The immune system is an incredibly intricate biological system found in almost all living organisms. It is multifaceted and complex, protecting against various pathogens and combating our own damaged cells. Every day, the immune system of younger and middle-aged individuals effectively fights off millions of viruses and pathogens they inhale. But what happens to this complex network of defences as we get older?
The immune system is composed of two distinct branches of cells that work together to maintain our well-being:
The first branch is the innate immune system, which consists of unspecialized cells and physical barriers that prevent harmful pathogens from entering the body, thus providing a standardised defence system.
The other branch is the adaptive immune system, which produces an immune response customised to the type of invading pathogen. This involves specific cells, including B lymphocytes, which generate antibodies.
As we age, we all know that we become more prone to disease, but the pathology behind it is a bit more complicated than you think. Imagine all of your immune cells as soldiers, working hard through war. When those hard-working soldiers get tired of their jobs, they stop fighting and finally retire in a transient state called cellular senescence.
The Adaptive Immune System
Immunosenescence primarily affects various components of the adaptive immune system such as B-lymphocytes (image below left) and T-lymphocytes (image below right).
Your body has B-lymphocytes that act as specialised missile factories to produce antibodies. B cells have receptors that identify antigens on pathogens and create antibodies that match them and as you age, the diversity of these receptors decreases, which weakens your immune system's ability to fight off different types of illnesses.
The other cells Immunosenescence mainly affects are the T cells which play a significant role in immune defence. Cytotoxic T cells work to eliminate enemy or infected cells, while Helper T cells bring backup to support the frontline immune cells. However, as a person ages, the thymus, a critical organ for the immune system, undergoes involution, causing it to shrink. This results in a decrease in the production of unspecialized T cells and a reduction in the diversity of these T Cells causing the immune system to be more prone to newer pathogens.
The decline of T cell function also reduces the production of IL2 cytokines which are messenger proteins that help immune system cells differ between body cells and pathogens. This would lead to a less effective overall immune response as the immune system may not effectively distinguish between some pathogens and body cells.
The Innate Immune System
The effects of cellular senescence are not limited to the adaptive immune system - they also have profound effects on the innate immune system, specifically dendritic cells and macrophages.
As we age, macrophages become less effective at both consuming their enemies in battle and presenting their antigens to T helper cells for assistance. For a macrophage to devour a pathogen, it needs to undergo a process known as phagocytosis, which involves engulfing the pathogen and forming a phagosome. Due to age-related changes, such as alterations in the composition and fluidity of the cell membrane, the formation of the phagosome may be affected, making it more difficult for the macrophage to envelop and devour a pathogen.
In addition, macrophages and dendritic cells have a type of receptor known as Toll-like receptors (TLRs) that help them identify pathogens. These receptors enable the cells to trigger an immune response, such as phagocytosis, or to present the antigens to cells in the adaptive immune system, which is one of their main functions as Antigen-Presenting Cells (APCs). Over time, these cells may undergo changes in their outer cell structure that reduce their sensitivity to Pathogen Associated Molecular Patterns (PAMPs), making these frontline immune cells less efficient in responding to pathogens.
These can also affect the maturation and antigen-presenting abilities of dendritic cells, potentially impacting the initiation of adaptive immunity:
Leukocytes with less sensitive TLRs may not be able to effectively identify pathogens, while those with overly sensitive TLRs may overreact and release pro-inflammatory cytokines. Although this is typically beneficial, it can become problematic when it occurs in response to minor pathogens.
The process of cellular senescence impacts many different types of cells in the body's immune system, but it has a more significant impact on these particular cells compared to others. But don't worry! Immunosenescence is unlikely to affect most people. Most of our cells naturally eliminate themselves through a process called apoptosis, which makes it highly unlikely for senescent cells to develop. Senescent cells tend to accumulate only in old age, and only a few of them produce severe symptoms that can harm the body.
COVID-19
The COVID-19 pandemic had a severe impact on the elderly population, largely due to Immunosenescence. While the immune system's frontline cells typically eliminate the virus, they are often insufficient in older individuals.
COVID-19 can penetrate the epithelial cells surrounding the alveoli and infect cytotoxic T cells, causing them to attack neighbouring cells. This results in the destruction of both viral and healthy cells, while also leaving the immune system weakened and vulnerable to bacterial infections.
Respiratory difficulties and other severe syndromes may occur if bacteria infect the alveoli in this manner. If the immune system is unable to regain control due to too many senescent or infected immune cells, it may resort to a cytokine storm. This unleashes all available defences, causing blood vessel dilation, low blood pressure, and dehydration.
SUMMARY
To summarise, as we age, our immune system undergoes substantial changes that make it less effective in combating pathogens and preserving our well-being. These changes primarily affect the adaptive immune system whilst still having major effects on the innate immune system, including dendritic cells and macrophages. Understanding the mechanisms of immunosenescence is crucial for developing effective strategies to prevent or treat age-related diseases and improve the quality of life for older adults.