Abstract
The phosphorylated form of histone H2AX (γ-H2AX) forms immunohistochemically detectable foci at DNA double strand breaks. In peripheral blood mononuclear cells (PBMCs) derived from leukapheresis from patients enrolled in the Baltimore Longitudinal Study of Aging, γ-H2AX foci increased in a linear fashion with regards to age, peaking at ∼57 years. The relationship between the frequency of γ-H2AX foci and age-related pathologies was assessed. We found a statistically significant (p = 0.023) 50% increase in foci in PBMCs derived from patients with a known history of vitamin D deficiency. In addition, there were trends toward increased γ-H2AX foci in patients with cataracts (34% increase, p<0.10) and in sleep apnea patients (44%, p<0.10). Among patients ≥57 y/o, we found a significant (p = 0.037) 36% increase in the number of γ-H2AX foci/cell for patients with hypertension compared to non-hypertensive patients. Our results support a role for increased DNA damage in the morbidity of age-related diseases. γ -H2AX may be a biomarker for human morbidity in age-related diseases.
Highlights
Preserving genome integrity and stability are crucial for cellular function
In our leukapheresis derived samples from Baltimore Longitudinal Study of Aging (BLSA) participants using fixed cells, we found an average of 4.25 c-H2AX foci/cell
Using piecewise linear regression analysis [13], c-H2AX foci/cell in our leukapheresis derived samples from BLSA participants had a change-point at age 57
Summary
Preserving genome integrity and stability are crucial for cellular function. Loss of integrity through DNA damage, which increases progressively with age, may contribute to diseases related to aging [1]. DNA double-strand breaks (DSBs), formed when both DNA strands are broken in close proximity (,20 bp), can severely damage genome integrity and threaten cell survival [2]. Cells have developed protective responses to DNA damage, including lesion repair, damage tolerance, and checkpoint pathways [1]. The inability to properly repair DSBs has been linked to several genetic diseases including, ataxia telangiectasia, ataxia telangiectasia-like syndrome, Nijmegen breakage syndrome, Fanconia anemia, and individuals with heterozygous BRCA1 or BRCA2 mutations who exhibit a greatly increased risk of breast and ovarian cancer [3]. There is an increased susceptibility to cancer in many of these syndromes
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