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[reason]

The author noted here sees aging as programmed, in the sense that it is an epigenetic program selected for by evolution because shorter life spans prevent population-level ecological issues. His writing is usually a good illustration of how this concept of aging as a selected epigenetic program leads to very different conclusions on the nature of aging as a whole, as well as on any specific research result. In the case of this post, the topic is the role of telomere length and telomerase in aging, and their relationship to the established DNA methylation biomarkers of aging.

The mainstream view of epigenetic change with age is that it is a reaction to accumulated cell and tissue damage, one that evolved in the limited selection pressure thought to characterize post-reproductive life span. Both damage and epigenetic changes are components of a decline that is an accidental outcome of the aggressive selection for success in early life. Evolution produces biological systems that do well initially, then corrode and fail in a haphazard fashion, because there was no selection for long-term function. Thus systems that generate damage as a side-effect of normal operation, and systems that have limited capacity that fills up and causes issues in later life are found everywhere in our biology.

The debate over programmed versus non-programmed aging, and the ordering of cause and effect between cell and tissue damage versus epigenetic change, will be settled over the next decade or two. If one side produces therapies that revert epigenetic changes and the other side produces therapies that repair cell and tissue damage, then simple observation of the results will determine who is right. The greatest extension of life span and health will point the way to the correct interpretation of the process of aging.

Just a few weeks ago, I learned of a new study linking telomerase to the changes in DNA methylation that the epigenetic clock associates with aging. The implication is that telomerase accelerates aging. It began with an investigation asking what genetic variations are associated with people who age faster or slower than average, according to the epigenetic clock? Researchers performed a genome-wide search for statistical correlates and the standout association was telomerase. People who have small genetic variations that support greater telomerase expression tend to have longer telomeres, but they also tend to age faster, as measured by the epigenetic clock.

The association between telomerase and accelerated aging (measured by methylation) was found in the genetic statistics, and then confirmed in a cell culture. When telomerase was artificially activated in the cell culture, the methylation patterns changed in the cells consistent with older age according to the epigenetic clock. In fact (and remarkably in my opinion) they found no epigenetic aging at all in the cell cultures that lacked telomerase. Could it be that telomerase is the one and only driver of epigenetic aging at the cellular level?

So, what's going on? My inclination is always to think in evolutionary terms. Fixed lifespan, (especially when modified conditions of food stress) is helpful in preventing population overshoot that can lead to famines, epidemics, and extinction. But whenever a trait is good for the community and bad for the individual, there is a temptation for the individual to cheat. In this case, cheating would mean evolving a longer lifespan via selfish genes, such as those enabling greater telomerase expression, that spread rapidly through the population. Individual competition would erase aging if left unchecked. The results would be great for individual fitness, but soon would be disastrous for the population. Thus evolution places barriers in the way of individual selection for ever longer lifespan.

My guess is that the connection between telomerase and epigenetic aging is an example of antagonistic pleiotropy crafted by natural selection in its long-term mode. Limiting lifespan has been so important to the viability of the population that evolution has arranged to protect it from leaking away due to cheating, and antagonistic pleiotropy is one of the ways in which this is arranged. I believe that the preponderance of evidence still indicates that activating telomerase has a net benefit for lifespan, but that probably we can add at most a few years by this route. I think that epigenetics is much closer to the core, the origin of aging, and that interventions to modify epigenetic aging will eventually be our holy grail.

Link: https://joshmitteldo...-and-downgrade/

View the full article at FightAging

[xEva]

again 'dangerous irresponsible'-?! who keeps doing it?

 
anyway, i wanted to point out an error, in red, not that reason comes here: 
 

"When telomerase was artificially activated in the cell culture, the methylation patterns changed in the cells consistent with older age according to the epigenetic clock. In fact (and remarkably in my opinion) they found no epigenetic aging at all in the cell cultures that lacked telomerase. Could it be that telomerase is the one and only driver of epigenetic aging at the cellular level?"

 
They had 3 sets of cell cultures going: 2 sets of TERT-expressing cells  + 1 culture of  non-TERT cells.  Between 2 sets of TERT-expressing cultures, one was continuously "passaged" (== 'encouraged' to proliferate) and one remained static (did not proliferate).  BOTH cultures had telomerase! The culture that kept proliferating unabated, after 150 days showed the methylation age of 50 years. The TERT-expressing culture that did not proliferate did not age at all after 170 days, Quote from the study: 

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 were not senescent, given that their subsequent passaging resulted in normal proliferation.

 
I think this is an important distinction. This is the second time I see the same error (first was in in another blog, not Josh Mitteldorf's).  iow, according to this in vitro study, If cells don't proliferate they don't age, despite having telomerase expressed.  

Edited by xEva, 31 March 2018 - 05:52 AM.

[HaplogroupW]

That's the spirit xEva. But the first red bit doesn't appear to be an error in the blog, near as I can tell. From later in that same paragraph of the study:

 

 

In the absence of TERT-expression, DNAm age did not increase with cell passage number, cell population doubling number, or time in culture.

 

[xEva]

 

That's the spirit xEva. But the first red bit doesn't appear to be an error in the blog, near as I can tell. From later in that same paragraph of the study:

 

 

In the absence of TERT-expression, DNAm age did not increase with cell passage number, cell population doubling number, or time in culture.

 

 

 

I guess this shows that we read in the same passage what we happen to read.

 

IMO, and without nitpicking, the message reads that, as long as telomerase is expressed, the cells Horvath clock keeps advancing -- while it would be more precise to say that, according to this in vitro study,  cells aged when 2 conditions were met: they expressed telomerase and they proliferated. To have either one, i.e. telomerase without proliferation -or- proliferation without telomerase, was not enough to keep the Horvath clock advancing.