Premature aging caused by some HIV drugs, study shows

A class of anti-retroviral drugs commonly used to treat HIV, particularly in Africa and low income countries, can cause premature ageing, according to research published today in the journal Nature Genetics. The study shows that the drugs damage DNA in the patient's mitochondria – the 'batteries' which power their cells.

27 june 2011--The findings may explain why HIV-infected people treated with antiretroviral drugs sometimes show advanced signs of frailty and age-associated diseases such as cardiovascular disease and dementia at an early age.

Nucleoside analogue reverse-transcriptase inhibitors (NRTIs) – of which the most well known is Zidovudine, also known as AZT – were the first class of drug developed to treat HIV. They were a major breakthrough in the treatment of the disease, greatly extending lifespan and leading the condition to be seen as a chronic, rather than terminal, condition.

In high income countries, such as Europe and North America, the older NRTIs are used less commonly now due to concerns over toxicity and side-effects when taken over a long period of time. However, as they are now off-licence and hence relatively cheap, the drugs have proved to be an important lifeline for people infected with HIV in Africa and low income countries.

Professor Patrick Chinnery, a Wellcome Senior Fellow in Clinical Science from the Institute of Genetic Medicine at Newcastle University, says: "HIV clinics were seeing patients who had otherwise been successfully treated but who showed signs of being much older than their years. This was a real mystery. But colleagues recognised many similarities with patients affected by mitochondrial diseases – conditions that affect energy production in our cells – and referred them to our clinic."

Mitochondria are the 'batteries' in our cells which provide them with the energy to carry out their functions. During natural human ageing, these mitochondria acquire mutations, though it is unclear whether these mutations are a cause of ageing or a consequence.

In an attempt to understand what was happening at a cellular level, Professor Chinnery and colleagues studied muscle cells from HIV-infected adults, some of whom had previously been given NRTIs.

The researchers found that patients who had been treated with NRTIs – even as long ago as a decade previously – had damaged mitochondria which resembled that of a healthy aged person.

"The DNA in our mitochondria gets copied throughout our lifetimes and, as we age, naturally accumulates errors," explains Professor Chinnery. "We believe that these HIV drugs accelerate the rate at which these errors build up. So over the space of, say, ten years, a person's mitochondrial DNA may have accumulated the same amount of errors as a person who has naturally aged twenty or thirty years. What is surprising, though, is that patients who came off the medication many years ago may still be vulnerable to these changes."

Co-author and HIV specialist, Dr Brendan Payne, a Medical Research Council fellow from the Department of Infection and Tropical Medicine at the Royal Victoria Infirmary, Newcastle, believes that despite the side effects caused by NRTIs, they are still important drugs and the risks are relative.

"These drugs may not be perfect, but we must remember that when they were introduced they gave people an extra ten or twenty years when they would otherwise have died," he says. "In Africa, where the HIV epidemic has hit hardest and where more expensive medications are not an option, they are an absolute necessity."

Provided by Wellcome Trust

Anti-cancer drug prevents, reverses cardiovascular damage in mouse model of premature aging disorder

10 oct 2008--An experimental anti-cancer drug can prevent -- and even reverse -- potentially fatal cardiovascular damage in a mouse model of progeria, a rare genetic disorder that causes the most dramatic form of human premature aging, National Institutes of Health (NIH) researchers reported today.
In a study published in the Oct. 6 early online edition of the Proceedings of the National Academy of Sciences, a team led by Francis S. Collins, M.D., Ph.D., of the National Human Genome Research Institute (NHGRI), and Elizabeth G. Nabel, M.D., director of the National Heart, Lung and Blood Institute (NHLBI), describes its effort to use transgenic mice to identify and test potential therapies for children with Hutchinson-Gilford progeria syndrome.
There currently are no treatments for progeria, which is estimated to affect about one child in 4 million. At birth, children with progeria appear normal. But soon growth slows, and the children begin to show signs of accelerated aging, such as hair loss, wrinkled skin and loss of body fat. The most lethal damage, however, occurs within the children's major blood vessels. The children develop premature cardiovascular disease, which typically leads to death from heart attack or stroke at about the age of 13.
Building upon its past experiments in cells and mice, the NIH-led team examined the effects of an experimental cancer drug, tipifarnib, in a strain of mice genetically engineered to develop cardiovascular damage similar to that seen in progeria patients. Tipifarnib belongs to a class of drugs known as farnesyltransferase inhibitors (FTIs), which are being tested in people with myeloid leukemia, neurofibromatosis and other conditions. The team had previously found that FTI drugs could reverse structural abnormalities in skin cells taken from progeria patients and grown in the laboratory.
"This approach worked much better than we thought it would. Not only did this drug prevent these mice from developing cardiovascular disease, it reversed the damage in mice that already had disease," said the study's senior author, Dr. Collins, who is the former director of NHGRI and who continues to conduct research as a special volunteer in the Genome Technology Branch of NHGRI's Division of Intramural Research.
Researchers emphasized that more work needs to be done to determine whether FTI drugs will reverse progeria-associated cardiovascular disease in humans the same way they do in mice. In children suffering from progeria, the cardiovascular disease process often remains relatively stable until late in life, when it dramatically accelerates.
"If these drugs are found to have similar effects in children, this could mark a major breakthrough for treating this devastating disease," said NHLBI's Dr. Nabel, who was a co-author of the study. "In addition, these findings shed light on the potential role of FTI drugs to treat other forms of coronary artery disease."
In 2007, researchers led by Mark Kieran, M.D., Ph.D., at the Dana-Farber Cancer Institute in Boston launched a clinical trial of another FTI drug, lonafarnib, in 28 progeria patients, ranging in age from 3 to 15, from 16 countries. Results of that study are not expected for at least a year.
Earlier this year, in experiments involving a different type of mouse model for progeria, a group of researchers from Spain and France reported that a combination of statin and bisphosphonate drugs slowed development of the visible symptoms of aging and extended life spans in the animals. Both drugs act upon the same biological pathway as FTI drugs.
While progeria affects only a few dozen children worldwide, efforts aimed at untangling the biological roots of this rare disease may prove valuable in understanding the human aging process in general. "What we learn through studies of rare genetic disorders often has implications for more common conditions," said NHGRI Scientific Director Eric D. Green, M.D., Ph.D. "For example, a growing body of evidence indicates that all people produce small amounts of the mutant protein found in progeria patients, and that this protein may play roles in aging or longevity."
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In addition to NHGRI and NHLBI, the team that conducted the most recent study included researchers from Emory University School of Medicine, Atlanta, and CVPath Institute, Inc., Gaithersburg, Md.
For more information about progeria, go to http://www.genome.gov/11007255.