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Intermittent fasting (IF) remains the most effective intervention to achieve robust anti-aging effects and attenuation of age-related diseases in various species. Epigenetic modifications mediate the biological effects of several environmental factors on gene expression; however, no information is available on the effects of IF on the epigenome. Here, we first found that IF for 3 months caused modulation of H3K9 trimethylation (H3K9me(3)) in the cerebellum, which in turn orchestrated a plethora of transcriptomic changes involved in robust metabolic switching processes commonly observed during IF. Second, a portion of both the epigenomic and transcriptomic modulations induced by IF was remarkably preserved for at least 3 months post-IF refeeding, indicating that memory of IF-induced epigenetic changes was maintained. Notably, though, we found that termination of IF resulted in a loss of H3K9me(3) regulation of the transcriptome. Collectively, our study characterizes the novel effects of IF on the epigenetic-transcriptomic axis, which controls myriad metabolic processes. The comprehensive analyses undertaken in this study reveal a molecular framework for understanding how IF impacts the metabolo-epigenetic axis of the brain and will serve as a valuable resource for future research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00537-z.

Current experimental stroke research has evolved to focus on detailed understanding of the brain's self-protective and restorative mechanisms, and harness this knowledge for development of new therapies. In this context, the role of peptidases and neuropeptides is of growing interest. In this focused review, peptidase neurolysin (Nln) and its extracellular peptide substrates are briefly discussed in relation to pathophysiology of ischemic stroke. Upregulation of Nln following stroke is viewed as a compensatory cerebroprotective mechanism in the acute phase of stroke, because the main neuropeptides inactivated by Nln are neuro/cerebrotoxic (bradykinin, substance P, neurotensin, angiotensin II, hemopressin), whereas the peptides generated by Nln are neuro/cerebroprotective (angiotensin-(1-7), Leu-/Met-enkephalins). This notion is confirmed by experimental studies documenting aggravation of stroke outcomes in mice after inhibition of Nln following stroke, and dramatic improvement of stroke outcomes in mice overexpressing Nln in the brain. The role of Nln in the (sub)chronic phase of stroke is less clear and it is likely, that this peptidase does not have a major role in neural repair mechanisms. This is because, the substrates of Nln are less uniform in modulating neurorestorative mechanisms in one direction, some appearing to have neural repair enhancing/stimulating potential, whereas others doing the opposite. Future studies focusing on the role of Nln in pathophysiology of stroke should determine its potential as a cerebroprotective target for stroke therapy, because its unique ability to modulate multiple neuropeptide systems critically involved in brain injury mechanisms is likely advantageous over modulation of one pathogenic pathway for stroke pharmacotherapy.

Estrogen metabolite 2-methoxyestradiol (2ME2) has therapeutic potential in a number of cardiovascular disorders, including hypertension. However, specific or potential targets remains to be determined. In this study, animals were surgically implanted with PA-C40 telemetry in the intra-aortic vessel and 2ME2 (20 mg/kg/day, i.p. injection) effects in AngII infused Wistar-Koyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were determined. In WKY rats 2ME2 treatment resulted in significant reduction in AngII induced blood pressure (BP) compared to vehicle control (systolic; 143.69 ± 2.68 vs. 169.75 ± 1.93 mm Hg, diastolic; 99.91 ± 2.49 vs. 120.16 ± 1.25 mm Hg, and mean arterial pressure; 118.94 ± 2.52 vs. 142.73 ± 1.47 mm Hg). We observed a decrease in heart rate in 2ME2 exposed animals compared to control group (272.67 ± 9.88 vs. 329.12 ± 6.14 BPM). In addition, 2ME2 mediated reduction in workload of the heart when we calculated the rate pressure product or pressure rate index by 13.46 ± 2.32 indicating that 2ME2 can reduce AngII induced hemodynamic stress of the heart. [ 3 H]AngII binding studies showed that in kidney cortex AT1R expression was inhibited by 2ME2 treatment compared to control (2112 ± 71 vs. 3341 ± 248 DPM/mg protein). In a separate 5-week study, 2ME2-treated SHRs displayed significant reduction in diastolic BP (114.31 ± 0.66 vs. 123.28 ± 0.70 mm Hg) and mean arterial pressure (146.35 ± 0.67 vs. 151.54 ± 0.89 mm Hg) without significant change in systolic BP compare to the vehicle treated animals. Moreover, we found significant decrease in heart rate in 2ME2-treated animals (290.03 ± 2.69 vs. 312.92 ± 1.50 BPM). Analyses of kidney cortical tissue revealed downregulation of AT1R expression after 2ME2 treatments (20227 ± 2211 vs. 9515 ± 2115 DPM/mg protein). Consistent with the reduction in BP, the indicators of cardiac hypertrophy including heart weight (1.28 ± 0.08 vs. 0.99 ± 0.02 gram), cardiac collagen deposit and α-smooth muscle actin (α-SMC) positive myofibroblasts were decreased. The data demonstrate for the first time that 2ME2 control BP through downregulation of AT1R in kidney and heart rate, which may provide an insight to the mechanism(s) of cardioprotective effects of 2ME2 through the blockade of AngII induced hypertension.