Some older HIV drugs linked to premature ageing

Older antiretroviral drugs still widely used in low and middle-income countries accelerate a process of mutation within the DNA of mitochondrial cells that has been linked to ageing, scientists from Newcastle University report in the journal Nature Genetics.

The authors of the study say that their findings raise the spectre of the large-scale emergence of early ageing in people treated with the older nucleoside analogues over the next decade. However, more studies will be needed to confirm these findings.

They also note that even in people no longer taking the drugs, the past mutations in mitochondrial DNA caused by AZT (zidovudine, Retrovir, also in Combivir), d4T (stavudine, Zerit) and ddI (didanosine, Videx) cannot be repaired by normal cellular mechanisms.

They estimate that any ageing effects of the drugs are likely to be greater when taken by older people.

There is some evidence of accelerated ageing in individuals with HIV disease, including a higher prevalence of frailty, deterioration in lower-limb strength, modest declines in physical function when compared to HIV-negative adults of the same age, and declines in limb muscle.

It is unclear to what extent these conditions are caused by antiretroviral treatment, or if they are the long-term consequence of past opportunistic infections. The fact that these problems tend to occur in individuals over the age of 50, who were likely to have been diagnosed with AIDS and to have suffered a series of opportunistic infections that may have resulted in permanent physical disability and reduced physical function, suggests that the notion of accelerated ageing may disguise the fact that many people with long-term HIV infection continue to experience poor health despite successful antiretroviral treatment.

Furthermore, other diseases of ageing that occur in people with HIV are either related to lifestyle, or strongly associated with immunosuppression. Examples include cancers and heart disease.

However, other forms of ageing, such as weight loss, ageing of the skin, fatigue and muscle loss, have been less comprehensively studied.

Some scientists argue that some of the manifestations of ageing are the result of the long-term accumulation of mutations in the mitochondrial DNA of human cells. Mitochondria are energy-producing bodies within cells. They are more prone to mutation when copying themselves because they lack the `proof-reading` mechanism present in other human cells.

However this explanation for ageing is not accepted by all scientists as the primary or predominant cause of age-related degeneration in bodily functions. Critics of the theory point to the vast array of factors that can cause cumulative cellular and tissue damage.

It is also unclear whether the mitochondrial changes are a cause of ageing, or just a reflection of larger processes at work in the ageing body.

In individuals without HIV mitochondrial disorders, some of them inherited, may develop, with symptoms ranging in severity from exercise intolerance to blindness, severe organ dysfunction and impaired growth, depending on the mutations and the tissues affected. These disorders are most likely to emerge in childhood.

Mitochondria in HIV infection

Nucleoside analogues can cause mutations in mitochondrial DNA and depletion of mitochondrial DNA.

Considerable research into the effects of nucleoside analogues on mitochondrial DNA has been carried out as a result of the recognition that many of the most serious toxicities of this class of antiretroviral drug are a consequence of mtDNA polymerase gamma inhibition. Side-effects linked to this mechanism include lactic acidosis, lipoatrophy (fat loss), myopathy (damage to skeletal and cardiac muscle) and liver failure.

The older nucleoside analogues d4T and ddI have a much greater effect on mitochondrial DNA than newer drugs such as abacavir and tenofovir. 3TC (lamivudine) and FTC (emtricitabine) appear to have very little effect on mitochondrial DNA. AZT (zidovudine) has an intermediate effect.

The Mitochondrial Research Group at Newcastle University’s Institute of Genetic Medicine, led by Professor Patrick Chinnery, investigated mitochondrial depletion in skeletal muscle in 33 HIV-infected adults below the age of 50 and compared the results with those of ten healthy age-matched HIV-negative controls.

They sought in particular to assess COX-SDH deficiency, a marker of ageing. COX-SDH deficiency in muscle fibre was no more common in untreated HIV-positive people (n=12) than in HIV-negative controls, but HIV-positive people treated with nucleoside analogues showed much greater frequency of COX-SDH-deficient muscle fibre (in some cases up to 10% of muscle fibre was deficient, compared to less than 0.5% in the control group).

The extent of the deficiency was strongly predicted by total lifetime nucleoside analogue exposure, not current treatment, “implicating a persistent and cumulative mitochondrial defect”, say the authors. The median duration of exposure was unspecified by the study authors.

The mechanism that led to COX-SDH deficiency was not loss of mitochondrial DNA, but the proliferation of mitochondrial DNA that contained mutations. Mitochondrial DNA proliferated in response to previous loss of DNA, and as a consequence existing age-related mutations were copied. Mitochondrial DNA from patients treated with nucleoside analogues contained a significantly higher number of mutations, to such an extent that the burden of mutations in patients with under 50 was equivalent to that seen in the over-80s.

However, the authors concluded that rather than increasing the rate of mutation in mitochondrial DNA, nucleoside analogue treatment is associated with a higher rate of clonal expansion, or bulk copying, of mitochondrial DNA containing age-related mutations.

This means that nucleoside analogue treatment which increases the rate of mitochondrial DNA turnover will have a much greater effect on markers of ageing if it is taken by older people with more pre-existing mutations. Those in the age range 40-50 would have a much higher chance of accumulating mutations than those in the 20030 age group.

“An HIV-infected individual treated with NRTIs during their third decade is predicted to develop ~5% COX deficient cells by age 60. This is similar to or exceeds that seen in the healthy very old.”

The authors say that one limitation of their methodology is that mutation rates could have been overestimated by the test they used to measure mtDNA mutations.

Validation of the findings in larger cohorts which can provide more information about antiretroviral exposure, immunosuppression and comorbidities will be needed, as will studies which look at correlations between mtDNA mutations, ageing and antiretroviral exposure in other cell types.

Mitochondrial toxicity is strongly correlated with the severity of immunosuppression, and mitochondrial damage is dependent on the extent to which a nucleoside analogue is phosphorylated, or taken up into the active form, by a particular cell type. Thus, if the Newcastle University group's hypothesis is correct, age-related mutation would be both drug and cell-type dependent, leading to a broad spectrum of early emergence of conditions normally seen in the elderly, rather than a single pattern of accelerated ageing.

Payne BAI et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nature Genetics, advance online publication, 26 June 2011.

Alexeyev MF et al. Mitochondrial DNA and aging (review). Clinical Science 107: 355-364, 2004.