Developmental Disorders Have Little To Do With Aging
One of the challenges inherent in talking to the public about aging is that there are many well-popularized rare conditions that have the superficial appearance of accelerated aging or slowed aging, but are in fact nothing of the sort. Take progeria, for example: it is a comparatively simple genetic dysfunction that induces a great deal of cellular dysfunction and damage. Aging itself is a matter of specific forms of cellular dysfunction and damage, but any vaguely similar limiting of cell activities will produce some of the same outcomes, such as failure of tissue maintenance and a decline in organ function and integrity. Progeria patients die young from cardiovascular disease as a result of these issues, and appear prematurely aged. Yet the type of damage to cells that occurs in progeria has next to no role in normal aging, and vice versa, and the outcomes only appear similar at the large scale because the essential high level functions of tissue are disrupted in both cases. In fact the two conditions, progeria and aging, have nothing to do with one another, and it is probably the case that little learned in progeria research will be applicable in the treatment of normal aging.
This is a moderately complex set of ideas to explain in enough detail for it all to make sense to someone not versed in the underlying science. It takes a little time, and good explanations are all too often obscured by simplified media stories that talk about accelerated aging in ways that make sound like progress in progeria research is a direct and useful approach to learning about normal aging. Not the case at all, however.
Another example of the type that has been making the rounds in the media for the past few years is a rare developmental disorder in which the child does not develop: one individual lived for two decades while remaining an infant. The colloquial sense of the word "aging" includes growing up to adulthood as well as getting old, and so the media breathlessly calls this arrested aging, but these are two quite different processes. The degeneration and loss of function in later aging is caused by accumulated damage that occurs as a side-effect of the normal operation of metabolism. The passage from childhood to adulthood is an evolved developmental program of growth and change. If that developmental program is broken, the individual will still age, will still accumulate cellular and tissue damage for so long as their metabolism is operating. It seems unlikely that there is anything of practical use for aging to be learned here, despite the hopes expressed by some of the people involved:
Epigenetic age analysis of children who seem to evade aging
We previously reported the unusual case of a teenage girl stricken with multifocal developmental dysfunctions whose physical development was dramatically delayed resulting in her appearing to be a toddler or at best a preschooler, even unto the occasion of her death at the age of 20 years. The pediatrician who cared for her from birth described his patient's strange affliction, that did not fit any disease category, as an "unknown syndrome" later to be called "syndrome X". As the result of her persistent "toddler-like" appearance, she received extensive notoriety from the media, and was featured as the "girl who doesn't age" in press articles and television broadcasts.While most of the individual defects she experienced are not uncommon in many children, it was her retaining toddler-like features while aging from birth to young adulthood that made the case particularly unusual. Even children with growth retardation or failure to thrive exhibit maturation of facial and other physical/functional features with passage of time, indicating that their developmental program is still functional. In contrast, the peculiar trait of the first case suggested that her rate of aging was dramatically delayed or even arrested. If so, then perhaps an etiological understanding of her pathology might lead to novel treatments for age related diseases.
The objectives of this study were two-fold. The first was to determine if other such cases of syndrome X actually exist and thus might represent a novel syndrome. Then, because the case's appearance remained that of a toddler despite the passage of time, our second objective was to determine if there was any evidence that the arrested development in such children is linked to a slowing down of aging at the molecular level.
We identified five new cases whose clinical presentations were similar to the first case. Thus, while extremely rare, the first case described was not unique in the world. Furthermore, since such children require extensive medical care to survive, especially during the first years after birth, it may be that most succumb before ever being diagnosed. All of the identified subjects were female. It is not known whether this occurrence was due to chance alone or is a sex linked aspect of the putative syndrome.
To objectively measure the age of blood tissue from these subjects, we used a highly accurate biomarker of aging known as "epigenetic clock" based on DNA methylation levels. Our results demonstrate that despite the clinical appearance of delayed maturation in children afflicted with syndrome X, the epigenetic clock indicates that the rate of development in blood and perhaps other tissues is normal. Thus, while we cannot exclude tissue-specific ageing as causal in syndrome X, the current findings suggest that the observed delay in whole body development results from other, yet undiscovered factors. Future studies should assess whether other tissue types from these subjects (or their bodies as a whole) evade epigenetic aging.
Though I totally agree with the main point of this post, which is that failure to develop does not mean failure to age, progeria is certainly a different case.
Scientists have known since 2006 that progerin, the farnesylated mutant lamin A present in progeria, is also overexpressed in aging wildtype human cells. It's expression is particularly noticeable in several different types of stem cells, including endothelial stem cells, and endothelial cell dysfunction has been strongly correlated to aging on multiple levels. Furthermore, progerin expression has been shown to be inversely correlated with telomere stability, results in dysfunctional DNA repair and aging associated epigenetic changes, and one paper has even shown that SIRT1 activation is dependent on functional lamin A and inhibited by progerin. Lastly, both progeria patients and typical aging humans die most frequently from cardiovascular disorders such as heart attack and stroke and show commonly display profound atherosclerosis.
Granted, progeria patients don't get cancer and don't display neurodegeneration or cognitive decline, but if aging is truly a multifaceted disease linked to individual instances of cellular damage we can't expect any one developmental model to recapitulate all the phenotypes of a typical 80 year old. I think that ignoring progerin as an important form of cellular damage is shortsighted and is itself very damaging to the cause of aging research.
Agree with Kris
@Kris: Can you provide a link demostrating that progerin is overexpressed in aging wildtype human cells?
Here are a few pubmed links to support my statements (my lab is already subscribed to all these journals so if you guys are having trouble accessing them tell me and I'll try to find a popular science article).
Progerin is expressed in normal aging cells (note: this was a very big paper published in Science, one of the worlds most prestigious journals)
http://www.ncbi.nlm.nih.gov/pubmed/16645051
Progerin is induced by telomere dysfunction in wildtype human fibroblasts:
http://www.ncbi.nlm.nih.gov/pubmed/21670498
Progerin expression recapitulates aging in young animals: http://www.ncbi.nlm.nih.gov/pubmed/25587796
Progerin disrupts endothelial cell dysfunction:
http://www.ncbi.nlm.nih.gov/pubmed/25567453
Progerin is associated with atherosclerosis in the aging population (review):
http://www.ncbi.nlm.nih.gov/pubmed/25667091
http://www.ncbi.nlm.nih.gov/pubmed/23217256
Oh and sorry, the last unlabeled link in the above comment is about progerin and SIRT1.
@Kris: Thanks for the links. The first one is open access. I will read it carefully.
The evidence I've seen suggests that progerin plays little if any role in normal aging. Here's part of Michael Rae's excellent analysis regarding progeria:
"It is true that the splicing defect responsible for formation of progerin is sporadically active in wild-type cells, and that number of cells in which progerin is present and the level at which it appears do appear to rise with aging.(8-12) However, such cells are rare enough, and their progerin levels low enough, as to seem highly unlikely to meaningfully contribute to tissue dysfunction with aging, at least within the bounds of a currently-normal lifespan. Additionally, there is evidence that progerin can be turned over in the nuclear lamnia,(9) and the causal relationship between the higher prevalence of progerin in aging cells and cellular senescence or disease are not clear, leaving open the possiblity that repair of well-established forms of aging damge may in turn lead to the reversal or obviation of this phenomenon. Notably, the need toremove "senescent" cells as part of a comprehensive panel of rejuvenation biotechnologies is already clear from first principles, and its potential to ameliorate aspects the frailty and disability of aging has been demonstrated in proof-of-concept rejuvenation research, rendering the specific role of progerin in the process moot. That is, removing "senescent" cells is essential whether progerin accumulation is a cause or a consequence of cellular senescence, and will be equally effective as a regenerative medical therapy against age-related disability in either case.
…
"…the phenotypic resemblance of HGPS to aging is much more limited than media and other accounts often imply. Thus, for instance, the vascular defects of HGPS bear only limited resemblance to atherosclerotic cardiovascular disease:(11,18) patients do not have hyperlipidemia, but the low serum cholesterol levels typical of children,(11,20) and there is only a limited and tenuous involvement of macrophages in the artery wall (as in 'normal' aging);(11) the lesions are not the result of cholesterol storage within foam cells, but instead arise primarily because of early thinning of the vasculature, caused by replicative and/or mutational senescence.(11) Similarly, the causes of bone decay in HGPS are very different from those seen in aging humans. And while HGPS patients do exhibit some phenotypes with a superficial resemblance to those associated with 'normal' aging (hair loss, thin-looking skin because of a a lack of subcutaneous fat, wrinkling, skeletal abnormalities), many age-related diseases are absent from progeroid patients: they are, happily, not plagued by dementia (except when caused by a stroke), cataracts, age-related macular degeneration, near- or farsightedness, diabetes (although ~50% of patients exhibit some insulin resistance), or cancer, and have only limited renal involvement (18-21). Moreover, while degenerative aging is characterized by progressive thymic involution that contributes to the progressive decline of adaptive immunity with age, the thymus of HGPS patients is of normal size and in some cases exhibits significant hyperplasia, and their hormone levels and immune function appear to be normal for their calendar age.(20)"
http://sens.org/research/research-blog/accelerated-aging-inspiration-beyond-equivocation
Florin,
I don't believe that anyone has enough evidence to definitively say that progerin is not expressed strongly enough or in enough cells during aging to have a significant effect. The Scaffidi et al. 2006 paper does find less progerin in cells from old patients compared to HGPS patients, but nonetheless still finds nuclear blebbing and some of the same phenotypic abnormalities in many cells. Likewise, whether or not progerin is turned over in the nuclear lamina, it apparently is not being turned over at a rate which prevents some accumulation and an apparent phenotype. Likewise, there is no definitive evidence that A2E lipofuscin (a compound which I'm currently working on, and which SENS is also working on) is directly pathogenic to the RPE except for a genetic disease called stargardt's with significant accumulation and an early blinding phenotype, and correlative evidence indicating that it may pose a problem in AMD.
The whole idea behind SENS is that some forms of damage accumulate with aging and that we are better off trying to treat them directly rather than spending a million hours trying to nail down the exact mechanism by which they do it, or by comparing one with the other. Are AGE's or oxidized cholesterol more important in aging? Does it matter? We need to treat both either way.
Eliminating senescent cells is an excellent strategy and may very well make progerin a moot point. Nonetheless, there are plenty of people around the world to try different strategies. What if combination FTI therapies are effective against some aspects of aging? In fact, if progerin contributes to cellular senescence, we may be able to reduce senescent cell formation directly in this manner! Or it may all fail. But why should we say that all strategies besides the SENS strategy for this particular issue are not even worth looking into?
In terms of your second point, it is entirely true that labeling HGPS a premature aging disease is frustrating and inaccurate. Obviously the only true model for aging is aging itself. And many components of aging are not observed in HGPS patients, including neurodegeneration, cancer, and many steps in the physiology of atherosclerosis. Nonetheless, to treat a multifaceted disease it often helps to have a model for specific forms of the associated damage. Why do we use APP mutant mice to study alzheimer's? There's a lot more than beta amyloid happening in alzheimer's disease. Nonetheless, we need to start treating the damage somewhere, purely because it's a multifaceted disease! There are a million people arguing whether beta amyloid or neurofibrillary tangles are more primary, just as there are a million people trying to figure out whether mitochondrial damage or MToR inhibition are the more primary component of aging, which is exactly why SENS is such a good organization: It doesn't jump into this pandora's box, doesn't waste time discriminating, and purely seeks to start engineering solutions to the damage. If progerin is directly associated with senescent phenotypes and epigenetic expression patterns and is upregulated in the elderly, there is certainly no reason to count it out.
Kris, apparently, the SRF has decided that the level of evidence for progerin as a cause of disease in normal aging is not strong enough to warrant funding research into eliminating it, and since the cells in which it accumulates will need to be eliminated anyway (as has been mentioned before), it would be a wasteful duplication of effort to fund research into the elimination of progerin. If the SRF concluded that level of evidence for A2E, mito dysfunction, or any other type of damage as a root cause of disease was the same as for progerin, I'm sure that it wouldn't fund research into ways of repairing those types of damage either. In fact, the SRF doesn't fund research into repairing DNA damage or calcification for this very reason.
In a world of unlimited resources, all potential aging targets could be given equal consideration, but unfortunately, we don't live in a utopia. Therefore, discrimination between damage targets is absolutely necessary.
Since you seem to think that progerin may have a similar level of evidence as a cause of disease as A2E, you might want to try to convince the SRF that their analysis regarding progerin is wrong. Aubrey and Michael are easy to reach.