Life span extension by targeting a link between metabolism and histone acetylation in Drosophila.

Old age is associated with a progressive decline of mitochondrial function and changes in nuclear chromatin. However, little is known about how metabolic activity and epigenetic modifications change as organisms reach their midlife. Here, we assessed how cellular metabolism and protein acetylation change during early aging in Drosophila melanogaster. Contrary to common assumptions, we find that flies increase oxygen consumption and become less sensitive to histone deacetylase inhibitors as they reach midlife. Further, midlife flies show changes in the metabolome, elevated acetyl-CoA levels, alterations in protein-notably histone-acetylation, as well as associated transcriptome changes. Based on these observations, we decreased the activity of the acetyl-CoA-synthesizing enzyme ATP citrate lyase (ATPCL) or the levels of the histone H4 K12-specific acetyltransferase Chameau. We find that these targeted interventions both alleviate the observed aging-associated changes and promote longevity. Our findings reveal a pathway that couples changes of intermediate metabolism during aging with the chromatin-mediated regulation of transcription and changes in the activity of associated enzymes that modulate organismal life span.

Cardiotoxicity of trastuzumab given for 12 months compared to shorter treatment periods: a systematic review and meta-analysis of six clinical trials.

BACKGROUND: Treatment de-escalation in early-stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been attempted in order to decrease costs and toxicities. One of the strategies pursued is decreasing trastuzumab treatment duration, with mixed results thus far. Trastuzumab-associated cardiotoxicity, however, may be more frequent with 12 months of trastuzumab compared with shorter treatment lengths. Therefore, we have conducted a meta-analysis to address this question. MATERIALS AND METHODS: A meta-analysis of trials testing 12 months of adjuvant trastuzumab versus shorter regimens, reporting cardiac outcomes in patients with HER2-positive BC was performed with the random effects model with inverse variance weighting. RESULTS: Clinical cardiac dysfunction associated with 12 months of trastuzumab versus shorter trastuzumab regimens, including 11 250 patients, showed a pooled OR (pOR) of 1.90 (95% CI 1.37 to 2.64; p value <0.001; I2=65.7%); in the subgroup comparison of 12 versus 6 months, the pOR was 1.57 (95% CI 1.30 to 1.90; p<0.001; I2=5.7%). pOR for low left ventricular ejection fraction was 1.45 (95% CI 1.19 to 1.75; p<0.001; I2=11.9%), 1.55 (95% CI 1.00 to 2.42; p=0.052; I2=0.0%) for congestive heart failure and 3.70 (95% CI 0.27 to 51.60; p=0.33; I2=78.8%) for premature trastuzumab discontinuation due to cardiotoxicity for 12 months versus shorter trastuzumab regimens. Funnel plot analyses indicated a low risk of publication bias. CONCLUSIONS: Compared to shorter treatment durations, there is sufficient evidence that 12 months of trastuzumab yields higher odds for the occurrence of relevant cardiac events. An individual patient-level data meta-analysis is needed in order to provide adequate data on risk factors for cardiotoxicity.