The most recent posts related to progeria diseases remind me again that when it comes to aging we seem to be dealing with different areas of a very large jigsaw puzzle where most of the pieces between the areas are still missing. The best we can do is assemble different portions of the puzzle without worrying too much about how the portions will eventually fit together. As we build those portions we find they have irregular shapes with holes in them where smaller collections of pieces are still missing. We may have put together a portion of the puzzle and not know what it means – is the blue area sky, water or the side of a building? Is the accumulation of progerin in cells with aging just another irrelevant buildup of a substance in cells with aging, a major cause of other aging effects, or what? As we proceed we constantly keep looking for how one portion of the puzzle might be joined with another. Being able to join up two major portions is a breakthrough event. As time progresses a more and more coherent pattern emerges and the job gets easier. If you have ever worked on a very large jigsaw puzzle you know what I mean.
There are differences between the two kinds of puzzles, however. You know what an assembled jigsaw puzzle looks like because the image is printed on the top of the box. This image gives important color clues for putting the puzzle together. And you know you the box should contain exactly the pieces you will need. You know the pieces are accurately cut. It might take a week off-and-on to finish a 3000 piece jigsaw puzzle but the job is finite.
For the longevity puzzle we don’t know what the puzzle will look like when it is finished. We have to be constantly fishing around in the world literature to find new pieces. And some of the new pieces we find may be inaccurately shaped even if at first they seem to fit with some other pieces. What works in a mouse study may not apply to humans. If we put together a part of the puzzle with inaccurately shaped pieces that part won’t fit in with the rest of the puzzle and will eventually have to be taken apart and built over. At any point, we don’t know how many pieces are still missing, and we don’t know whether we will live long enough to find them all. So, the longevity puzzle is open-ended and might take 5 years or a lifetime before the picture is reasonably clear. What fun!
Hi Vince
This is what I think.
Telomere length is what decides the aging process. How close the end of the telomere is to the end of the dna strand is what decides the age.
So the heyflick limit ultimately decides the lifespan of the organism.
The telomere length gets affected by various chemicals such as cortisol, oxidants, glycated products and of course progerin.
The accumulation of progerin and other chemicals have the bearings on the effects of aging such as skin health, immunity, diabetic, cholestrol and such.
So the target for anti aging is two pronged. One is to remove the elimination and clearing of the unwanted byproducts of living. Another is to extend the telomeres to such a length that is optimal (neither too long or too short)
Res
My thoughts have been very similar to yours but are now more nuanced. See my comments * on your points.
This is what I think.
Telomere length is what decides the aging process. How close the end of the telomere is to the end of the dna strand is what decides the age.
* This has been my most central working assumption since 1995. However some of the newer theories of what causes aging (decline in adult stem cell differentiation and programmed genomic changes) also have a lot going for them and how these theories relate to the telomere shoretning theory is only partially understood. So for the present at least I don’t want to come down absolutely on the telomere shortening theory as necessarily being the central one. Remember, mice and rats have very long telomeres and yet they age and die from other causes besides cell senescence due to telomere shortening..
So the heyflick limit ultimately decides the lifespan of the organism.
* If the Hayflick Limit is measured classically, by the number of cell divisions, not really. In an earlier posting I talked about a study where some people’s telomeres actually became longer over a multi-year period. Telomere length is a function both of the number of cell divisions and endogenous effective expression of telomerase. Numerous proteins and factors intervene. In any event, when telomeres get too short bad stuff happens without question. It is good to keep them long.
The telomere length gets affected by various chemicals such as cortisol, oxidants, glycated products and of course progerin.
* Yes, but cause-and-effect relationships are mostly a matter of conjecture because studies that tell us what happens in detail don’t exist yet. Does Ink4a accumulate faster in cells because of shorter telomeres? And is the most damage caused by senescent cells because of too-short telomeres or by excessive apoptosis and decline in stem cell proliferation due to the accumulation of Ink4a? A similar question exists with respect to progerin. Is more harm caused by defective LMNA and consequently wretched internal cell structures or by cell senescence? Are the factors independent or does one drive another?
The accumulation of progerin and other chemicals have the bearings on the effects of aging such as skin health, immunity, diabetic, cholestrol and such.
* Right. But a problem in hormone balance or in the immune system can throw telomere length erosion in immune cells into high gear, so cause and effect are confounded. There are feedback loops in which just about everything is effected by everything else. As a general principle there are lots of widely differing conditions that can cause an organism to age faster. This can be seen in the two kins of progeria we talked about.
So the target for anti aging is two pronged. One is to remove the elimination and clearing of the unwanted byproducts of living. Another is to extend the telomeres to such a length that is optimal (neither too long or too short)
* In very simplistic terms this is the objective of the anti-aging firewalls regimens, both the lifestyle and dietary supplement ones. As time goes on additional objectives have emerged such as Assure continuing division and proliferation of adult stem cells. Whether these new objectives can be subsumed under your two objectives is not clear at this point.
Good discussion.
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