Researchers know that many factors contribute to the aging process. But what is common in animal aging is inflammation, which scientists think may be intensified by repetitive selfish genetic elements that do not seem to offer any benefit to their hosts but serve only to propagate themselves by inserting new copies into their host genomes.
It turns out that the human genome is littered with selfish genetic elements, specifically LINE1 retrotransposons. Approximately 20% of both human and mice genomes are composed of LINE1s.
Scientists have long suspected that LINE1s contribute to cancer and genomic instability. However, the damage caused by these genomic parasites reaches much further than researchers had at first thought, according to a paper (“LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation”) in Cell Metabolism.
A team from the from the University of Rochester, including Vera Gorbunova, PhD, and Andrei Seluanov, PhD, demonstrated that LINE1 retrotransposons become more active with age and may cause age-related diseases by triggering inflammation. By understanding the impacts of retrotransposons, researchers can better recognize the processes by which cells age and how to combat the deleterious effects of aging, according to Gorbunova and Seluanov.
“Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity,” wrote the paper’s authors. “We report that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response.
“In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.”
Human cells have evolved multiple molecular mechanisms (for example, gene silencing) to keep selfish genetic elements like LINE1s at bay. However, these mechanisms become less efficient during the aging process, allowing LINE1s to be reactivated.
“As LINE1s become active, some of their copies leak outside the cell nucleus into the cytoplasm,” Gorbunova says. “Any DNA in the cytoplasm is a signal for alarm, as it resembles viruses that are invading the cell.”
Cytoplasmic “guardians” (types of DNA sensors) detect invaders and trigger immune responses such as inflammation. This process, which normally functions to protect humans from viruses and foreign DNA, recognizes leaked LINE1 copies in the old cells and triggers a false alarm in the form of age-related inflammation.
The researchers found that they can reduce LINE1s using drugs that inhibit reverse transcriptase, which catalyzes LINE1 DNA formation. These drugs were originally developed to combat reverse transcriptase in HIV patients. Using these drugs to reduce LINE1s improves health in mice and reduces inflammation, in addition to improving lifespan, notes Seluanov, who adds that “sterile inflammation triggered by LINE1 elements is a new mechanism of aging. We can now develop strategies that target LINE1s and the pathways that lead to inflammation.”
With these new insights, researchers may develop interventions that inhibit LINE1s. “These interventions,” says Gorbunova, “may serve as new forms of therapy for age-related diseases fueled by inflammation, such as neurodegeneration, cancer, diabetes, and autoimmune diseases.”