Anti‐aging drugs reduce hypothalamic inflammation in a sex‐specific manner

Abstract

SummaryAging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF‐1 signals. Early‐life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM‐HET3 mice in a sex‐specific way: acarbose (ACA), 17‐α‐estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. In this study, we examined the effect of these anti‐aging drugs on neuro‐inflammation in hypothalamus and hippocampus. We found that age‐associated hypothalamic inflammation is reduced in males but not in females at 12 months of age by ACA and 17αE2 and at 22 months of age in NDGA‐treated mice. The three drugs blocked indices of hypothalamic reactive gliosis associated with aging, such as Iba‐1‐positive microglia and GFAP‐positive astrocytes, as well as age‐associated overproduction of TNF‐α. This effect was not observed in drug‐treated female mice or in the hippocampus of the drug‐treated animals. On the other hand, caloric restriction (CR; an intervention that extends the lifespan in both sexes) significantly reduced hypothalamic microglia and TNF‐α in both sexes at 12 months of age. Together, these results suggest that the extent of drug‐induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long‐lived nutrient restricted or mutant mice.

Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure

“…Accordingly, 4-weeks of benzene exposure resulted in a significant increase in GFAP + astrocytes in the different areas of the medial basal hypothalamus (MBH) such as the arcuate nucleus (ARC), the ventromedial (VMH), the dorsomedial (DM) hypothalamus as compared to control male mice ( Figure 3A and B). Consistent with previous studies [42,46,47], control females demonstrated a significantly lower number of immunostained GFAP + astrocytes in the MBH compared to control male mice ( Figure 3A and B).…”

“…Similarly to metformin, ACA has beneficial effects on body weight, onset of diabetes and cardiovascular risk [36,37]. In mice, ACA effect replicates some aspects of diet or caloric restriction associated with increased lifespan [38][39][40][41], and with inhibition of age-associated hypothalamic inflammation in a sex-specific manner [42]. Our findings indicate that hypothalamic ER stress and hypothalamic inflammation might be critical for benzene diabetogenic effects, while ACA feeding, protects against benzene induced hypothalamic inflammation, ER stress and peripheral metabolic imbalance.…”

“…All mice were provided ad libitum access to standard chow diet (Purina Lab Diet 5001), highfat diet (HFD) (Research Diets, #D12451) or Acarbose diet, as before [38,39,42]. Acarbose diet (Spectrum Chemical Mfg.…”

“…To determine whether ACA would mitigate the effects of benzene on metabolic imbalance and hypothalamic inflammation, we fed benzene exposed male mice and their controls with ACA (1,000 mg/kg diet (ppm), as before [39,42]) for the period of 4 weeks while in the benzene exposure chambers. ACA feeding normalized glucose tolerance, fasted insulin levels and HOMA-IR scores in benzene-treated mice, and they were comparable to control animals ( Figure 6A-C).…”

Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice

“…Such sex‐specific effects on a metabolomic scale are consistent with the sex‐specific effects of 17aE2 on glucose tolerance (Garratt et al., 2017) and hypothalamic inflammation (Sadagurski, Cady & Miller, 2017). Furthermore, the response is not observed in males castrated prior to treatment onset, suggesting that this metabolic response to 17aE2 requires the presence of male gonadal hormones.…”