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One has to be somewhat careful when declaring that an intervention produces accelerated aging. Interventions that reduce health and life span in ways that mimic aspects of aging tend to be narrow in effect, causing elevated levels of a specific form of molecular damage, often one of those thought to be involved in natural aging. DNA repair deficiencies cause what looks a lot like accelerated aging, but should really be thought of as an excess of only one type of age-related damage, nuclear DNA damage. It might be possible to learn things from this type of malfunction, but given that it is very unlike natural aging, it is more likely that a close inspection of the cellular biochemistry and tissue dysfunction involved would be misleading. One can make similar, more difficult arguments regarding whether or not excess visceral fat tissue produces accelerated aging by increasing the burden of cellular senescence, or whether this should be viewed in much the same way as DNA repair deficiencies.
In today’s open access paper, researchers note that engineering a greater activity of retrotransposons, in effect producing DNA damage as the transposable elements replicate themselves to break the parts of the genome they copy into, accelerates aspects of aging in flies. This is a closer analogy to DNA repair deficiencies than the question of obesity, again a way to amplify natural processes of DNA damage with consequences that can mimic natural aging in some ways. Retrotransposons are tightly controlled in youth, but epigenetic aging allows them ever greater freedom to replicate in later life. There is a fair amount of evidence to implicate this process in age-related disease and loss of function, but as is the case for so much of aging it is hard to pin down exactly how much harm is caused by this one process, versus all of the other processes of aging. Speeding it up in isolation of other mechanisms is one way to make an estimate, but it is nowhere near as compelling as the much harder demonstration, yet to be achieved, of slowing it down.
Transposable elements (TE) are mobile sequences of DNA that can become transcriptionally active as an animal ages. Whether TE activity is simply a byproduct of heterochromatin breakdown or can contribute towards the aging process is not known. Here we place the TE gypsy under the control of the UAS GAL4 system to model TE activation during aging. We find that increased TE activity shortens the lifespan of male D. melanogaster. The effect is only apparent in middle aged animals. The increase in mortality is not seen in young animals. An intact reverse transcriptase is necessary for the decrease in lifespan implicating a DNA mediated process in the effect.
The decline in lifespan in the active gypsy flies is accompanied by the acceleration of a subset of aging phenotypes. TE activity increases sensitivity to oxidative stress and promotes a decline in circadian rhythmicity. The overexpression of the Forkhead-box O family (FOXO) stress response transcription factor can partially rescue the detrimental effects of increased TE activity on lifespan. Our results provide evidence that active TEs can behave as effectors in the aging process and suggest a potential novel role for dFOXO in its promotion of longevity in D. melanogaster.