Tier 3 — preclinical

LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation

Matthew Simon, Michael Van Meter, Julia Ablaeva, Zhonghe Ke, Raul S Gonzalez, Taketo Taguchi, Marco De Cecco, Katerina I Leonova, Valeria Kogan, Stephen L Helfand, Nicola Neretti, Asael Roichman, Haim Y Cohen, Margarita V Meer, Vadim N Gladyshev, Marina P Antoch, Andrei V Gudkov, John M Sedivy, Andrei Seluanov, Vera Gorbunova
Cell Metabolism 2019 29(4):871-885.e5

Bibliography

PubMed
PMID 30853213
DOI
10.1016/j.cmet.2019.02.014
Funding
Supported by NIH grants to S.L.H., J.M.S., A.S., A.V.G. and V.G.; Roswell Park Alliance Foundation support to A.V.G.; and Life Extension Foundation support to A.S. and V.G.
Competing interests
The authors declared no competing interests.

Study snapshot

DesignMechanistic aging study testing LINE1 derepression, cytosolic DNA sensing and inflammatory signaling in SIRT6-deficient and aged wild-type mice.
ModelSIRT6-deficient mice, aged wild-type mice and associated cellular models.
SamplePreclinical experiments; sample sizes vary by endpoint.
InterventionGenetic SIRT6 deficiency and reverse-transcriptase inhibition in mechanistic experiments.
DurationExperiment-dependent.
EndpointsLINE1 expression/cDNA; cGAS/type-I interferon signaling; systemic inflammation; health/lifespan outcomes in SIRT6-deficient mice

What the study showed, in plain terms

This paper extended the LINE1 mechanism into inflammation. In aged wild-type and SIRT6-deficient mice, LINE1 derepression generated cytosolic DNA that activated innate immune signaling; reverse-transcriptase inhibition reduced inflammatory signaling in the experimental models.

Key findings

LINE1 activity can function upstream of cGAS/type-I-interferon inflammation when SIRT6-dependent repression fails.

What this study can and cannot tell us

The causal experiments were performed in mice and cells; the study does not establish that activating SIRT6 improves clinical aging outcomes in humans.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability