Longevity Briefs: Could We Vaccinate 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:

Vaccines don’t have to be used exclusively to prevent infectious diseases. A vaccine simply teaches the immune system to recognise and attack a target molecule. That molecule could be a component of a bacteria or virus, or it could be something native to the body but undesirable, such as amyloid plaque that accumulates in the brain or oxidised cholesterol that clogs the arteries.

In this study, researchers test out a vaccine targeting a protein called CD38. This is a protein that is typically expressed by cells with age-related problems in energy supply caused by dysfunctional mitochondria. The mitochondria are responsible for producing the universal ‘cellular fuel’ ATP, and rely on another molecule called NADH to sustain ATP production. Aged and damaged mitochondria become inefficient at this process, leading to a buildup of NADH within the cell and a depletion of NAD+, the ‘spent’ form of NADH. Studies show that this change in NAD+/NADH ratio is linked to higher expression of CD38 as both a cause and a consequence, meaning that dysfunctional cells could potentially be targeted with a vaccine.

The discovery:

Researchers started by developing and optimising a CD38 vaccine, which involved testing different vaccine candidates targeting different parts of the CD38 protein to see which one caused the strongest immune response in mice. They then gave the vaccine to 12 month-old mice (which could be considered ‘middle aged’), while control mice were given a control vaccine. The mice were then vaccinated again at nearly 19 months of age.

The researchers assessed various aspects of the mice’s health. They also examined the levels of CD38 and other molecules related to ageing and inflammation in their tissues. They found that the CD38 vaccine was associated with multiple significantly improved aspects of health compared to the control vaccine. The vaccine reduced the number cells expressing high CD38 levels, improved blood sugar control, increased oxygen consumption, reduced the number of senescent cells (cells that are no longer able to divide), and improved performance in various physical and cognitive tests. Study of liver proteins also suggested metabolic improvements in the treated mice. These measurements and tests were performed at varying times depending on the nature of the measurement, generally between 4-8 months after the vaccine was administered.

The implications:

This research suggests that targeting CD38 with a vaccine could be a promising strategy for slowing down age-related decline, by teaching the immune system to eliminate cells expressing high levels of CD38 (and therefore, with depleted NAD+ and dysfunctional mitochondria). Cells with dysfunctional mitochondria pass those mitochondria on when they divide. There are also mechanisms through which cells with dysfunctional mitochondria may accelerate dysfunction in nearby cells. Eliminating them may therefore help keep the tissue as a whole healthier by preventing dysfunctional cells from becoming a significant proportion of the cell population.

Vaccines that work to slow aspects of the ageing process are enticing because they would only need to be administered once or a few times to provide long-lasting protection. However, we do need to be cautious about vaccinating against molecules that are native to the human body. In this case, CD38 plays a role in the immune system’s response to infection, so there is a risk that CD38 vaccines might disrupt immune function.

Simple healthy lifestyle practices like exercise, sleep and a healthy diet will support NAD+ levels and mitochondrial health. Certain supplements like nicotinamide riboside mononucleotide (NMN) may also boost NAD+ levels, though their benefits in humans are not well established currently.