Miroslav Radman, 20/02/2015
Proteostasis is the constant renewal of the pool of functional proteins that involves "cleaning", i.e., breakdown of misfunctional damaged proteins, and their replacement by the newly synthesized functional proteins. The cleaning involves 20S and 26S proteasome activities and the lysozomal autophagy of protein aggregates, whereas resynthesis involves transcription and translation of genes encoding eliminated proteins. The latter is often regulated "upstream" by the state of DNA methylation of the CpG islands in the promoter area of the relevant gene as well as of other genes that control its expression, i.e., specific transcriptional and translational activities.
Therefore, the persistant damage to any of the proteins involved in the turnover of a particular protein should affect the efficiency of its turnover, starting with the accuracy of the maintenance of DNA methylation patterns. This could be the reason why changes in DNA methylation correlate with age (ref 1) and predict the all-cause human mortality in later life (ref 2).
Our hypothesis that the root cause of aging is persistent damage to the proteome (ref 3,4) stipulates the reversibility of aging by increased protein turnover, unless some irreversible effect of aging, e.g., mutation or a stable epigenetic change, locks-in the morbid cellular physiology caused by the deficit of some proteins. While mutations are quasi irreversible, how reversible are epigenetic changes such as DNA methylation? In the case of cellular rejuvenation by reprogramming (iPSC), DNA methylation patterns are reversed (ref 1). In the case of rejuvenation of old mice by heterochronic parabiosis (ref 5), which originates largely from factors (GDF/BMP) present in the plasma of young mice, the analysis of DNA methylation patters has not been published.
In all medical regeneration and rejuvenation efforts, it is necessary to know to what degree is cellular aging reversible. Because, if it is reversible, then an endogenous systemic in situ cell rejuvenation is preferable to exogeneous localised regeneration by the stem cell therapy. If the most upstream cause of aging is oxidative protein damage, then oxidative damage to the system of DNA methylation maintenance may be the root cause of cell-transmissible changes in DNA methylation patterns. We need to find out if such epigenetic change is subject to reversion by means other than cell reprogramming.
(1) M. Jung and G. P. Pfeifer, Aging and DNA methylation, BMC Biology (2015) 13:7, 1-8. (DOI 10.1186/s12915-015-0118-4
(2) E. Marioni et al., DNA methylation age of blood predicts all-cause mortality in later life, Genome Biology (2015) doi:10.1186/s13059-015-0584-6 - http://dx.doi.org/10.1186/s13059-015-0584-6
(3) A. Krisko and M. Radman, Phenotypic and genetic consequences of protein damage, PLoS Genetics (2013); 9: e10003810
(4) A. Krisko and M. Radman, Biology of extreme radiation resistance: the way of Deinococcus radiodurans, Cold Spring Harb Perspect Biol (2013) doi: 10.1101/cshperspect.a012765
(5) R. E. Andersen and D. A. Lim, An ingredient for the elixir of youth, Cell Research (2014): 1-2; doi:10.1038/cr.2014.107