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Safe, inexpensive chemical reverses progeria

A new finding could lead to treatments for rare genetic illness and normal aging. New work from the University of Maryland suggests that a common, inexpensive and safe chemical called methylene blue could be used to treat progeria — and possibly symptoms of normal aging as well.

Progeria is a rare genetic disease that mimics normal aging but at a much accelerated rate. Symptoms typically appear within the first year of life, and individuals with the disease develop thin, wrinkled skin, fragile bones and joints, complete body hair loss, organ failure, and more. Most children suffering with progeria do not survive past their teens.

It is caused by a single-nucleotide, the building blocks of DNA, mutation on the LMNA gene. Single nucleotide polymorphisms, frequently called SNPs and pronounced “snips”, are the most common type of genetic variation people harbor.

Researchers found swollen, fragmented mitochondria and reduced mitochondrial mobility in HGPS fibroblast cells — the cells in connective tissue that produce collagen. They also found progerin inhibited expression of the protein PGC-1α, a central regulator of mitochondrial biogenesis — or the process by which new mitochondria are formed in a cell.

In order to rescue mitochondrial defects, HGPS cells were treated with the antioxidant, methylene blue (MB). Amazingly, MB treatment not only alleviated mitochondrial defects but also rescued nuclear abnormalities — a hallmark of HGPS cells.

Analysis suggested methylene blue (MB) released progerin from the nuclear membrane, which rescued DNA specifically replicating it at the end of the S phase and corrected errors in HGPS gene expression.

These results demonstrate how mitochondrial dysfunction develops in prematurely aging HGPS cells and suggests MB as a promising therapeutic approach for HGPS.

This is the first time that small doses of methylene blue almost completely repaired defects in cells afflicted with progeria, while also repairing age-related damage to healthy cells. The study was published online in the journal Aging Cell on December 10, 2015.

"We tried very hard to examine the effect of methylene blue on all known progeria symptoms within the cell. It seems that methylene blue rescues every affected structure within the cell. When we looked at the treated cells, it was hard to tell that they were progeria cells at all.

"It's like magic."

Kan Cao PhD, Associate Professor, Cell Biology and Molecular Genetics, University of Maryland, and senior author.

Progeria results from a defect in a single gene, PGC-1α, a key regulator of energy metabolism. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene.  This gene interacts with the protein lamin A, which sits inside the cell nucleus, under the nuclear membrane. Healthy cell interactions snip off a piece of the lamin A molecule — a small edit needed for lamin A to function properly. Progeria cells, however, skip this important editing step.

Defective lamin A interferes with the nuclear membrane, causing the nucleus to bulge and deform making normal function impossible.

Cells with progeria also have misshapen and defective mitochondria, the small organelles meant to produce energy for the cell.

Although previous studies suggested damage to mitochondria in progeria cells, the current study is the first to document the nature and extent of this damage in detail.

Cao and her colleagues found that a majority of mitochondria in progeria cells are swollen and fragmented, making function impossible for them.

Yet, the team found methylene blue reverses the damages to both the nucleus and mitochondria in progeria cells remarkably well. The precise mechanism is still unclear, but treating the cells with MB effectively improved every defect, causing progeria cells to be almost indistinguishable from normal cells.

Cao and her colleagues also tested methylene blue on healthy cells allowed to age normally. Normal aging degrades mitochondria over time, causing them to resemble the mitochondria seen in progeria cells. Once again, methylene blue repaired these damaged mitochondria.

"We have repeated these experiments many times and have not seen a single one fail.

"This is such an exciting result with so much potential, both for progeria and normal aging. Methylene blue is common and inexpensive. It is fully water soluble and non-toxic. People use it to clean fish tanks because it is so safe for the fish eggs."

Zheng-Mei Xiong, lead author on the study and a postdoctoral associate in the UMD Department of Cell Biology and Molecular Genetics.

Because methylene blue can repair cell defects that ultimately lead to whole-body symptoms in progeria patients, Cao, Xiong and their colleagues believe methylene blue could be used as a treatment for the disease in the future. Similarly, methylene blue shows promise as an over-the-counter treatment for symptoms of normal aging, perhaps as an additive to cosmetic products or through nutritional food supplements.

Cao and her team are moving quickly to complete the next crucial step: testing in animal models.

"So far, we have done all of our work in stem cell lines. It is critical to see whether the effect extends to whole animals. We also want to see if methylene blue can repair specific effects of progeria in various cell types, such as bone, skin, cardiovascular cells and others. Further down the line, other groups might begin human clinical trials.

"It's very exciting."

Kan Cao PhD

Hutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single-nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high-resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC-1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial-targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

The research paper, "Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria," Zheng-Mei Xiong, Ji Young Choi, Kun Wang, Haoyue Zhang, Zeshan Tariq, Di Wu, Eunae Ko, Christina LaDana, Hiromi Sesaki and Kan Cao, was published online in the journal Aging Cell on December 10, 2015.

This research was supported by the National Institutes of Health's National Human Genome Research Institute (Award Nos R01HG007104 and R21AG043801). The content of this article does not necessarily reflect the views of this organization.

University of Maryland
College of Computer, Mathematical, and Natural Sciences
2300 Symons Hall
College Park, MD 20742

About the College of Computer, Mathematical, and Natural Sciences
The College of Computer, Mathematical, and Natural Sciences at the University of Maryland educates more than 7,000 future scientific leaders in its undergraduate and graduate programs each year. The college's 10 departments and more than a dozen interdisciplinary research centers foster scientific discovery with annual sponsored research funding exceeding $150 million.

Related Research

The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises

Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. Here, we report a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. Using this animal model, we have developed an antisense morpholino–based therapy that prevents the pathogenic Lmna splicing, markedly reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotide–based therapies for treating human diseases of accelerated aging.

The story of HGPS is an impressive example of the interplay of basic and clinical science. It is also a showcase for how modern biology deals with disease (Figure 2). Within less than two years, we have gone from only knowing the symptoms of the disease to identifying the disease-causing gene and learning much about how the mutant protein behaves in patient cells. The challenge ahead is to close the circle and to apply what we have learned about the cell biology of this disease to the development of therapeutic approaches. The insights from HGPS have also opened an entirely new and fascinating vista on the aging process. Who would have guessed two years ago that architectural elements of the cell nucleus might contribute to aging? These advances have put us in the rare and desirable situation of possibly being able to making significant steps towards understanding one of the most fascinating problems in biology—and at the same time do some good for patients and their families.

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Hutchinson-Gilford Progeria Syndrome. HGPS is a childhood disorder caused by
mutations in one of the major architectural proteins of the cell nucleus.
In HGPS patients the cell nucleus has dramatically aberrant morphology (bottom, right)
rather than the uniform shape typically found in healthy individuals (top, right).

Image Credit: The Cell Nucleus and Aging:
Tantalizing Clues and Hopeful Promises





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