Longevity Briefs: Some DNA Breaks Might Protect Against Ageing

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

DNA damage is bad. The DNA is the instruction book at the centre of each cell, containing the code necessary to produce any protein the cell may need. When the DNA is damaged, this can result in errors in that code, resulting in faulty proteins or, at worst, a loss of control over cell division leading to cancer. The accumulation of DNA damage throughout life is thought to be a primary driver of the ageing process, slowly eroding cellular function and increasing the risk of cancer in old age.

While breaks in the DNA molecule are generally viewed as harmful, DNA repair mechanisms sometimes involves33(involve) creating purposeful breaks in the DNA strand known as DNA gaps. The purposes33(purpose) of DNA gaps are33(is) not fully known, but it is thought that they help to alleviate mechanical stress in the DNA molecule itself and prevent further damage. Interestingly, the number of DNA gaps appears to decline with age in human cells, hinting that it33(they) might play a role in the ageing process. In this study, which is published in preprint and is awaiting peer review, scientists investigate whether DNA gaps influence ageing in non-human primates. Specifically, they investigate a protein called High Mobility Group Box 1 (HMGB1). HMGB1 contains a region called the Box A domain, which binds to DNA and regulates the formation of DNA gaps.

The discovery:

Researchers conducted their experiment in female cynomolgus macaque monkeys that were divided into three groups: a group of 3 young monkeys (5-7 years old), and two groups of 4 aged monkeys (12-27 years old). Researchers then created a plasmid (a circular section of DNA) containing genetic code for the Box A domain. This plasmid was injected into the monkeys in one of the aged groups so that their cells would produce the Box A domain, while the other groups were given a control plasmid that did not contain the Box A code.

Researchers then used a sophisticated technique to analyse the “plasma proteome” (the complete set of proteins found in the blood plasma) in each group after nine weekly injections. When comparing the young monkeys to the aged control group who did not receive Box A plasmid, they found that the levels of 114 proteins changed significantly33(were significantly different), mostly those proteins involved in immune function, cellular stress responses and lipid (fat) transport. However, in the aged monkeys that received Box A plasmid, some of these disturbances33(differences) in protein levels were reversed. For example, the levels of apolipoporotein E, which is involved in fat metabolism and influences the risk of several age-related diseases including Alzheimer’s and atherosclerosis, was33(levels…were or level…was) found to be elevated in aged control monkeys. However, it was reduced significantly in the treated group, returning to levels closer to those seen in younger monkeys. Conversely, Sex Hormone-Binding Globulin (SHBG), a protein that binds to sex hormones and appears to protect against various age-related diseases through unclear mechanisms, was found to be reduced with age, but significantly increased in in the treated monkeys, also approaching ‘youthful’ levels.

The implications:

It seems as though Box A is able to have a beneficial effect on gene expression to shift the plasma proteome towards a more ‘youthful’ state, possibly by making DNA more stable and resistant to damage thanks to the introduction of DNA gaps. However, since researchers didn’t actually confirm that DNA gaps were increased in monkeys that were given Box A plasmid, it’s possible that Box A was working through other mechanisms.

The ability of Box A plasmid to produce beneficial changes in plasma protein levels in monkeys, which are biologically similar to humans, suggests that it may have some therapeutic potential in humans. Of course, simply altering protein levels in the blood to resemble those of a younger animal doesn’t necessarily mean that ageing has been reversed. However, based on what we know about the role of these proteins, we might expect the risk of age-related diseases to be reduced.