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Retrotransposon Mediated “Inflammaging” – A Target for The Treatment of Age-associated Disorders?

Review of “L1 drives IFN in senescent cells and promotes age-associated inflammation” from Nature by Stuart P. Atkinson 

Recent research has linked the activation of retrotransposable elements to some cancers and the aging process [1-3]; however, the full contribution of retrotransposon activity to aging and age-associated diseases remains unknown. A recent Nature article from the laboratory of John M. Sedivy (Brown University, Providence, RI, USA) aimed to fill this knowledge gap by assessing the activity of L1 retrotransposons [4] during the senescence of human fibroblasts in vitro. Excitingly, this new study now suggests that the activation of retrotransposons contributes to aging-associated inflammation (“inflammaging”) and that L1 reverse transcriptase represents a potential target for the treatment of age-associated disorders [5].

De Cecco et al. discovered that L1 retrotransposons became exponentially transcriptionally activated during the senescence of human fibroblasts leading to heightened levels of cytoplasmic L1 cDNA at 16 weeks after cessation of proliferation (late senescence). Importantly, skin biopsies of aged human individuals also displayed L1 activation, suggesting that this response is not a culture artifact.

Mechanistically, the study established that the loss of RB1, the gain of FOXA1, and the loss of TREX1 contributed to the activation of L1 in senescent cells by relieving heterochromatin repression, activating the L1 promoter, and compromising the removal of L1 cDNA, respectively. In turn, the accumulation of L1cDNA then activated a type-I interferon response, which then contributed to the senescence-associated secretory phenotype and the pro-inflammatory phenotype of senescent cells.

Encouragingly, treatment of senescent human cells with the nucleoside reverse transcriptase inhibitor lamivudine or L1 short hairpin RNA inhibited the type-I interferon response-mediated senescence-associated secretory phenotype response, while treatment of aged mice (26 weeks old) with lamivudine, a nucleoside reverse transcriptase inhibitor, also downregulated the type-I interferon response and inflammaging in several of the tissues examined.

Given these findings, the authors now propose that the activation of L1 elements promotes inflammaging, which contributes to age-related diseases [6, 7], and that the L1 reverse transcriptase represents an exciting target for the development of advanced strategies to treat age-associated disorders.

For more on inflammaging and the development of strategies to target age-associated disorders, stay tuned to the Stem Cells Portal.

References

  1. Rodić N, Sharma R, Sharma R, et al., Long Interspersed Element-1 Protein Expression Is a Hallmark of Many Human Cancers. The American Journal of Pathology 2014;184:1280-1286.
  2. Van Meter M, Kashyap M, Rezazadeh S, et al., SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nature Communications 2014;5:5011.
  3. De Cecco M, Criscione SW, Peckham EJ, et al., Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 2013;12:247-256.
  4. Hancks DC and Kazazian HH, Active human retrotransposons: variation and disease. Current Opinion in Genetics & Development 2012;22:191-203.
  5. De Cecco M, Ito T, Petrashen AP, et al., L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 2019;566:73-78.
  6. Franceschi C and Campisi J, Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases. The Journals of Gerontology: Series A 2014;69:S4-S9.
  7. López-Otín C, Blasco MA, Partridge L, et al., The Hallmarks of Aging. Cell 2013;153:1194-1217.