Age-Related Decline Of The Immune System
The human immune system weakens with the passing of time, thus making us more susceptible to cancer and infectious diseases. This aging also affects the ability of our organism to take advantage of vaccination. A new study conducted by scientists at the Stanford University School of Medicine shows that if a certain protein is blocked, the response of the cells to vaccines and other atingens like cancer or microbial antigens can be restored. The levels of this particular protein increase with age.
Doctor Jorg Goronzy, a professor of rheumatology and the lead author of the paper says that this discovery is very important for long-term therapies. He added that in the near future the possibility of countering the effects of aging on our immune system might be achievable through pharmacology. The paper was published on the 30th of September in the online journal Nature Medicine.
The research team discovered a protein, named DUSP6 (Dual specificity phosphatase 6), that impedes the capacity of an entire class of immune cells, thus preventing them from interacting with foreign bodies or substances. These substances include pathogens and vaccines. Another finding was that of a possible compound that is able to restore the responsiveness of the immune cells back to normal, once the DUSP6 protein is inhibited.
Dr Goronzy says that the human immune system decades with aging, starting from around the age of 40. Goronzy added that even though almost 90% of adults below the age of 40 respond to vaccines, the rate of responsiveness drops to almost 40% after the age of 60. An example of poor responsiveness in older patients is that of influenza deaths, most of which are registered in patients older than 65.
A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body’s immune system to recognize the agent as foreign, destroy it, and “remember” it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.
A part of cells involved in the process, the T-helper cells, stimulate the B cells, which have an important role in the response to prophylactic vaccines. The exposure to the pathogenic agent or the antigen found in vaccines leads to the activation and proliferation of B cells. This further leads to the production of antibodies. The antibodies will immobilize the pathogenic agent which will be destroyed by more powerful immune cells.
For patients that have a low responsiveness to vaccines, the dose of the vaccine can be increased in order to boost its potency. Another method to boost the potency of vaccines is to use adjuvant elements, such as chemicals or other molecules. Researchers note that a previous study, led by Dr Cornelia Dekker, has shown that the response of elderly patients to the seasonal flu vaccine was improved through the use of an experimental adjuvant.
The T-cells that make up a part of the immune system of the elderly patients are somewhat deteriorated, thus having a reduced activation and proliferation capacity. This factor reduces its cancer-fighting effectiveness so as the effect of vaccines that contain adjuvants. Dr Goronzy said that “Some age-associated defect or defects raise the threshold of responsiveness to the presented antigen, so a vaccine dose that triggers T-cell activation in a younger person doesn’t in an older person. Adjuvants can’t compensate for these defects”. His team of researchers tried to identify which of these age-related defects cause the deterioration of T-helper cells, whilst also trying to find a way to counteract them.
The circulating T-helper cells are divided into two large categories. The first category, called naïve T-helper cells, are the ones that have never encountered an antigen but are able to respond if they do. Almost two weeks are needed for these cells to reach their full capacity. The second category, called memory T-helper cells, are the cells that have already encountered an antigen. These cells are rapidly activated if they are exposed to the same antigen a second time.
In a previous study published by Dr Goronzy in the journal Proceedings of the National Academy of Sciences, it was shown that the defective regulation of the memory T-helper cells, caused by the increased levels of DUSP4, inhibits the cellular activation, thus leading to a subsequent failure in the activation of B-cells. The increased levels of DUSP4 was shown to be related to age.
In the current study, a similar effect was attributed to the increase of DUSP6. Researchers compared blood cells extracted from patients between the ages of 20 and 35 with the blood cells taken from patients between the ages of 70 and 85. Age-associated differences were only discovered in the naïve T-helper cells. These differences consisted in faulty activation, proliferation and differentiation. These laboratory tests linked DUSP6 with the damage sustained by the naïve T-helper cells. The levels of DUSP6 were significantly higher in elderly patients, compared to young patients.
Further research divulged that the increase of DUSP6 in these naïve T-helper cells is caused by a molecule called miR-181a, a micro-RNA precursor that regulates the production of proteins. Dr Goronzy and his team discovered that miR-181a is directly involved in the production of DUSP6 and revealed that the levels of miR-181a decreases with age, until around the age of 70, when it reaches its minimum level. This causes the growth of DUSP6. Through the use of artificial boosting, researchers managed to reduce the levels of DUSP6 in the naïve human T-helper cells, thus effectively increasing the effect of a given dose of influenza vaccine.
Another precedent study, published in 2009 in the journal Nature Chemical Biology, led by researchers from the University of Pittsburgh, showed that a certain compound, named BCI, was used to block the action of DUSP6 in zebrafish. This result was recorded in specific heart cells. Dr Goronzy’s team found out that if he increased the dose of BCI, the activation of naïve T-helper was accentuated.
“We are still far from application in the clinic. We need to keep tweaking the compound and testing it in mice to make absolutely sure it’s safe enough to try in humans. But improving vaccine responses to overcome age-related immune defects represents a unique opportunity to attain healthy aging”, concluded Dr Goronzy.
For more detailed information please read the study abstract which can be found here.