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The constantly changing structure of nuclear DNA, packaged into chromatin, determines which genes are accessible to the machinery of gene expression, which determines protein production, which determines cell behavior and state. Chromatin structure and all of the determinants of that structure, including epigenetic marks such as DNA methylation, change as a cell ages towards the Hayflick limit and cellular senescence, and change in aged tissues versus young tissues. Given the advent of epigenetic reprogramming as a potential strategy for rejuvenation, questions regarding the ways in which epigenetics determines cell function in cellular senescence and aging become more pressing.
Comprehending the role of molecular processes such as DNA damage repair, telomere shortening, nuclear and chromatin changes along with epigenetic alterations which drive aging as well as aging related diseases may hold a key to the “elixir of life.” Of late the resurrection of aged cells back to cellular proliferation has garnered attention from various molecular biologists. The use of Yamanaka factors reprograms cells to a partially undifferentiated stage which is shown to ameliorate some of the functions of aged fibroblasts. The transient expression of these factors rescued the levels of H3K9me3 and DNA damage marks such as γ-H2AX. These studies fortify the beneficial role of heterochromatin in protecting the genome from DNA damage and neoplastic transformation.
However, there remain several uncharted domains: Is heterochromatin alone sufficient to extend lifespan? Is the reorganization of the heterochromatin guided by the changed DNA methylome in aged cells? A varied number of histone variants are expressed inside as well as outside of the senescence associated heterochromatin foci (SAHF). What directs them to their specific genomic location upon senescence? The complexity and confusion arise as cells induced by different stress mediated pathways show different epigenetic signatures or varied chromatin organization. Senescent cells found in the pre-cancerous lesions exhibit increased levels of heterochromatic histone modifications (H3K9me2/3 and HP1γ) but lack in SAHF. This discrepancy might be due to the variation in the extent of heterochromatinization of the genome.
We posit that analyzing the biophysical and mechanical nature of aged chromatin polymer in different cell types might provide clues to its natural decay and dysfunction. Despite current technological challenges, even elucidating the half-life or turnover of chromatin factors, including post-translational modifications of nucleosomes, repair factors, chromatin remodelers could be an important start. Knowing these parameters, we can better understand and potentially model how the nuclear landscape changes as cells age.