Figure 7 |. L1 transcripts and interferon response are elevated in WT aged mice and are rescued by treatment with NRTIs and SIRT6 overexpression.

A, L1 transcripts are elevated in tissues of aged (24 month old) animals, and are repressed in aged MOSES mice overexpressing SIRT6.

B, C, Aged tissues show elevated IFN-α/β expression whereas MOSES mice show decreased expression.

Tissues from 4 months and 24 months old BL/6 and 28 months old MOSES animals were analyzed for L1 expression. Young intestine was used as a reference for the other samples after normalization to actin. Statistical significance determined by t-test asterisk indicate p < 0.05.

D, E, F, Treatment with NRTI reduces IFN-α/β and L1 DNA content in 55-week old mice. The data was normalized to actin and WT heart used as a reference. n=5 animals per group, error bars show SEM. Statistical significance was determined by t-test; asterisk indicate p < 0.05.

G, H, MMP3 and IL6 show significant reduction in several tissues of d4T-treated 55-week old mice. The data was normalized to actin and WT heart was used as a reference. n=5 animals per group, Error bars show SEM. Statistical significance was determined by t-test. Asterisks indicate p < 0.05.

I, D4T treatment ameliorates age-related increase in p16 expression in female p16(LUC) reporter mice. n=10 animals per sex per treatment. Statistical significance determined by t-test, asterisk indicate p < 0.05.

J, DNA methylation age estimated with a multi-tissue DNA methylation clock. Analysis is based on 370 out of 435 clock sites. Each group included aged-matched male (n = 3) and female (n = mice. The mean normalized age was 32 weeks for the control (water) group and 23 weeks for the d4T-treated samples. p = 0.046, two-tailed Mann–Whitney U test.

K, Model. L1 activation causes age-related pathologies through induction of DNA damage and a type I interferon response. These pathologies are rescued or attenuated by inhibition of L1 reverse transcriptase with NRTIs.