This might suggest that two recently published studies by teams at the Salk Institute for Biological Studies in La Jolla, California. Human aging remains now a poorly understood phenomenon and its study is complicated by the fact that this process stretches over a lifespan exceeding 80 years. Moreover, the very causes of aging are poorly known and many processes appear to be combined, at different levels, to contribute to this phenomenon. At the genetic level, telomeres appear to be the cause of aging in our DNA. At the protein level, accumulation of malformed proteins are the cause of death of certain cells. At the cellular level, oxidative stress associated with the activity of mitochondria is also a source of toxicity that is his due with age. At the macroscopic scale, environment and nutrition also play roles. The two studies conducted at the Salk Institute used to clarify some of these points.
A Spartan regime for longevity
Recently, studies have shown that it is possible to substantially increase the life span of certain animals and reduce their risk of age-related diseases (cancer , diabetes, cardiovascular diseases, etc..) reducing their daily nutritional intake, especially the amount of calories each day. The study of caloric restriction has shown that it was originally the activation of an enzyme called AMPK (AMP-activated protein kinase) present in many animal species. The action of this enzyme on the regulation of metabolism had already been studied in research on obesity [1] [2]. In the context of aging research, it was shown that reducing calorie activates AMPK, which then regulates the cellular activity to reduce their energy consumption. This slowdown is causing metabolic the increase in life span observed, but the process initiated by AMPK and biomolecules with which it interacts in this hitherto unknown mechanism. A team led by Andrew Dillin and Reuben Shaw studied at Ceanorhabditis elegans (a worm used as a model), possible targets of AMPK [3].
By studying the genome of the worm, they found a likely target: a protein called CRTC1 (CREB-regulated transcription coactivator 1). By inhibiting the production of CRTC1 in Ceanorhabditis elegans, researchers have observed an increase of 40% of its useful life. The team subsequently confirmed the link between AMPK and CRTC1 showing that the first second inactive in catalyzing the phosphorylation of the second. The addition of a phosphate group on a site specific CRTC1 off because this protein. The key role of CRTC1 in the process has also been confirmed by studying its interaction with another enzyme called calcineurin, which plays the opposite role of AMPK and removes the phosphate group that disables CRTC1. In summary, CRTC1 can be compared to a switch of aging, which can be ignited by either calcineurin or extinguished by AMPK. In addition, the site of phosphorylation of key CRTC1 is widely retained within the animal kingdom.
The combination of these two properties makes this protein an excellent target for the development of a pharmaceutical treatment. By developing a compound that inhibits directly CRTC1, researchers hope to reach replicate the beneficial effects of calorie restriction on longevity, while avoiding its greatest flaw: the fact of having to maintain a state of perpetual hunger.
study the pathologies of aging to better understand the phenomenon
Meanwhile, another team from the Salk Institute, led by Juan-Carlos Izpisua Belmonte has focused on the study of human disease very rare and currently incurable syndrome called Hutchinson-Gilford (progeria or) to understand the mechanisms linked to cellular aging. This disease is indeed characterized by accelerated aging of the human being, who is showing signs of senescence at the age of two years. Children with this disease are very rare (64 cases listed in the world today) and usually die from vascular disease before the age of 13. This disease is caused by a single mutation of the gene encoding lamin A, a protein that plays a critical role in organizing the cell nucleus. The mutation causes the synthesis of a shortened version of the lamin A, progerin called, which therefore plays more role in structuring the kernel, therefore causing many problems on the genetic activity of the cell. The cells are then very quickly look "old" characterized by a malformed nucleus and DNA folded incorrectly.
Dr. Belmonte's team has created a line of induced pluripotent stem cells from fibroblasts (skin cells) from patients with progeria. Their goal is to use stem cells to create different types of differentiated cells and observe the effects of accelerated aging in each of these lineages. It is thus possible to observe in the space of two weeks of the phenomena that take several decades for most people. However, it could suggest that stem cell line obtained is also subjected to accelerated aging. The fact that this is not the case constitutes an achievement in itself and an additional study showed that lamin A / progerin was not synthesized in stem cells but only in cells differentiated. Once these stem cells are differentiated, the synthesis of progerin cell begins and symptoms of progeria occur again.
The stem cell line obtained not only to study the effects of aging in different cell types but also some other action of progerin. The team of Dr. Belmonte has shown that progerin accumulates and form clusters, mainly in the smooth muscle cells lining the arterial blood vessels. Clusters cause degeneration of these cells, causing vascular disease often fatal for people with progeria. The accumulation of protein in these cells could be a biomarker of interest for monitoring of physiological aging.
Finally, researchers have shown that it is possible to prevent the appearance of accelerated aging in genetically modifying the stem cells induced to inhibit the synthesis of progerin. This could be a trail of treatment for progeria. In all cases, obtaining this new cell line is an interesting development for the study of aging. The study was published in the journal Nature [4].
These two studies show the complexity and variety of phenomena associated with aging. Demographic trends observed across the world make the study of aging, a subject of great importance in the field of biology.
For more information, contact:
- [3] Article (in English, subscription required to access the full text):
http://www.nature.com/nature/journal/v470 / n7334/full/nature09706.html
- [4] Article (in English, subscription required to access the full text) :
http://redirectix.bulletins-electroniques.com/x0bok
- The Salk Institute (in English): http://www.salk.edu/
Source:
- [1] discovered in mice a drug that "burn" fat, Alexander Touvat, Bulletin U.S. 195,
http://www.bulletins-electroniques.com/actualites/62275.htm
- [2] The woodchuck model of human obesity research, Alexander Touvat, Bulletin U.S. 214, http://www.bulletins-electroniques.com/actualites/63881.htm
- Hungering for Longevity - Salk Scientists Identify The confluence of aging signals, The Salk Institute for Biological Studies, February 17, 2011, http://www.salk.edu/news/pressrelease_details.php?press_id=472
- Aging, interrupted, The Salk Institute for Biological Studies, February 23, 2011, http://www.salk.edu/news/pressrelease_details.php?press_id=473
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