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Kevin Paul Erazo Castillo

Reversing Thymic Involution & Immune-Driven Longevity Therapies

March 24, 2021

Introduction

One of the great ironies of history is that the United Nation’s Decade of Healthy Ageing (2020-2030)1 began with the global COVID-19 pandemic, a disease that preferentially kills the elderly. The scope of this historical juncture highlights the many levels at which the challenge of ageing must be confronted in the early 21st century. First, the UN’s commitment to ensuring a decade of healthy ageing is in response to the inverting of population pyramids in developed nations which will bring social, medical and financial challenges. Second, COVID-19 has made it painfully clear that, for various reasons, age and likelihood of death are strongly correlated later in life. This last point might seem obvious, as old age and frailty are inseparable in the popular imagination, but if “healthy ageing” is possible, it will have to be analyzed like any other biological phenomenon, without cultural blind spots or presuppositions. In short, a decade of healthy ageing can only come about if we can understand the mechanisms that underlie physical decline, if we ask the seemingly obvious question: “yes, but why are the elderly more frail?”

            The study of ageing biology, per se, is not particularly new because many longevity studies have been carried out with short lived organisms2. What is more recent is the expansion of this research to include mammals, in particular primates and humans. A recent development in the field of ageing biology has been the integration of various lines of evidence from myriad organisms into two mostly overlapping paradigms of biological aging. They are commonly referred to as The Hallmarks of Aging3 and The Pillars of Aging4; although they do overlap, there are 9 hallmarks and 7 pillars. Both the hallmarks and the pillars of aging are described in terms of damage at the gene, protein, or cellular level; some of the smallest units of biological function. This means that the various of levels of organization from cells to organisms might be aging in different ways and at different rates. This idea was recently formalized by the development of ageotypes5 (organ/system-specific aging patterns: immune, metabolic, etc.) in a longitudinal cohort of healthy humans.

One of the pillars singles out inflammation as a key research area, but rampant inflammation is just one facet of age-related immune dysfunction. Along with the discovery of the immune ageotype, this would suggest that focusing on age-related immune dysfunction could significantly enhance our understanding of human ageing. Furthermore, I would maintain that immune system rejuvenation could facilitate the development of other longevity immunotherapies. Basically, if this one pillar of aging can be restored, it could be used to undo the damage that time has made in other biological processes. But a detailed discussion of immune system rejuvenation requires an understanding of the known forms of age-related immune dysfunction.

 

Immunosenescense: Age-Related Immune Dysfunction

            The time-dependent functional decline of the immune system is sometimes referred to as immunosenescense6, which can be thought of as the application of the hallmarks of aging to the cells and organs that make up the immune system. It is important for immunosenescense to be distinguished early on from a related phenotype called “inflammaging”, which is persistent low-grade inflammation commonly found in the elderly. The distinction between these two age-related immune phenomena might be more conceptual than physiological7, but the core of this discussion will center around the cell-based decline in immune function with an emphasis on adaptive immunity.

            So, what is immunosenescense8? This phenotype has various components which can be described at various levels of cellular differentiation:

  • Hematopoietic stem cells (HSCs), found in the bone marrow, are multi-potent cells that differentiate to create the major types of cells making up the immune system: B cells, T cells, NK cells, etc. In the elderly, HSCs have reduced repopulation and differentiation ability, leading to decreased numbers of functional immune cells.
  • Macrophages and neutrophils, both components of the innate immune system, have reduced phagocytic activity (encapsulation of cells/molecules identified as foreign) and superoxide anion production (compound used to destroy foreign cells/molecules) in older patients.
  • Naïve B cells, a component of adaptive immunity, are impaired in elderly by being produced in lower numbers (in the bone marrow) with decreased antibody diversity and affinity. B cell/antibody maturation occurs in structures within secondary lymph organs called “germinal centers” which become disrupted with age. Mature B cells experience other forms of functional decline such as aberrant receptor signaling and disrupted interaction with T cells.
  • Chronic thymic atrophy, also referred to as thymic involution, occurs in all vertebrates and severely limits the production and maturation of T cells. Although the shrinking of the thymus is a well-known phenomenon, the molecular mechanisms underlying this evolutionarily conserved process remain to be elucidated. Thymus rejuvenation is a critical step towards maintaining immune health in old age because T cells can directly eliminate pathogenic cells and orchestrate other aspects of an immune response.

Despite the plurality of phenomena that make up immunosenescense, there are three structures that underpin all the sources of dysfunction: bone marrow (the source of all HSCs), secondary lymph organs (the site of B cell maturation), and the thymus (the site of T cell maturation). It’s generally accepted that the first two structures could be rejuvenated via bone marrow transplant (BMT), but the evidence for BMT-driven rejuvenation of the thymus is mixed at best. Although there are a handful of proposed therapies to reverse thymic involution (sex hormone ablation or IL-7 supplementation)9, the most durable therapy would be an injection of thymic stem cells. The necessity for a stem-cell based approach to reverse thymic involution will become clear after examining the complications associated with other types of therapies. 

 

(Reversing) Thymic Involution

            At a high level, the thymus is a gland with a cortex and medulla compartments suspended in a perivascular space inside a capsule10. Over time, the cortex and medulla, which are made up of thymic epithelial cells (TECs), shrink leading to the phenomenon known as thymic involution. Unsurprisingly, this leads to decreased production of healthy naïve T cells over time which ultimately results in diminished T cell receptor (TCR) repertoire diversity for an organism. TCRs are surface proteins on T cells (part of the adaptive immune system) that get exposed to antigens by macrophages or other antigen-presenting cells (APCs) from the innate immune system. Effectively, thymic involution leads to a diminished immune response to novel pathogens in the elderly; the immune response to remembered antigens depends on the health of other components of the innate and adaptive immune system.

            Unlike other forms of aging which seem stochastic, thymic involution is an evolutionarily conserved stage in vertebrate development. The shrinking of the thymus seems to be a feature and not a bug, but why would we be set up to lose a critical immune organ over time? The common answer to this puzzle, surprisingly, loops back to human lifespan: by the time humans reach adulthood, they’ve been exposed to a significant portion of pathogens and have some degree of immunity to them so there is no need to maintain a large supply of native T cells ready to detect new pathogens. Thymic involution is a reasonable evolutionarily compromise if the expected human lifespan is about 40 to 50 years (once reproduction has taken place), as opposed to the current 70+ years we can all expect to enjoy. This is one of the reasons why the immune system doesn’t mount a significant response against diseases of old age (i.e., cancer); these new pathogens show up at a point in human life where TCR diversity is severely depleted.

            Given the significance of the thymus in fighting disease in old age, what can be done to reverse thymic involution? Currently, there are various promising therapies for increasing thymic cellularity9: (1) treatment with keratinocyte growth factor (KGF), also known as fibroblast growth factor 7 (FGF7), (2) treatment with IL-7, which is not required for normal B cell development in humans, and (3) sex steroid ablation, preferably via targeted chemical blockade. The upside is that all of these therapies demonstrate the plasticity of thymic tissue and the possibility of reversing thymic involution. The vastly unexplored downside is the potential side effects of long-term supplementation or ablation of key signaling biomolecules that affect the thymus and other organs. In light of these limitations, the ideal solution to thymic involution (and other aspects of immunosenescense) is to use autologous stem cells to directly reconstitute the thymus. How can we make thymic stem cell therapy a reality for the majority of people?

 

Stem Cell Banking: The Ultimate Health Insurance

            An understanding of basic and translational immunology is necessary, but not sufficient to create therapies that are effective and widely accepted. The possibility of generating personalized thymic stem cell therapies (autologous grafts) can only be realized with the expansion of a nascent practice called stem cell banking11. The idea is that young adults voluntarily make regular stem cell donations to a stem cell bank that keeps them frozen until they’re needed for therapeutic purposes later in life. Currently, it’s mostly hematopoietic stem cells that are collected because they’re the easiest to acquire, but over time this could be expanded to stem cells from other tissues; adipose tissue is of particular interest. In principle, an autologous graft of HSCs could be used to recreate young healthy thymic epithelial cells (TECs) that are then transplanted into an elderly subject’s atrophied thymus. This was recently done with induced pluripotent stem cells (iPSCs) for TEC allograft transplantation12, but this strategy has some extra burdens and risks: (1) limited and variable differentiation potential of iPSCs compared to HSCs and (2) the possibility of allograft rejection which is bypassed autologous stem cells. Fortunately, there is exciting thymus-centered research going on (like the recent ex vivo reconstitution of a functional thymus13) that could guide and improve future regeneration therapies.

            Regeneration of the immune system via autologous stem cell therapies has the potential to significantly extend healthspan and lifespan. Maintaining a competent immune system well into old age could open the door to many other immune-driven therapies to address other age-related dysfunction. In the same way that modern immuno-oncology therapies have trained the immune system (of mostly older subjects) to detect cancer cells, a rejuvenated immune system could also be coached to eliminate other pathogenic host cells that currently go unnoticed. From this optimistic vantage point, immune rejuvenation could be as significant in human history as the development of vaccines and antibiotics. A cynic might counter that despite their effectiveness, people still challenge and oppose the use of vaccines, so stem cell rejuvenation therapies are bound to encounter even greater opposition and misinformation.

            Although this cynicism is not unwarranted, its potency comes entirely from our existing (flawed and inadequate) social and medical arrangements. The most emblematically flawed social-medical institution is health insurance as currently practiced in all developed nations. Setting aside the differences between health care systems, the basic strategy employed by all rich countries is to cover the costs of treating the sick and elderly by using money from the young and healthy. The younger generation pays to keep the older generation healthy, to the extent that it’s possible. Stem cell banking, in contrast, would bypass this group-based dynamic by making each individual responsible for their future health. A series of donations in one’s youth could solve many health complications that arise down the road. I call this the “ultimate health insurance” because it’s superior to the current paradigm in several respects: (1) it encourages individuals to take their health into their own hands, (2) it reduces intergenerational resentment, and (3) it is preventive as opposed to reactive, like the majority of current medical interventions. Much more can be said about this approach to healthcare, but what is beyond dispute is that adopting this more optimal strategy will require social, cultural, and policy changes to match on-going scientific developments.

 

References

  1. Dixon, A. The United Nations Decade of Healthy Ageing requires concerted global action. Nat. Aging 1, 2–2 (2021).
  2. Murthy, M. & Ram, J. L. Invertebrates as model organisms for research on aging biology. Invertebr. Reprod. Dev. 59, 1–4 (2015).
  3. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194 (2013).
  4. Kennedy, B. K. et al. Geroscience: Linking aging to chronic disease. Cell 159, 709–713 (2014).
  5. Ahadi, S. et al. Personal aging markers and ageotypes revealed by deep longitudinal profiling. Nat. Med. 26, 83–90 (2020).
  6. Pawelec, G. Age and immunity: What is “immunosenescence”? Exp. Gerontol. 105, 4–9 (2018).
  7. Fulop, T. et al. Immunosenescence and inflamm-aging as two sides of the same coin: Friends or Foes? Front. Immunol. 8, (2018).
  8. Aw, D., Silva, A. B. & Palmer, D. B. Immunosenescence: Emerging challenges for an ageing population. Immunology 120, 435–446 (2007).
  9. Lynch, H. E. et al. Thymic involution and immune reconstitution. Trends Immunol. 30, 366–373 (2009).
  10. Rezzani, R., Nardo, L., Favero, G., Peroni, M. & Rodella, L. F. Thymus and aging: Morphological, radiological, and functional overview. Age (Omaha). 36, 313–351 (2014).
  11. Harris, D. T. Stem cell banking for regenerative and personalized medicine. Biomedicines 2, 50–79 (2014).
  12. Otsuka, R. et al. Efficient generation of thymic epithelium from induced pluripotent stem cells that prolongs allograft survival. Sci. Rep. 10, 1–8 (2020).
  13. Campinoti, S. et al. Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds. Nat. Commun. 11, (2020).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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