New Data on Progerin and Cellular Senescence in Normal Aging

One of the interesting items that has emerged from the discovery of the cause of progeria, a condition that strongly resembles accelerated aging, is that this single molecular cause is also present to a much smaller degree in normally old individuals. Progeria is caused by a mutation in the lamin A (LMNA) gene, important in the establishment of cell structure, and therefore also important to the correct function of just about every vital cellular process. The condition is very rare because this mutation must randomly occur in a germ cell or during very early embryonic development. It is an inherited condition in that sense, but patients don’t live long enough to have children of their own. The mutated form of the lamin A protein is known as progerin, and over the past decade researchers have noted that small amounts of progerin can also be found in normal individuals.

Here, it is important to note that what are commonly referred to as accelerated aging conditions, progeria being one example, are not in fact accelerated aging. They look that way, superficially at least, but they are better thought of as runaway damage conditions. One type of cellular damage, in many cases a type of cellular damage that – so far as we know – has little to no relevance in normal aging, runs amok. The result is some combination of impaired regeneration, impaired DNA maintenance, cells that become broken and dysfunctional, tissues and organs with failing functionality. This sounds a lot like aging, true, but then so does poisoning or viral disease when it is expressed in those terms. The result is functional decline, dysfunction, and death, but the details are different, and the deeper you look into the biochemistry, the more different they become. Just as you can’t learn much about aging from examining victims of slow poisoning, you also can’t learn much about aging from any narrow form of molecular breakage that doesn’t occur to a significant degree in normal aging.

What about progerin, however? Did I not just mention that it does appear in normally aged tissues? Well, this is true, it does. So do a great many other things, however. The trick lies in proving that there is a significant contribution to degenerative aging resulting from progerin. A number of research groups have been slowly chasing this down over the past fifteen years, with an increasing focus on cellular senescence, as the cells of progeria patients appear to have at least some aspects in common with senescent cells, even if there are marked differences between the two. Senescent cells, of course, are now well recognized to be a contributing cause of normal degenerative aging. Another area of interest is the possible impact of progerin on stem cell activity, required for tissue maintenance. This maintenance activity declines with aging, likely a response to rising levels of cellular damage that serves to reduce cancer risk, but the research community is a fair way from being able to pin down specific causes and the degree to which they contribute to this loss of function.

The open access paper noted here is representative of the state of the field, in which researchers are starting to be confident enough in their understanding of progerin in normal aging to advance possible mechanisms for its effects, and run animal studies to try to put some numbers to those claims. The authors link progerin with cellular senescence in fat tissue, in the sense they think a small number of progerin-loaded cells are accelerating the creation of lingering senescent cells, which go on to carry out their characteristic damage to health and tissue function. Unfortunately, I’d say the results published here are a little too tentative to provide good support for the authors’ theory on what is taking place under the hood, for all that it sounds plausible. It is an interesting direction, however, and I would expect to see further similar work on this topic in the years ahead.

Rare progerin-expressing preadipocytes and adipocytes contribute to tissue depletion over time

One of the major physiological changes that arises with aging is the loss of subcutaneous white adipose tissue (sWAT). White adipose tissue is known to be involved in energy storage, in the form of lipids, but also in immunity, adipokine and inflammatory cytokine production. Different fat depots can be found in both humans and mice, which appear to have distinct functions. Subcutaneous fat works as an endocrine organ, secreting, in particular, the hormones leptin and resistin. Its role is to store triglycerides and free-fatty acids in order to prevent their ectopic deposition. In the case of lipoatrophy, sWAT’s ability to store energy is impaired, which results in ectopic fat deposition either in visceral depots or in non-adipose sites.

The investigation of premature aging syndromes has had a considerable impact on the understanding of some of the bases of physiological aging. One of these syndromes is the Hutchinson-Gilford Progeria Syndrome (HGPS), commonly known as Progeria, a rare genetic disease characterized by clinical features resembling certain aspects of premature aging. Although several mutations have been reported to cause HGPS, this disease most often results from a de novo point mutation in the LMNA gene. Progerin accumulates at the inner nuclear membrane causing distortion of the membrane and disrupting nuclear functions. Accumulation of progerin is thought to be responsible for abnormal functional changes associated with HGPS including suppressed Nrf2 antioxidant pathway signalling and impaired adult stem cell function.

HGPS shares several features with normal aging, one of them being the loss of sWAT. Several studies have revealed the presence of low levels of progerin or rare progerin-expressing cells in normal fibroblasts (between 0.5% and 3%) and arteries (between 0.001% and 1.97%), with amounts sometimes increasing during aging. Low tissue levels of progerin can either be attributed to low expression in many cells, or to high expression in a small fraction of cells. However, it is still arguable that low levels of progerin significantly contribute to the reduced tissue function associated with aging.

In this study, we used a mouse model with sustained long-term expression of human progerin in a low frequency of cells of the adipose tissue to determine the contribution of progerin to progressive sWAT depletion. Our results provide evidence that adipose tissue is highly sensitive to progerin expression and further emphasize progerin’s possible causal role in certain tissue alterations during aging. However, the frequency of progerin positive cells in the sWAT of our mouse model was higher than what was observed in healthy human sWAT, in which progerin could not be detected on protein level. Other researchers have suggested a hypothetical model whereby aging of adipose tissue results in cellular senescence and consequent tissue pathology. Our results provide evidence that a similar mechanism is to be found in subcutaneous fat, with progerin accumulation during aging triggering a cascade of events contributing to progressive tissue depletion.

We propose that with chronic exposure to low numbers of progerin expressing cells, sWAT pathology begins, initially with hyperproliferation. Hyperproliferation in turn contributes to abnormal cellular development and subsequent senescence. As paracrine activity is high in adipose tissue, senescence spreads to surrounding cells through activation of the senescence-associated secretory phenotype (SASP). Simultaneously, aging sWAT accumulates DNA double-strand breaks, which upon reaching a certain threshold lead to an increase in cell death, encouraging macrophage infiltration, as well as exacerbating the senescence phenotype. This pro-inflammatory environment of the adipose tissue ultimately activates the immune system machinery resulting in systemic inflammation.

📍

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s