Different processes give feedback about timing at different timescales. At the sub second scales we have ions and channels. From second to day scale we have hormones. For daily and yearly changes we have the DNA methylation clock.
I think there are two processes that need to be understood. One is the cellular state defined by the chromatin state (mostly histone modifications). This defines the current type of the cell and also what the next stages can potentially be. This is like finite state machine, like digital logical.
Then we have the long range timing process - demethylation of methyalated DNA and methylation of unmethylated DNA sites -as time goes by this can change the state of the cell, for example demethylating regulatory elements that kick off transition to a new chromatin state.
In order to get young again, we need to set back the timing and keep the state intact. This is hard because such program probably does not exist. The only event that turns back the DNA methylation clock is the fertilization. But it also resets the cellular state and restarts the development program.
This coupling makes aging an especially hard to crack nut.
About rapamycin, senolytics, CR, DR and the likes. They dont reset the methylation clock and they dont change the cellular state either. They just alleviate the degenerative effects of the methylation clock I belive.
About parabiosis: I believe that must be true. In order to become a robust process the individual cellular clocks have to be synchronized. I guess mostly via hormones and other chemical signalling. So we can perturb the process, but it is a one way road, hormones and chemicals wont turn it back. Its a maze of chromatin states and methylation levels and the only winner combination leads to the development of a new organism. All other combinations lead to senescence, apoptosis or cancer.
Oxidativd theories: true as well. Oxidation might be a strong driver leading DNA demethylation. Very hard to turn back otherwise we die of hunger.
Pleiotropy: DNA methylation is probably a true driver of the development process and the continuation of this process is degenerative that we call aging.
Programmed aging: might be true as well. The group benefits from having weaker species as well as from the quick recombination of the gene pool.
I wouldnt give it up though. We might be able to traverse chromatin states in a different way that it happens in nature. Also we might be able to run the methylation clock backwards like in the blastocyst. Quick demethylation followed by strong methylation, while keeping the important histone modification sites protected from DNA methylation by PRC binding - this is essentially what happens after fertilization. But we may be able to do it in a differen state, not embryonic stem cell state.
