Clonal Hematopoiesis Analyses in Clinical, Epidemiologic, and Genetic Aging Studies to Unravel Underlying Mechanisms of Age-Related Dysfunction in Humans

Abstract

Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that expand with age in otherwise normal tissues. In the hematopoietic system, this phenomenon has generally been referred to as “clonal hematopoiesis of indeterminate potential” (CHIP) when it applies to a subset of clones in which mutations in driver genes of hematologic malignancies are found. Other mechanisms of clonal hematopoiesis, including large chromosomal alterations, can also give rise to clonal expansion in the absence of conventional CHIP driver gene mutations. Both types of clonal hematopoiesis (CH) have been observed in studies of animal models and humans in association with altered immune responses, increased mortality, and disease risk. Studies in murine models have found that some of these clonal events are involved in abnormal inflammatory and metabolic changes, altered DNA damage repair and epigenetic changes. Studies in long-lived individuals also show the accumulation of somatic mutations, yet at this advanced age, carriership of somatic mutations is no longer associated with an increased risk of mortality. While it remains to be elucidated what factors modify this genotype-phenotype association, i.e., compensatory germline genetics, cellular context of the mutations, protective effects to diseases at exceptional age, it points out that the exceptionally long-lived are key to understand the phenotypic consequences of CHIP mutations. Assessment of the clinical significance of somatic mutations occurring in blood cell types for age-related outcomes in human populations of varied life and health span, environmental exposures, and germline genetic risk factors will be valuable in the development of personalized strategies tailored to specific somatic mutations for healthy aging.

Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom

“…Indeed, this mechanistic evidence from mice is consistent with the association we found between mLOY and atrial fibrillation risk and is consistent with the pathology of atrial fibrillation. Furthermore, evidence from sequencing data suggests that mLOY is genetically linked to clonal hematopoiesis of indeterminate potential (CHIP) [38][39][40] , a mosaic expansion of hematopoietic stem cells driven by certain somatic mutations 41 , which has been recently associated with risk of CVDs and heart failure syndrome [42][43][44][45][46] . Additionally, it has been hypothesized that mLOY in leukocytes potentially reflects altered immunosurveillance and inflammatory processes, which can influence cardiovascular disease pathogenesis 3,47 .…”

Anemia and Its Connections to Inflammation in Older Adults: A Review

“…Age-related progressive changes such as epigenetic alterations, genetic instability, telomere shortening, and accumulation of p53 damage have all been reported to affect cellular aging [96,97]. Progressive somatic mutations cause an increase in clonal hematopoiesis of indeterminate potential (CHIP) in an average of 25% of the human population aged over 65 years, with a further increase observed with aging.…”

Cell cycle arrest: A breakthrough in the supportive care of older cancer patients

“…A number of data in human and experimental animals suggest that the reserve of HSCs and pluripotent progenitors may become depleted with age 41 . In addition, these elements become dysfunctional with aging due to generalized inflammation 42,43 ; increased expression of senescence‐related genes such as P16INK4a 44 ; decreased homing ability 41,42 and perhaps most important increased prevalence of genomic mutations 45–47 . It is estimated that a 70 year old adult may host an average of 70 mutations per gene in their HSCs 47 .…”

“…41 In addition, these elements become dysfunctional with aging due to generalized inflammation 42,43 ; increased expression of senescence-related genes such as P16INK4a 44 ; decreased homing ability 41,42 and perhaps most important increased prevalence of genomic mutations. [45][46][47] It is estimated that a 70 year old adult may host an average of 70 mutations per gene in their HSCs. 47 Most of these mutations are clinically irrelevant, but some may compromise function and survival of the stem cells.…”