) NfL variance in plasma with aging (n = 122). NfL variance was calculated using a 10-year sliding window. Local polynomial regression fitting using LOESS was done. Thick lines represent LOESS fitted values and shaded areas representing the standard errors around the model estimates. Although the cohort appears too small for a reliable description of the age-related changes, the data are consistent with previous work of a slow and more linear increase until approximately 70 years of age, followed by a much more rapid increase (Khalil, M., et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun 11, 812, 2020). Interestingly, the present data may suggest that this rapid increase reaches a plateau in nonagenarians and centenarians. It is possible that at these ages individuals with very high NfL levels die out and thus reduce the further increase on a population level (Christensen, K., McGue, M., Petersen, I., Jeune, B. & Vaupel, J.W. Exceptional longevity does not result in excessive levels of disability. Proc Natl Acad Sci U S A 105, 13274, 2008). d-f, Plasma NfL concentration of the aging C57BL/6 J mouse cohort presented in Figure 3a-c. Scatter plots for (d) log NfL concentration; (e) log NfL concentration for females versus males; and (f) NfL variance in plasma with aging (n = 114). NfL variance was calculated using a 5-month sliding window. Local polynomial regression fitting using LOESS was done. Thick lines represent LOESS fitted values and shaded areas represent the standard errors around the model estimates. Similar to the human data, a slow and more linear increase until approximately 15–18 months of age is followed by a much more rapid increase with an increased variance towards the end of the lifespan.
a, NfL gene expression in humans from the GTEx consortium (see Online Methods). NEFL is highly expressed in all brain regions. In all other tissues the expression is lower. b, Tissue-specific NfL gene expression in C57BL/6JN mice (see Methods). Again, Nefl is highly expressed in brain and lowly expressed in other tissues. Data represent mice at 3 months of age (top) and 18 months of age (bottom). Box plots are showing center line as the median, the box as the first and third quartile and the whiskers as the adjacent values which are the largest observation that is less or equal than the third quartile + 1.5 x interquartile range and the lowest observation that is greater or equal than the first quartile - 1.5 x interquartile range. c, NfL gene expression in non-myeloid brain cells from the Tabula Muris Senis consortium (see Online Methods). The FACS data is visualized using a UMAP. Murine brain cells are color-coded according cell ontology class (left). Cells expressing Nefl (log cpm threshold of 1.954) are visualized on the right where 22 % (66/303) of the cells correspond to medium spiny neurons and 61% (185/303) to neurons.
Extended Data Fig. 3 Physical activity and cognitive ability in centenarians as predictors of survival and their association with plasma NfL.
a, b, Kaplan-Meier survival curve for Activity of Daily Living (ADL: no (n = 38), moderate (n = 53), severe disability(n = 44)) and Mini-Mental State Estimation (MMSE: 0–17 (n = 37), 18–23 (n = 45), 24–30 (n = 46)). For Cox regression analysis see Table 2. c, d, Plasma NfL concentrations (Box plots showing center line as the median, the box as the first and third quartile and the whiskers as the adjacent values which are the largest observation that is less or equal than the third quartile + 1.5 x interquartile range and the lowest observation that is greater or equal than the first quartile - 1.5 x interquartile range) for the different ADL and MMSE categories. The association between NfL and ADL across all three groups was not significant with an estimated median increase of NfL of 3.7 pg/ml with increasing disability (95% CI: (−4.2; 11.7), p = 0.354). In contrast, the association between NfL and MMSE was significant across all three groups with an estimated median decrease of NfL of 8.5pg/ml with increasing MMSE (95% CI: (2.3; 14.7), p = 0.008).
The size of the prediction was estimated as area under the curve (AUC) from the prediction of survival from blood sample until a certain age (the x-axis of time-dependent AUC). a, Survival prediction for the centenarians up to 103 years of age. The average AUC over the follow-up period were for the centenarians 0.65, 95% CI: (0.56: 0.75), 0.62, 95% CI: (0.52: 0.72) and 0.64, 95% CI: (0.54: 0.73) for NfL, MMSE and ADL, respectively. b, Survival prediction for the 93-year-old nonagenarians up to 100 years of age. The average AUC over the follow-up period were for the nonagenarians 0.68, 95% CI: (0.59: 0.76), 0.55, 95% CI: (0.46: 0.64) and 0.63, 95% CI: (0.54: 0.71) for NfL, MMSE and ADL, respectively. These observations indicate that blood NfL predicts survival better compared to MMSE and ADL.
Supplementary Table 3.
Nomenclature of 1,305 proteins analyzed in the Stanford aging cohort using the SOMAscan assay. Corresponding external identifiers were provided by SomaLogic.
Associations between plasma NfL levels and 1,305 protein levels measured by the SOMAscan assay. A linear model for each of the 1,305 proteins was fitted and adjusted for age, sex and subcohort (n = 122). Type II SS were calculated and tested using a two-tailed F-test. Q values were estimated using the BH approach.
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Kaeser, S.A., Lehallier, B., Thinggaard, M. et al. A neuronal blood marker is associated with mortality in old age. Nat Aging 1, 218–225 (2021). https://doi.org/10.1038/s43587-021-00028-4