Chromatin is a key determinant of cell phenotype and function. Therefore, chromatin stability over the lifespan
is presumably a pre-requisite for maintenance of cell and tissue phenotype and function, and hence healthy
aging and longevity. However, chromatin is not a static fixed structure, but is a dynamic and plastic “breathing”
assembly. As a dynamic and plastic entity, chromatin is prone to change or drift, a process likely exacerbated
by intrinsic cellular processes and extrinsic/environmental influences. Therefore, this dynamic chromatin likely
represents a challenge for a cell to achieve phenotypic stability, healthy aging and longevity, especially for long-
lived cells. In other words, given their dynamic chromatin, how do healthy human neurons and cardiomyocytes
remain as such for decades? To explain this, we have proposed that cells possess mechanisms of chromatin
homeostasis, or chromostasis, that preserve chromatin integrity, suppress phenotypic instability or “plasticity”,
and so slow the pace of aging and promote healthy aging. We will test this hypothesis as follows:
Specific Aim 1. Test whether altered nucleosome stability affects features of chromostasis and cell phenotypic
Specific Aim 2. Identify candidate chromostasis genes and small molecule modulators and test their impact on
cell phenotypic plasticity.
Specific Aim 3. Test whether enhanced chromostasis promotes healthy aging and longevity.
This proposal is broadly significant because it will reveal basic mechanisms of physiological chromatin/epigenetic
control and how this impinges on healthy aging and longevity, pathological states such as cell transformation,
and therapeutic applications such as cell reprogramming. Accordingly, this proposal can have a major impact on
scientific understanding and human health by revealing: 1) mechanisms that underlie stable cell phenotype; 2)
biomarkers of age-associated degeneration and predisposition to disease; 3) targets for interventions to promote
healthy aging, prevent degenerative disease and cancer, and facilitate therapeutic cell reprogramming.