HIV Drugs Contribute to Accelerated Aging
people with HIV live longer
due to effective antiretroviral
therapy (ART), aging has become a key concern. A growing
body of evidence suggests that HIV positive people may experience
faster than normal aging, characterized by premature progressive
organ disease and frailty.
HIV patients treated with early NRTI drugs show evidence
of mitochondrial DNA damage similar to that usually seen
in much older people.
nucleoside reverse transcriptase inhibitors (NRTIs) such as
(ddI; Videx), and stavudine
(d4T; Zerit) have been linked to mitochondrial toxicity,
or damage to energy-producing structures within cells. While
these drugs are no longer recommended in the U.S. and Europe,
they are inexpensive and therefore still commonly used in
recently in the advance online edition of Nature Genetics
suggest that this mitochondrial DNA damage plays a role in
accelerated aging. Below is an edited excerpt from a press
release issued by the Wellcome Trust in the UK describing
Aging Caused By Some HIV Drugs, Study Shows
26, 2011 -- 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.
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-license 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 recognized many similarities with patients
affected by mitochondrial diseases -- conditions that affect
energy production in our cells -- and referred them to our
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
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."
Professor Chinnery and colleagues are now looking at ways
to repair or stall some of the damage caused by the medication
and believe that focusing on exercise -- which appears to
have a beneficial effect on patients with mitochondrial diseases
-- may help.
The study was funded by the Medical Research Council, the
British Infection Society, the Newcastle Healthcare Charity,
the UK NIHR Biomedical Research Centre for Aging and Age-related
Disease and the Wellcome Trust.
Investigator affiliations: Mitochondrial Research Group,
Institute of Genetic Medicine, Newcastle University, Newcastle
upon Tyne, UK. Department of Infection and Tropical Medicine,
Royal Victoria Infirmary, Newcastle upon Tyne, UK; Centre
for Human Genetics Research, Vanderbilt University, Nashville,
BA Payne, IJ Wilson, CA hateley, et al. Mitochondrial
aging is accelerated by anti-retroviral therapy through the
clonal expansion of mtDNA mutations. Nature Genetics
June 26, 2011 (Epub ahead of print).
Trust. Premature Aging Caused By Some HIV Drugs, Study Shows.
Press release. June 26, 2011.