BDNF Gene Therapy Slows Measures of Metabolic Aging in Mice

Researchers here test a gene therapy that mimics the normal regulatory mechanisms governing BDNF expression in the hypothalamus, enhancing BDNF activity only when it is called for. In aging mice, this slows the expected decline of metabolism, as measured by a variety of metrics and markers. As a basis for a human enhancement therapy, this is intriguing, but not a near term prospect. I think we are at present quite a long way removed from a world of reliable, widely available gene therapies targeted to the brain, even under the most aggressive timelines.

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. The single rAAV vector harbors two cassettes, one expresses human BDNF driven by a constitutive promoter, the other expresses a microRNA targeting BDNF under the control of agouti-related peptide (AGRP) promoter that is activated by weight loss and fat depletion. This dual-cassette vector mimics the body's natural feedback system to achieve autoregulation of the transgene.

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.



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