Theorizing on H3.3 and Heterochromin in Aging

There are very many speculative theories on mechanisms of aging that await studies to prove or disprove their effects, as well as to demonstrate whether or not those effects are significant over a human life span. Here is one of them:

We propose to focus on cells that either do not replicate in adults or accomplish very few divisions during the lifespan of an organism - that is, far less than set by the Hayflick limit. For the purpose of this review, we will term these cells below Hayflick limit (BHL) cells. Below Hayflick limit cells include postmitotic cells such as terminally differentiated neurons and muscle cells, and female ova, which are formed during embryonic development and remain in a nonproliferating state for decades. Below Hayflick limit cells are interesting for the following reason: On the one hand, they are far from entering the replicative senescence state; on the other hand, due to the constant molecular turnover and active metabolism in these cells (even in the absence of replication), the lifespan of an adult organism should lead to accumulation of irreversible changes, which could contribute to organismal aging.

One principal carrier of epigenetic information is chromatin - a hierarchically organized complex of DNA, histones, and nonhistone proteins. Not surprisingly, the recent interest in 'all things epigenetic' begat new ideas on the role of chromatin in aging. It has been known since the 60s that DNA methylation is progressively lost with aging. Could epigenetic changes also irreversibly accumulate with time in BHL cells thus contributing to organismal, but not replicative, senescence?

We discuss the possibility that in nonreplicating cells, epigenetic modifications, and more specifically very particular changes in chromatin structure - the gradual replacement of canonical histones H3.1/H3.2 with variant histone H3.3 - could contribute to organismal aging by inducing aberrations in gene regulation and other functions in BHL cells. Although this hypothesis has not been directly supported by a plethora of experimental data as yet, the aggregation of existing claims and accumulating evidence leads almost inevitably to paradoxical conclusions about the role of H3.3 in BHL cells with tempting implications with regard to the aging process. The 'H3.3 dilemma', as we term this situation in the field, is both sufficiently intriguing and convincing to be worth-raising, in the hope that it will trigger new directions and efforts for research.



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