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. 2018 Apr;40(2):193-199.
doi: 10.1007/s11357-018-0015-1. Epub 2018 Apr 12.

Correlations between age, functional status, and the senescence-associated proteins HMGB2 and p16INK4a

Ibiyonu Lawrence  1 , Michael Bene  1   2 , Timothy Nacarelli  3   4 , Ashley Azar  1   5 , Justin Z Cohen  1 , Claudio Torres  1 , Gregg Johannes  1 , Christian Sell  6
Affiliations

Correlations between age, functional status, and the senescence-associated proteins HMGB2 and p16INK4a

Ibiyonu Lawrence et al. Geroscience. 2018 Apr.

Abstract

Cellular senescence is a central component of the aging process. This cellular response has been found to be induced by multiple forms of molecular damage and senescent cells increase in number with age in all tissues examined to date. We have examined the correlation with age of two key proteins involved in the senescence program, p16INK4a and HMGB2. These proteins are involved in cell cycle arrest and chromatin remodeling during senescence. Circulating levels of these markers increases with age and correlates with functional status. The levels of HMGB2 appear to be significantly correlated with functional status, whereas p16INK4a levels are more weakly associated. Interestingly, there is a strong correlation between the two proteins independent of age. In particular, a single high-functioning individual over 90 years of age displays a disproportionately low level of HGMB2. The results suggest that with improved testing methodology, it may be possible to monitor circulating protein markers of senescence in human populations.

Keywords: Aging; Biomarker; Chromatin; Cognition; Frailty; HMGB2; Senescence; p16.

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Figures

Fig. 1
Fig. 1
HMGB2 levels correlate with age and functional status in humans. HMGB2 levels were measured in a cohort of patients ranging in age from 60 to 100 as well as four healthy donors aged 20–24. HMGB2 levels are plotted against age
Fig. 2
Fig. 2
HMGB2 levels correlate with functional status. Patients were grouped by functional status, either mental health (Panel A) or mobility (Panel B) as assessed by clinical observation. Mean HMGB2 levels in each group (high, medium, or low) were then graphed and analyzed by ANOVA and student’s T test. The difference between high and low groups was significant by ANOVA analysis at P < 0.05. In panel C and D, patients over 90 years of age (C), or between 70 and 80 years of age (D) were subjected to the same analysis. Values for the medium group and the low-functioning groups are not included respectively due to low numbers, less than two per group. Differences between groups were not significant by ANOVA
Fig. 3
Fig. 3
Levels of ranging in age from 60 to 100 as well as four healthy donors aged 20–24. HMGB2 levels are plotted against age. Correlate with age and functional status. In panel A, p16Ink4a levels are plotted against age in patients ranging in age from 60 to 100 as well as 4 healthy donors aged 20–24. HMGB2 levels are plotted against age. In panel B and C, patients were grouped according to functional status and the mean levels of p16Ink4a are presented for each group according to mental health score (C) or mobility score (D). Differences between groups were not significant by ANOVA
Fig. 4
Fig. 4
Levels of HMGB2 and p16Ink4a correlate regardless of patient age. Levels of HMGB2 and p16Ink4a are plotted independently of other variables. Removal of the single high-functioning individual at 100 years results in a correlation of 0.864 and a Pearson’s correlation coefficient of 0.929
Fig. 5
Fig. 5
HMGB2 is released from senescent endothelial cells. Panel A contains the results of an ELISA for HMGB2 protein in the supernatant of pre senescent human endothelial cells and human endothelial cells induced to enter senescence through mitochondrial stress. Differences in HMGB2 levels in the ELISA are significant at P < 0.05 by Student’s T test
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References

    1. Aird KM, Iwasaki O, Kossenkov AV, Tanizawa H, Fatkhutdinov N, Bitler BG, le L, Alicea G, Yang TL, Johnson FB, Noma KI, Zhang R. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J Cell Biol. 2016;215(3):325–334. doi: 10.1083/jcb.201608026. - DOI - PMC - PubMed
    1. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232–236. doi: 10.1038/nature10600. - DOI - PMC - PubMed
    1. Bianchi ME, Agresti A. HMG proteins: dynamic players in gene regulation and differentiation. Curr Opin Genet Dev. 2005;15(5):496–506. doi: 10.1016/j.gde.2005.08.007. - DOI - PubMed
    1. Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, Beausejour CM, Coppe JP, Rodier F, Campisi J. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol. 2013;201(4):613–629. doi: 10.1083/jcb.201206006. - DOI - PMC - PubMed
    1. He S, Sharpless NE. Senescence in health and disease. Cell. 2017;169(6):1000–1011. doi: 10.1016/j.cell.2017.05.015. - DOI - PMC - PubMed

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