Hypothalamic gene transfer of BDNF promotes healthy aging in mice

Abstract

The aging process and age‐related diseases all involve perturbed energy adaption and impaired ability to cope with adversity. Brain‐derived neurotrophic factor (BDNF) in the hypothalamus plays important role in regulation of energy balance. Our previous studies show that recombinant adeno‐associated virus (AAV)‐mediated hypothalamic BDNF gene transfer alleviates obesity, diabetes, and metabolic syndromes in both diet‐induced and genetic models. Here we examined the efficacy and safety of a built‐in autoregulatory system to control transgene BDNF expression mimicking the body's natural feedback systems in middle‐aged mice. Twelve‐month‐old mice were treated with either autoregulatory BDNF vector or yellow fluorescence protein (YFP) control, maintained on normal diet, and monitored for 28 weeks. BDNF gene transfer prevented the development of aging‐associated metabolic declines characterized by: preventing aging‐associated weight gain, reducing adiposity, reversing the decline of brown fat activity, increasing adiponectin while reducing leptin and insulin in circulation, improving glucose tolerance, increasing energy expenditure, alleviating hepatic steatosis, and suppressing inflammatory genes in the hypothalamus and adipose tissues. Moreover, BDNF treatment reduced anxiety‐like and depression‐like behaviors. These safety and efficacy data provide evidence that hypothalamic BDNF is a target for promoting healthy aging.

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice

“…In the CNS, EE acted to change microglial morphology and microglial gene expression in middle-aged mice. These findings appear consistent with long-term EE housing and long-term viral expression of BDNF in middle-aged mice [8,11,12]. Several of these effects remained or were compounded in response to CSF1R inhibition and depletion of microglia, suggesting that the stimulus behind hypothalamic changes causing microglial responses remains in the presence of PLX for remaining microglia.…”

“…A major candidate for this stimulus is BDNF, the central coordinator for many CNS and peripheral effects of EE. We previously demonstrated that neuronal overexpression of BDNF reproduces various effects of EE including systemic metabolism, adipose remodeling, immune modulations, cancer, and aging [9][10][11][40][41][42].…”

“…We previously identified a specific brainadipose axis, the hypothalamic-sympathoneural-adipocyte (HSA) axis, through which EE-induced hypothalamic brain-derived neurotrophic factor (BDNF) expression leads to increased sympathetic tone to adipose tissue [9,10]. Activation of the HSA axis results in the induction of a brown fat program in white adipose tissue, the suppression of leptin production and secretion, and an anti-obesity phenotype in middle-aged mice [8,11,12]. Importantly, adipose tissue response to sympathetic norepinephrine (NE) is impaired in old and obese mice by adipose tissue macrophages (ATMs) [13,14].…”

“…Ly6D is expressed in certain lymphoid and dendritic cell immune populations not resident in the brain, which allows it to serve as a proxy for CNS immune trafficking. We have previously shown hypothalamic Ly6D expression is also reduced following long-term hypothalamic expression of BDNF [11]. Major histocompatibility complex class II (MHC II, encoded by H2Ab1) is highly expressed on primed microglia, which are abundant in aged brains [31,32].…”

Regulation of aging and cancer by enhanced environmental activation of a hypothalamic-sympathoneural-adipocyte axis

“…Similarly, hypothalamic administration of an rAAV-BDNF vector promoted healthy aging ( 83 ) largely mimicking EE effects. BDNF gene therapy was found to prevent the development of age-related metabolic decline and reduce anxiety-and depression-like behavior.…”