Aging disease in children sheds light on normal aging

By Jeffrey Norris

(Medical Xpress) -- Aging of individual cells in the body leads to aging of the whole person. New evidence for this comes from studies of very rare children born with a genetic mutation that wrinkles, ages and kills them before they reach adulthood.

Thanks to research led by the director of the National Institutes of Health, Francis Collins, MD, PhD, a treatment that might offer longer, better lives to children with Hutchinson–Gilford progeria syndrome now is in clinical trials.

The clinical trial and the research that led to it is stimulating scientists to think about ways to fight aging at the cellular level, similar to the way they already have begun to do battle against this most dramatic premature aging disease.

Children born with this form of progeria become strikingly wizened as they age without ever growing to . They die by about age 12 or so, usually due to heart disease.

Progeria – Not a Cartoon of Aging

Progeria has often been portrayed as a “cartoon of aging,” from which little could be learned about normal aging, according to Collins, this year’s Charles J. and Lois B. Epstein Visiting Professor. He does not share this view. “I think we can counter that with molecular data,” he said during a talk at the UCSF Mission Bay campus on Oct. 3, part of a daylong symposium hosted by the Institute for Human Genetics.

The common culprit Collins has identified in normal and premature aging arises for different reasons. In normal aging, Collins suspects damage or loss of telomeres — protective DNA that caps genes at the tips of chromosomes within all our living cells.

Telomeres seem to be turning up everywhere in aging research. UCSF’s Elizabeth Blackburn, PhD, shared a Nobel Prize for the discovery of an enzyme that replenishes bits of telomeres that are lost every time a cell divides. Now she and her colleagues are finding links between telomere shortening and chronic diseases of aging. During his talk Collins served up another possible connection between telomeres and aging.

Collins and collaborators found the mutation that causes Hutchinson-Gilford progeria syndrome — a single-letter mistake in the genetic code. The mutation causes a splicing error in the genetic blueprint used to make one of the cell’s important structural proteins. Instead the cell makes an abnormal protein — called progerin — that messes up the cell’s orderly structure, and the mess just gets worse every time a cell divides to make daughter cells.

In progeria, this happens in all cells. After several generations daughter cells become misshapen. Individual cells senesce faster than normal. The overall potential for cells to undergo cell division is abnormally limited.

Treatment for Aging Disease

Fortunately, Collin’s research team identified not only a cause, but also a treatment -- an off-the-shelf drug developed to treat cancer but which was never successful for that purpose. Now a three-year clinical trial in which 28 children are being treated with the drug is ending, and during his symposium talk Collins said the yet-to-be published results are “encouraging.”

But in one of those expansive, “I hate to ruin your morning,” moments, Collins went on to present evidence that progerin is being made by a fraction of cells in all of us as we , albeit in much less dramatic fashion.

Telomeres, Progerin and Normal Aging

Rather than being caused by any deadly genetic mutation we are born with, these more leisurely cellular breakdowns might involve a loss or shortening of protective telomeres, Collins suggested. Collin’s lab team found that in cells growing in the lab, when they used a chemical to un-cap the chromosome ends, it altered gene splicing and led to progerin production and cellular senescence.

“It’s clear that progerin turns on as a cell is approaching senescence,” Collins said.

“It’s not ubiquitous low-level expression.” In cells that are affected, he said, “The make almost as much as in a patient with the disease.”

“While I can’t prove it, it seems likely that progerin itself is part of normal, programmed senescence,” Collins said. “If we understood that, maybe we would be able to come up with a strategy to deal with the process of normal aging.”

Blackburn’s lab team recently completed an analysis of telomere length in more than 100,000 individuals as part of a joint genotyping collaboration between UCSF and Kaiser Permanente’s Research Program on Genes, Environment, and Health (RPGEH). Perhaps researchers will want to revisit the Kaiser patient cohort and ask for some skin, to see whether telomere length is associated with progerin.

Related Stories

Possible new drug for children with progeria

date Jun 30, 2011

(Medical Xpress) -- A new study published in the journal Science Translational Medicine shows that rapamycin and its derivative everolimus, which is currently used to treat cancer and transplant rejections, may wo ...

Researchers find new clues about aging

date Jun 13, 2011

National Institutes of Health researchers have identified a new pathway that sets the clock for programmed aging in normal cells. The study provides insights about the interaction between a toxic protein called progerin and ...

DNA 'off switch' may reverse premature aging

date Jun 15, 2011

The secret to preventing or reversing premature aging may be found in a DNA “off switch” that humans share with common yeast, according to new research from the University of Toronto.

Recommended for you

Blood test may shed new light on Fragile X related disorders

date 10 hours ago

A blood test may shed new light on Fragile X syndrome related disorders in women, according to a new study published in the March 25, 2015, online issue of Neurology, the medical journal of the American Academy of Neurol ...

Recycling histones through transcription

date 14 hours ago

Cells reuse a part of the histones which are used to pack DNA, according to a current study by Karolinska Institutet. The study, which is published in the journal Genome Research, was conducted on yeast cells, but it is ...

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.