The Role of Hematopoietic Loss of Y Chromosome on Aging Phenotypes

Project Summary
Mosaic loss of Y chromosome in the hematopoietic system (mLOY) is the most common post-zygotic mutation
in humans. This form of aneuploidy, in a subset of hematopoietic stem cells, increases with age and affects
~45% of men by age 70. Epidemiological data have associated this condition with mortality, cancer, dementia,
and other age-associated conditions. Recently, our group has produced the first causal, mechanistic, and
epidemiological data linking mLOY to age-associated heart failure and other conditions associated with an
exuberant fibrotic response. A mouse model of mLOY showed diminished lifespan and increased progression of
age-associated pathologies, including cardiomyopathy, lung and renal fibrosis, and cognitive decline. The mLOY
recipient mice also showed increased progression of cardiac fibrosis and increased number of fibroblasts in the
myocardial tissue after cardiac injury. Further analysis using single cell RNA sequencing revealed that the mLOY
macrophages showed both an increased propensity towards pro-fibrotic macrophage polarization and increased
expression of pro-fibrotic ligands. These novel findings suggest that age-related mLOY in blood cells may be a
strong driver of tissue aging and fibrosis. However, the mechanistic connections between Y chromosome loss,
immune cell dysfunction, systemic fibrosis, and aging are not yet known.
Preliminary data suggests that mLOY macrophages may contribute to aging through multiple
mechanisms. Single cell RNA sequencing showed a reduced propensity of mLOY macrophages towards a pro-
inflammatory polarization, reduced expression of Il1b and Tnf, and reduced recruitment of leukocytes to injured
cardiac tissue. As inflammatory macrophage processes are required to clear senescent cells, mLOY may result
in the accumulation of senescent cells in tissues and thereby contribute to biological aging. Additionally, mLOY
macrophages show increased expression of Tgfb1, which can induce a mesenchymal transition in endothelial
cells and promote tissue fibrosis. Therefore, mLOY may promote this mesenchymal transition in aged tissues.
Finally, the effector locus on the Y chromosome that may be responsible for the cardiac fibrosis phenotype is a
gene with histone modification function. This effector locus may regulate macrophage polarization through
histone modifications that allow for transcription factor binding and subsequent expression of pro-fibrotic genes.
Thus, I hypothesis that mLOY promotes aging phenotypes by accumulation of senescent cells and promotion
of mesenchymal transition through epigenetic modification of histones to dysregulate macrophage polarization.
To this end, I will use novel transgenic mouse models, advanced single cell analyses, and cell culture methods
to determine the effects of mLOY macrophages on aging phenotypes and to elucidate the mechanisms by
which mLOY regulates macrophage polarization. Within this transition project, my training plan will build on my
current expertise in cell biology and allow me to gain critical skills to establish and maintain an independent
research program investigating mLOY and aging phenotypes.

Grant Number: 5K22AG081323-02
NIH Institute/Center: NIH
Principal Investigator: Nicholas Chavkin