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

Aging Cell. 2017 Aug;16(4):652-660. doi: 10.1111/acel.12590. Epub 2017 May 20.

Abstract

Aging 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.

Keywords: NDGA; 17-α Estradiol; Acarbose; aging; hypothalamus; inflammation; longevity; sexual dimorphism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acarbose / pharmacology*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Caloric Restriction*
  • Estradiol / pharmacology*
  • Female
  • Gene Expression Regulation, Developmental
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hypothalamus / drug effects*
  • Hypothalamus / metabolism
  • Hypothalamus / pathology
  • Inflammation / prevention & control
  • Longevity / drug effects*
  • Longevity / genetics
  • Male
  • Masoprocol / pharmacology*
  • Mice
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Sex Factors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Aif1 protein, mouse
  • Calcium-Binding Proteins
  • Glial Fibrillary Acidic Protein
  • Microfilament Proteins
  • Tumor Necrosis Factor-alpha
  • glial fibrillary astrocytic protein, mouse
  • Estradiol
  • Masoprocol
  • Acarbose