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Can anti-ageing drugs improve vaccine response in the elderly population?

Unlike fine wine or cheese, the human body does not age with grace (biologically speaking). Our joints begin to weaken, our hearing starts to fade, and our memory slowly deteriorates. On top of that, the body’s immune system struggles to fight against infections. This explains why the elderly population is most heavily affected by the COVID-19 pandemic.


You will have most likely heard of the current struggle in trying to find an effective COVID-19 vaccine. A vaccine, which prompts immune cells to fight against invading viruses, appears to be the light at the end of this tunnel. But the problem is that vaccines are sometimes unable to benefit the people that need them the most.


A guide on how vaccines generally work


To understand how vaccines work, we must first understand how our immune system normally functions.


Let’s use the common flu as an example. When a flu virus enters our body, our immune cells are able to identify it as an invader because the flu virus expresses foreign antigens on its surface that are not normally found in the body. Upon recognising these antigens, B cells are a type of immune cell that secretes Y-shaped proteins known as antibodies that specifically latch onto viral antigens to neutralise (i.e. kill) them.


However, the process of producing the correct antibody is a matter of trial and error, taking up to several days to weeks. In the meantime, the flu virus will have infected some of our cells, explaining why we experience mild flu symptoms. Nonetheless, the great thing about our immune system is that it has impeccable memory; it is able to recall every strain of virus it has ever encountered and match it with the correct antibody required. Therefore, the next time the same flu virus attacks, there will already be pre-made weapons (a.k.a. the antibodies) at hand ready to attack the virus before it is able to infect our cells.


A vaccine works by introducing a fake, weakened, or modified version of the virus into our body. This, in turn, alerts our immune system to produce the correct antibodies in preparation for the real viral infection without eliciting any major disease-causing effects (Figure 1). Hence, this is why vaccines can be a great way to protect ourselves against various infections.


Meanwhile, if you happen to be curious about how the COVID-19 vaccines work specifically, check out this website for a simplified animation (spoiler alert: the graphic design is adorable).

Figure 1: How a vaccine works. (1) A weakened/modified/fake version of the virus is introduced into a patient. (2) B cells are then triggered to produce the correct antibodies to fight against this version of the virus. (3) The immune system “remembers” the viruses it has previously encountered. So, if the same virus invades the patient again later in life, existing antibodies will neutralise (i.e. kill) the virus before it can attack the body’s cells. This figure was created using Adobe Illustrator.


Nonetheless, it is important to note that flu viruses mutate frequently, as they are RNA viruses and viral RNA is more prone to mutations. When viruses mutate, they make small changes to their surface antigens, so our immune system is unable to recognise the old flu virus. In other words, it is almost like these viruses are putting on a different costume to disguise themselves. This process is termed ‘antigenic drift’. This means that protection against a new virus strain would require a new vaccine. Hence, this is why we are often advised to take flu jabs every year, because a 2018 flu vaccine, for example, would not be very effective in 2019 if the virus has mutated.


Based on the discussion, it should hopefully help you understand that vaccines are most effective when we have well-functioning immune systems. Though unfortunately, this presents an issue as the functionality of our immune system tends to worsen with age.


Factors contributing to ageing


Ageing is commonly characterised by the progressive loss of physiological functions that are needed for our survival and fertility. This usually results in increased susceptibility to disease and ultimately, death.


In general, there are many obvious disadvantages to ageing. From an evolutionary perspective, it is puzzling as to why this phenomenon has not been ruled out by natural selection. As we dive a little deeper into the current research efforts on ageing, there are many different theories postulating the biological causes of this phenomenon; in fact, so many to the extent that scientists are still far from reaching a common consensus.


At the moment, senescence is thought to be one of the key causes of ageing-related diseases, and it is defined as the process by which a cell ages and no longer undergoes cell division but does not die. This process is thought to be driven by several factors, a few examples being:

Figure 2: Factors contributing to senescence. Telomere shortening, mitochondrial dysfunction, DNA damage, and epigenetic dysregulation are the primary drivers of senescence, which is thought to be one of the key causes of ageing. This figure was adapted from Lopez-Otin et al. (2013) and created using Adobe Illustrator.


If our immune system weakens with age, will vaccines work in the elderly?


Ageing is an extremely complex process that we simply have yet to fully comprehend. However, what we do know is that most cells will become senescent as we age, and that includes our immune cells. This process is termed ‘immunosenescence and can be described as the gradual worsening of the immune system as we grow older, which in turn increases our vulnerability to diseases.


To ensure that the efficacy of the COVID-19 vaccine is decent when administered to the elderly population, many COVID-19 clinical trials have tested or are testing on adults who are aged 50 and above. This gives us an idea of whether the newly developed vaccine will have beneficial effects on the elderly. Although there are yet to be any definitive results, a recent analysis of 18 vaccine trials suggested that the beneficial effects of a vaccine will most likely not apply to the elderly. All in all, this implies that the elderly population who receive a vaccine would most likely have an immune system that is too weak to produce the correct antibodies which are crucial in helping them defend against the real COVID-19 virus.


But, is there a way for us to overcome this?


Is there a way to delay ageing, and could this enhance the elderlies’ response to vaccines?


As previously mentioned, there are many causes (and therefore many cellular pathways) involved in ageing. Therefore, understanding the molecular mechanisms involved could be a way for us to delay, or even halt, the ageing process.


As a result, this raises the question of whether we are able to strengthen immune function by reversing the process of biological ageing.


There are currently a promising set of anti-ageing drugs that act by inhibiting a protein called mTOR. The mTOR pathway has been well-studied over the past decade and is shown to be involved in regulating life span and ageing. Do bear in mind that there are other pathways involved in the ageing process, but we will focus on mTOR in this article.


mTOR inhibitors – a type of anti-ageing drug


Let’s take a look at a study by Joan Mannick, co-founder of resTORbio – a company focused on the commercialisation of therapeutics targeted towards ageing-related diseases. Mannick and her colleagues investigated if inhibiting mTOR using anti-ageing drugs could improve immune function in the elderly.


The drugs used in this study were RAD001 and BEZ235. RAD001 is an allosteric mTOR inhibitor, which means that it binds to the allosteric site of the enzyme, which is at a different location to that of the active site. Upon binding, the enzyme changes shape and loses its affinity to the substrate or becomes inactive. On the other hand, BEZ235 is a competitive inhibitor; it competes with the substrate to bind at the active/allosteric site. If you are still a little confused about the differences between allosteric and competitive inhibition, check out this website as a guide.


For this study, 264 elderly subjects were recruited and given either RAD001, BEZ235, a combination of RAD001 + BEZ235, or a placebo (a substance made to resemble the real drug but contains another substance that possesses no therapeutic value; e.g. sugar).


Patients were required to take the drugs once a day over a period of six weeks. Following that, patients were injected with an influenza vaccine and had their blood samples collected for analysis. Once that’s done, all patients were monitored over the next year to record any side effects or infections they may have experienced (Figure 3).

Figure 3: A flow chart of the clinical trial conducted to investigate the effect of mTOR inhibitor drugs (RAD001 and BEZ235) on immune response in the elderly. 264 elderly subjects were recruited and were randomly allocated into one of four different drug treatment groups – RAD001, BEZ235, a combination of RAD001 and BEZ235, or a placebo. After six weeks, the subjects were injected with an influenza vaccine. Blood samples were then collected to measure antibody production in response to the vaccine. Subjects were monitored for up to one year to observe any side effects of the drug and to determine if the drug reduced the annual infection rate.


Generally, the mTOR inhibitor drugs were well tolerated and considered safe to use in humans. In addition, the results showed that patients who received the combination of RAD001 and BEZ235 had the strongest immune system (measured by antibody production against influenza vaccine) and thus had the lowest number of infections during the length of study.


In summary, this study shows that mTOR inhibitors (a type of anti-ageing drug) enhance immune function in the elderly, showing potential for improved vaccine response in the elderly.


Nevertheless, further experiments remain a necessity so we can better understand the biology behind the improved immune response induced by the anti-ageing drug treatment. If we think of genes in our DNA as light switches, these drugs function by “switching on” a set of genes that are responsible for fighting viruses. This, in turn, activates a range of cell signalling pathways. And basically, due to the complexity of the immune system, we need to continue investigating in order to pinpoint the exact genes and pathways responsible for this phenomenon.


Metformin – a type-2 diabetes drug that also inhibits mTOR


The good news is that - RAD001 and BEZ235 aren’t the only mTOR inhibitor drugs out there, whereby another type of drug worth discussing would be the type-2 diabetes drug metformin.


A retrospective study conducted in China recruited 283 diabetic patients diagnosed with COVID-19. 104 patients received metformin alone or complemented with other anti-diabetic medications, whereas the remaining patients received one or more anti-diabetic drugs that were not metformin. A multivariate analysis then demonstrated that patients who took metformin had a lower mortality rate (2.9%) compared to those who didn’t take the drug (12.3%).


Meanwhile, intriguingly, previous evidence also suggested that metformin not only acts on mTOR (indirectly), but also acts on multiple other targets. In particular, metformin showcased potential in improving immune response and reducing inflammation by promoting the formation of macrophages and the differentiation of T cells into regulatory and memory T cells.


Macrophages are immune cells that engulf and destroy pathogens. The digested/processed parts of these pathogens are then presented as antigens on the surface of these cells. Following that, T cells recognise these antigens with their antigen receptor. This, in turn, activates their “kill mode” and thereby resulting in these T cells proceeding to kill the pathogen directly or to differentiate into regulatory T cells (which are responsible for regulating or suppressing other immune cells) or memory T cells (which remains dormant and only reactivates when the same pathogen attacks the body).


If metformin really proves to work against COVID-19, researchers will still need to find out the precise action of metformin in order to prevent any unnecessary side effects. But to look at the bright side of things, metformin has been on the market for decades and has proven to be generally safe (can be used in children and pregnant women) and is cheap (costing less than $4 a month), so it may not be too much of a worry after all. We’ll see what unfolds over time.


Anti-ageing drugs show potential in improving vaccine response in elderly


In essence, vaccines are gaining a lot more attention, especially now that we are living in the middle of an ongoing COVID-19 pandemic. However, the main problem is that the population group most heavily affected by COVID-19 do not reap the maximum benefits a vaccine has to offer because of their weakened immune system.


But fret not, because several studies over the recent years have discovered that targeting the fundamental mechanisms of ageing could improve immune function in the elderly. Therefore, it is very possible that giving one of these anti-ageing drugs, after testing its safety and effectiveness, as a primer before vaccination could improve elderly immune response to a vaccine.


So, all hope is not lost!


Author


Vy Wien Lai

MSc Genes, Drugs & Stem Cells – Novel Therapies

Imperial College London


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