A number of research programs in recent years have pointed to an increased level of retrotransposon activity with aging. Retrotransposons are DNA sequences that can copy themselves to different locations in the genome, a parasitic addition that originated deep in evolutionary history. Retrotransposons are normally suppressed in youth, but increased retrotransposon activity occurs in later life, and is thought to bring disarray to cellular function. As is the case for most observed aspects of aging, there is plenty of room to debate just where retrotransposon activity sits in the complex web of cause and consequence.
Researchers here note that one class of retrotransposons escapes suppression in senescent cells, and this increased activity is important to the senescence-associated secretory phenotype (SASP) by which lingering senescent cells cause great harm to surrounding tissues. The SASP is highly inflammatory, and chronic inflammation is responsible for much of the downstream harms of aging. Removing senescent cells is the present preferred approach to building rejuvenation therapies capable of turning back age-related inflammation, but a sizable contingent of researchers are nonetheless interested in finding ways to dial down the SASP. This seems a more challenging task, one that will proceed increment by increment, as this is a very complex phenomenon.
Retrotransposons are related to ancient retroviruses that, when left unchecked, can produce DNA copies of themselves that can insert in other parts of a cell's genome. Cells have evolved ways to keep these "jumping genes" under wraps, but as the cells age, the retrotransposons can escape this control. A research team has now shown that an important class of retrotransposons, called L1, escaped from cellular control and began to replicate in both senescent human cells - old cells that no longer divide - and old mice. Retrotransposon replication, specifically the DNA copies of L1, is detected by an antiviral immune response, called the interferon response, and ultimately triggers inflammation in neighboring cells.
These retrotransposons are present in every type of tissue, which makes them a compelling suspect for a unified component of cellular aging. Understanding that, the team uncovered the interferon response, the potential mechanism through which these jumping genes may cause cellular inflammation without necessarily causing damage to the genome. The interferon-stimulating copies of L1 DNA require a specific protein called reverse transcriptase. HIV and other retroviruses also require reverse transcriptase proteins to replicate. In fact, AZT, the first drug developed to treat HIV/AIDS, halts HIV reverse transcriptase. Researchers thought that this class of drugs may keep the viral-like L1 retrotransposon from replicating and thereby prevent the inflammatory immune response.
One generic HIV drug, lamivudine, stood out because of its activity and low side effects. Growing human cells in the presence of lamivudine did not impact when the cells reached senescence or kill the senescent cells. But lamivudine did decrease the interferon response and the late-stage senescence-associated secretory phenotype (SASP) - the important characteristics of senescent cells that promote inflammation in their neighbors. "When we started giving this HIV drug to mice, we noticed they had these amazing anti-inflammatory effects. Our explanation is that although L1s are activated relatively late in senescence, the interferon response reinforces the SASP response and is responsible for age-associated inflammation."