Information loss can drive us crazy – from ruining a potential culinary masterpiece to turning a Lego-building afternoon into a nightmare, but can “losing it” at the epigenetic level drive aging and turn a young whippersnapper into an old fogey?
We know all too well about age-related epigenetic changes, and now a team led by Jae-Hyun Yang and David A. Sinclair (Harvard Medical School) sought to confirm whether epigenetic changes cause mammalian aging by developing a system (inducible changes to the epigenome or “ICE”) that degrades/resets epigenetic information. ICE involves the induction of I-PpoI endonuclease expression, which creates non-mutagenic DNA double-strand breaks (DSBs) and DNA damage responses that temporarily displace epigenetic modifiers from regulatory elements.
Let’s hear from Yang, Hayano, and Colleagues on their “cool” 13-year study (!) linking the loss of epigenetic info to aging:
- ICE mice resemble middle-aged wild-type mice after a month and exhibit classic features of old age and significantly increased frailty after ten months
- Age-related defects include coordination/long-term memory loss, a decline in spatial/memory consolidation, increased brain inflammation, reduced endurance/strength, and signs of dilated cardiomyopathy
- ICE mice display gene expression profiles similar to old mice, with a 50% increased rate of epigenetic aging
- Mass spectrometry, ChIP-seq, and ATAC-seq in ICE cells provide evidence for an age-related “erosion” of the histone acetylation landscape and a decrease in chromatin accessibility, which prompts cells to lose their identity
- More aberrant displacement of epigenetic modifiers over time represents the basis for this erosion, which disrupts developmentally-associated gene expression and significantly alters spatial chromatin contacts, chromatin insulation, and promoter-enhancer communication (measured by Hi-C and HiChIP)
- “Rejuvenating” the epigenome of ICE cells by the forced expression of the Oct4, Sox2, and Klf4 (OSK) reprogramming factors reverses age-associated gene expression profiles and returns epigenetic aging to close to control
- Expression of reprogramming factors also reverses the appearance of tissue aging markers in ICE mice; therefore, manipulating the epigenome to “rejuvenate” old cells/tissues may represent an exciting therapeutic approach to aging-related conditions
Far from sounding outlandish, this ice-cold study provides evidence that molecular aging occurs through an epigenetic mechanism. So, what may come of this exciting new advance? First author Jae-Hyun Yang shares that they are interested in examining “…other ways to manipulate the epigenome, like drugs and small molecule chemicals that induce gentle stress. This work opens a door for applying those other methods to rejuvenate cells and tissues.”
Don’t lose any of the vast amounts of information on this epic ice-cold new study by heading over to Cell, January 2022.