Regenerating the thymus for immune health and longevity
Immune function declines steadily with age
Over the past few decades, the largest global health challenges were primarily driven by chronic age-related diseases. Many believed we had infectious diseases well under control, at least in the developed world, and so the sudden new threat from infectious agents came as a surprise. Nonetheless, it is essential to note that age and age-related co-morbidities are a central risk factor for more severe courses of disease. And why is that?
Immune function declines steadily with age, and past 65, this declined resilience leaves us both more open to infectious diseases and renders vaccines less effective. Furthermore, deterioration of the immune system with aging also contributes to increased autoimmunity and cancer, thus increasing the rates of morbidity and mortality in elderly humans.
One potential key player in the immune defenses’ decline with age may be found in a small organ called the thymus gland, which also dramatically declines with age — indeed much earlier than most other tissues. May this early decline be the underlying driver of the deterioration of the aging human immune system?
Thymic involution drives aging of the immune system
The thymus is a little organ that is located in the center of the chest behind the sternum, just above the heart, and was long-considered a vestigial organ with no known function. However, in 1961 scientists discovered that the thymus is the primary site where immune progenitor cells — so called thymocytes — mature and differentiate into mature T cells (T for thymus). It therefore represents a key organ for the immune system. Many populations of naïve T cells that leave the thymus eventually serve in a wide array of roles, killing specific pathogens or even cancer cells, helping antibody-producing cells recognize antibody targets, while also suppressing an unintended immune response against the cells in our body. In addition to the role that the thymus plays in T-cell development, it also produces various factors that can act in either a localized or a secreted manner. These are important for immune system development and function, and are also involved in the development of other tissues.
The thymus is fully developed before we are born and is at its largest and most active during the neonatal and pre-adolescent periods. Unfortunately, it gradually starts deteriorating after birth and is replaced by fat, resulting in less efficient T-cell development and decreased emigration of naïve T cells to the periphery. This process — known as thymic involution — is one of the most dramatic and ubiquitous changes seen in the aging immune system, triggering immune deterioration in elderly people and thus contributing to susceptibility of infection, autoimmunity, and an increased risk of cancer.
The drastic reduction in the thymic output of naïve T cells around the age of 65 directly correlates with an exponential increase in mortality from age-related diseases as well as infectious diseases.
Would it be possible to slow or reverse this age-related decline if one could target the thymus to halt its deterioration, induce its regeneration, or even just by replacing some of its functions later in life?
Addressing the root cause of immune aging — regenerate the thymus
Given the importance of thymus function for immunity and consequently human longevity, research has focused on understanding the cellular physiology of the thymus and the mechanisms underlying thymic involution. Regenerating the thymus may boost the immune system of older people so they can better fight infections, replenish the immune system — particularly in people who have bone marrow transplants or cancer treatments — and treat people with immunodeficiencies.
In addition to its ability to produce new T cells, the thymus synthesizes and secretes factors that exert systemic functions, which have previously been observed to directly contribute to beneficial effects beyond immune function and lifespan extension by around 20% in mice.
The longevity hormone FGF21, which is normally induced by caloric restriction, extends lifespan in mice by up to 40%. Interestingly, besides its pleiotropic roles in metabolism, increased FGF21 activity has also been shown to delay thymic involution.
A recent study demonstrated that functional thymus can be generated from reprogrammed cells and the matrix of a thymus, and produced a functional immune system in a mouse. Another prior study showed that transplantation of young thymus tissue in middle-aged rats extended their average and maximum lifespan by 20%. These studies demonstrate the potential of rejuvenating the immune system and possibly extending healthspan via thymic transplant in humans.
Prior evidence also suggests that growth hormone both stimulates regeneration of the thymus and stimulates the secretion of thymic hormones. To counteract side-effects of growth hormone therapy, one group is testing a treatment cocktail, combining growth hormone injections with dehydroepiandrosterone (DHEA) and metformin, which may also induce FGF21. They previously observed a promising trend towards increased thymic mass in a small pilot trial, although the trial size and lack of a control group limit the ability to interpret the data with confidence. An ongoing clinical trial aims to generate further evidence that targeting thymic involution in humans can reverse biological age.
In summary, several studies have demonstrated the importance of the thymus for immune function, and the potential to affect aging and lifespan by targeting the thymus. However, only very few groups have started developing such thymus-based interventions for the clinic. We believe that the reversal of thymic involution presents a tremendous opportunity to enhance human healthspan and counteract the multitude of chronic illnesses that arise from an aged immune system.
