Fight Aging!

In today's open access paper, researchers note that the characteristic loss of maintainance of heterochromatin structure that occurs with age appears sufficient to produce signatures of aging in female germline cells, oocytes, accompanied by a rising level of transposon activity. Along with thymic involution, loss of function in female germline cells is one of the more rapid aspects of aging. This is the subject of a range of research programs, investigating the causes, and potential means of addressing the issue, ranging from tissue engineered ovaries to the usual panoply of pharmacological approaches to slow the mechanisms of aging.

Heterochromatin is the packaged form of nuclear DNA, tended by complex protein machinery and various decorating molecules that keep it folded in such a way as to hide away most genes from the expression machinery that would otherwise jump in and start to produce RNA molecules from their genetic blueprints. When heterochromatin is correctly packaged and maintained, most of the genome is silenced, including parasitic transposon sequences, the remnants of ancient viral infections. Most cellular systems are impacted with age, and heterochromatin packaging is no exception. As it becomes more ragged, transposons can begin to replicate themselves, causing harm. The cause of this disarray in heterochromatin machinery may result from stochastic DNA damage, in that double strand break repair depletes necessary resources - but this is a fairly recent discovery that needs more validation.

Loss of heterochromatin and retrotransposon silencing as determinants in oocyte aging

Reproductive aging is defined as the age-related loss of fertility due to increasing damage to the reproductive and other systems. Oocytes themselves accumulate damage in an age-related manner and deteriorate to the point where they are non-functional. In human, females this occurs at a relatively early age, before the onset of aging in other organs and tissues. In our era of increased rate of delayed childbearing, it is becoming crucial to understand the mechanisms underlying the compromised quality of oocytes with age.

Changes in epigenetic regulation of gene expression and chromosome structure have been recognized as contributors to aging, and epigenetic changes during aging have been listed among the "hallmarks of aging". The loss of heterochromatin histone marks has been associated with the aging process in many systems and tissues. It was shown that epigenetic changes occur in mouse oocytes of advanced maternal age, at ages where aneuploidy is considerable. However, the mechanisms that are altered by these changes, and the ways they affect the different aspects of oocyte aging are yet to be explored. The consequences of heterochromatin de-regulation in aging may be related to the activated transcription of transposable elements (TE) in the genome, and their subsequent effect on genome stability and cellular integrity. This was shown to occur in several organisms and systems. Currently, it is unclear whether TE are activated in older oocytes, and whether, and when exactly, TE expression is involved in oocyte aging and epigenetics.

In this work, we study the role of heterochromatin loss in the aging of oocytes. We show that heterochromatin loss in oocytes can be detected at an age of 9 months in mice, when low aneuploidy rates are present, but a decrease in oocyte quality is evident, as previously reported. We show that these changes are characterized by the loss of repressive histone marks, elevation of specific retrotransposon mRNA transcription, elevated processing of repeated sequences and retrotransposons, and increased activation of the DNA repair machinery. Treatment of oocytes with chemical compounds that inhibit heterochromatin formation can mimic the effect of aging and cause a decrease in oocyte maturation rates and elevation in L1 retrotransposon activity and DNA damage.

Importantly, we find that the effect of heterochromatin loss and L1 retrotransposon activity on oocyte maturation with age is partially reversible through treatment of oocytes with AZT, a SIRT1 activating molecule-SRT-1720, or overexpression of Sirt1 or Ezh2 in older oocytes. Treatment with AZT does not prevent epigenetic failure in older oocytes while the other interventions do. This fact demonstrates that the epigenetic effect is upstream to retrotransposon activation at this stage of the aging process.