Table 2.

Comparison of biologic features in MDS and Aging (for references, see the main text)

Biology of MDS and aging—a comparison
Mechanism	MDS	Aging
Genomic instability	Initiates clonal hematopoiesis and is a driver of clonal evolution and progression in MDS	Genomic damage is associated with aging. Disorders with chromosomal instability such as Werner syndrome are characterized by a progeroid phenotype
Cellular senescence and telomere attrition	Telomere shortening as a factor for chromosomal instability	Telomere length determines the so-called replicative senescence Increase in the number of senescent cells
Epigenetic alterations	Main factor for dysregulated gene expression of relevant genes that leads to MDS phenotype of dysplasia and cytopenia	Profound impact in aging. Manipulation of the epigenome may improve age-related diseases and increase lifespan
RNA splicing	In many subtypes of MDS, RNA splicing defects confer altered protein expression patterns that in consequence produce the MDS phenotype	Alterations in RNA splicing are associated with senescence and aging Splicing defects occur in progeroid syndromes
Mitochondrial dysfunction	Affected in MDS with splicing mutations. ROS in tissue damage due to iron overload (MDS = iron loading anemia)	Results in altered multiple cellular functions. An increase in ROS impacts aging as suggested by the free radical theory
Stem cell exhaustion and selection	Selection pressure may be similar in their effect on aging hematopoiesis and in clonal evolution that is a main driver of MDS propagation	Functional defects of stem cells and selection from clonal pools result in cellular senescence Plays a role in inflammaging Impaired homing and mobilization and age-associated defects of HSC—microenvironment interaction
Stromal niche	An interplay between microenvironment and stem cells is propagating the disease by impaired stem cell supporting functions	Changes in cellular composition and function. Direct effects on stem cell aging Effect on impaired function and regenerative capacity of HSCs reflect a common denominator of aging
Inflammation/immune system	Both innate and adaptive immune responses are shown to be affected. Immune activation and hyperinflammation in MDS are highlighted by systemic autoimmune and autoinflammatory manifestations (SIAM)	Infllammaging describes a subclinical systemic sterile inflammation Inflammaging is associated with a variety of common age-associated diseases such as cardiovascular disease, neurodegenerative diseases, sarcopenia, and osteoporosis
Altered intercellular communication	Signaling alterations affect the regulation of hematopoiesis, proliferation, and inflammatory responses/activation	Inflammaging represents an essential feature of aging and of age-associated diseases
Regulation of transcription	Role in enhanced proliferation	DNA damage may lead to deregulation of gene expression and to increased transcriptional noise
Deregulated nutrient sensing	Not yet established in MDS pathophysiology	Nutrient-sensing pathways (mTOR, IGF-1) play an essential role in aging processes. Dietary restriction increases the healthy lifespan of many species
Loss of proteostasis	Not yet established in MDS pathophysiology	Proteostasis is impaired in aging processes and in age-related diseases such as neuro-degenerative disorders