Abstract
Memory decline is one of the greatest health threats of the twenty-first century. Because of the widespread increase in life expectancy, 20 percent of the global population will be over 60 in 2050 and the problems caused by age-related memory loss will be dramatically aggravated. However, the molecular mechanisms underlying this inevitable process are not well understood. Here we show that the activity of the recently discovered mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) declines with age in the brain of both fruit flies and rodents and that the loss of mTORC2-mediated actin polymerization contributes to age-associated memory loss. Intriguingly, treatment with a small molecule that activates mTORC2 (A-443654) reverses long-term memory (LTM) deficits in both aged mice and flies. In addition, we found that pharmacologically boosting either mTORC2 or actin polymerization enhances LTM. In contrast to the current approaches to enhance memory that have primarily targeted the regulation of gene expression (epigenetic, transcriptional, and translational), our data points to a novel, evolutionarily conserved mechanism for restoring memory that is dependent on structural plasticity. These insights into the molecular basis of age-related memory loss may hold promise for new treatments for cognitive disorders.
Highlights
0.0 3 21 Age was recently discovered, is largely insensitive to rapamycin and consists of mTOR, mSIN1, mLST8 and Rictor[12,13,14]
Given that a) human brain aging is associated with memory loss[3,4,5], b) specific regions of the aging brain exhibit reduced synaptic connectivity[7,8], c) inhibition of mTORC2 decreases life span[26] and d) mTORC2 regulates structural changes required for memory consolidation[15,16,17], we investigated the role of mTORC2 deficiency as a novel mechanism of age-associated memory loss, and the therapeutic potential of mTORC2 as a target for the treatment of memory loss in aged animals
Given the successful use of Drosophila as a model of age-related disorders[27,28,29], we first decided to utilize the fly to investigate the mechanisms that contribute to age-associated memory loss
Summary
0.0 3 21 Age (day) was recently discovered, is largely insensitive to rapamycin and consists of mTOR, mSIN1, mLST8 and Rictor[12,13,14]. By regulating actin polymerization, mTORC2 controls the structural changes at synapses that are necessary for memory consolidation[15]. Changes in synaptic actin polymerization are crucially involved in memory formation[23,24,25]. Given that a) human brain aging is associated with memory loss[3,4,5], b) specific regions of the aging brain exhibit reduced synaptic connectivity[7,8], c) inhibition of mTORC2 decreases life span[26] and d) mTORC2 regulates structural changes required for memory consolidation[15,16,17], we investigated the role of mTORC2 deficiency as a novel mechanism of age-associated memory loss, and the therapeutic potential of mTORC2 as a target for the treatment of memory loss in aged animals
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