Arguing that Progeria Mechanisms are Significant Enough in Normal Aging to Be Worth Addressing

Today I'll point out a very long post that argues we should pay more attention to the mechanisms of Hutchinson-Gilford progeria syndrome (HGPS, or simply progeria) in normal aging. Progeria is one of a small number of rare conditions in which patients have the appearance of accelerated aging. It isn't really accelerated aging, but it is at root a form of biological breakage that leads to greatly increased rates of cellular damage and dysfunction. This produces medical conditions that overlap with those of normal aging since they, also, are the consequence of high levels of cellular damage and dysfunction. Both aging and progeria result in cardiovascular disease and kidney failure, for example, but the root causes are very different. In the case of progeria damage results from a mutation in the lamin A gene, and as a consequence an encoded protein that is vital to cellular function has abnormal behavior. Among other issues observed in progeroid tissues, cell nuclei are misshapen and the ability for cells to replicate is consequently limited.

The cause of progeria was discovered not so long after the turn of the century, and researchers have since then made some inroads towards a treatment. The latest and most promising - and perhaps also the most surprising - is the use of methylene blue, one of the oldest of modern medical compounds. Along the way, evidence has accumulated for the basic mechanism of progeria, damaged lamin A, to be present to a small degree in normally aged tissues. It is far from clear that this has any meaningful impact in comparison to the other forms of cell and tissue damage that cause aging, and for my part I would be surprised to find that it rivals the others to a level that demands action now. This is still a scientific discussion in progress, however, and opinions can differ.

The post linked here is written from a programmed aging perspective, which I think tends to make people look for links that are not there. In search of a genetic program for degenerative aging, the author proposes that lamin A mutations can act as a trigger for that program, and therefore it is worth following the chain of cause and consequence to see what falls out of that investigation. In the alternative view of aging as the consequence of accumulated damage, there is no need for such work: damage causes dysfunction, and progeria is just a much more uniform source of fundamental cellular damage than is the normal aging process. Our level of concern with progeria should therefore match the degree that it contributes to normal aging, which is at present an open question with the presumption that the answer will probably be "not greatly."

Hutchinson-Gilford Progeria Syndrome - a disease of accelerated aging due to Alternative Splicing

HGPS has received attention because it so closely mimics the normal picture of aging. A main difference between normal aging and HGPS is that the entire "aging program" is completed in about 15 years with HGPS, whereas with normal aging, the "aging program" takes almost 100 years to complete. Whereas a few people with normal aging can live as long as 122 years, almost all of the people with HGPS die by 16-20 years of age. The most common findings in HGPS include features that mimic normal aging, such as alopecia, skin atrophy, mottled pigmentation of the skin, generalized lipodystrophy, joint stiffness, arthritis, arteriosclerosis, coronary artery disease, left ventricular enlargement, and strokes. However, HGPS children also have unique findings that do not "mimic" normal aging, such as absent eyebrows, prominent eyes/proptosis, micrognathia, open cranial bone fontanelles, and absent sexual maturation. This is why some have called HGPS a "caricature of normal aging", rather than a "copy of normal aging."

Until 2006, no one really thought that there was much true overlap between HGPS and normal aging. Even expert scientists studying the biology of aging did not think that progerin, the mutant form of prelamin A, accumulated in cells undergoing normal aging. No one says that today. Several independent research teams have published data between 2006 and 2013 which confirm that progerin accumulates in normal skin cells with aging and triggers the same cellular and molecular features of HGPS. Another recent study showed that cellular senescence induces progerin production, whereas immortalized cells suppressed progerin production. Further, progerin accumulates as a function of chronological aging in the blood vessel walls of normal individuals who do not have HGPS. Although the adventitia has the highest concentration of progerin, it also accumulates in the media and intima as well. Progerin accumulation in the walls of blood vessels only affects 1 out of every 1,000 cells at birth and increases at a rate of 3.34% per year. As the endothelial cells divide, they "pass on" the progerin to subsequent generations of daughter cells.

The first obvious lesson we can learn from HGPS is that "a single gene abnormality can trigger the entire aging program". This is not to say that aging is simply due to a cryptic space site mutation in the LMNA gene, but rather that one cryptic splice site can trigger all of aging. HGPS is not the only disease that can do this. Several other diseases due to single point mutations in completely different genes can do the same thing (Ex: DNA repair deficiencies such as Werner's syndrome). However none of these other mutations produce an "aging phenotype" at such a young age or that has such a close resemblance to normal aging. For instance, Werner's syndrome does produce an accelerated aging phenotype that looks like normal aging, but occurs later in life (This is why Werner's syndrome is often called "adult progeria").

Another important lesson we can learn from HGPS is that this disease shows that aging is more like a program which is accelerated from the normal 100 years (normal aging) to 15 years (HGPS). Nature has given us many examples of "molecular programs", such as gestation and embryogenesis. It is hard for most people to accept that aging is programmed too, but there is good evidence for this. The best line of evidence against a non-programmed type of aging is that 100% of humans develop the same set of features with aging in a similar order of events. If aging was truly a random, stochastic event, the features of aging would occur in random order and would not affect 100% of human beings (i.e. random events don't happen 100% of the time in the same order). The fact that over 80% of the features of normal aging are also seen in children with HGPS suggest that this disease is truly an accelerated aging model. The million dollar question, however, is can this aging program be reversed or slowed?

Needless to say I don't agree with any of the above thinking on programmed aging and the relevance of progeria in that light. The ordering argument doesn't seem a good one to me: people do develop age-related conditions in different orders, and the overall progression of aging is the gestalt of countless trillions of molecular events, meaning that randomness is smoothed over time. The author does present and comment on a great many papers on the molecular biochemistry of progeria and aging, and the post is well worth reading for that regardless of where you stand on aging as a process.

Comments

"The best line of evidence against a non-programmed type of aging is that 100% of humans develop the same set of features with aging in a similar order of events. If aging was truly a random, stochastic event, the features of aging would occur in random order and would not affect 100% of human beings (i.e. random events don't happen 100% of the time in the same order)."

Sigh. This betrays a real lack of understanding of the damage model, as well as a lack of observation of normal human aging. No one claims that aging damage is "random" or "stochastic", except when considering a single molecule. Various damage mechanisms (for example, glycation) proceed at a rather constant rate, as dictated by the physical chemistry involved.

What sends people down this programmed aging blind alley?

Posted by: niner at February 10th, 2016 9:52 PM

Hi there,

''Another recent study showed that cellular senescence induces progerin production, whereas immortalized cells suppressed progerin production. Further, progerin accumulates as a function of chronological aging in the blood vessel walls of normal individuals who do not have HGPS''

That is very telling and shows that progeria, of the HGPS and Werner, are truly an accelerated intrinsic aging, wethere caused by lamin mutation, progerin, chromsome 21 breakage or not; the end result is the same - oxidative stress by folds. Chromosome breakage (trisomy 21, Down syndrome) and loss of telomeres; accerelarting replicative senescence. Which means, indeed, accelerated intrinsic aging, just in a different type/form; yielding the same final result.
The fact that immortal cells suppress progerin is the most important element that this paper points another paper who researched progerin accumulation in immortal cells.
If that's where we are going (immortality) progerin absolutely needs to be removed. Replicative senescence accelerates progerin; so we must absolutely twarth replicative senescence.
HPGS and Werner, akin to Diabetes, are forms of accelerated mitochondrial DNA damage, that is brought upon by increased oxidative stress and/at nuclear chromosome/telomere dysfunction - which is causal in regular 'normal' intrinsic aging of healthy people, too.

HPGS fibroblast (fast progerin) have a replicative lifespan senescence of 15 PDs.
Werner fibroblast (slow progerin) have a replicative lifespan senescence of 30-40 PDs.
Healthy human (slowest progerin) fibroblasts have a replicative senescence of 65 PDs.
'semi'-Immortal Werner-SV40 infected (no progerin) fibroblasts reach 275 PDs in continuous culture.

'''Another recent study showed that cellular senescence induces progerin production, whereas immortalized cells suppressed progerin production.''

'' The million dollar question, however, is can this aging program be reversed or slowed? ''

In part, yes and no.
Reversed - totally, that's hard to believe because there too much irreversible damages going on that will 'escape' therapies, but with the 7 therapies, they can reverse aging in certain percentage and they definitely slow it; but Total Reversal, I have some doubts lingering. Plus, there is the problem of how old you are when you take the therapy (how much damage you accrued so far, below 40 you're ok). Total reversal of damages is near impossible because of oxidative stress mechanism in the trillions of mitochondrias producing these cascade of damages and as said, some of them, being irreversible, will still accumulate/show up/escape - while the therapies happen. Only if we modulate oxidative stress in it entirety of mitochondrias, do we have a chance at total reversal.

Posted by: CANanonymity at February 11th, 2016 9:55 AM

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