Aging, interrupted

February 23, 2011

Aging, interrupted

February 23, 2011

LA JOLLA, CA—The current pace of population aging is without parallel in human history but surprisingly little is known about the human aging process, because lifespans of eight decades or more make it difficult to study. Now, researchers at the Salk Institute for Biological Studies replicated premature aging in the lab, allowing them to study ageing-related disease in a dish.

In the February 23, 2011 advance online edition of the journal 自然, 胡安-卡洛斯·伊斯皮苏亚·贝尔蒙特, Ph.D. a professor in the Salk Institute’s Gene Expression Laboratory, and his team report that they successfully generated induced pluripotent stem (iPS) cells from skin cells obtained from patients with Hutchinson-Gilford progeria-who age eight to 10 times faster than the rest of us-and differentiated them into smooth muscle cells displaying the telltale signs of vascular aging.

“The slow progression and complexity of the aging process makes it very hard to study the pathogenesis of cardiovascular and other ageing-related disorders,” says Izpisúa Belmonte. “Having a human model of accelerated aging may give us new insights into how we age. It may also help prevent or treat heart disease in the general aging population.

Progeria’s striking features resemble the aging process put on fast-forward and afflicted people rarely live beyond 13 years. Almost all of the patients die from complications of arteriosclerosis-the clogging or hardening of arteries or blood vessels caused by plaques-which leads to heart attack and stroke.

Scientists are particularly interested in progeria in the hopes that it might reveal clues to the normal human aging process. However, the disease is exceedingly rare and only 64 children living with progeria are known making access to patients very difficult.

Hutchinson-Gilford progeria is caused by a single point mutation in the gene encoding lamin A, which forms a protein scaffold on the inner edge of the nucleus that helps maintain chromatin structure and organize nuclear processes such as RNA and DNA synthesis. The mutation creates an alternative splice site that leads to the production of a truncated version of the protein known as progerin. Unlike the full-length protein, progerin does not properly integrate into the nuclear lamina, which disrupts the nuclear scaffold and causes a host of problems.

“There is also evidence that defective lamin A accumulates during the normal aging process via the sporadic use of the alternative splice site, ” explains Izpis&uactue;a Belmonte. “Therefore we are very keen on using our in vitro iPS cell-based model to identify new aging markers and explore other aspects of human premature and physiological aging.”

Compared to normal skin fibroblasts, cells from progeria patients have misshapen nuclei and a range of other nuclear defects, including a disorganized nuclear lamina, loss of super-condensed DNA, telomere shortening and genomic instability. Yet, despite their “old” appearance and against all predictions, these cells could be readily converted into iPS cells.

“The reprogramming process erased all nuclear and epigenetic defects and the rejuvenated pluripotent cells looked and acted like perfectly normal healthy cells,” says first author Guang-Hui Liu, Ph.D., a postdoctoral researcher in the Belmonte lab.

Since lamin A is only expressed in differentiated cells but is absent from embryonic stem cells, he wondered whether iPS cells produce lamin A and/or progerin, which should follow the same expression pattern as lamin A. In his experiments, he couldn’t detect either one. “The biological clock is reset in these cells because lamin A is silenced,” explains Liu.

As soon as the Salk researchers differentiated progeria-derived iPS cells, progerin expression was reactivated. “This reversible suppression of progerin expression by reprogramming and subsequent reactivation during differentiation, provides a unique model system to study human premature ageing pathologies,” says Izpisúa Belmonte.

Progerin accumulates mainly in smooth muscle cells found within the walls of arterial blood vessels, and vascular smooth muscle cells degeneration is one of the hallmarks of Hutchinson-Gilford progeria syndrome-associated arteriosclerosis. In fact, vascular smooth muscle cell senescence also plays a role in advanced arteriosclerosis within the normal aging population.

Upon directed differentiation of progeria-derived iPS cells into smooth muscle cells the premature aging phenotype, including misshapen nuclei, the loss of gene silencing marks and compromised proliferation, reappeared. Genetically modifying progeria-derived iPS cells to shut down the expression of progerin staved off the premature appearance of aging phenotypes after differentiation. “Transplantation of the progenitor cells derived from the “corrected” progeria iPS cells might hold the promise to treat these progeria children in the future.” says Liu.

Other researchers contributing the study include Basam Z. Barkho, Sergio Ruiz, Jing Qu, Scheng-Liang Yang, Athanasia D. Panopoulos, Keiichiro Suzuki, Leo Kuraian, Christopher Walsh and Ignacio Sancho-Martinez in the Gene Expression Laboratory at the Salk Institute, Dinh Diep and Ho Lim Fung in the Department of Engineering at the University of California, San Diego, James Thompson and John Yates III in the Department of Cell Biology at the Scripps Research Institute and Stephanie Boue at the Center for Regenerative Medicine in Barcelona.

For information on the commercialization of this technology, please contact Claudia Hetzer at 858-453-4100, x 1704 (chetzer@salk.edu) in the Salk Office of Technology Management and Development.

The study was supported by the California Institute of Regenerative Medicine, the AFAR/Ellison Medical Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi-Aventis, MICINN, the Fundacion Cellex and grants from the National Institutes of Health.

关于索尔克生物研究所：

索尔克生物研究所是世界顶尖的基础研究机构之一，其国际知名的教职人员在一个独特、协作和富有创造性的环境中，深入探究生命科学的基本问题。索尔克科学家们致力于发现和指导未来几代研究人员，通过研究神经科学、遗传学、细胞和植物生物学以及相关学科，在癌症、衰老、阿尔茨海默氏症、糖尿病和传染病的认识方面做出了开创性的贡献。.

学院取得了许多成就，获得了包括诺贝尔奖和美国国家科学院院士在内的无数荣誉。该研究所由脊髓灰质炎疫苗先驱 Jonas Salk 博士于 1960 年创立，是一家独立的非营利组织和建筑地标。.