Myelodysplasia, Clonal Hematopoiesis, and Aging

Asking whether an age-associated disease is a part of normal aging is an exercise in boundary drawing. The very definition of an age-related disease as something distinct from aging is the result of past boundary drawing. Many of these boundaries are quite arbitrary. Aging is a complex phenomenon, and people like to lay taxonomies on top of a complex space of many interacting mechanisms in order to try to make some sense of it. The results are sometimes helpful, sometimes not. The discussion in this open access paper is perhaps a good example of where the exercise of drawing boundaries can lead, while trying to separate out categories from the interplay of cancer, precancerous processes, and mechanisms of aging.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders characterized by ineffective hematopoiesis resulting in peripheral blood cytopenias. MDS typically occur at an advanced age with a median age at diagnosis of 68 to 75 years. MDS as clonal disorders may be preceded by a state of clonal hematopoiesis (CHIP) in which MDS defining features cannot (yet) be substantiated. Whereas CHIP-specific somatic mutations are rarely detected in persons younger than 40 years, they reveal an increasing incidence with advanced age.

Considerable progress has been made in deciphering the biology of normal aging, which includes the distinction of normal aging from pathologies associated with aging; additional progress has been made in describing MDS preceding states and elucidating initiation and progression of this disease. Despite these data, the provocative question, if MDS is simply a variant of the aging process, remains challenging.

The earliest answers supporting this hypothesis come from epidemiologic data with a clearly increasing incidence of MDS with age. As always, this observed correlation needs to be supported by establishing a causal relationship. Some similarities between aging and MDS have undoubtedly been defined. Especially changes affecting hematopoiesis are suggestive for an involvement of aging in the development of a hematologic disorder. One example is aging hematopoiesis as a result of clonal selection of hematopoietic stem cells leading to an alteration of the HSC pool. Another is clonal hematopoiesis such as defined in CHIP which is recognized as a potential pre-MDS state with a continuous increase at an advanced age.

CHIP has not only implications for MDS but also for other conditions or diseases associated with aging such as cardiovascular disease which further supports the connection with aging. Finally, many of the biologic features that drive the MDS process can also be observed in processes of aging or are key players in non-hematologic diseases of the elderly. On the other hand, there are clear data demonstrating that MDS is not inevitable with aging: for example, the risk of developing hematologic malignancies, particularly MDS, is higher in patients with clonal hematopoiesis than in persons without, but by far not all of them develop MDS. In addition, as far as we know, not every person contracts MDS, if he or she gets just old enough.

A possible solution for this conundrum is the notion that aging certainly contributes to the development of MDS. One might hypothesize that in many cases aging is the main driver of MDS, whereas in others aging promotes the specific phenotype. MDS might thus be seen as an interplay of clonal disease and normal or premature aging. Probably different subtypes or disease entities of MDS are distinctively affected by aging.


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