Josh Mitteldorf's latest post on telomerase and epigenetic clock is worth reading -- and discussing here is better coz in his blog it takes a while for him to post the comments.
The key study: GWAS of epigenetic aging rates in blood reveals a critical role for TERT, 2017
Turns out, telomerase also regulates the epigenetic clock (as measured by DNA methylation patterns in a subset of SNPs, selected to strongly correlate with chronological age -- the so called Horvath clock).
The idea that Josh drives at is that telomerase accelerates the Horvath clock. ...though I'm not sure why he views these particular changes in methylation patterns as detrimental, considering that the advancing age, as shown by the clock, did not affect the vigor with which the cultured cells kept dividing. Here is quote from the study, broken up for easier reading, the underline mine:
While non-TERT cells senesced after ~150 days, TERT-expressing cells continued to proliferate unabated at a constant rate with time in culture. Single-time point analyses showed that TERT-expressing cells exhibited a linear relationship between time in culture and the Horvath estimate of DNAm age (equivalent to a DNAm age of 50 years at 150 days), whereas in non-TERT cells DNAm age plateaued (equivalent to a DNAm age of 13 years) in spite of continued proliferation to the point of replicative senescence.
Notably, DNAm age did not increase in TERT-expressing cells that received regular media change but were not passaged throughout the entire observation period of 170 days [== these cells did not proliferate but remained static, fig.3d]. These cells were not senescent, given that their subsequent passaging resulted in normal proliferation.
In multivariable regression analysis, the associations of DNAm age with cell passage number and cell population doubling number were highly modified by TERT-expression. In the absence of TERT-expression, DNAm age did not increase with cell passage number, cell population doubling number, or time in culture.
So, if the advancement in the Horvath clock has no effect on cells viability, why view it as detrimental? Until it is shown that, as the Horvath clock advances, the cell's machinery begins to falter, I'd rather view it as a sort of a memory of the cell, sort of its way of keeping time.
Regarding the correlation of short telomeres with cardiovascular disease -- it can be interpreted differently: If we take another strong correlation of CVD, which is with chronic infections (e.g. gum disease), then shorter telomeres in leukocytes could simply reflect the fact that the immune cells are proliferating rapidly trying to contain the infection -- and that's what, currently, makes their telomeres shorter.
In this regard, NASA recently reported an interesting observation in their 'twin study'. Apparently, spending substantial time in space significantly increases telomere length, but the return to Earth shortens them, within just 2 days (!). So I was wondering why would leukocyte telomeres shorten so dramatically in such a short time -- and the only thing I could think of is the sudden change in the environment: i.e. after Scott spent many month in the space station in orbit, which must be an unusual yet stable environment, suddenly, his immune sys had to deal with a wide variety of microbes back on Earth (-?)
It stands to reason that, all things being equal (including the level of telomerase expression), shorter telomeres in a given tissue type (compared to the average for a this tissue type in a population) reflect the stress on this tissue in the given individual -- and this stress could be due to trauma, toxins (metabolic or xenobiotic) or, again, infection (which may cause apoptosis in infected cells and trigger the need to replace them).
So, we could view the telomere length as the reflection of the rate of living, so to speak -- the demands made on organism by various stressors. Then the difference between a faster and a slower aging person will boil down to two major factors: 1. how many stressors these people encountered in a given period; and 2. how resistant they are to stress (and resistance to stress is usually a measure of expression of certain genes, like HSR for example, and BTW, caloric restriction tends to upregulate them).
IOW, rather than seeing the advancement of the Horvath clock as 'aging', in detrimental sense, we could view it as memory of the number of divisions. I intend to keep this view -- until it will be shown that at certain point the Horvath clock starts to correlate with the decline in cell's viability.
PS
Actually, the fact that the viability of the cells in culture does not seem to decline with ticking of the Horvath clock gives an important clue to what drives aging: it's the mileu, the immediate environment of the cell, that determines its behavior (e.g. research in heterochronic parabiosis and its variants where 'old' or 'young' cells are cultured in old on young serum). Currently, the consensus seems to converge on the idea that some molecule(s) secreted in the brain --could be something in the hippocampus-- act as ever-growing in persistence signal directed at a cell faced with accumulating damage of all sorts; and the message of this signal is, don't bother fixing that!
Edited by xEva, 25 March 2018 - 07:34 PM.