Targeting neuroinflammation - a potential for anti-aging interventions

Increased inflammatory activity and associated upregulation of inflammatory cytokines are responsible for normal brain aging and local glial cell activation.The hypothalamus is the main controller of various physiological processes, including energy regulation and metabolism [1].Recent research in the crossdisciplinary field of neurobiology and aging revealed a fundamental role of age-associated hypothalamic inflammation as the essential process involved in neural mechanisms of aging.Slowing of the murine aging process can be achieved by inhibiting activation of hypothalamic proinflammatory axis comprising IκB kinase-β (IKKβ) and its downstream nuclear transcription factor NF-κB (IKKβ/NF-κB signaling) [1].Our recent studies demonstrated that age-associated hypothalamic inflammation is reduced in the long-lived Snell dwarf, Ames dwarf or growth hormone receptor deficient (GHRKO) mice [2].Thus, a reduction in hypothalamic -mediated inflammation may attenuate the aging process as well as mitigate age-associated disorders.Recent NIA Interventions Testing Program (ITP) lifespan results demonstrated significant gender differences of pharmacological and dietary interventions.Pharmacological treatments, including aspirin, nordihydroguaiaretic acid (NDGA), acarbose (ACA), Protandim, and 17-α estradiol (17αE2), extend mouse lifespan to a greater degree in males [3,4].By contrast, mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition), an inhibitor of the mTOR pathway, extends the median and maximal lifespan of both male and female mice [5].Similarly, caloric restriction(definition) (CR) markedly increases both overall mean and maximum life span among different mouse stocks [6].In our new study, we demonstrated that age-associated hypothalamic inflammation is similarly reduced solely in males at 12 months of age by ACA and 17αE2, and at 22 months of age in NDGA-treated mice.This effect was not observed either in drug-treated female mice or in the hippocampus of the drug-treated animals.However, CR significantly reduced hypothalamic inflammation in both genders at 12-months of age [7].This lends credence to the concept that inhibition of the hypothalamic inflammatory responses may result in significant gains in the murine lifespan.Moreover, our data provide evidence that drugs that extend lifespan might be effective in inhibiting hypothalamic inflammatory processes in a gender-dependent manner.