Exploring mortality-linked proteins: Understanding their association with biological aging, disease phenotypes, signaling pathways, and their implications for longevity
*Correspondence to:
Nir Barzilai, Department of Medicine, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
E-mail: nir.barzilai@einsteinmed.edu
Sanish Sathyan, Department of Neurology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Molecular Biology, Kannur University, Kannur, Keralam 670661, India. E-mail: sanishsathyan@kannuruniv.ac.in
Sanish Sathyan, Department of Neurology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Molecular Biology, Kannur University, Kannur, Keralam 670661, India. E-mail: sanishsathyan@kannuruniv.ac.in
Geromedicine. 2027;3:202609. 10.70401/Geromedicine.2026.0042
Received: February 13, 2026Accepted: October 09, 2026Published: October 09, 2026
This manuscript is made available in its unedited form to allow early access to the
reported findings. Further editing will be completed before final publication. As
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Abstract
Aims: To identify plasma proteins associated with all-cause mortality and determine their relationships with chronic disease burden and biological aging at both the organismal and organ-specific levels, thereby providing insights into the biological mechanisms underlying healthy aging and longevity.
Methods: We conducted a prospective cohort study of 1,025 older adults from the LonGenity study, analyzing 4,265 plasma proteins. Associations between protein levels and all-cause mortality were evaluated using Cox proportional hazards regression over a mean follow-up of 8.05 years. Mortality-associated proteins were further examined for their relationships with chronic disease burden and proteome-derived measures of organismal and organ-specific biological aging. Findings were independently validated in 1,124 participants from the Baltimore Longitudinal Study of Aging (BLSA).
Results: Seventeen plasma proteins were significantly associated with all-cause mortality. Higher levels of Epidermal Growth Factor Receptor (ERBB1) and Anthrax Toxin Receptor 2 (ANTXR2) were associated with lower mortality risk and younger biological age across multiple organ systems. Conversely, higher levels of MIC-1 (GDF15), HE4, and IGFBP-2 were associated with increased mortality and older biological age across multiple organ systems. Specifically, elevated MIC-1 was associated with older organismal biological age, whereas ERBB1 was associated with younger liver biological age. These associations were independently replicated in the BLSA cohort.
Conclusion: Mortality-associated plasma proteins reflect key biological pathways involved in biological aging, physiological homeostasis, and systemic stress. These biomarkers may have potential utility for identifying individuals at increased mortality risk and advancing the development of biomarkers for healthy aging and longevity.
Keywords
Mortality, proteomics, SomaScan® assay, death, biological aging
References
-
1. Herrmann W, Herrmann M. The importance of telomere shortening for atherosclerosis and mortality. J Cardiovasc Dev Dis. 2020;7(3):29.[DOI]
-
3. Kumar N, Walia HK. Cellular senescence and stem cell exhaustion: Implications for aging and regeneration. In: Qamar I, Maurya PK, editors. Cellular senescence, age-related disorders, and emerging treatments. Singapore: Springer; 2025. p. 103-133.[DOI]
-
5. Niedernhofer LJ, Gurkar AU, Wang Y, Vijg J, Hoeijmakers JHJ, Robbins PD. Nuclear genomic instability and aging. Annu Rev Biochem. 2018;87:295-322.[DOI]
-
6. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217.[DOI]
-
7. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-278.[DOI]
-
8. Payne SH. The utility of protein and mRNA correlation. Trends Biochem Sci. 2015;40(1):1-3.[DOI]
-
9. Eiriksdottir T, Ardal S, Jonsson BA, Lund SH, Ivarsdottir EV, Norland K, et al. Predicting the probability of death using proteomics. Commun Biol. 2021;4:758.[DOI]
-
13. Earls JC, Rappaport N, Heath L, Wilmanski T, Magis AT, Schork NJ, et al. Multi-omic biological age estimation and its correlation with wellness and disease phenotypes: A longitudinal study of 3,558 individuals. J Gerontol Ser A. 2019;74(Supplement_1):S52-S60.[DOI]
-
18. Shock NW, Greulich RC, Andres R, Arenberg D, Costa PT, Lakatta EG, et al. Normal human aging: The Baltimore longitudinal study of aging. Washington, DC: U.S. Government Printing Office; 1984. p. 767.
-
19. Sathyan S, Milman S, Ayers E, Gao T, Verghese J, Barzilai N. Plasma proteomic profile of abdominal obesity in older adults. Obesity. 2024;32(5):938-948.[DOI]
-
20. Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol Ser A Biol Sci Med Sci. 2007;62(7):722-727.[DOI]
-
22. Candia J, Cheung F, Kotliarov Y, Fantoni G, Sellers B, Griesman T, et al. Assessment of variability in the SOMAscan assay. Sci Rep. 2017;7:14248.[DOI]
-
24. Candia J, Daya GN, Tanaka T, Ferrucci L, Walker KA. Assessment of variability in the plasma 7k SomaScan proteomics assay. Sci Rep. 2022;12:17147.[DOI]
-
29. Dehkhoda F, Lee CMM, Medina J, Brooks AJ. The growth hormone receptor: Mechanism of receptor activation, cell signaling, and physiological aspects. Front Endocrinol. 2018;9:35.[DOI]
-
30. Van Den Beld AW, Carlson OD, Doyle ME, Rizopoulos D, Ferrucci L, van der Lely AJ, et al. IGFBP-2 and aging: A 20-year longitudinal study on IGFBP-2, IGF-I, BMI, insulin sensitivity and mortality in an aging population. Eur J Endocrinol. 2019;180(2):109-116.[DOI]
-
31. Wiklund FE, Bennet AM, Magnusson PKE, Eriksson UK, Lindmark F, Liyun W, et al. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): A new marker of all-cause mortality. Aging Cell. 2010;9(6):1057-1064.[DOI]
-
32. Roskoski R Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2014;79:34-74.[DOI]
-
34. Huang X, Zhang L, Luo W, Zeng Y, Li X, Yang N, et al. Endothelial anthrax toxin receptor 2 plays a protective role in liver fibrosis. Front Cell Dev Biol. 2024;11:1278968.[DOI]
-
37. Machelak W, Szczepaniak A, Jacenik D, Zielińska M. The role of GDF11 during inflammation-An overview. Life Sci. 2023;322:121650.[DOI]
-
38. Bartke A. Growth hormone and aging: Updated review. World J Mens Health. 2019;37(1):19.[DOI]
-
39. Hertlein L, Stieber P, Kirschenhofer A, Fürst S, Mayr D, Hofmann K, et al. Human epididymis protein 4 (HE4) in benign and malignant diseases. Clin Chem Lab Med. 2012;50(12):2181-2188.[DOI]
-
42. Barutaut M, Fournier P, Peacock WF, Evaristi MF, Caubère C, Turkieh A, et al. Insulin-like growth factor binding protein 2 predicts mortality risk in heart failure. Int J Cardiol. 2020;300:245-251.[DOI]
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Garvey N, Sathyan S, Tanaka T, Joynes C, Oh H, Gao T, et al. Exploring mortality-linked proteins: Understanding their association with biological aging, disease phenotypes, signaling pathways, and their implications for longevity. Geromedicine. 2027;3:202609. https://doi.org/10.70401/Geromedicine.2026.0042
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Garvey N, Sathyan S, Tanaka T, Joynes C, Oh H, Gao T, et al. Exploring mortality-linked proteins: Understanding their association with biological aging, disease phenotypes, signaling pathways, and their implications for longevity. Geromedicine. 2027;3:202609. https://doi.org/10.70401/Geromedicine.2026.0042
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