Control over the structure of nuclear DNA is critical to both gene expression and interactions between DNA damage and DNA repair systems. Most of us are by now at least passingly familiar with the concept of the chromosomes of nuclear DNA existing as a mix of (a) spooled and tightly packaged regions known as heterochromatin, where gene sequences are hidden from transcriptional machinery and genes are thus not expressed, versus (b) unspooled regions where transcription can take place, the gene sequences read to allow assembly of corresponding RNA molecules. Epigenetic decorations to DNA and supporting molecules drive a constant shift between spooled and unspooled structures. This necessary regulation of structure and function all changes for the worse with advancing age for reasons that are incompletely understood.
There is a lot more to DNA structure than just this, however. For example, the intricate regulation of nuclear DNA structure incorporates the presence of double-strand breaks known as DNA gaps, distinct from the harmful DNA double strand breaks that occur as a form of damage. These DNA gaps are thought to reduce potentially damage-inducing stress forces, but this may or may not be their primary function. Researchers have observed that the number of these DNA gaps declines with age, and have speculated that this change may produce harm. In today's open access paper, researchers provide fairly direct evidence for this proposition via use of a gene therapy that directly induces DNA gap formation in aged non-human primates. The researchers observe a range of improvements in biomarkers of health following treatment, suggesting that more DNA gaps leads to improved cell and tissue function; all in all, quite an interesting outcome.
A characteristic feature of aging is the accumulation of DNA damage, which plays a significant role in the deterioration of cellular function. The sustained destruction of DNA and the subsequent activation or failure of the DNA-damage response (DDR) are pivotal in the aging process, often leading to detrimental cellular outcomes such as senescence, apoptosis, and telomere shortening. Maintaining DNA integrity is crucial for cell viability. One mechanism employed by cells to ensure this integrity involves the dynamic regulation of DNA structures, often observed as DNA gaps, known as youth-DNA-gaps. These gaps are believed to minimize mechanical stress and torsion forces within the DNA structure, thereby protecting it from damage. Interestingly, the number of these physiological DNA gaps typically is reduced in yeast, rats, and human cells as they age, as well as in chemically-induced senescent cells.
High Mobility Group Box 1 (HMGB1) protein has emerged as a key molecule involved in various biological processes highly relevant to aging, including inflammation, DNA repair, and cell senescence. The Box A domain of HMGB1 is a highly conserved DNA-binding domain crucial for modulating HMGB1's biological functions. Box A is known to bind DNA and interact with other proteins, acting as a molecular regulator that influences the formation of DNA gaps to enhance DNA integrity and protection. Growing evidence suggests that Box A-induced DNA gaps may reverse aging characteristics in vivo and in vitro, having been shown to inhibit liver fibrosis and improve aging brain functions in aged rat models. Furthermore, Box A can enhance stemness, suggesting a role in improving stem cell activity compromised by illness and aging. This study investigates the potential role of the Box A domain HMGB1 in modulating age-related changes. We utilized a label-free quantitative proteomic technique to analyze the plasma proteome of three female adult and eight female perimenopausal cynomolgus macaques (Macaca fascicularis), with the perimenopausal group receiving an intravenous administration of the Box A plasmid. Proteomic analysis revealed differential expressions in proteins primarily associated with stress response, immune regulation, lipid transport, and cellular homeostasis following Box A plasmid intervention. Notably, the expression levels of key proteins, such as apolipoprotein E (APOE) and sex hormone-binding globulin (SHBG), showed a reversal effect, restoring levels closer to those observed in the younger, adult monkeys. These findings highlight the potential of the Box A of HMGB1 plasmid as a therapeutic candidate to mitigate age-related proteomic alterations, offering a novel avenue for targeted interventions in aging and associated diseases.
View the full article at FightAging
